The Pituitary (Pituitary (Melmed))

The Pituitary

Notice: The indications and dosages of all drugs in this book have been recommended in the medical literature and conform to the practices of the general community. The medications described do not necessarily have specific approval by the Food and Drug Administration for use in

the diseases and dosages for which they are recommended. The package insert for each drug should be consulted for use and dosage as approved by the FDA. Because standards for usage change, it is advisable to keep abreast of revised recommendations, particularly those concerning new drugs.

The Pituitary EDITED BY

SHLOMO MELMED, Senior Vice-President, Academic Affairs Cedars-Sinai Medical Center Professor and Director, Burns & Allen Research Institute UCLA School of Medicine Los Angeles, California

SECOND EDITION

Blackwell Science

MD

© 2002 by Blackwell Science, Inc. Editorial Offices: Commerce Place, 350 Main Street, Malden, Massachusetts 02148, USA Osney Mead, Oxford OX2 0EL, England 25 John Street, London WC1N 2BS, England 23 Ainslie Place, Edinburgh EH3 6AJ, Scotland 54 University Street, Carlton, Victoria 3053, Australia Other Editorial Offices: Blackwell Wissenschafts-Verlag GmbH, Kurfürstendamm 57, 10707 Berlin, Germany Blackwell Science KK, MG Kodenmacho Building, 7-10 Kodenmacho Nihombashi, Chuo-ku, Tokyo 104, Japan Iowa State University Press, A Blackwell Science Company, 2121 S. State Avenue, Ames, Iowa 50014-8300, USA

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Contents

Contributors vii Preface

Section 3. PITUITARY TUMORS

x

10.

Pituitary Surgery 405 Rudolf Fahlbusch, Michael Buchfelder and Panos Nomikos

11.

Acromegaly 419 Shlomo Melmed

12.

Prolactinoma 455 Mark E. Molitch

13.

Cushing’s Disease 496 Xavier Bertagna, Marie-Charles Raux-Demay, Brigitte Guilhaume, François Girard and Jean-Pierre Luton

14.

Thyrotropin-secreting Pituitary Tumors 561 Yona Greenman and Shlomo Melmed

15.

Gonadotroph Adenomas Peter J. Snyder

16.

Nonpituitary Tumors of the Sellar Region 592 Steffen Albrecht, Juan M. Bilbao and Kalman Kovacs

Section 1. HYPOTHALAMIC–PITUITARY FUNCTION 1.

2.

Functional Anatomy of the Hypothalamic Pituitary Axis 3 Sylvia L. Asa, Kalman Kovacs and Shlomo Melmed Adrenocorticotropin 45 Mark A. Herman and Joseph A. Majzoub

3.

Growth Hormone 79 Vivien S. Herman-Bonert and Shlomo Melmed

4.

Prolactin 119 Mark E. Molitch

5.

Thyroid-stimulating Hormone 172 Virginia D. Sarapura, Mary H. Samuels and E. Chester Ridgway

6.

Follicle-stimulating Hormone and Luteinizing Hormone 216 Shalender Bhasin, Charles E. Fisher and Ronald S. Swerdloff

7.

The Posterior Pituitary Daniel G. Bichet

279

Section 2. HYPOTHALAMIC–PITUITARY DYSFUNCTION 8.

The Hypothalamus 317 Glenn D. Braunstein

9.

Anterior Pituitary Failure Charles F. Abboud

349

575

Section 4. PITUITARY DISEASE IN SYSTEMIC DISORDERS 17.

Pituitary Function in Systemic Disorders 613 Harold E. Carlson

18.

The Pituitary Gland in Pregnancy and the Puerperium 628 Harold E. Carlson

19.

Drugs and Pituitary Function Harold E. Carlson

642 v

vi

Contents

Section 5.

DIAGNOSTIC PROCEDURES

20.

Pituitary Imaging 663 Barry D. Pressman

21.

Neuro-ophthalmologic Evaluation of Pituitary Disorders 687 Anthony C. Arnold

22. Index

Evaluation of Normal Pituitary Function 709 Gillian L. Booth, Afshan Zahedi and Shereen Ezzat 727

Contributors

Charles F. Abboud, MD David Eisenberg Professor of Medicine Consultant, Internal Medicine and Endocrinolgy Mayo Clinic, Mayo Medical School Rochester, MN Steffen Albrecht, MD FRCP(C) Department of Pathology Sir Mortimer B. Davis Jewish General Hospital Montreal, Canada Anthony C. Arnold, MD Associate Professor of Ophthalmology and Chief, Neuro-Ophthalmology Division Jules Stein Eye Institute, UCLA Department of Ophthalmology Los Angles, CA Sylvia L. Asa, MD, PhD Associate Professor of Pathology Mount Sinai Hospital University of Toronto Toronto, Canada Xavier Bertagna, MD Professor of Endocrinology Clinique des Maladies Endocriniennes et Metaboliques Hôpital Cochin Paris, France Shalender Bhasin, MD Chief, Division of Endocrinology, Metabolism, and Molecular Medicine Professor of Medicine Charles R. Drew University School of Medicine and Science Los Angeles, CA

Daniel G. Bichet, MD, FRCP(C) Service de néphrologie et Centre de recherche Hôpital du Sarcé-Coeur de Montréal Department of Medicine Université de Montréal Montréal, Quebec Canada Juan M. Bilbao, MD, FRCP(C) Neuropathologist, Department of Pathology Saint Michael’s Hospital University of Toronto Toronto, Canada Gillian L. Booth, MD Department of Medicine University of Toronto Mount Sinai Hospital Toronto, Canada Glenn D. Braunstein, MD Chairman, Department of Medicine Cedars-Sinai Medical Center Professor of Medicine UCLA School of Medicine Los Angles, CA Michael Buchfelder, MD Associate Professor Department of Neurosurgery University of Erlangen-Nürnberg Erlangen, Germany vii

viii

Contributors

Harold E. Carlson, MD Chief, Endocrinology Section Northport Veterans Affairs Hospital, Northport Professor of Medicine State University of New York at Stony Brook Stony Brook, NY

Kalman Kovacs, MD, PhD, DSc, FRCP(C), FCAP, FRC Path. Professor of Pathology Saint Michael’s Hospital University of Toronto Toronto, Canada

Shereen Ezzat, MD, FRCP(C), FACP Assistant Professor of Medicine University of Toronto Consultant Endocrinologist Wellesley Hospital Toronto, Canada

Jean-Pierre Luton, MD Professor of Endocrinology and Director Clinique des Maladies Endocriniennes et Metaboliques Hôpital Cochin Dean, Cochin Medical School University René Descartes Paris, France

Rudolf Fahlbusch, MD Professor of Neurosurgery Department of Neurosurgery University of Erlangen-Nürnberg Erlangen, Germany Charles Ellis Fisher, MD Division of Endocrinology and Metabolism King Drew Medical Center Los Angeles, CA François Girard, MD Professor of Physiology and Director Laboratoire d’Explorations Fonctionnelles Endocriniennes Hôpital Trousseau Paris, France Yona Greenman, MD Tel-Aviv Sourasky Medical Center Tel-Aviv, Israel Brigitte Guilhaume, MD Clinique des Maladies Endocriniennes et Metaboliques Hôpital Cochin Paris, France Mark A. Herman, MD Fellow in Medicine Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas Vivien S. Herman-Bonert, MD Division of Endocrinology Cedars-Sinai Medical Center Associate Professor of Medicine UCLA School of Medicine Los Angeles, CA

Joseph A. Majzoub, MD Chief, Division of Endocrinology Department of Pediatrics Children’s Hospital Professor of Pediatrics Harvard Medical School Boston, MA Shlomo Melmed, MD Senior Vice-President, Academic Affairs Director, Burns & Allen Research Institute Associate Dean, UCLA School of Medicine Cedars-Sinai Medical Center Los Angeles, CA Mark E. Molitch, MD Professor of Medicine Center for Endocrinology, Metabolism, and Molecular Medicine Northwestern University Medical School Chicago, IL Panos Nomikos, MD Neurosurgical Fellow Department of Neurosurgery University of Erlangen-Nürnberg Erlangen, Germany Barry D. Pressman, MD, FACR Chief, Section of Neuroradiology and Chairman, Department of Imaging Cedars-Sinai Medical Center Los Angles, CA Marie-Charles Raux-Demay, MD Laboratoire d’Explorations Fonctionnelles Endocriniennes Hôpital Trousseau Paris, France

Contributors

Chester E. Ridgway, MD Professor of Medicine and Head, Division of Endocrinology University of Colorado Health Sciences Center Denver, CO Mary H. Samuels, MD Assistant Professor of Medicine Division of Endocrinology Oregon Health Science University Portland, OR Virginia D. Sarapura, MD Assistant Professor of Medicine Department of Medicine, Division of Endocrinology University of Colorado Health Sciences Center Denver, CO

Peter J. Snyder, MD Professor of Medicine University of Pennsylvania School of Medicine Philadelphia, PA Ronald S. Swerdloff, MD Professor of Medicine and Chief, Division of Endocrinology Department of Medicine Harbor/UCLA Medical Center UCLA School of Medicine Torrance, CA Afshan Zahedi, MD Department of Medicine University of Toronto Mount Sinai Hospital Toronto, Canada

ix

Preface

The second edition of The Pituitary follows the successful initial 1995 debut of this comprehensive text devoted to understanding pathogenesis and treatment of pituitary disorders. The new edition is extensively revised to reflect the wealth of novel information derived from advances in molecular biology, biochemistry and therapeutics as they apply to the pituitary gland. Notably, a new chapter devoted to pituitary surgery has been added to complement a comprehensive overview of management options for patients harboring pituitary tumors. The wide spectrum of clinical disorders emanating from disordered function of the “master gland” are described in detail by experts in the field. Furthermore, fundamental mechanisms underlying disease pathogenesis are presented to provide the reader with an in-depth understanding of mechanisms underlying pituitary hormone secretion and action.

Thus the volume continues to reflect the cogent blend of basic science and clinical medicine which was the successful hallmark of the first edition. I am especially indebted to my erudite colleagues for their scholarly contributions and dedicated efforts in compiling this body of knowledge for physicians and scientists dedicated to caring for patients with pituitary disorders. Our desire is to provide medical students, clinical and basic endocrinology trainees, endocrinologists, internists pediatricians, gynecologists and neurosurgeons with a comprehensive single text devoted to the science and art of pituitary medicine. Shlomo Melmed, MD Los Angeles 2002

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Hypothalamic–Pituitary Function

C h a p t e r

1 Functional Anatomy of the Hypothalamic Pituitary Axis Sylvia L. Asa Kalman Kovacs Shlomo Melmed

INTRODUCTION

Historical Review Descartes was the first to recognize that the brain was an organ integrating the functions of the mind and body [1]. The association was reinforced by Zander [2] who noted the connection between the adrenals and the brain, referring to observations on the absence of the adrenal cortex in anencephaly as recorded by Morgagni in 1733, Soemmering in 1792, and Meckel in 1802. It was only in 1849 that direct evidence of a role for the hypothalamus in endocrinology was provided by Claude Bernard [3] when he demonstrated that injury to the floor of the fourth ventricle, the “piqûre diabetique,’ caused polyuria and glucosuria; subsequently, numerous studies in the late 19th century and early 20th century confirmed that the hypothalamic–posterior pituitary system was the site of production of a major osmoregulatory substance. Galen (129–201 ad) had described the pituitary as the site of drainage of phlegm from the brain to the nasopharynx. Soon after the description of acromegaly by Pierre Marie in 1886 [4], the association of acromegaly with pituitary tumor was noted by Minkowski in 1887 [5], and the recognition of endocrine functions of the pituitary followed rapidly thereafter, with major contributions by Cushing [6] and Simmonds [7]. The early part of the 20th century saw the identification, isolation and characterization of the hormones of the anterior pituitary. Their regulation by the hypothalamus was the subject of a landmark monograph by Harris in 1948 [8]. The concept that neurons could release secretory materials into the bloodstream, proposed by Du Bois Reymond

in 1877 [9] and Schiefferdecker in 1905 [10], was revolutionary. The anatomic basis of a hypothalamic–pituitary vascular connection was already known to exist in the form of a system of capillaries, which were identified joining the medial basal hypothalamus to the anterior pituitary by Lieutaud in 1742 [11] and von Luschka in 1860 [12] and given the name “portal plexus” by Popa and Fielding in 1930 [13]. These vessels were thought at first to carry blood from the pituitary upwards to the hypothalamus; however, subsequent studies confirmed that they provided the main blood supply to the adenohypophysis. The concept of neurosecretion was suggested in the 1940s by Scharrer and Scharrer [14] and Bargmann and Scharrer [15], who demonstrated that peptide synthesized by neurons in the supraoptic and paraventricular nuclei of the hypothalamus passed through nerve fibers, was stored in nerve endings in the posterior pituitary and subsequently was released into the general circulation; the analysis and synthesis of oxytocin and vasopressin in 1954 [16] led to a Nobel Prize for du Vigneaud. In the 1950s and 1960s, evidence for the presence of hypothalamic releasing and inhibiting factors accumulated [17]. The isolation and characterization of the first of these yielded shared Nobel prizes for Guillemin and Schally in 1977 and by the mid 1980s, the isolation and characterization of many had been achieved [18–26].

Methodology Progress in the understanding of hypothalamic and pituitary endocrinology has utilized numerous techniques which have allowed the identification of hormones, their isolation and characterization, their localization, and recognition of their cell of origin. At the beginning of the 20th century, Benda [27], Erdheim [28], Cushing [6], and others [29,30] utilized histologic staining methods for the investigation of the human pituitary. Morphologic studies of the hypothalamus were 3

4

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Hypothalamic–Pituitary Function

dependent on conventional neurohistologic methods to demonstrate neurosecretory material and the silver stains that allowed visualization of neuronal cell processes [31]. The tinctorial properties of cell cytoplasm using hematoxylin–eosin, hematoxylin–phloxine, or hematoxylin– phloxine–saffron methods allowed the distinction of three cell types in the adenohypophysis. Clinical observations, correlated with morphologic changes, led to the classification of acidophils as cells thought to produce growth hormone (GH), basophils as those believed to contain adrenocorticotropin (ACTH) and chromophobes as functionally inactive cells. In the 1930s, Rasmussen [32] quantitated the three cell types in relation to sex, age, and body weight and determined their distributions within the gland. In 1940, Romeis [33] used a modification of the trichrome technique to establish that more than three cell types were identifiable in the adenohypo-physis. Application of the periodic acid–Schiff (PAS) method distinguished the PASpositive corticotrophs, thyrotrophs and gonadotrophs; similar results were obtained with lead hema-toxylin. Various trichrome stains, the aldehyde fuchsin and aldehyde thionin techniques were used to separate basophils [34] and the addition of Herlant’s erythrosin [35] and Brookes’ carmoisine [36] were useful to distinguish lactotrophs from the orange G-positive somatotrophs. Physiologic and biochemical studies provided evidence that six different hormones are produced by the anterior pituitary; however, histologic techniques failed to correlate cell type with clinical hormone production or secretory function. The search for correlations between structure and function led to the application of novel techniques including immunocytology [37,38] and electron microscopy [39,40] to the study of pituitary morphology. Ultrastructural immunocytochemistry [41], greatly improved by the use of the immunogold technique [40,42], and the application of the reverse hemolytic plaque assay [43], tissue culture methods [44] and molecular probes [45], have made pituitary and hypothalamic morphology significant for assessing pituitary function and pathology. HYPOTHALAMUS AND POSTERIOR PITUITARY

Topographic Anatomy The hypothalamus is a phylogenetically primitive structure. Understanding of its role in endocrine regulation is largely derived from animal studies; early data regarding functional localization were based on selective stimulation and ablation experiments. However, there are considerable anatomic and physiologic species variations which make extrapolation to the human difficult. Only the advent of sophisticated neurophysiologic methods and the recent applications of immunocytochemistry, as well as experiments of nature in which careful analyses of the location of pathologic lesions are performed, have allowed structure–function correlations in the human hypothalamus.

The hypothalamus is a poorly defined anatomic region which constitutes less than 1% of brain volume and weighs approximately 5 g [46,47]. The superior border of this region is the hypothalamic sulcus which courses from the interventricular foramen to the cerebral aqueduct, demarcating the hypothalamus from the thalamus (Fig. 1.1). The anterior delineation is roughly defined as a line through the anterior commissure, lamina terminalis, and optic chiasm. Posteriorly, it is bordered on the superior aspect by the midbrain tegmentum and inferiorly by the mamillary bodies. The lateral borders are defined conventionally as the substantia innominata, the internal capsule, the subthalamic nucleus, and the cerebral peduncle. The inferior aspect of the hypothalamus, known as the tuber cinereum, contains the median eminence and gives rise to the infundibulum, the neural stalk and the posterior lobe of the pituitary.

Vascular Supply A significant number of afferent and efferent signals of the hypothalamus are not neural, but rather represent bloodborne information, such as temperature, osmotic pressure, hormones, and glucose levels, thus endorsing the importance of the vascular supply of this area. The blood supply of the hypothalamus is derived from small arterial branches of the circle of Willis and the superior hypophysial artery. It is divided into three parts: (i) an anterior group which arises from the internal carotid artery, the anterior cerebral artery, and the anterior portion of the posterior communicating artery; (ii) an intermediate group from the posterior communicating artery; and (iii) a posterior group from the posterior communicating artery, posterior cerebral, and basilar arteries. Individual hypothalamic nuclei receive blood from more than one small artery. The microvascular pattern of the hypothalamus resembles that of the remainder of the brain with the exception of the magnocellular nuclei, the supraoptic and paraventricular nuclei. These are some of the most richly vascularized structures in the brain, in which the neurons are intimately associated with capillaries. The capillary endothelium is fenestrated and the blood–brain barrier is absent in many areas of the hypothalamus, including the subfornical organ, the organum vasculosum of the lamina terminalis (OVLT), the median eminence, and the neurohypophysis. The arterial supply of the median eminence and posterior pituitary has been extensively studied [48–51] (Fig. 1.2). It is derived from two (or three, in some species) paired arteries that arise from the intracranial portions of the internal carotid arteries. The superior hypophysial arteries branch into a plexus of small arteries that surrounds the upper half of the stalk (the external plexus), giving rise to a mesh of capillaries, and the gomitoli (the internal plexus). The latter are unique vascular structures composed of a central muscular artery surrounded by a spiral of capillaries, the arteriole communicating with the capillaries by way of small

Chapter 1

Functional Anatomy of the Hypothalamic Pituitary Axis

5

FIGURE 1.1. Schematic representation of the human hypothalamus and pituitary, the disposition of hypothalamic nuclei and principal fiber tracts. From Scheithauer [47]

orifices surrounded by muscular sphincters. The gomitoli, which measure 1–2 mm in length and 0.1 mm in width, are found in large numbers in the infundibulum and proximal hypophysial stalk. Flow through these complex structures continues on through the portal vessels to the adenohypophysial capillaries. Although their function is not certain, the unique structure of gomitoli suggests that they may affect the rate of blood flow to the anterior pituitary, thereby influencing the entry of hypothalamic regulatory hormones into the portal circulation. In some individuals, a pair of middle hypophysial arteries also contributes to the trabecular or loral arteries which descend from the superior hypophysial arteries along the external surface of the pituitary stalk. These then divide to contribute to the subcapsular artery and the artery of the fibrous core (which provide a minor contribution to the blood supply of the adenohypophysis) and return upwards along the pituitary stalk as the long stalk arteries. The inferior hypophysial

arteries enter the sella just beneath its diaphragm and supply the pituitary capsule, the neural lobe, and the lower pituitary stalk. They enter the intralobar groove where they divide into ascending and descending branches that join their opposite partners to form an arterial circle about the neural lobe. They also give off a branch to the lower pituitary stalk, the communicating artery, which anastomoses with the trabecular arteries. Notably, the capillaries of the neurohypophysis are fenestrated and lie outside the blood–brain barrier. The earliest studies of the hypophysial portal vasculature assumed that blood flowed from the pituitary upwards to the hypothalamus [13]. Subsequently, it was found that the predominant blood flow is from the hypothalamus to the adenohypophysis, carrying hypothalamic regulatory factors. Recent studies suggest that the direction of blood flow is variable and there may be a component of reverse flow within the neurohypophysis, providing a route by which

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FIGURE 1.2. Schematic representation of the blood supply of the hypothalamus and pituitary. From Scheithauer [47]

neuro- and adenohypophysial hormones gain access to the long portal system, the pars tuberalis of the adenohypophysis, the median eminence, and the cerebrospinal fluid of the third ventricle [50,51].

Nerve Supply A number of afferent neural pathways provide the hypothalamus with input from the forebrain, limbic system, visual cortex, thalamus, and brain stem [47,52]. The median forebrain bundle, a large unmyelinated structure lateral to the fornix, carries information to and from the brain stem and provides important input from the limbic system and olfactory forebrain structures. Olfactory connections are more extensively from the piriform cortex and

amygdaloid nuclear complex via the stria terminalis and ventral amygdalofugal pathway. The hippocampal–hypothalamic tract originates in the hippocampus, a limbic structure, and enters the anterolateral portion of the mamillary bodies. The amygdalo–hypothalamic tract provides entry of emotional data from the amygdaloid nucleus into the hypothalamus. The retino–hypothalamic tract originates in the ganglion cells of the retina and affects the pineal gland, playing a role in the regulation of circadian rhythms. In addition, a small number of cortico–hypothalamic fibers from the posterior orbital gyrus of the frontal lobe is a potential source of input from the neocortex into the hypothalamus.

Chapter 1

The hypothalamus sends efferent projections to the forebrain, brain stem, spinal cord and neurohypophysis. The median forebrain bundle carries fibers to the septal nuclei, integrating visceral and olfactory functions. The dorsal longitudinal fasciculus carries efferents to the midbrain tegmentum where it innervates visceral and sympathetic motor neurons. Fibers emanating from the mamillary body divide into the mamillo–thalamic tract, serving the anterior nucleus of the thalamus and memory function, and the mamillotegmental tract which projects to the midline tegmentum. Efferents from the ventral medial nucleus project to the amygdaloid nucleus via the stria terminalis. The hypothalamo–hypophysial tract consists primarily of nerve fibers from the supraoptic and paraventricular nuclei carrying vasopressin, oxytocin and their neurophysins to the posterior lobe of the pituitary, where the hormones are released into capillaries. The tubero–infundibular tract, originating from neurosecretory neurons which produce hypophysiotropic hormones, projects from several nuclei to the median eminence where the hormones are released into the hypophysial portal vascular system.

Nuclei and Nucleoinfundibular Pathways Within the hypothalamus, distinct clusters of neurons are called “nuclei.” The hypothalamic nuclei are generally divided into four anatomic regions, the preoptic, supraoptic and lateral, tuberal, and mamillary regions. In general, the nuclei are topographically discrete in many species and, although relatively well demarcated in the human fetus, they are poorly defined in the mature human hypothalamus [46]. In a few cases, the existence of some nuclei is inferred entirely from studies of experimental animals. A schematic illustration is provided in Fig. 1.1. Structure–function correlations are difficult because of cellular heterogeneity of many hypothalamic nuclei. Any given hypothalamic hormone is often produced in more than one nucleus and, in many cases, a single nucleus may express more than one hormone. The physiologic roles of many nuclei remain unknown. The most anterior nuclei are the paired medial and lateral nuclei that have been associated with autonomic function, particularly temperature control and olfaction. The suprachiasmatic nucleus is found in the preoptic area dorsal to the optic chiasm and anterior to the supraoptic nucleus. This sexually dimorphic cell group shows a striking decrease in volume and cell number with age [53]. It is located in an area that is essential for gonadotropin release and sexual behavior in lower animals and may play a role in maintaining circadian rhythms. It is thought that the nucleus also plays a role in the sexual differentiation of the brain which, in the absence of male gonadal hormones, remains female but, if exposed to these at a critical stage in development, becomes male [54]. It is also associated with fibers of the supraoptic commissure, and receives afferents from the retina and the lateral geniculate bodies.

Functional Anatomy of the Hypothalamic Pituitary Axis

7

The anterior hypothalamic nucleus is composed of small neurons which mediate parasympathetic effects; it has connections to the insular cortex, substantia innominata and thalamus. The lateral hypothalamic nuclei are poorly defined areas composed of larger neurons which receive fibers from and contribute efferents to the median forebrain bundle. The paraventricular nuclei lie adjacent to the third ventricle and ventromedial to the fornix. They are composed mainly of large “magnocellular” neurons along with the supraoptic nuclei and also contain a number of “parvicellular” neurons. Efferent fibers to the pituitary stalk terminate in the posterior lobe of the pituitary. These nuclei are a major site of oxytocin and vasopressin synthesis. In patients with traumatic or surgical stalk section and in those with long-standing hypopituitarism, there is a marked reduction in the number of magnocellular neurons and stalk nerve fibers [46]; the parvicellular component remains. The supraoptic nuclei are the other paired magnocellular nuclei of the hypothalamus; they have no significant parvicellular component. They overlie the anterior optic tract and posteriorly are divided by the optic tract into anterolateral and posteromedial components, united by a thin stream of cells. Patients with stalk section or long-standing hypopituitarism also have atrophy of these nuclei [55]. The dorsomedial and ventromedial nuclei are involved in autonomic function and emotional behavior. They are situated between the tuber cinereum and paraventricular nuclei. Stimulation of the dorsomedial and destruction of the ventromedial nuclei produces rage in experimental animals. The ventromedial nuclei are concerned with control of balance between hunger and satiety. Destruction of the ventromedial nucleus results in obesity [56,57]; conversely, destruction of the ventrolateral nucleus, known as the “feeding center,” is associated with anorexia and cachexia [56]. These nuclei show a large number of afferent connections from olfactory and retinal fibers, the reticular formation, and the nucleus of the solitary tract which receives input from the vagus. Afferents from the cortex enter by way of the thalamus. Ventral to the third ventricle and paraventricular nuclei lies the arcuate (infundibular) nucleus which is another important component of the hypophysiotropic region and plays a major role in the modulation of anterior pituitary function. The subventricular nucleus lies on the floor of the third ventricle posterior to the arcuate and anteromedial to the tuberal nuclei. This usually parvicellular nucleus shows marked hypertrophy of the neurons which become magnocellular in postmenopausal women [58,59], in young women suffering from postpartum hypopituitarism with complete gonadal atrophy [60], in hypogonadal men and women, in starvation [61], after hypophysectomy [62], and in late pregnancy. The neurons develop a distinctive nucleolar change considered a manifestation of feedback effect; a similar change is also observed in neurons of the arcuate

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Hypothalamic–Pituitary Function

nucleus [60]. In some of these conditions, the change is thought to reflect lack of estrogens [59,63,64]. The tuberal nuclei consist of irregularly grouped masses of large neurons inferior to the lateral nuclei that give rise to efferent fibers of the hypothalamus. After stalk section, a slight increase in coarsely granular basophilic cytoplasmic material may occur [46]. The posterior hypothalamic nucleus, situated between the third ventricle and the mamillo–thalamic tract, lies superior to the mamillary bodies. When stimulated, it produces sympathetic effects; it may play a role in temperature regulation and its large neurons may be the source of hypothalamic efferents that descend to the reticular formation of the brain stem. The paired mamillary nuclei and a variety of minor nuclei in the supramamillary area, including the nucleus intracalatus, form the most posterior portion of the hypothalamus. These nuclei integrate incoming information from the limbic system and the midbrain tegmentum and send out efferent fibers to the anterior nucleus of the thalamus and to the brain stem.

Embryology The forebrain of the human embryo can be identified at 4 weeks postconception; by 5 weeks it has divided into a central diencephalon and two lateral telencephalic structures. Three swellings appear in the diencephalon which represent the anlages of epithalamus, thalamus, and hypothalamus. The nuclei of the hypothalamus and the supraoptico-hypophysial tract are recognizable at 8 weeks of gestation [65]. The nerve cells originate from proliferating neuroblasts and form several closely associated nuclei in the hypothalamus. At 6 weeks, a thickening of neuroblasts projects caudally to become the median eminence and infundibulum and establishes direct contact with the upward invagination of the roof of the primitive oral cavity, Rathke’s pouch. By 3 months, the rudimentary neural lobe consists of a short wide sac with a thick wall and a lumen lined by columnar ependymal cells [66]. Proliferation of spongioblasts gives rise to the modified neuroglia of the neurohypophysis known as pituicytes while the ependymal cells become dispersed in the neuroglial substance. Downgrowth of unmyelinated axons of neurons of magnocellular nuclei of the hypothalamus reaches the median eminence by 3 months, passes through the stalk and terminates in the neural lobe by 6 months of gestation. Monoamine fluoresence can be detected at 10 weeks in hypothalamic nuclei and at 13 weeks in the median eminence [67]. The supraoptic nucleus matures earlier than the paraventricular nucleus; vasopressin is demonstrated earlier and in higher concentrations than oxytocin in the neural lobe [68]. Arginine vasopressin is identified by radioimmunoassay at 12 weeks of gestation [69]. Intracellular granules have been demonstrated in hypothalamic nuclei at 19 weeks and in the posterior lobe at 23 weeks of gestation. The

neurosecretory material is clearly visible in the supraoptic and paraventricular nuclei as well as the posterior lobe at 23–28 weeks of gestation [70–72]. Ultrastructurally, clusters of small clear vesicles and axon profiles have been identified in a fetus at 7.5 weeks of age. Granular vesicles become apparent in the axon profiles at 8.5 weeks of gestation. Fenestration of capillaries and expansion of perivascular spaces are noted with the appearance of intraaxonal vesicles [73]. Growth hormone-releasing hormone (GHRH) has been identified by immunohistochemistry in the fetal hypothalamus at 18 weeks of gestation [74]. Somatostatin (somatotropin release-inhibiting hormone; SRIH) is identified in fetal hypothalami in a large molecular form at 10 weeks of gestation and there is a gradual increase in both the number of somatostatin-containing neurons and the 14-amino acid form of this peptide with fetal age [75,76]. Dopamine is present in high concentrations in the fetal hypothalamus by 15 weeks of gestation [67]. Corticotropin-releasing hormone (CRH) has been detected in fetal median eminence at 16 weeks of gestation [77]. Thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH) are the first adenohypophysiotropic substances, being detectable in fetal hypothalami at 4.5 weeks and present in significant amounts by 10 weeks of gestation [78,79]. GnRH is localized by immunocytochemistry at 13 weeks and GnRH-containing nerve terminals are detected on portal vessels at 16 weeks [80]. Sexual dimorphism of GnRH concentration has been documented and correlates with sexual dimorphism of fetal gonadotropic hormones [81].

Functional Anatomy and Control of Anterior Pituitary Function Control of anterior pituitary hormone secretion is under a complex set of central and peripheral neural and chemical signals. The hypothalamus synthesizes and secretes unique releasing and inhibitory hormones that control the anterior pituitary hormones (Fig. 1.3). The polypeptide hormones are secreted into the hypothalamic pituitary portal vasculature, impinge upon specialized anterior pituitary cells and bind to specific surface receptors. The cell signal elicits regulation of pituitary trophic hormone gene transcription, translation, and/or secretion. The resultant secretion of anterior pituitary hormones into the systemic circulation depends upon a carefully controlled dynamic balance of hypothalamic hormone input, feedback regulation from peripheral target hormones, nonhormonal neurotransmitter agents, and paracrine or autocrine pituitary growth factors and peptides. These factors all contribute to the amount of each pituitary hormone secreted, as well as to their pattern of secretion. Complex feedback regulation loops interact to regulate the hypothalamic–pituitary axis. The target gland peripheral hormone usually exerts negative feedback regulation directly at the level of pituitary synthesis or secretion of the respective trophic hormone (Fig. 1.4). Pituitary

Chapter 1

Functional Anatomy of the Hypothalamic Pituitary Axis

9

FIGURE 1.3. Amino acid sequences of human hypothalamic hormones. CRH, corticotropin-releasing hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; SRIH, somatostatin; TRH, thyrotropin-releasing hormone.

FIGURE 1.4. General control of anterior pituitary hormone release by central and hypothalamic inputs and feedback regulation by peripheral and trophic hormones. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DA, dopamine; FSH, folliclestimulating hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; IGF-I, insulin-like growth factor-I; LH, luteinizing hormone; PRL, prolactin; SRIH, somatostatin; TRH, thyrotropin-releasing hormone; TSH, thyrotropin; VIP, vasoactive intestinal polypeptide.

trophic hormones may feed back in a very short loop to autoregulate their own secretion. They may also participate in short loop feedback regulation of the secretion of their respective hypothalamic releasing or inhibiting hormone. Finally, peripheral hormones may participate indirectly by feedback regulation of hypothalamic releasing and inhibiting hormones.

The central nervous system also influences the control of hypothalamic hormonal secretion by efferent signals emanating from exteroceptive organs including the ears, eyes, and skin, and from interoceptive senses of indices of metabolic and electrolyte homeostasis. The transduction of neuronal inputs to neurochemical signaling by the hypothalamus appears to occur in an oscil-

10

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latory fashion. The temporal nature of pituitary hormone secretion is a manifestation of this rhythmicity resulting in at least two patterns of circadian rhythm including sleeprelated hormone secretory cycles and 24-hour rhythm cycles entrained by a light–dark cycle. The peptidergic neurons of the hypothalamus are not classified into distinct cell types and there is no known correlation between cell structure and function. In fact, neurons of any anatomic area often contain more than one neuropeptide or candidate neurotransmitter. The functional anatomy of the hypothalamus is, therefore, best approached by discussion of each hormone or peptide. GHRH

The presence of the factor responsible for stimulating release of growth hormone (GH) was known for many years, but it was only in 1982 that GHRH was isolated and characterized [25,26]. It is now known to have two forms, a 40- and a 44-amino acid peptide; the active portion of the molecule is the 29-amino acid N-terminus. GHRH binds to the surface of the somatotrophs. The intracellular actions of GHRH are probably mediated by cyclic adenosine monophosphate (cAMP), resulting in stimulation of GH gene transcription, translation, and secretion. Somatostatin attenuates the secretion of GH by the somatotroph. GH stimulates predominantly the liver to produce insulin-like growth factor-I (IGF-I) which acts as a target hormone to induce tissue growth. GH itself also acts directly on the chondrocytes and possesses antiinsulin metabolic activity. Immunocytochemical studies have identified GHRH in neuronal cell bodies of the arcuate nucleus [82,83] (Fig. 1.5). Nerve fibers from this nucleus project mainly to the median eminence, are found in the external zone, and terminate on capillaries of the plexus of the hypothalamohypophysial portal system. In monkey hypothalamus, small groups of immunoreactive neurons are also found in ventral

portions of the ventromedial nucleus. In the rat, scattered cells are also seen in the lateral basal hypothalamus, the medial and lateral portion of the ventromedial nucleus, and the dorsal medial and paraventricular nuclei [84,85]. The primary anatomic localization of GHRH to the arcuate nucleus is in agreement with earlier physiologic studies which indicated that a region including the ventromedial and arcuate nuclei was facilitatory in GH regulation. Extrapituitary effects of GHRH have been reported in the rat. Administration of small doses of the peptide into the cerebral ventricles induces behavioral sedation as well as an increase in food intake [86]. No extra-hypothalamic sites of GHRH synthesis are known to exist in the human under normal circumstances, but endocrine tumors of lung, pancreas, gut, adrenal medulla, and C-cells of thyroid can give rise to GHRH excess and acromegaly [87] (see Chapter 11). Somatostatin (SRIH)

A hypothalamic factor with GH release-inhibiting activity was first described in 1968 [88]. In 1973, Brazeau and colleagues [23] isolated and characterized a 14-amino acid peptide which they called somatostatin, or somatotropin release-inhibiting hormone (SRIH). This peptide was also shown to inhibit thyrotropin (thyroid-stimulating hormone; TSH) secretion and to produce a variety of other effects not related to its action on the pituitary. The hypothalamic distribution of SRIH shows marked species variation [89–92]. In the human hypothalamus, SRIH-containing neurons are concentrated in the anterior portion of the arcuate nucleus [90]. No positivity has been found in the paraventricular nucleus, unlike the distribution observed in rodents where SRIH is found in the paraventricular nucleus in a narrow field extending 1–2 mm from the midline. Nerve fibers staining for SRIH are observed in the medial basal hypothalamus; nerve endings are concentrated in the external zone of the median eminence and the neurovascular zone of the pituitary stalk. Fibers containing SRIH are also localized in the ventromedial, arcuate, suprachiasmatic, and paraventricular nuclei. Somatostatincontaining neurons store the hormone in dense core cytoplasmic vesicles which measure 80–110 nm in diameter and are found in both the cell bodies and the nerve endings [92]. Somatostatin is also found in extrahypothalamic regions of the rat brain, including the preoptic region, central gray mesencephalon, amygdala, olfactory area, and spinal cord. In humans it is detectable in cortex, brain stem, pineal, retina, optic nerve, auditory nerve, and spinal cord. Somatostatin is also found in pancreatic islet cells, gut endocrine cells, thyroid C-cells, salivary gland, and placenta [93–95]. Prolactin-inhibiting Factor

FIGURE 1.5. Neurons containing immunoreactive growth hormone-releasing hormone are localized by immunocytochemistry in the arcuate nucleus. (Magnification ¥64)

Prolactin (PRL) secretion by the adenohypophysis is known to be under tonic inhibition by the hypothalamus [96]. The PRL-inhibiting activity of dopamine is well documented and, currently, it is widely accepted that dopaminergic

Chapter 1

control is the main PRL regulatory function of the hypothalamus. Dopamine is the only nonpeptidergic hypothalamic compound with a well-defined hypophysiotropic function. It exerts primarily inhibitory effects on the lactotroph and inhibits both PRL gene transcription and lactotroph mitotic activity. PRL acts to induce lactation in concert with other peripheral hormones. Although TRH also stimulates lactotroph function, its effect is probably not physiologic. Vasoactive intestinal peptide (VIP) has also been shown to stimulate the production of PRL although its physiologic role has not yet been clarified. Dopamine has been localized to the arcuate and periventricular nuclei of the mediobasal hypothalamus as well as being widespread throughout the brain [97,98]. The medium-sized dopaminergic neurons are scattered among other neurosecretory cells and are further subdivided into the tuberoinfundibular group, with terminals in the median eminence and pituitary stalk, and the tuberohypophysial group, with ends terminating in the neural and intermediate lobes of the pituitary. The dopamine projections to the intermediate and neural lobes of the pituitary originate primarily in the anterior and central portions of the arcuate nucleus, respectively. Dopamine-containing axon terminals are abundant in the zona externa of the median eminence and are characterized by dense core vesicles that measure 15–120 nm in diameter. They do not appear to form true synaptic connections. CRH

Despite being the first hypothalamic regulatory factor postulated, CRH was among the last identified. In 1981, a 41-amino acid peptide was extracted from the ovine hypothalamus, characterized and shown to stimulate specifically the release of ACTH and other pituitary peptides derived from proopiomelanocortin (POMC) [24]. CRH binds to the surface of the corticotroph and elicits transcription of the POMC gene, whose products include ACTH and bendorphin. ACTH stimulates the adrenal gland to synthesize corticosteroids which are critical for essential stress responses and cellular homeostasis. Antibodies against CRH have localized this peptide to neuronal cell bodies, mainly in the parvocellular portion of the paraventricular nucleus but also in a few magnocellular neurons [99–104]. In the rat hypothalamus, scattered cell bodies containing CRH are also detected in the lateral preoptic and hypothalamic areas and in some portions of the dorsal medial nucleus. CRH-immunoreactive fibers are observed in the area of the paraventricular nucleus, the neurovascular zone of the median eminence, the pituitary stalk, and the neurohypophysis. CRH is colocalized with arginine vasopressin in a subpopulation of magnocellular neurons of the paraventricular nucleus [103,104]; it is found together with enkephalin, peptide histidine isoleucine (PHI, a member of the secretin–glucagon family) and neurotensin in parvocellular neurons as well as in a discrete subset of oxytocinergic magnocelluar neurons [104]. Adrenalectomy

Functional Anatomy of the Hypothalamic Pituitary Axis

11

increases CRH immunoreactivity in parvocellular neurons of the paraventricular nucleus, consistent with established negative feedback effects of adrenal steroids on CRH production [104]. Vasopressin can also be found in the majority of CRH-containing parvocellular neurons after adrenalectomy [104]; it has been suggested that this plasticity allows for synergy of stimulation of ACTH secretion by the two peptides [104]. CRH is also widely distributed throughout the brain in the cerebral cortex, limbic system, brain stem, and spinal cord [98–101]. It is also found extracerebrally, particularly in placenta; some investigators have also localized CRH in endocrine cells of the pancreas, gut and lung; in liver, adrenal [105], and testicular Leydig cells [106]. TRH

The first adenohypophysiotropic hypothalamic hormone identified was the tripetide TRH [17,18]. At first demonstrated to release TSH, TRH was rapidly also shown to release PRL. TRH binds to specific receptors on the thyrotroph and stimulates the transcription and secretion of TSH. TSH stimulates the thyroid gland to secrete primarily thyroxine, and triiodothyronine. The major source of triiodothyronine, however, is hepatic deiodination of thyroxine. These hormones act to regulate thermogenesis and protein synthesis. Immunocytochemical studies have localized TRH in the rat brain, in neuronal cell bodies of the preoptic nucleus, the parvocellular portion of the paraventricular nucleus, the perifornical region, dorsomedial nucleus, and basolateral hypothalamus [107,108]. TRH-positive terminals that contain dense core vesicles are found in high concentrations in the median eminence as well as in several of the hypothalamic nuclei, which also contain TRH-positive neuronal cell bodies. The tripetide is widely distributed throughout the brain and spinal cord, suggesting that it may act as a neurotransmitter in other areas [107,108]. Several effects of TRH not mediated by the pituitary gland have been demonstrated, including hyperthermia, behavioral excitation and the ability to reverse or prevent anesthesia from barbiturates and other depressants [109]. TRH has been reported in fetal and neonatal pancreatic islet cells [110] and gut endocrine cells [111], where it is thought to inhibit gastric secretion, gastric motility, and exocrine pancreatic secretion; it has also been localized in several human tumors [112]. GnRH

The second hypothalamic adenohypophysiotropic peptide to be characterized was originally called luteinizing hormone (LH)-releasing hormone (LRH) but was subsequently shown to release both gonadotropins, follicle stimulating hormone (FSH), and LH, by the pituitary gland [20–22]. The gonads are thereby stimulated to produce sex steroids and secondary sex characteristics. GnRH is also thought to stimulate sexual activity in experimental animals of both

12

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Hypothalamic–Pituitary Function

sexes, an effect that appears to be independent of its hypophysiotropic action [113]. GnRH has been localized in the hypothalami of several species [113–115]. In primates, GnRH neurons are located in large areas extending caudally from the preoptic region to the premamillary nucleus [96]. The neurons are bipolar or multipolar cells with multiple dendrites. The highest concentration of these cells is found in the mediobasal hypothalamus (infundibular and premamillary nuclei) and in the preoptic area. These neurons give rise to an infundibular GnRH pathway ending on the capillaries of the pituitary portal plexus as well as to a preopticoterminal tract projecting to the capillaries of the OVLT. In rodents, the majority of neuronal cell bodies are located in the septal preoptic regions and the anterior hypothalamus, and are particularly in the dorsal and medial septal nuclei, the nucleus of the diagonal band of Broca and anterior hypothalamic nuclei, and the OVLT. These neurons are usually elongated with eccentric nuclei and are unipolar. They project to the external zone of the median eminence as well as to the OVLT. Immunoelectron microscopy has documented localization of GnRH in dense core vesicles which measure 75–95 nm in diameter and are found in cell bodies as well as nerve endings [115]. Extrahypothalamic localization of GnRH includes several areas of the limbic system (septum, hippocampus, and olfactory bulb), the breast, and placenta [116]. Vasopressin and Oxytocin

Vasopressin, oxytocin, and their binding proteins, neurophysins I and II, are detected by immunohistochemistry in the perikarya of magnocellular neurons in the supraoptic (Fig. 1.6) and paraventricular (Fig. 1.7) nuclei [117,118]. Fibers emanating from these neurons converge towards the median eminence, pass caudally through its internal zone and end in dilated nerve terminals of the pars nervosa of

the pituitary known as Herring bodies (Fig. 1.8). The nerve fibers, their axonal swellings and the exceedingly large and characteristic swellings which can exceed 20 mm in diameter contain secretory granules of variable electron density and electron-lucent vesicles (Fig. 1.9). The secretory granules originate in the perikarya of the neurons and mature, growing from 60 to 220 nm in diameter, as they travel to the nerve endings [119,120]. It has been clearly shown that vasopressin and oxytocin are produced by different magnocellular neurons in both nuclei. Immunostaining for vasopressin is markedly increased after adrenalectomy in the external zone but not the internal zone of the rat median eminence [121,122]. Vasopressin is colocalized in some neurons with CRH and is additive with that substance in the regulation of ACTH release. Interestingly, it is found in high concentrations in portal blood draining to the anterior pituitary, suggesting that it may play a physiologic role in ACTH release [104]. A subset of oxytocin-containing neurons also may contain CRH. Immunoreactive vasopressin has been demonstrated in various other areas of the central nervous system as well as testis, ovary, uterus, adrenal, and thymus [123]. VIP

This 28-amino acid peptide, first isolated from intestine, has been localized in mammalian brain [124]. Immunoreactive fibers are present in high concentrations in the cortex, hippocampus, dentate gyrus, amygdala, nucleus of the stria terminalis, suprachiasmatic nucleus, and periaqueductal gray matter. Fibers containing immunoreactive VIP and its related PHI are also detected in areas that do not contain cell bodies. In the hypothalamus, VIP has been localized in the ventromedial nucleus, where it may affect appetite [56], in the suprachiasmatic nucleus, where it is thought to play a role in circadian rhythmicity, and in parvocellular neurons of the paraventricular nucleus [125]. It is known to modulate secretion of GH, PRL, and LH at the level of their hypothalamic regulation [126–128] and also stimulates PRL release directly [126]; some investigators have suggested that VIP is the physiologic PRL-releasing factor. After adrenalectomy, the number and intensity of VIP-containing small neurons in the paraventricular nucleus increase, suggesting a possible role for this substance in PRL regulation during stress. Cholecystokinin (CCK)

FIGURE 1.6. Perikarya and axonal processes of magnocellular neurons in the supraoptic nucleus contain strong immunopositivity for vasopressin. (Magnification ¥64)

This hormone, which was first discovered in the gut, was detected in the brain by immunocytochemistry [129–131]. CCK-containing cell bodies are prominent in the cerebral cortex and are also widely distributed throughout the olfactory and limbic systems. In the hypothalamus, they are found in several nuclei, including the magnocellular paraventricular and supraoptic nuclei. The midbrain also contains a striking concentration of CCK-immunoreactive cell bodies in the ventral tegmentum and raphe. This peptide modulates dopaminergic, noradrenergic, and opioid systems. It also inhibits feeding, probably at the level

Chapter 1

Functional Anatomy of the Hypothalamic Pituitary Axis

13

FIGURE 1.7. Adjacent to the third ventricle (V), magnocellular neurons in the paraventricular nucleus demonstrate strong immunoreactivity for vasopressin. (Magnification (a) ¥26; (b) ¥64)

FIGURE 1.8. The posterior lobe of the pituitary contains nerve fibers of the hypothalamohypophysial tract with axonal swellings and globular Herring bodies that stain with aldehyde thionin (a) and contain intense immunopositivity for vasopressin (b). (Magnification (a) ¥102; (b) ¥64)

of the ventromedial hypothalamus, and alters the pain threshold [132].

release, and to enhance GH release in response to GHRH in humans and rats [141], suggesting that hypothalamic galanin may modulate secretion of those hormones.

Galanin

Galanin is a 29-amino acid peptide that was originally isolated from intestine [133]. Immunoreactive galanin has been demonstrated in the central nervous system [134]; in hypothalamus, it colocalizes with dopamine and g-aminobutyric acid (GABA) [135]. It is also present in peripheral neural elements of the respiratory tract, gastrointestinal tract, pituitary, pancreas, urogentital tract, and adrenal medulla of humans and several mammalian species [136–139]. Galaninpositive neurons have been observed in several hypothalamic tumors [139]. Galanin is thought to act as a neurotransmitter although its functional roles have not been fully clarified. It has been shown to inhibit dopamine [140], thereby stimulating PRL

Gastrin

Gastrin is a gut peptide which is known to be produced in stomach and in numerous endocrine tumors of gut and pancreas. Specific antibodies have also localized gastrin in cerebral cortex, hypothalamus, and neurohypophysis [142,143]. Gastrin is known to modulate GH secretion at the hypothalamic level, either by reducing somatostatin release or by enhancing GHRH secretion [144]. Glucagon

Glucagon is expressed in the pancreatic islets and intestine, and has also been reported in other tissues, including thymus, thyroid, and adrenal medulla. A growing body of

14

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Hypothalamic–Pituitary Function

levels of NPY immunoreactivity are found in hypophysial portal blood. This peptide stimulates appetite when injected into the hypothalamus and appears to modulate the secretion of both LH and ACTH [150]. NPY-containing fibers also are known to contact TRH-synthesizing perikarya and neuronal processes in the paraventricular nucleus where it may mediate the neuroendocrine regulation of TRH [151]. Neurotensin

This 13-amino acid gut–brain peptide is found in the highest concentration in the ileum and hypothalamus [152]. In the rat, it is localized in the medial preoptic region, infundibular nucleus, paraventricular nucleus, and lateral hypothalamus with fibers most dense in the paraventricular and periventricular regions and in the median eminence. It has been shown to colocalize in neurons with catecholamines, possibly dopamine, in the periventricular and arcuate regions, and with CRH in the paraventricular nucleus. Some investigators have shown that it alters PRL release and blunts the response of that hormone to TRH [153]; it may also play a role in the regulation of GH and LH. Substance P

FIGURE 1.9. By electron microscopy, the normal human posterior lobe of pituitary contains numerous axonal processes filled with neurosecretory material (arrows). A large, dilated nerve terminal is the ultrastructural equivalent of the Herring body. (Magnification ¥7960)

evidence suggests that the brain is a site of glucagon biosynthesis. Neurons staining for glucagon and glucagon-like peptides have been detected in different regions of the brain including retina, hypothalamus, and medulla oblongata [145,146] and glucagon gene expression has been demonstrated in the brain stem and hypothalamus [147]. Intracerebral injections of glucagon produce dosedependent hyperglycemia, suggesting that this substance plays a role in the regulation of glucose metabolism centrally as well as peripherally [148]. Neuropeptide Y (NPY)

This 36-amino acid peptide is found by immunocytochemistry in a widely distributed pattern throughout the brain [149,150]. NPY-containing neurons are particularly numerous in the arcuate nucleus of the hypothalamus, striatum, hippocampus, and cortex. Nerve fibers are abundant in the paraventricular and suprachiasmastic nuclei and fibers are found in the internal zone of the median eminence. High

Substance P has been found in neurons in various regions of the brain. There are multiple substance P-containing afferents to the hypothalamus from the amygdala via the stria terminalis. Hypothalamic neurons containing this peptide are abundant in the arcuate, dorsomedial, ventromedial, and premamillary nuclei [152,154]. It is colocalized with vasopressin, is probably involved in pain perception within the limbic system, and may be secreted into the hypophysial portal vasculature where it is thought to affect blood flow. Substance P has been shown to alter GH regulation in vivo, but this is postulated to act via regulation of somatostatin neurons. It has variable effects on release of PRL, TSH, and LH. Bombesin/Gastrin-releasing Peptide (GRP)/Neuromedin

Bombesin was originally isolated from the skin of amphibians and stimulated great interest when it was shown to have potent biologic activity in mammals. Mammalian counterparts were soon discovered and given the names gastrin-releasing peptide and neuronedin. Bombesin-like immunoreactivity was found in neurons of the external zone of the median eminence near small blood vessels and colocalized with CRH [155]. Pharmacologic studies showed that bombesin can alter the release of adenohypophysial hormones including GH, PRL, and LH. The discovery of immunoreactivity for homologous peptides in hypothalamus suggests a possible role for these substances in the regulation of pituitary function. Calcitonin Gene-related Peptide (CGRP)

This 37-amino acid peptide is derived from the calcitonin gene by alternative messenger RNA (mRNA) processing.

Chapter 1

It is detected primarily in nervous tissue; CGRPimmunoreactive cell bodies are found in the supraoptic, paraventricular, and infundibular nuclei of the human hypothalamus [156]. CGRP inhibits GH release both in vitro and in vivo. It may also affect PRL release [157]. POMC-derived Peptides b-Endorphin

and other POMC-derived peptides are widespread in the central nervous system, their highest concentration being in the arcuate nucleus of the hypothalamus [158]. Nerve fibers containing b-endorphin and melanocyte-stimulating hormone-a (MSH-a) extend throughout many regions and innervate the median eminence, amygdala, preoptic area, ventromedial nucleus, and capillaries of the median eminence and portal system. There is another distinct and complex network of fibers containing the opiate methionine enkephalin (met-enkephalin). In addition to the multiple effects of these peptides on behavior, pain perception, immunomodulation, and many other functions too numerous to review here, they are also thought to modulate pituitary function [159], by inhibiting ACTH and LH release and stimulating PRL secretion. The effect on PRL is likely both direct and by reducing dopaminergic inhibition; the inhibition of LH appears to be only indirect via GnRH inhibition. The pituitary actions of endogenous opioids are complex, since they are themselves regulated by gonadal steroids and opioids may play a role in the negative-feedback effects of gonadal steroids on gonadotropins. Opioids also suppress the release of vasopressin and oxytocin, directly and possibly via noradrenergic regulation [160]. Cytokines

The close link between the neuroendocrine and immune systems has become widely recognized. Hormones are known to modulate the reactivity of immunocompetent cells and cytokines secreted by members of the immune system simulate secretion of hormones, most notably in the hypothalamus–pituitary–adrenal axis [161]. Interleukins are a family of peptides that mediate the immune response. Interleukin-1 (IL-1) is a monokine produced by macrophages in response to antigenic challenge. IL-1 stimulates ACTH and suppresses GH, LH and TSH secretion [162]. IL-1b immunoreactivity has been reported in neuronal fibers of the human brain, including the subfornical organ, stria terminalis, ventromedial nucleus of the hypothalamus, the posterior hypothalamus, and around the vessels of the median eminence. It is found in areas containing CRH-immunoreactive neurons and is known to increase CPH-mediated ACTH but is not found in the same synaptic vesicles as CRH. In fact, it is not released by depolarizing stimuli and it is not clear that IL-1b is even produced by neurons [161]. It also stimulates somatostatin biosynthesis in cultures of fetal rat brain [163], providing a

15

Functional Anatomy of the Hypothalamic Pituitary Axis

likely explanation for the in vivo reduction of GH and TSH secretion. Other interleukins are not known to be hypothalamic peptides but affect pituitary function. Interleukin-6 (IL-6) stimulates release of GH, PRL, and LH; tumor necrosis factor-a (TNF-a) and interferon-g also affect release of PRL and LH [164–166]. This information has significant neuroendocrinologic implications in the study of reproduction, autoimmunity, and other diseases. Growth Factors

A number of peptide growth factors, classified into several major families, are known to modulate cell proliferation. [167] Some are also known to affect hormone production (Table 1.1) and some are, in turn, modulated by hormones. Only a few have been identified in the hypothalamus and are thought to play a physiologic role in pituitary regulation; these include fibroblast growth factor (FGF) [168] and transforming growth factor-a (TGF-a) [169]. The former increases release of PRL and reduces basal GH; it also modifies the response of pituitary hormone release to TRH [170]. The latter has been localized by immunocytochemistry mainly in magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus. It is structurally homologous to epidermal growth factor (EGF) and may mediate some EGF effects on adenohypophysial production of GH, PRL, and TSH as well as cell proliferation [171].

Classification of Hypothalamic and Neurohypophysial Pathology Numerous pathologic processes involve the hypothalamus and neurohypophysis [46,47], giving rise to various symptoms, signs, and clinical syndromes. Among these, endocrine changes may be conspicuous. The local symptoms, such as visual defects, nerve palsy, and headache, may be secondary

Table 1.1. factors

Hormone regulation by pituitary-derived growth

Peptide

GH

PRL

EGF Activin FGF IGF-I IGF-II Insulin Endothelin Interleukin-1

Ø Ø

≠

Ø

FSH/LH

ACTH ≠

≠ ≠

Ø Ø Ø

TSH

≠

≠ ≠

≠ ≠

≠

GH, growth hormone; PRL, prolactin; TSH, thyroid-stimulating hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; ACTH, adrenocorticotropic hormone; EGF, epidermal growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factor.

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to increased intracranial pressure or may be due to compression, invasion, injury, or destruction of tissue components. Involvement of certain parts of the hypothalamus can give rise to nonendocrine pathology, including abnormalities of appetite and temperature regulation. The endocrine sequela of hypothalamic disorders can be classified into two categories: (i) those giving rise to hypothalamic hormone deficiency; and (ii) those giving rise to hypothalamic hormone excess. The major pathologic processes causing these disorders are reviewed briefly and their features are fully discussed in ensuing chapters. Hypothalamic Hormone Deficiency

Insufficient secretion of hypothalamic adenohypophysiotropic hormones may be caused by destructive lesions of the hypothalamus. Lesions such as granulomas, meningitis or other inflammatory processes, pituitary adenomas, craniopharyngiomas, lymphomas, histiocytosis-X, metastatic carcinomas, craniocerebral trauma or hypoxic tissue injury may impair the synthesis of numerous hormones, including vasopressin, oxytocin, and the various adenohypophysiotropic hormones. These lesions give rise to true hypothalamic hypopituitarism. Similarly, lesions affecting the pituitary stalk, such as surgical or traumatic sectioning of the hypophysial stalk or its interruption by various pathologic processes, block the transport of the hypothalamic hypophysiotropic hormones from their sites of production in the hypothalamus to the anterior pituitary. It is obvious that any disconnection of the direct link between the hypothalamus and pituitary results in various degrees of hypopituitarism. Hypocortisolism, hypogonadism, and/or hypothyroidism have been demonstrated conclusively in patients with destructive diseases of the hypothalamus. Deficiency of GHRH usually results in growth retardation or in dwarfism [172]. Destructive lesions may manifest as growth retardation of hypothalamic origin in which patients respond to administration of GHRH. Idiopathic GH deficiency may be associated with other pituitary insufficiency and hypothalamic hormone abnormalities. Of particular interest is an autosomal recessive form of hypothalamic dwarfism due to failure to produce GHRH [173,174]; this disorder represents approximately 10% of cases of inherited growth retardation. The limited morphologic studies of patients with GHRH deficiency have documented that pituitary somatotrophs have normal morphology and GH content and administration of GHRH elicits a normal GH response [175]. Destructive lesions of the hypothalamus may impair the synthesis and/or release of dopamine and therefore may give rise to hyperprolactinemia [96]. Elevated blood PRL levels are also found in patients with disruption of, or damage to, the pituitary stalk. As a result of decreased transport of dopamine, lactotrophs are relieved from their tonic hypothalamic inhibition, leading to hyperprolactinemia. Hypothalamic hypothyroidism is usually not an isolated deficiency; it is most often associated with multiple hypo-

thalamic hormone deficiencies caused by organic hypothalamic pathology. Hypothalamic hypogonadism may be attributed to lack of GnRH or to nonpulsatile release of that hormone [176]. It may be an isolated defect of GnRH neurons [177]; in patients with hemochromatosis it is attributable to a combination of iron-induced damage to GnRH neurons and pituitary abnormalities [178]. Kallmann’s syndrome is an uncommon variant of hypothalamic hypogonadism which occurs in both men and women. The hypogonadism is associated with anosmia [179]. These deficits are due to defective development of the GnRH-secreting part of the hypothalamus associated with hypoplasia or aplasia of the olfactory area of the brain that can be documented by magnetic resonance imaging (MRI) [180]. Kallman’s syndrome is now known to be attributed to deletion or mutations of the KAL gene, located at Xp22.3; this gene encodes a 680 amino acid protein, anosmin, that has homology to other molecules implicated in neural development [181]. The pathology of the hypothalamus in this disorder has been thoroughly described in a histologic study in which abnormalities were found in various hypothalamic nuclei [182]; the lateral tuberal nuclei were underdeveloped and the subventricular nucleus exhibited neuronal hypertrophy. The number of pituitary gonadotrophs was markedly decreased as documented by immunohistochemistry and electron microscopy [182]. Detailed pathologic examination of the hypothalamus is yet to be reported in most patients with no major organic hypothalamic disease and apparently idiopathic deficiency of hypothalamic adenohypophysiotropic hormones. Diabetes insipidus is an uncommon but distinct clinical syndrome characterized by polyuria and polydipsia and results from vasopressin deficiency [46,47]. The extent of disease varies with the location of tissue destruction. Because vasopressin is transported through the pituitary stalk to the posterior lobe where it is stored in nerve endings, destruction of the posterior pituitary may interfere with storage and release of the hormone, resulting in its deficiency. This situation is usually transient and selective lesions of the posterior lobe usually cause only mild and temporary polyuria and polydipsia. Destruction high in the infundibulum results in permanent diabetes insipidus due to retrograde axonal degeneration and atrophy of neurons in the supraoptic and paraventricular nuclei [183]. Destruction of the supraoptic and/or paraventricular nuclei gives rise to permanent disease; approximately 90% destruction is required to cause significant and permanent disease [184], explaining why section low in the stalk, which creates atrophy of a minority of neuronal axons, causes only a transient disorder. Rare forms of hereditary idiopathic diabetes insipidus are usually unassociated with gross destruction of the hypothalamus [185]; detailed histologic studies reveal severe atrophy of neurons in the supraoptic and paraventricular nuclei in most patients but the etiology of these disorders remains unknown. In a few instances, neurons of the

Chapter 1

two magnocellular nuclei have been microscopically normal but devoid of vasopressin [186]. Some studies have suggested that this disorder may in some cases represent autoimmune destruction of vasopressin-producing neurons [187]. Oxytoxin deficiency, resulting from a decrease in the production of oxytocin, causes no major clinical abnormalities. Hypothalamic Hormone Excess

Hypersecretion of hypothalamic hormones, although rare, can result in endocrine symptomatology. Certain endocrine diseases characterized by hyperfunction of the anterior pituitary may be due primarily to adenohypophysiotropic hormone excess as a result of excessive secretion of hypothalamic releasing hormones. As yet, there is no evidence that hypersecretion of hypothalamic inhibiting hormones causes pituitary hypofunction. Acromegaly, a syndrome resulting from sustained GH hypersecretion, is almost always the result of a pituitary adenoma. Only one case of proven ectopic GH production has been reported [188]. More numerous are cases of production of GHRH by tumors that result in somatotroph hyperplasia or adenoma in the pituitary and produce clinical features of GH excess [87]. Extrahypothalamic GHRH production has been documented in endocrine tumors of lung, pancreas, thymus, medullary thyroid carcinoma, and pheochromocytoma. Primary tumors of the hypothalamus, called variously hypothalamic neuronal hamartomas, hypothalamic gangliocytomas and adenohypophysial neuronal choristomas, are lesions consisting of neurons with hypothalamic differentiation. Some of these tumors have been shown to contain GHRH and have been associated with pituitary somatotroph adenoma and acromegaly [189]. Several have been shown to be plurihormonal, containing GnRH, glucagon, gastrin, and somatostatin. Gigantism with pituitary GH excess has been described occasionally in the McCune–Albright syndrome [190]; this disorder is characterized by polyostotic fibrous dysplasia, pigmentary abnormalities and a variety of endocrine abnormalities, most commonly precocious puberty in female children. The pituitary may show mammosomatotroph hyperplasia that is attributed to activation of the signal transduction pathway generating cyclic AMP in these cells. These various manifestations are now known to be due to activating mutations of the Gs alpha gene (gsp mutations) [191,192]. Mammosomatotroph hyperplasia has also been reported as a cause of gigantism in the absence of McCune–Albright syndrome [193]. No proof of GHRH excess, either of hypothalamic or ectopic origin, has been offered in these patients; however, the pathogenetic role of GHRH in mammosomatotroph proliferation has been proven in mice transgenic for GHRH who have mammosomatotroph hyperplasia resembling that seen in these human disorders [194]. Cerebral gigantism (Sotos’ syndrome) has also been postulated to be a primary hypothalamic endocrinopathy. However, in patients with this

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disorder, hormone levels are normal and a morphologic study of the hypothalamus and pituitary showed no specific abnormality [47]. Cushing’s disease is known to be associated with pituitary corticotroph hyperplasia in some cases [195]; it has been suggested that the corticotroph hyperplasia may be secondary to excess production of CRH [196]. Ectopic production of CRH has been shown with increasing frequency and can cause Cushing’s disease; it must be considered in the differential diagnosis of that disorder [197,198]. In some cases, CRH has been elaborated in association with ACTH, suggesting autocrine regulation of some cases of ectopic ACTH syndrome. Rarely, a hypothalamic CRH-producing neuronal tumor has been reported in association with pituitary corticotroph hyperplasia or adenoma and Cushing’s disease [196,199–201]. Precocious puberty is an uncommon clinical syndrome which is in most instances idiopathic or attributable to androgen- or estrogen-producing neoplasms. Idiopathic precocious puberty is assumed to be hypothalamic in origin despite the absence of any anatomic lesion; less than 10% of cases are due to demonstrable hypothalamic pathology. Electroencephalographic abnormalities and behavioral disturbances have been observed in otherwise neurologically normal patients with this disorder [202]. Some patients respond to therapy directed against hypothalamic stimulation, but the disease may also be GnRH independent [203]. Structural lesions in and around the hypothalamus associated with precocious puberty fall into two groups. Some lesions actively participate in the production of precocious puberty by elaborating GnRH; these consist primarily of hypothalamic neuronal hamartomas which have been shown to contain GnRH in some cases [204,205]. The second group consists of hormonally inactive lesions which nonspecifically stimulate or inhibit hypothalamic centers involved in the regulation of sexual maturation. These are primarily lesions in the region of the posterior hypothalamus and include tumors of the pineal and hypothalamus, astrocytic gliomas, infections, hydrocephalus, head trauma, arachnoid cysts, and, occasionally, craniopharyngiomas. Precocious puberty is a prominent feature of the McCune–Albright syndrome [200]; in this disease, there is no demonstrable hypothalamic lesion and the patients may develop normal sexual function in adulthood. The hypothalamus has been implicated as the cause of some cases of hyperthyroidism but this has not been proven [206]. Vasopressin excess may cause water intoxication. The syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) may be due to idiopathic hypothalamic vasopressin excess or may be associated with various disease, including malignant tumors, most often bronchogenic carcinoma, and tuberculosis [207]. In the latter instances, this syndrome may be due to secretion of vasopressin or a similar peptide by tumoral or diseased pulmonary tissue [208,209]. In patients in whom no underlying cause is found, the

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idiopathic syndrome is likely due to posterior pituitary hyperfunction but no morphologic characteristics of this disorder have been described. The pathologic process in the brain may be in a number of areas; inhibitory osmoreceptors are found diffusely in the brain, as far away as the brain stem, and lesions can reduce the tonic inhibition of vasopressin, thereby increasing its release. Evidence of this widespread control is found in the increase in vasopressin release associated with congestive heart failure, cirrhosis, renal disease, brain trauma, positive pressure ventilation, and neurosurgical manipulation of the pituitary and hypothalamus. Age Related Changes in the Hypothalamus

Age related changes in the hypothalamus and neurohypophysis are few. The most striking is a morphologic curiosity, the accumulation of corpora amylacea, most often seen in the region of the supraoptic nuclei. The magnocellular nuclei are remarkably unaffected by age; immunohistochemistry shows no significant change in staining of vasopressin and oxytocin in older subjects [210]. The volume of the mamillary bodies is reduced but cell numbers appear normal [211]. Lipofuscin accumulation is commonly seen in the aging brain but does not appear to affect hypothalamic neuronal function. The suprachiasmatic nucleus decreases in volume and cell number with age [53]. The subventricular nucleus, in contrast, undergoes marked hypertrophy of its usually parvicellular neurons in postmenopausal women, as well as in starvation, posthypophysectomy, late pregnancy, and in patients suffering from prolonged postpartum hypopituitarism [58–64]. ADENOHYPOPHYSIS

Anatomy The adenohypophysis is composed of three parts, the pars distalis, the pars intermedia, and the pars tuberalis (Fig.

(a)

1.10). The pars distalis constitutes the largest portion of the gland; it is also known as the anterior lobe or the pars glandularis. The pars intermedia is rudimentary in the human pituitary; it is the vestigial posterior limb of Rathke’s pouch and is found in its underdeveloped form behind the medial cleft of the pituitary. It is also known as the intermediate lobe. The pars tuberalis is an upward extension of a few layers of adenohypophysial cells surrounding the external aspect of the lower hypophysial stalk; it is also known as the pars infundibularis. The adult human pituitary is bean shaped, bilaterally symmetrical, and measures approximately 13 mm transversely, 9 mm anteroposteriorly, and 6 mm vertically. It weighs approximately 0.6 g. The anterior lobe comprises about 80% of the pituitary. The pituitary of women is somewhat larger than that of men; moreover, the pituitary is heavier in multiparous than in nulliparous women. The increased size is attributable to the marked hyperplasia of the pituitary during pregnancy and lactation, which may increase the weight to 1 g or more; postlactational involution occurs but the gland does not return to its prepregnancy size. A slight to moderate weight reduction is seen with advancing age. The hypophysis is found within the sella turcica where it is lined by dura mater, a dense layer of connective tissue. The uppermost portion of the adenohypophysis is covered by the diaphragma sellae, a reflection of the dura that constitutes the roof of the sella turcica. The sellar diaphragm has a small central opening for the hypophysial stalk and protects the pituitary from the pressure of cerebrospinal fluid (CSF). Defective development or absence of this structure may lead to the so-called empty sella syndrome in which the pituitary is compressed by CSF pressure. The increased pressure results in enlargement of the sella turcica and flattening of the pituitary, which may be compressed to a thin layer of tissue at the bottom of the sella turcica. This lesion is usually unassociated with functional

(b)

FIGURE 1.10. (a) Sagittal section of an adult human pituitary obtained at autopsy illustrates the adenohypophysis (A) and neurohypophysis (N) attached to the pituitary stalk. (b) Horizontal cross-section of an adult human autopsy pituitary allows accurate identification of the neural lobe (N) and the anterior lobe (A) with subtle distinction between the two lateral lobes and the median wedge. The cystic remnants of Rathke’s cleft that represent the pars intermedia in humans are indistinct (arrow head).

Chapter 1

hypophysial abnormalities [206] but is important in differential diagnosis. Other anatomic variations in the shape of the hypophysis, the size and width of the sellar diaphragm, and relation to pituitary structures have been reported [207]. Minor changes have no endocrine significance.

Vascular Supply The blood circulation of the human hypophysis has major implications for the regulation of adenohypophysial hormone secretion [48–51]. The gland receives blood through the hypophysial portal circulation which carries the hypothalamic stimulatory and inhibitory hormones from the infundibulum to adenohypophysial cells. As described above (see Fig. 1.2), the branches of the superior hypophysial arteries penetrate the stalk, form a superficial network of vessels (external plexus) and give rise to a mesh of capillaries and gomitoli (internal plexus). The latter presumably regulate blood flow, thereby affecting transport of hypothalamic hormones to the adenohypophysis. The long portal vessels that arise from the infundibular plexuses and the short portal vessels that originate in the lower pituitary stalk and posterior lobe enter the pars distalis carrying adenohypophysiotropic hormones; the former carry 70–90% of the blood flow while only 10–30% originates in the short portal vessels. The trabecular or loral arteries transport blood to the adenohypophysis via the neural lobe, but, in addition, some arterial blood is directed to the adenohypophysis via two branches of the inferior hypophysial artery: (i) the capsular artery, which serves the connective tissue of the pituitary capsule and penetrates to the superficial cell rows of the adenohypophysis; and (ii) the artery of the fibrous core. In some individuals, the middle hypophysial artery may vascularize the adenohypophysis directly [212]. The volume of veins leading away from the adenohypophysis is considerably smaller than that of portal vessels entering the gland. The meager venous connections drain adenohypophysial and neurohypophysial blood to the cavernous sinus. It has been shown that the short portal vessels also serve as efferent channels, giving rise to reversal of blood flow in the neurohypophysial vascular bed. This implies that secretory products of the adenohypophysis may also enter the neurohypophysis and, by reverse flow to the median eminence, play a role in the regulation of hypothalamic factors via blood flow [50,51]. Pituitary capillaries are lined by fenestrated endothelium with a thin subendothelial space. Hormones released by adenohypophysial cells must therefore pass through the basement membrane of their cell of origin, capillary basement membrane, subendothelial space, and the endothelial cell layer to reach the bloodstream.

Nerve Supply The adenohypophysis has no direct nerve supply, apart from small sympathetic nerve fibers which are associated with and

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presumably innervate capillaries [195]. In some species, the intermediate lobe has rich innervation [213]. Thus, although neural connections may affect blood flow to the adenohypophysis, it is unlikely that they are involved in the regulation of adenohypophysial hormone secretion, which is predominantly neurohumoral.

Embryology All three portions of the adenohypophysis are assumed to derive from Rathke’s pouch, an endodermal pouch of the primitive oral cavity. At the third week of gestation, endoderm from the roof of the stomodeum thickens and begins to invaginate; by 5 weeks, Rathke’s pouch is a long tube with a narrow lumen and a thick wall composed of stratified cuboidal epithelium. By 6 weeks, the connection with the oropharynx is totally obliterated and Rathke’s pouch establishes direct contact with the downward extension of the hypothalamus that gives rise to the infundibulum. The two tissues are enclosed by the cartilage anlage of the sphenoid bone, separating them from the stomodeum; the sella turcica is formed by 7 weeks [66]. It was suggested that Rathke’s pouch arises from the ventral neural ridge in the pharyngeal region, thus sharing with the hypothalamus and posterior pituitary a common neuroectodermal origin [214–217]. Some features of adenohypophysial cells suggest that they are members of the APUD (amine precursor uptake and decarboxylation) cell system. The use of avian allografts, biologic markers, and serial sections of early chick embryos has provided indirect evidence for this theory; however, further proof is required for its validation. As the cells of Rathke’s pouch proliferate, the anterior portion forms the pars distalis and pars tuberalis whereas the posterior wall lies in direct contact with the posterior lobe anlage and becomes the pars intermedia [218,219]. The growth of the anterior limb extends laterally and follows a triradiate pattern; the lateral borders become the lateral wings of the adult gland and the midline portion becomes the anteromedial “mucoid wedge.” By midgestation, the medial cleft becomes a residual lumen and growth of the pars nervosa reverses the convexity of the posterior wall of the cleft to a concave structure. The border between Rathke’s pouch and the pars nervosa becomes indistinct; it consists of remnants of the obliterating lumen, and a few cystic cavities lined by cuboidal or columnar epithelium. This represents the rudimentary pars intermedia of the human hypophysis. The pituitary grows rapidly in early fetal life: the mean weight at 10–14 weeks of gestation is 3 mg, at 25–29 weeks 50 mg, and at term approximately 100 mg [218]. The pituitary portal vascular system begins to form before 7 weeks of gestation, and by 12 weeks the anterior pituitary and median eminence are well vascularized. Portal vessels are recognized at 11.5–14 weeks, are well developed by 15–16 weeks, and are fully established by 18–20 weeks [71,72].

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The first cell type to develop in the human fetal pituitary is the corticotroph [219–221]; at 6 weeks of gestation, cells with ultrastructural features of differentiating corticotrophs are found, and by 7 weeks, ACTH immunoreactivity is detectable. At 8 weeks of gestation, somatotrophs are identified by ultrastructural criteria and contain intense GH immunoreactivity. a-Subunit of the glycoprotein hormones is found in cells which have features of the glycoprotein hormone cell line; differentiated thyrotrophs and gonadotrophs are found subsequently at 12 weeks when b-subunits of those hormones are immunolocalized. Gonadotrophs show sexual dimorphism in the fetus; the differences are most marked from 15–25 weeks when this cell type is more numerous in female glands. Throughout gestation, LH-containing cells predominate in male glands, unlike the more equal distribution of LH- and FSHcontaining cells in female tissues [220]. Lactotrophs are the last cells to differentiate in the human fetal pituitary. PRL is found only at 12 weeks of gestation and is localized in mammosomatotrophs, bihormonal cells which appear to be the sole source of PRL until 24 weeks of gestation [221]. Differentiated lactotrophs are found after that time and undergo a striking hyperplasia in the late third trimester, analogous to that seen in late gestation and lactation in the pituitary of the mother. Novel transcription factors that play a role in anterior primordial development are being identified at a rapid pace. Many of these are implicated in early pituitary organogenesis, including the bicoid-related pituitary homeobox factor Ptx1 [222], Pituitary homeobox factor 2 (Ptx2), structurally related to Ptx1 [223], two members of the Lhx gene family, a group of LIM homeobox genes, Lhx3 and Lhx4 [224] and P-LIM, another LIM homeobox protein transcription factor that is selectively expressed in the pituitary with highest levels at the early stages of Rathke’s pouch development [225]. Another early marker of pituitary differentiation is the Rathke’s pouch homeobox (Rpx) protein which is identified in the pituitary primordium prior to the onset of known pituitary hormone production [226]. The Prophet of Pit-1 (PROP-1) is a paired-like homeodomain protein that is expressed early in pituitary development. It induces Pit-1 expression and plays a role in downregulation of Rpx [227,228]. Inactivating mutations of PROP-1 have been identified as the cause of Pit-1 deficiency in Ames dwarf mice [227] and in humans with combined pituitary hormone deficiency [229,230]. Id, a member of the helix-loop-helix (HLH) family of transcription factors is also found early in development and in some pituitary tumor cell lines but is decreased or absent in differentiated cells [231]. Its role in pituitary cytodifferentiation remains unclear. The molecular factors that determine hormone production have now been identified as transcription factors that target specific hormone genes. These factors have clarified three main pathways of cell differentiation [232,233]. ACTHproducing corticotrophs are determined by a novel T box

factor in cooperation with Ptx1 and corticotropin upstream transcription-binding element (CUTE) proteins including neuroD1/beta2 [234,235]. Bihormonal gonadotrophs require expression of steroidogenic factor (SF)-1 [236,237]. Pit-1 [238] directs differentiation of a complex family of cells that can mature into somatotrophs, mammosomatotrophs, lactotrophs or thyrotrophs [239–241] with the additional expression of estrogen receptor (ER) a [242], which enhances PRL secretion, or thyrotroph embryonic factor (TEF) which stimulates TSH-beta production [243]. The recognition of these molecular determinants of adenohypophysial cytodifferentiation has clarified the patterns of plurihormonality which have been recognized in pituitary adenomas and provide a framework for classification of these tumors. In rodents and humans, differentiation and/or maintenance of somatotroph, lactotroph and thyrotroph phenotypes are dependent on expression of a functional pit-1 gene; mutations in the pit-1 gene result in hypopituitarism [244–247] and hypoplasia of somatotrophs, lactotrophs and thyrotrophs [244]. An interesting observation is that Pit-1 mRNA and protein are highly expressed during human pituitary development at 17–19 weeks, when GH levels are extremely high, and near term when there is proliferation of lactotrophs [248]. These data suggest that Pit-1 plays an important role not only in the differentiation process, but also in the regulation of hormonal activity and possibly also of cell proliferation. Gonadotroph differentiation likewise requires SF-1; mice with disruption of SF-1 fail to develop pituitary gonadotrophs [236] as well as a ventromedial nucleus of the hypothalamus and steroidogenic glands [249].

Functional Anatomy In contrast with the hypothalamus, the cell types of the adenohypophysis are highly characterized with respect to structure and function. It is notable that with the exception of ACTH and a-subunit of the glycoprotein hormones, ectopic production of pituitary hormones is rare. Somatotrophs

Approximately 50% of the cells of the adenohypophysis produce GH. Most of these are located in the lateral wings of the anterior lobe; scattered somatotrophs are found in the median wedge [195]. These cells can usually be identified by light microscopy as medium-sized acidophilic cells that stain with eosin, phloxin, and orange G. They are spherical or oval in shape, with central, spherical nuclei. Immunohistochemistry reveals intense positivity for GH distributed throughout the cytoplasm [38] and for Pit-1 in the nucleus [221,250]. Occasionally, smaller cells contain GH positivity in a globular structure which represents the Golgi complex; these may be sparsely granulated, actively secreting cells. In situ hybridization localizes GH mRNA to both densely granulated acidophils and to occasional chromophobes (Fig. 1.11). By electron microscopy, somatotrophs are spher-

Chapter 1

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FIGURE 1.11. In situ hybridization localizes growth hormone messenger RNA in the normal pituitary in large cells with acidophilic cytoplasm and in occasional chromophobes. (Magnification ¥102)

ical or oval cells with centrally located spherical nuclei and cytoplasm of relatively low electron density [40]. The prominence of rough endoplasmic reticulum and Golgi regions varies with the secretory activity of the cell; active cells generally have well-developed, lamellar rough endoplasmic reticulum, and a large Golgi complex, whereas less active ones tend to have less conspicuous synthetic organelles. In the majority of somatotrophs, the cytoplasm is occupied by spherical, evenly electron-dense secretory granules which store hormone (Fig. 1.12). The limiting membrane of the granules is tightly opposed. The secretory granules range widely in size from 150 to 800 nm in diameter with an average of 350–500 nm. Secretory granules may be found accumulated at the cell periphery but granule extrusions are not detected. Ultrastructural immunocytology confirms the presence of GH in secretory granules and within the Golgi region of actively secreting cells. A subset of these cells has been recognized to contain a-subunit of glycoprotein hormones [40]. The incidence, distribution, morphology, and hormone content of somatotrophs are remarkably constant in the human pituitary. They do not appear to be affected by age, sex, various disease states, or drug therapies. Even in glands containing GH-producing adenomas the nontumorous somatotrophs show no evidence of suppression and cannot be distinguished from those in normal glands [40]. An exception to this morphologic uniformity is the case of long-standing hypothyroidism in which some degranulation of somatotrophs may occur; this change is much less marked than the almost complete degranulation of somatotrophs due to hypothyroidism which has been documented in rodents [250]. In pituitary adenomas, somatotrophs display a striking dimorphism [195]. Despite the morphologic differences between densely granulated and sparsely granulated soma-

FIGURE 1.12. A nontumorous somatotroph contains short profiles of rough endoplasmic reticulum (arrow head), a moderately developed Golgi complex (G) and numerous spherical, evenly electron-dense secretory granules with tightly fitted limiting membranes. (Magnification ¥5500)

totroph adenomas, both types have similar clinical features with elevated blood GH levels and acromegaly. Although the GH concentration in the tumor is proportional to the degree of granularity, neither of these correlate with blood GH levels. The morphine variant does, however, predict response to octreotide therapy [251]. Densely granulated somatotroph adenomas are composed of intensely acidophilic cells which contain strong immunoreactivity for GH throughout their cytoplasm. The tumor cells resemble resting nontumorous somatotrophs, with welldeveloped rough endoplasmic reticulum, prominent Golgi complexes and numerous spherical, evenly electron-dense secretory granules which measure 300–600 nm in diameter. These tumors may contain immunoreactivity for prolactin and/or a-subunit of glycoprotein hormones. The presence of these substances and GH in the same secretory granules has been documented by ultrastructural immunocytology using the double immunogold technique [252]. The use of keratin immunocytochemistry distinguishes these cells from

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FIGURE 1.13. A sparsely granulated adenomatous somatotroph harbors a characteristic juxtanuclear fibrous body composed of intermediate filaments that trap smooth endoplasmic reticulum, Golgi saccules (arrowheads), centrioles (arrows) and pleomorphic forming secretory granules. (Magnification ¥11390)

other somatotroph adenomas. Densely granulated cells have perinuclear low molecular weight cytokeratin filaments. Sparsely granulated somatotroph adenomas are composed predominantly of chromophobic or only slightly acidophilic cells which may show considerable nuclear pleomorphism. The nuclei are generally concave and binucleate; multinucleate cells are easily found. By light microscopy, spherical light areas can be seen adjacent to the nuclei; these correspond to the fibrous bodies seen by electron microscopy and are known to contain immunoreactive keratin [254]. The application of cytokeratin staining allows recognition of fibrous bodies that characterize this tumor [253]. GH positivity is found generally in the juxtanuclear Golgi region, while secretory granules, which are few, can be seen usually only with oil immersion. By electron microscopy, this tumor has a highly characteristic ultrastructure which differs significantly from that of nontumorous somatotrophs (Fig. 1.13). The tumor cells are irregularly shaped with numerous indentations and have lobulated pleomorphic and eccentrically located nuclei. The globular cytoplasmic

fibrous body, found in up to 95% of cells in sparsely granulated somatotroph adenomas, consists of intermediate-sized filaments that accumulate in the Golgi region, close to the concave side of an indented eccentric nucleus. The nearly perfectly globular structure traps tubular smooth endoplasmic reticulum, Golgi saccules, centrioles, mitochondria, lysosomes, and secretory granules. The secretory granules in the cells are scattered throughout the cytoplasm and are smaller than in densely granulated cells, measuring 100 – 250 nm in diameter. No exocytoses are seen. GHRH has been shown to stimulate proliferation of GH-containing cells in vitro during long-term incubations [255]. The effects of chronic exposure to GHRH in humans can be deduced from the study of pituitaries of patients with tumors producing GHRH [40,87]. These patients have marked somatotroph hyperplasia; the somatotrophs are generally large with very well-developed rough endoplasmic reticulum profiles and large Golgi complexes. The hyperplastic cells have numerous large electron-dense secretory granules characteristic of nontumorous cells; sparsely granulated cells with fibrous bodies are generally not seen. Although short-term exposure to GHRH is known to deplete the GH pool [256] and to convert densely granulated cells to more sparsely granulated forms [257], cells of densely granulated somatotroph adenomas chronically exposed to GHRH in vitro show an increase in the cytoplasmic volume densities of rough endoplasmic reticulum and Golgi complexes and a decrease in cytoplasmic volume density of secretory granules. However, they do not assume the characteristics of sparsely granulated cells and do not contain fibrous bodies [258]. Sparsely granulated adenomas undergo similar alterations during long-term exposure to GHRH in vitro and retain their characteristic fibrous bodies [258]. Although GHRH stimulates somatotroph proliferation in patients with GHRH-producing tumors, the hyperplastic adenohypophysial cell population in mice transgenic for this hormone is dominated by mammosomatotrophs as well as somatotrophs [194]. The presence of mammosomatotrophs may be attributed to exposure to GHRH excess in these animals during fetal life, at which time mammosomatotrophs are numerous, in contrast to the usual onset of tumoral GHRH excess in adulthood. Further studies are required to clarify the complex regulation of somatotroph and mammosomatotroph differentiation and proliferation by GHRH. The morphologic effects of somatostatin exposure on nontumorous somatotrophs has not been documented. The use of somatostatin analogs, such as SMS 201–995 (Sandostatin or Octreotide) in the therapy of acromegaly has allowed morphologic study of the effects of that substance on somatotroph adenoma cells. Both in vivo [259–261] and in vitro [262], somatostatin and its long acting analogs induce inconsistent morphologic alterations. In some tumors, there is no change, while in others, cell size is reportedly reduced. In some cases, there is an increase in the cytoplasmic volume density of lysosomes unassociated with significant alteration

Chapter 1

of other subcellular organelles. A few studies have indicated that these substances may induce fibrosis; others have found vascular changes which may cause cell necrosis and tumor shrinkage but direct cytotoxic effects have not been documented in vitro. No inhibition of hormone synthesis has been identified, as indicated by reduction in the cytoplasmic volume density of rough endoplasmic reticulum or Golgi complexes; this suggestion confirms molecular studies which have shown no suppression of mRNA in somatostatinexposed nontumorous adenohypophysial cells [263] or tumors [264]. The morphologic studies suggest that somatostatin suppresses hormone release and may stimulate lysosomal degradation of stored hormones. There is, however, differential response to octreotide in vivo by the two somatotroph adenoma types; densely granulated tumors exhibit greater reduction of growth hormone secretion than do sparsely granulated tumors [251]. Lactotrophs

Lactotrophs, or PRL cells, represent approximately 15% of the cells of the adenohypophysis. However, the number of these cells shows wide variation, related to age, sex, and parity in women. In adult men and nulliparous women they constitute approximately 9% of adenohypophysial cells, whereas in multiparous women they represent up to 31% of the cell population [266]. PRL cells are randomly distributed throughout the anterior lobe but are most numerous in the posteromedial portions, with large numbers extending to the posterolateral aspect [195]. Using conventional stains, PRL cells are acidophils that are indistinguishable from somatotrophs; however, Herlant’s erythrosin and Brookes’ carmoisine allow selective visualization of densely granulated lactotrophs, although these techniques are inconsistent and are not

FIGURE 1.14. Immunocytochemistry identifies prolactin diffusely in the cytoplasm of polyhedral and elongated densely granulated cells (arrow), and in the juxtanuclear globular Golgi region of sparsely granulated cells (arrow head). (Magnification ¥102)

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sufficiently sensitive to detect sparsely granulated forms. Immunohistochemistry reveals larger numbers of PRLcontaining cells among which two populations can be distinguished [38] (Fig. 1.14). Densely granulated, polyhedral, or elongated cells are frequently found close to capillaries randomly distributed throughout the anterior lobe; they have abundant cytoplasm almost completely filled with dense granular positivity corresponding to secretory granules. Sparsely granulated cells, in contrast, are more numerous and are found predominantly in clusters at the posterolateral portion of the gland. They are elongated or angular cells with long cytoplasmic processes and strong immunoreactivity for PRL in a juxtanuclear globular Golgi complex. It has been postulated that the densely granulated cells store PRL, whereas the sparsely granulated cells are actively secreting forms. In addition to nuclear Pit-1 reactivity these cells may also exhibit staining for estrogen receptor a [265a,265b]. By electron microscopy, the two cell types are readily distinguishable [40] (Fig. 1.15). Densely granulated cells are

FIGURE 1.15. A nontumorous lactotroph has abundant cytoplasm with highly developed rough endoplasmic reticulum in parallel arrays (*) and few, small secretory granules. (Magnification ¥6080)

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rare in the adult pituitary but are more common in childhood and adolescence. They have ovoid or elongated cell bodies, well-developed rough endoplasmic reticulum at the cell periphery and a spherical or oval Golgi complex containing a few forming granules. The cell cytoplasm is almost completely filled with spherical, oval, or irregularly shaped large granules that have evenly electron-dense cores and measure up to 650 nm in diameter. Granule extrusions are seen occasionally, usually on the cell surfaces overlying basement membrane. The majority of lactotrophs in the adult gland are sparsely granulated, elongated or polygonal cells which may have multiple cell processes extending from the center of acini to the basement membrane and intimately surrounding gonadotrophs. They contain richly developed rough endoplasmic reticulum found in parallel arrays and occasionally forming concentric structures known as “Nebenkern” formations. The Golgi apparatus is prominent and contains pleomorphic immature secretory granules. Scattered secretory granules are fewer and smaller than in storing cells; the diameters range from 150 to 250 nm. Granule extrusions are common and are found not only at the basal cell surface but also on the lateral cell borders, distant from capillaries and basement membranes; the term “misplaced exocytosis” is used to designate this form of granule extrusion. Ultrastructural immunocytology localizes PRL in secretory granules of both cell types; cloudy positivity can also be found in the Golgi region of sparsely granulated forms. In the fetus [220] and newborn as well as during pregnancy and lactation [266,267] there is marked hyperplasia of PRL cells which has been attributed to stimulation by estrogens. During pregnancy and lactation the weight of the pituitary gland may increase to more than 1 g and almost 50% of the total pituitary cell population is composed of PRLcontaining cells. Exogenous estrogens are known to induce only mild hyperplasia of lactotrophs in the human pituitary; the increased cell population is composed predominantly of the small sparsely granulated cell type [268a]. With sustained stimulation of PRL synthesis due to decreased dopamine inhibition or increased estrogen levels, there is a progressive increase in cytoplasmic volume and accumulation of highly organized rough endoplasmic reticulum, enlarged Golgi, numerous forming granules, and few small stored granules [40]. In animals lacking the dopamine D2 receptor, there is extensive lactotroph hyperplasia that progresses to adenoma [268b]. Suppressed lactotrophs are found in some pituitary glands containing PRL-producing adenoma or in patients treated with dopamine agonists. These inactive cells have a reduced nuclear volume, irregular indented nucleus with coarse clumped heterochromatin, small cytoplasm with poorly developed organelles, and secretory granules which measure 50–300 nm; the granules have an increased relative cytoplasmic volume due to the markedly reduced total cytoplasmic volume. Occasional exocytoses may be found at the basal cell surface. These suppressed lactotrophs are identified by immunocytology at the electron microscopic level; they

cannot be characterized on the basis of their ultrastructural features alone, which are not unlike those of null cells. PRL cell adenomas also occur in densely and, more commonly, in sparsely granulated varieties [195]. There is no correlation between morphology and blood PRL levels, age, or sex of the patient. The cells resemble the densely and sparsely granulated cells of the nontumorous pituitary. Effects of dopamine agonists on the cells of lactotroph adenomas include significant reduction of cytoplasmic, nuclear, and nucleolar areas [269]. There is also a marked reduction in the cytoplasmic volume densities of rough endoplasmic reticulum and Golgi complexes, whereas secretory granules increase in size and cytoplasmic volume density. The size reduction of bromocriptine-treated prolactinomas is therefore attributable to reduction of individual cell size rather than to a decrease in cell number. Protracted therapy may result in fibrosis which can adversely affect surgical outcome [270]. Mammosomatotrophs

The existence of bihormonal cells containing both GH and PRL in the nontumorous human pituitary has been recognized only in the last few years [40]. This cell type was initially identified in pituitary tumors [195]; it was subsequently found to be the cell of origin of PRL in the fetal pituitary during the first half of gestation [221]. Mammosomatotrophs are thought to be randomly distributed throughout the anterior lobe. They cannot be recognized using conventional histologic techniques; they are acidophils and are indistinguishable from somatotrophs. Immunohistochemistry reveals intense GH content within these densely granulated, polyhedral cells. PRL content is also identified but staining is usually less intense. Nuclear Pit-1 and ER staining is usually strong [239,240,265a,265b] and these cells often contain a-subunits [253]. By electron microscopy these cells resemble densely granulated somatotrophs (Fig. 1.16a). They are fairly large, polyhedral cells with ovoid or slightly irregular nuclei. They have abundant electron-lucent cytoplasm which contains well-developed rough endoplasmic reticulum and a prominent Golgi apparatus which often harbors numerous immature secretory granules. The mitochondria vary from ovoid to rod-shaped; they have a light matrix and lamellar cristae. The distinctive feature of these cells is their unique population of secretory granules. Some are small, spherical, or slightly ovoid, electron-dense granules which measure 150–400 nm; they have tightly fitting limiting membranes. The larger granules are irregular, often extremely elongated structures which can measure from 350 to 2000 nm; they contain secretory material of variable electron density and are bound by a loosely fitting membrane. These secretory granules frequently show misplaced exocytosis with fusion of the limiting membrane to the cell membrane. Unlike the granule extrusions of lactotrophs, the contents that are emptied into the intercellular space persist and retain electron density. Ultrastructural

Chapter 1

(a)

Functional Anatomy of the Hypothalamic Pituitary Axis

25

(b)

FIGURE 1.16. (a) By electron microscopy, mammosomatotrophs resemble densely granulated somatotrophs but have numerous conspicuous large secretory granules of irregular shape and variable electron density, as well as the hallmark of prolactin secretion, the misplaced exocytosis (arrow). (Magnification ¥7300) (b) For the definitive evidence of bihormonal differentiation of mammosomatotrophs, ultrastructural immunocytology localizes both growth hormone (15 nm gold particles) and prolactin (40 nm gold particles) to the same cell, often within the same secretory granule. (Magnification ¥20160) (b) From Felix et al. [271]

immunocytology using the double immunogold technique documents the presence of both GH and PRL in a single cell, frequently within the same secretory granule (Fig. 1.16b). Hyperplasia of mammosomatotroph cells has been identified as a cause of gigantism of early onset [193] and has been associated with acromegaly and hyperprolactinemia in the McCune–Albright syndrome [190]. Although the pathogenesis of this lesion in human patients remains unclear, an animal model for this disorder is provided by giant mice transgenic for GHRH in whom chronic exposure to excess GHRH causes mammosomatotroph hyperplasia [194]; continued long-term GHRH stimulation leads to the development of mammosomatotroph adenoma in old animals [272]. In human patients, tumors composed of mammosomatotrophs are more common than assumed in the past; they are slowly growing adenomas most often found in young patients with gigantism and mild hyperprolactinemia [195,252]. Corticotrophs

A single cell type in the human pituitary is responsible for the production of the POMC molecule and its various derivatives, including ACTH, MSH, lipotropic hormone (LPH), and endorphins [195]. Corticotrophs comprise approximately 15–20% of the adenohypophysial cell popu-

lation. The vast majority of these cells are found in clusters in the central mucoid wedge of the adenohypophysis; occasional scattered cells are also found in the lateral wings of the anterior lobe. Corticotrophs are also the predominant cell type in the poorly developed intermediate lobe of the human pituitary where they are found scattered in follicular structures. By light microscopy these medium-sized cells have varying degrees of cytoplasmic basophilia and stain strongly with PAS; the affinity is attributed to the carbohydrate moiety present in ACTH precursors. They also stain with lead hematoxylin. The most reliable method of identifying corticotrophs is the immunoperoxidase technique which reveals strong granular cytoplasmic positivity for ACTH. The presence of a large unstained perinuclear lysosomal vacuole known as the “enigmatic body” may be helpful in identifying these cells. Corticotrophs can also be identified by in situ hybridization which localizes the POMC mRNA [273]. Immunocytologic studies have indicated that almost all corticotrophs contain immunoreactive MSH, LPH, endorphins and other fragments of the POMC molecule which are derived by differing posttranslational processing [158]. By electron microscopy (Fig. 1.17), corticotroph cells are oval or slightly angular medium-sized cells with spherical or oval eccentric nuclei and a spherical nucleolus which is

26

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Hypothalamic–Pituitary Function

FIGURE 1.18. In the pituitary of a patient treated with high doses of glucocorticoids, corticotrophs with Crooke’s hyaline change have glassy cytoplasm and their periodic acid–Schiff (PAS) positive secretory material is pushed to the rim of the cell; the large juxtanuclear globule (arrow head) is the enigmatic body. (PAS stain; magnification ¥256)

FIGURE 1.17. The nontumorous corticotroph has widely dispersed short rough endoplasmic reticulum membranes, a prominent Golgi complex (G) and numerous secretory granules of variable size, shape and electron density. The two highly characteristic features of this cell type are the perinuclear and cytoplasmic bundles of intermediate filaments (arrows) and the large lysosomal enigmatic body (EB). (Magnification ¥5150)

usually attached to the nuclear membrane [40]. The cytoplasm has varying electron density and is frequently moderately electron-opaque. The rough endoplasmic reticulum is moderately developed and takes the form of widely dispersed membranes. Numerous free ribosomes can be found. The Golgi apparatus is spherical or flattened and is often displaced by the “enigmatic body.” This large structure is membrane-bound and has an electron-dense periphery that exhibits acid phosphatase activity, confirming its lysosomal nature [274]. Mitochondria are spherical or oviod, with lamellar or tubular cristae and a moderately electron-dense matrix. Variable numbers of intermediate filaments of the cytokeratin type [275], previously described as type I microfilaments, are found in small bundles usually adjacent to the nucleus; they measure about 7 nm in width and show no periodicity. They vary considerably in amount and are not numerous under physiologic conditions. The secretory granules are usually numerous and extremely variable in size,

shape, and electron density. They may be spherical, flattened, dented, heart shaped, or tear-drop shaped. They vary in electron density and may be 150–700 nm in diameter, most measuring 150–400 nm. While secretory granules may be found lined up along the cell membrane, exocytosis is not described in this cell type. Immunoelectron microscopy identifies the various POMC-derived peptides in the secretory granules of corticotrophs; however, there is no evidence that the morphologic differences of granule populations reflect their content [38]. Corticotrophs are the first cell type to differentiate in the fetal pituitary [220,221]; however, they are found in significantly decreased numbers in anencephaly [276]; it has been suggested that after autonomous differentiation, they are dependent on hypothalamic factors for normal growth and development. Their numbers do not vary with age or changes in the hormonal environment; however, they do develop specific morphologic features that reflect changes in endocrine homeostasis. In the human pituitary exposed to glucocorticoid excess due to administration of exogenous corticosteroids or any cause of endogenous glucocorticoid hypersecretion (including ectopic secretion of ACTH), corticotrophs undergo a distinctive morphologic alteration known as Crooke’s hyaline change [195]. By light microscopy, the cells accumulate a glassy, homogeneous, slightly acidophilic substance in the cytoplasm; the PAS positivity and ACTH immunoreactivity, corresponding to secretory granules, are displaced to the perinuclear rim and the periphery of the cell [38] (Fig. 1.18). The hyaline material does not contain immunoreactive POMC derivatives. This material has been shown to be composed of keratin filaments and stains with several antibodies directed against low-molecular-weight keratin proteins [275]. By electron microscopy, Crooke’s hyaline

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27

FIGURE 1.20. Corticotrophs invade the neural lobe of the pituitary (N) in a normal age-related phenomenon that is unassociated with endocrinopathy. This case, the same as that illustrated in Fig. 1.18, shows that the population of corticotrophs participating in “basophil invasion,” like those lining the pars intermedia cysts (arrow head), do not undergo Crooke’s hyaline change. (Periodic acid–Schiff stain; magnification ¥102)

FIGURE 1.19. Corticotroph with Crooke’s change in the pituitary of a patient with cortisol excess has a ring of intermediate filaments filling the cytoplasm, surrounding the nucleus and trapping numerous secretory granules in a juxtanuclear location. (Magnification ¥5090)

material is composed of an accumulation of intermediate filaments, resembling the smaller bundles seen in nontumorous corticotrophs (Fig. 1.19). The accumulation of microfilaments can be so extensive as to occupy almost the entire cytoplasm, leaving only a small juxtanuclear Golgi region and a thin rim of secretory granules adjacent to the cell membrane. Crooke’s hyaline change is reversible [195]. In the pituitaries of patients with inadequately treated adrenal insufficiency, the corticotrophs become hypertrophied, with large nuclei, prominent nucleoli, and a poorly granulated cytoplasm. In cases of long-standing Addison’s disease, focal nodular hyperplasia of corticotrophs and corticotroph adenomas may be present [277]. The ultrastructural appearance of these “adrenalectomy” cells in the human pituitary has not been well documented. However, in adrenalectomized rats, the markedly enlarged cells contain abundant rough endoplasmic reticulum and Golgi membranes and an increased number of secretory granules [278]. Chronic administration of CRH to rats increases the number of ACTH-containing cells, but no significant ultra-

structural changes have been documented [279]. Morphometric analysis indicated that there was no change in cell area; the nuclear area increased slightly and the secretory granule diameter was greater in corticotrophs of CRHexposed animals. These data suggest that the proliferation of corticotrophs in Addison’s disease may be mediated by CRH, but the morphologic characteristics of adrenalectomy cells cannot be attributed solely to CRH excess. The pars intermedia corticotrophs also are strongly (PASpositive and exhibit intense immunostaining for ACTH and other POMC derivatives [195]. The border between the pars intermedia and the pars distalis is often indistinct; occasionally a thin layer of connective tissue is noticeable between these two portions of the adenohypophysis. On the posterior aspect of the pars intermedia, basophil cells are frequently identified, often in clusters within the neuropil of the pars nervosa. These clusters vary in number and in some cases they may be found spreading deeply into the neural lobe (Fig. 1.20). This process, known as “basophil invasion,” is found in older individuals; it is more frequent and pronounced with advancing age and is said to be more prominent in men than in women. Its functional significance is not known but it is not thought to be associated with endocrine abnormalities. Some studies have suggested that the presence of a-MSH immunoreactivity is indicative of intermediate lobe differentiation [280,281]. By electron microscopy, corticotrophs of the pars intermedia are smaller, more dense, and contain fewer intermediate filaments [192]. They are also known to be less sensitive to the feedback effect of glucocorticoids, in most cases showing absent or only mild filament accumulation in patients with glucocorticoid excess and lacking the Crooke’s hyaline change that is found in pars distalis corticotrophs of those patients [195].

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The corticotrophs of the pars intermedia and those which form the basophil invasion of the pars nervosa may give rise to a specific group of corticotroph adenomas. These tumors may represent one form of the silent corticotroph adenomas which are unassociated with signs or symptoms of ACTH excess [252]; they are probably capable of secreting biologically and immunologically active substances that remain uncharacterized. As is the case with pars intermedia corticotrophs, these tumors do not show striking accumulations of intermediate filaments and, in some cases, may lack filaments totally. The derivation of corticotroph cell adenomas from this subpopulation of corticotrophs is difficult to prove. The morphology of corticotrophs in most adenomas associated with ACTH excess resembles that of nontumorous corticotrophs [195,252]. Occasional tumors are composed of cells with Crooke’s hyaline change [252], suggesting that the adenomatous cells are sensitive to feedback inhibition by glucocorticoids. Morphologic studies of functioning corticotroph adenomas in vitro [282] confirm the response of most such tumors to CRH stimulation associated with slight ultrastructural changes indicative of increased hormone synthesis. Incubation of tumor cells with glucocorticoids inhibits ACTH release and causes accumulation of intermediate filaments; however, it remains to be seen if the threshold for suppression is altered in tumor cells.

idase technique reveals granular positivity for TSH; this stain reveals the characteristic angular shape of these cells and their long cytoplasmic processes that establish contact with the basement membrane (Fig. 1.21). Ultrastructurally, these cells are characterized by their marked angularity and well-developed cytoplasmic processes [40] (Fig. 1.22). The nucleus is spherical and often eccentric while the cytoplasm contains numerous short, slightly dilated rough endoplasmic reticulum profiles, a globoid Golgi complex and small, spherical secretory granules that measure 100–200 nm in diameter. When scanty, the secretory granules characteristically are aligned under the plasmalemma and may contain rod-shaped or irregularly electron-dense contents; more densely granulated cells have granules scattered throughout the cytoplasm. Although the numbers of thyrotrophs do not appear to vary with age, these cells undergo morphologic changes in association with altered hormonal status. In patients with primary hyperthyroidism, thyrotrophs are few and small;

Thyrotrophs

The least common cell type in the adenohypophysis is the thyrotroph. These comprise approximately 5% of the total adenohypophysial cell population and are found primarily singly or in small clusters in the anteromedial portion of the gland. These medium-sized cells are basophilic when stained with conventional dyes, contain PAS positivity, stain with aldehyde fuchsin and aldehyde thionin. The immunoperox-

FIGURE 1.21. Immunohistochemical localization of thyrotropin identifies scattered angular thyrotrophs in the nontumorous human autopsy pituitary. (Magnification ¥102)

FIGURE 1.22. Nontumorous thyrotrophs have welldeveloped cytoplasm with short, slightly dilated profiles of rough endoplasmic reticulum (arrow heads), a large Golgi region (G), small secretory granules lined up along the plasma membrane and small numerous secondary lysosomes (L). (Magnification ¥7440)

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29

subset of altered somatotrophs which are bihormonal [283]; the morphologic changes are reversible in the experimental animal. Gonadotrophs

FIGURE 1.23. In a patient with long-standing hypothyroidism, the cytoplasm of these “thyroidectomy cells” is dominated by the abundant widely dilated rough endoplasmic reticulum with flocculent contents; they also contain expanded Golgi complexes (G), few small secretory granules and prominent lysosomes (L). (Magnification ¥4380)

their ultrastructural features are not well documented. In cases of untreated primary hypothyroidism, thyrotrophs are released from the negative feedback effects of thyroid hormones and TSH secretion is increased. The number and size of thyrotrophs are increased; the enlarged cytoplasm is less strongly positive using the PAS, aldehyde fuchsin and aldehyde thionin stains, and TSH immunoreactivity is faint but diffuse. These cells exhibit strong nuclear positivity for Pit-1 [195,239]. By electron microscopy, these stimulated thyrotrophs, known as “thyroidectomy cells” or “thyroid deficiency cells,” have abundant dilated rough endoplasmic reticulum cisternae and an expanded Golgi complex, whereas the number of secretory granules is reduced [40] (Fig. 1.23). Large cytoplasmic spherical, PAS-positive lysosomal globules are prominent. With prolonged stimulation, nodular hyperplasia and thyrotroph adenomas may occur [195]; TRH may be implicated in the pathogenesis of this cell proliferation [252]. In the rat, there is evidence that at least some of the thyroidectomy cells may derive from a

The cells which produce the gonadotropins, FSH and LH are the gonadotrophs; these probably represent up to 10% of the human adenohypophysial cell population [195]. No reliable cell count is, however, available. In rats, the number of gonadotrophs containing each hormone varies with age, sex, and hormonal status [40]. Gonadotrophs are scattered throughout the pars distalis and comprise the major constituent of the pars tuberalis [284]. They stain with basic dyes, the PAS technique, aldehyde thionin, and aldehyde fuchsin. The immunoperoxidase technique reveals cytoplasmic positivity for FSH and LH, often both present in the same cell, indicating that one cell type is capable of producing both gonadotropins. There are, however, variations in the number of cells containing FSH and LH, indicating that some gonadotrophs contain only one of these two hormones and there are likely fluctuations with functional demand. Nuclear reactivity for SF-1 defines the gonadotroph population [237]. The ultrastructural features of gonadotrophs reveal a single cell population which is responsible for both FSH and LH production (Fig. 1.24). The large oval or elongated cells have spherical, eccentric nuclei which are oriented with distinct polarity at the base of the cell [40,252]. Their abundant, slightly dilated rough endoplasmic reticulum profiles contain a flocculent electron-lucent substance. The Golgi is prominent and globoid, composed of sacculi and vesicles associated with immature secretory granules. Mature secretory granules are unevenly distributed in the cytoplasm and fall into two groups which vary in size and density. The distribution of these two granule populations may show sexual dimorphism. In men, smaller secretory granules are usually numerous; they have an average diameter of 250 nm. In women, larger secretory granules predominate and measure 300–600 nm in diameter. Ultrastructural immunocytology localizes FSH and LH within the same cells and, in some cases, within the same secretory granule. Gonadotrophs are found in close proximity to the basement membrane and exhibit an intriguing intimate contact with lactotrophs. The latter frequently extend cell processes around gonadotrophs and there are intercellular junctions between the two cell types [285], suggesting paracrine interactions which are not well understood. Gonadotrophs are found in the pituitaries of fetuses and show sex-related dimorphism during gestation [220]. Between 15 and 25 weeks of gestation, pituitaries of female fetuses contain more numerous gonadotrophs than pituitaries of male fetuses. Throughout gestation, LH-containing cells predominate in male pituitaries, whereas the number of LHand FSH-containing cells are almost equal in females. This dimorphism correlates with differences in the levels of hypothalamic GnRH at the same stages of gestation. In the adult

30

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Hypothalamic–Pituitary Function

FIGURE 1.24. A nontumorous gonadotroph is large and oval with short profiles of dilated rough endoplasmic reticulum containing electron-lucent contents (*), ring-like Golgi complex (G) and large, dense but irregular secretory granules. (Magnification ¥8170)

pituitary, no such dimorphism of gonadotroph numbers has been identified; however, the ultrastructural differences in males and females have been described above. Gonadotroph adenomas of the adult pituitary show an even more striking fine-structural sexual dimorphism [195,286]. Gonadotroph adenomas in women are usually well-differentiated tumors consisting of polyhedral cells with long cytoplasmic processes, dilated profiles of well-developed endoplasmic reticulum, and the characteristic “honeycomb” Golgi apparatus, a large saccular structure associated with developing secretory granules. The secretory granules in this tumor type are spherical and membrane-bound with varying electron density; they measure about 400–450 nm in diameter. The tumors in adult men are less differentiated, with poorly to moderately developed rough endoplasmic reticulum profiles, a moderately developed Golgi complex and fewer, generally smaller secretory granules. Strong nuclear SF-1 positivity is a reliable marker [237]. Gonadotrophs of the pars distalis show morphologic changes which reflect their hormonal environment; in con-

trast, the gonadotrophs of the pars tuberalis show signs of functional inactivity in most circumstances. In patients treated with pharmacologic doses of estrogen, the gonadotroph cells are small and dense [195]. During pregnancy, the number of cells immunoreactive for FSH and/or LH is also significantly reduced [264]. Gonadotrophs are morphologically abnormal in Kallmann’s syndrome, an uncommon variant of hypothalamic hypogonadism due to GnRH deficiency and associated with anosmia [182]; there is a marked decrease in the number of these cells and the remaining small cells are only weakly positive for FSH and LH. Castration leads to characteristic morphology in gonadotrophs [40,195,287]. Prolonged lack of the negative feedback effect of gonadal steroids results in stimulation of gonadotrophs to secrete FSH and LH in higher quantities. These stimulated cells are enlarged and are found in increased numbers. They have vacuolated cytoplasm which may take the form of several small vacuoles or one large vacuole; the latter displaces the nucleus to the cell periphery, giving the cell a “signet ring” appearance. By electron microscopy, these so-called “gonadectomy cells,” “gonadal deficiency cells,” or “castration cells” (Fig. 1.25) have markedly dilated rough endoplasmic reticulum, which is responsible for the cytoplasmic vacuoles seen by light microscopy. The Golgi complex is enlarged and hormone storage is decreased but not lost, despite the marked increase in secretory activity, since secretory granules are present in reduced numbers. It has been suggested that secretory granule formation is bypassed and that discharge of hormone takes place in an unconventional way not discernible by electron microscopy. An unusual prominence of large active gonadotrophs has been noted in the nontumorous adenohypophysis of some women with PRL-producing adenomas [40]. The factors underlying this change are not clear, but it has been suggested as the explanation for the LH hyperresponse to GnRH which has been found in these patients. Follicular Cells

Follicular cells are found throughout the adenohypophysis surrounding follicles, lumina lined mainly by agranular or poorly granulated cells that are joined at their apex by junctional complexes [195,288]. By electron microscopy, it was shown that granulated adenohypophysial cells can form follicles around damaged cells which have disrupted cell membranes. The surrounding cells form specialized intercellular attachments and the participating cells undergo degranulation and dedifferentiation. These follicular cells may derive from somatotrophs, lactotrophs, or corticotrophs. The follicular cells form specialized junctions, macula adhaerens, between each other and with adjacent granulated adenohypophysial cells; in contrast, granulated adenohypophysial cells form only the less prominent zonulae adhaerentes. Follicles are found in areas with increased cell destruction, particu-

Chapter 1

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31

FIGURE 1.26. Immunolocalization of S-100 protein identifies a pituitary stellate cell with long branched cytoplasmic processes surrounding granulated adenohypophysial cells. (Magnification ¥256)

FIGURE 1.25. After castration, “gonadectomy cells” have markedly dilated rough endoplasmic reticulum and large globoid Golgi regions (G) which harbor forming secretory granules. (Magnification ¥4620)

been implicated as the source of FGF and vascular endothelial growth factor [293], but are not found in the pituitaries of anencephalics [294]. They are numerous in the compressed adenohypophysis at the periphery of adenomas. Some investigators have found no S-100-reactive sustentacular cells within pituitary adenomas [290]; in contrast, others have identified S-100-containing cells within tumors of several types [295]. They are also found in large numbers at the periphery of other pituitary lesions, such as abscesses, amyloid deposits and in the residual hypophysis after surgery, but not adjacent to metastatic tumor deposits, infarcts, or Rathke’s cleft cysts [296]. Null Cells

larly surrounding tumors [40]. They are assumed to play a role in isolating and processing cell debris. Some pituitary adenomas contain follicles. Folliculostellate Cells

Immunocytochemical studies have localized S-100 protein to a specific subtype of cells in the normal human pituitary gland [289,290]. These cells are agranular and do not contain immunoreactive hormones. Some also contain immunoreactivity for glial fibrillary acidic protein (GFAP). They have a characteristic morphology, with long, branched cytoplasmic processes embracing granulated adenohypophysial cells (Fig. 1.26). Because of confusion with the follicular cells described above, some authors have suggested that these cells be called “stellate cells” [289]. They are believed to have a supportive role similar to that played by the S-100-positive sustentacular cells of the adrenal medulla and carotid body. In addition, they are thought to play a role in paracrine regulation [291] and have been shown to produce IL-6, a cytokine which may participate in local regulation of hormone secretion [292]. These cells have also

The term null cell was used to identify cells that show evidence of adenohypophysial differentiation, possessing organelles required for hormone synthesis and storage, but whose differentiation is incomplete and does not resemble any of the known adenohypophysial cell types [297]. The term was applied initially to a group of tumors which possessed no histologic, immunocytochemical, or ultrastructural markers revealing their cellular differentiation and which were unassociated with clinical evidence of hormone excess. Application of increasingly sensitive techniques of cell identification have shown that most tumors with morphologic features of null cells are in fact gonadotroph adenomas [298,237]; however, only a small subpopulation of tumor cells may be hormonally active at any one time, as indicated by the reverse hemolytic plaque assay [299]. Immunohistochemical analyses [221] and studies of hormone mRNA [300] have shown that the majority of these tumors contain cells capable of producing glycoprotein hormone subunits. Focal ultrastructural differentiation along several lines has also been documented [301]. It has been suggested that these tumors may originate from uncommitted or

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committed stem cells or from dedifferentiated adenohypophysial cells. Null cells may also represent unstimulated or resting cells that are not actively engaged in hormone production and cannot be recognized with currently available investigative techniques [302]. The nontumorous pituitary contains cells that cannot be identified conclusively by ultrastructural criteria. These may represent resting cells, uncommitted or committed stem cells. In the fetal pituitary, a population of cells with features of the glycoprotein hormone cell line can be identified prior to the recognition of differentiated thyrotrophs or gonadotrophs [221]; a-subunit immunoreactivity is present in fetal glands at the same stage of gestation and b-subunits are not yet detected [220]. It has been suggested that these primitive cells which resemble null cells may represent the source of a-subunit and may be precursors of the glycoprotein hormone cell line; they may be the cell of origin of some null cell adenomas. The null cells are chromophobic and by immunocytochemistry, usually contain no hormones [195,252]. A small number of these cells may contain various pituitary hormones, most commonly a-subunit of the glycoprotein hormones followed by b-subunits of FSH and/or LH. They usually exhibit SF-1 nuclear staining, indicating gonadotrophin differentiation [237]. By electron microscopy, the cells are polyhedral with irregular nuclei. The poorly developed cytoplasm contains short, scattered rough endoplasmic reticulum profiles, an inconspicuous or only moderately developed Golgi apparatus and small, dense, rodshaped mitochondria. Secretory granules are few and small, measuring less than 250 nm in diameter, frequently with central electron-dense cores, peripheral electron-lucent halos, and a prominent limiting membrane (Fig. 1.27). Oncocytes

Oncocytes are large cells which have abundant acidophilic granular cytoplasm due to the numerous mitochondria that take up acid dyes [195,252]. By electron microscopy, they are characterized by a striking increase in the number and size of mitochondria. A varying number of oncocytic cells may be found in the normal human hypophysis [303]. The number of these cells appears to increase with advancing age, a phenomenon also found in other organs including thyroid, parathyroid, and salivary glands. Cells in hormonally active adenomas only rarely show oncocytic transformation; the tumors usually retain their fine structural and immunocytochemical markers and can be recognized as showing various degrees of oncocytic change. In contrast, null cells, which have no other identifying markers, more frequently undergo oncocytic change. Gonadotroph adenomas regularly contain a varying number of cells with oncocytic change, and the number of oncocytes in any given tumor often increases with tumor recurrence [195]. Oncocytomas are found more commonly in elderly patients. In vitro studies using tissue culture techniques [298] and the reverse hemolytic plaque

FIGURE 1.27. A null cell in the nontumorous human pituitary has poorly developed organelles in a scant cytoplasm. However, there are short profiles of rough endoplasmic reticulum (arrow heads) and a few small secretory granules, indicating the potential for hormone synthesis. This cell has no features which allow recognition of its differentiation. (Magnification ¥5950)

assay [299] have indicated that there is no functional difference between null cell adenomas and oncocytomas of the human pituitary. The factors underlying oncocytic change are unknown, but they may lie in abnormalities of the mitochondrial DNA which is independent of the cellular DNA [304]. Oncocytes are large polyhedral cells with abundant granular cytoplasm that varies from strongly acidophilic to chromophobic. These cells may show ill-defined purple coloration with trichrome stains using aniline blue; this may lead to misinterpretation as basophilia. The phosphotungstic acid–hematoxylin method is helpful to demonstrate mitochrondrial abundance. Oncocytes showing ultrastructural features of differentiated adenohypophysial cells may contain the appropriate immunoreactive hormone. The majority of oncocytes, which are thought to be derived from null cells of gonadotrophs contain no immunoreactive hormones or may contain a-subunit, FSH LH. They often have nuclear SF-1 reactivity [237].

Chapter 1

FIGURE 1.28. In the nontumorous human pituitary, an isolated oncocyte has abundant cytoplasm which is almost totally occupied by numerous spherulated mitochondria. Rough endoplasmic reticulum (arrow heads), a small Golgi complex (G) and small secretory granules suggest that the cell is capable of hormone synthesis and storage. (Magnification ¥5590)

By electron microscopy, oncocytes are readily identified as large, polyhedral cells with irregular nuclei and a cytoplasm almost totally filled with numerous mitochondria. Histologically some oncocytes are dark or acidophilic; these cells contain tightly packed oblong mitochondria with granular matrix and numerous transverse cristae. Other oncocytes may be histologically light, i.e., only slightly acidophilic or chromophobic; their crowded mitochondria appear swollen and rarefied, with loss of cristae. Oncocytes contain small, short profiles of rough endoplasmic reticulum, inconspicuous Golgi regions and few scattered secretory granules (Fig. 1.28). Others

Acidophil Stem Cells are recognized primarily in pituitary adenomas producing both GH and PRL [195,305]. They are rare and are not known to occur in the nontumorous pituitary. The cell type is assumed to derive from a common precursor of somatotrophs and lactotrophs; while

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mammosomatotrophs have been recognized as the source of GH and PRL early in gestation, no cells resembling tumorous acidophil stem cells have yet been identified in the human fetal pituitary [221]. Immunohistochemistry reveals the presence of PRL and GH in the cells. The positivity for PRL is usually stronger and patients with tumors composed of these cells have hyperprolactinemia; GH production may be reflected in the phenomenon known as “fugitive acromegaly.” By electron microscopy, these cells resemble sparsely granulated lactotrophs and have some features of somatotrophs. They are irregular in shape and have large nuclei containing fine chromatin and inconspicuous nucleoli. The cytoplasm contains scattered rough endoplasmic reticulum profiles and relatively small Golgi regions. The Golgi sacculi are flat and may contain a few forming granules. The mitochondria may be abundant, indicating oncocytic transformation, and often show focal cavitation as well as a unique mitochondrial gigantism not identified in other pituitary cell types. Giant mitochondria may reach the size of a nucleus and be visible by light microscopy as cytoplasmic vacuoles. The mitochondria retain their double limiting membranes but lose their cristae and are filled with electron-lucent granular matrix. Occasionally, they contain electron-dense tubular structures resembling tubules of centrioles and cilia. The secretory granules in this cell type are sparse and small, ranging from 50 to 300 nm. Characteristically, granule extrusions or “misplaced exocytoses” are identified, similar to those of sparsely granulated lactotrophs. In addition, these cells have a structural marker of sparsely granulated somatotrophs, the fibrous body, a juxtanuclear aggregate of smooth endoplasmic reticulum membranes, and keratin immunoreactive intermediate filaments. These features of lactotrophs and somatotrophs are frequently found in the same cell; ultrastructural immunocytochemistry confirms the localization of GH and prolactin in the same cell. A tumor type identified as silent subtype III adenoma is composed of chromophobic or slightly acidophilic cells which contain immunocytochemical evidence of multiple hormones. Staining for ACTH is generally weak, bendorphin immunoreactivity may be strong and the tumor cells may contain GH, PRL, and/or a-subunit immunoreactivity. In some cases, the tumors contain no recognizable hormones. By electron microscopy, large, elongated cells have an eccentric nucleus, a prominent nucleolus which may harbor spheridia, and a highly differentiated cytoplasm with abundant rough and smooth endoplasmic reticulum profiles and a well-developed Golgi apparatus. The secretory granules are small, measuring less than 200 nm in diameter, and have variable electron density; they are mainly spherical but occasionally irregular or dropshaped granules are found. These cells bear no similarity to any of the known nontumorous adenohypophysial cells and their cytodifferentiation is unknown. Other unclassified plurihormonal cells have been identified in the nontumorous pituitary and adenomas [40,195]. The

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most common types produce GH, a-subunit, TSH, and/or PRL in any combination. Some of these cells have ultrastructural features of somatotrophs or mammosomatotrophs, while others resemble thyrotrophs [40]. Studies of the rat pituitary have confirmed the existence of these cells and indicate a role for them in some pathologic states; for example, some somatotrophs transform into a population of thyroidectomy cells in hypothyroidism [283]. This common pattern of plurihormonality is easily explained by the expression of Pit-1, the transcription factor implicated in activation of the genes encoding GH, PRL and bTSH. However, occasionally other patterns of plurihormonality have been reported. Very rarely, cells producing POMC derivatives with ultrastructural features of corticotrophs may produce gonadotropins or other hormones both in human tumors [195,306] and in the rat nontumorous pituitary [307]. Conversely, cells with gonadotroph morphology may contain ACTH as well as gonadotropins [308]; it is intriguing, however, that ACTH, which is so commonly expressed in extrapituitary tumors, is rarely found in plurihormonal cells of the adenohypophysis.

Localization of Other Peptides in the Adenohypophysis A number of substances not initially thought to be of pituitary origin are detectable in adenohypophysial cells. Hypothalamic Adenohypophysiotropic Hormones

GHRH, somatostatin, TRH, and GnRH have been identified in pituitary adenohypophysial cells [308–311]. Large amounts of GHRH and somatostatin were measured in culture media of perifused normal pituitaries and GHsecreting adenomas and their release was stimulated by other peptides [309]. Preprosomatostatin mRNA has been detected in nontumorous adenohypophysis as well as several types of pituitary adenomas [310]. It is known that GnRH binds to gonadotrophs and becomes internalized [311]; however, it has also been shown that TRH and GnRH are released by pituitary cells maintained in culture for a prolonged period [308]. GnRH is colocalized with b-LH and some gonadotrophs also contain TRH. These data suggest production of hypothalamic peptides by de novo synthesis in a multipotential pituitary cell. Angiotensin II

Angiotensin II, as well as renin and angiotensin converting enzyme, have been localized in pituitary gonadotrophs [312]. These substances colocalize with b-LH. Angiotensin II has been shown to stimulate PRL release in vitro; this is a dosedependent phenomenon. It has also been found to stimulate ACTH and b-endorphin release. Lactotrophs and corticotrophs have high-affinity binding sites for angiotensin II. Bombesin/GRP

Bombesin-like immunoreactivity has been found in the pituitary gland [313]; however, cell localization has not been

demonstrated. Bombesin-related peptides stimulate pituitary hormone release, mediated by the hypothalamus. CGRP

CGRP is found in the pituitary in small amounts and the concentration is known to increase with age. It is unclear if this substance is present in adenohypophysial cells or in nerve terminals of the posterior lobe [314], since CGRP is found in the hypothalamus (see above). CCK

CCK is found in the adenohypophysis but in a form which differs from that present in other CCK-synthesizing tissues [315]. The pituitary is devoid of CCK-8 but contains substantial amounts of three large nonamidated pro-CCK fragments and small amounts of a-amidated CCK (CCK-58, CCK-33, component I). No immunocytochemical localization has been reported but CCK has been found in corticotroph adenomas in large amounts and in some tumors associated with acromegaly which also contained ACTH. It therefore seems that pituitary CCK derives from corticotrophs [316]. The form found in tumors is smaller and less sulfated than in the normal pituitary; tumors contain CCK-8-like forms similar to those found in brain and gut [315]. Galanin

In humans, galanin has been localized in corticotrophs of the nontumorous pituitary, including Crooke’s cells and cells of basophil invasion in the posterior lobe. Galanin is also present in some corticotroph adenomas [139,317]. In contrast, in rats, galanin mRNA is found in estrogen-induced pituitary tumors [318] and galanin has been localized in PRL- and GH-producing cells as well as some TSHcontaining cells [319]. The reason for this species-specific regulation is unknown. In the rat, galanin expression shows sexual dimorphism [319], is inducible by estrogen [318–320] and is altered by changes in adrenal, thyroid, or gonadal status [319]. It appears to be involved in the modulation of pituitary GH and PRL secretion, probably mediated by alterations in their hypothalamic regulation [140,141]. Gastrin

The neurohypophysis is known to contain gastrin [142], but there appears to be species-specific variation in the adenohypophysis. The human adenohypophysis contains only traces of this substance which is localized to corticotrophs [321] and corticotroph adenomas [322]. Analogy has been drawn to cosynthesis with POMC in other tissues; the significance of this colocalization is unknown and gastrin is not thought to act directly on the pituitary but rather in the hypothalamus. NPY

NPY immunoreactivity and mRNA are found in the pituitary and can be localized by immunocytochemistry

Chapter 1

in adenohypophysial cells consistent with a subset of thyrotrophs [323]. These cells increase in size and NPYimmunoreactivity after thyroidectomy. NPY may have autocrine or paracrine activity in the modulation of release of GH and gonadotropins. Neurotensin

Neurotensin has been localized to the anterior pituitary and is thought to be present in gonadotrophs. It is also known to be affected by thyroid status, being found in reduced amounts in both hypothyroidism and hyperthyroidism [151,324]. The role of neurotensin in the pituitary is not known. Substance P

Immunoreactive substance P has been found in the rodent anterior pituitary. In rats it is localized in gonadotrophs and lactotrophs [325], but in the guinea pig it is found in thyrotrophs [326]. Thyroidectomy increases and thyroid hormone treatment decreases the amount of substance P in the pituitary [152]; the amount also varies with levels of gonadal steriods. It is not clear if thyroid hormone and corticosteroids act directly to influence pituitary content. Substance P may play a local or paracrine role in the adenohypophysis. VIP

There is evidence that VIP is synthesized in the pituitary [327] in lactotrophs [127,328]; it is also inducible by estrogen and may be altered by other changes in the hormonal environment. Recently, it was found to be present in increased amounts in hypothyroidism [329] and VIP production by adenohypophysial cells in vitro was found to be stimulated by TRH as well as GHRH, but not by CRH or GnRH. Tissue culture studies have shown that VIP regulates tonic PRL secretion but does not affect TRH- or GHRHinduced PRL release [329]. Cytokines

Cytokines are known to modulate pituitary function and some have been shown to be produced in the hypothalamus (see above and references 161–166). IL-6 has been demonstrated in stellate cells within the pituitary [292] and is known to modulate GH and PRL responses to appropriate stimuli [164]. Growth Factors

Growth factors regulate cell replication and functional differentiation by directly altering the expression of specific genes. Several polypeptide growth factors regulate anterior pituitary hormone secretion. Growth factor action in the pituitary, however, must be understood in the context that the pituitary itself is a site of both synthesis and action of growth factors [330,331]. Several pituitary-derived growth factors are also regulated within the pituitary by peripheral hormones including triiodothyronine and hydrocortisone.

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Pituitary-derived growth factors include EGF, FGF, TGF-a and TGF-b, IGF, endothelin, and IL-1 [331]. Several partially characterized growth factors have also been described, including thyroid hormone-inducible growth factor, vascular endothelial growth factor mammary cell growth factor, chondrocyte growth factor, mammary cell growth factor, chondrocyte growth factor, and adipocyte growth factor [331]. EGF, a potent stimulator of PRL and ACTH secretion in vitro, also attenuates GH secretion [332–334]. EGF may also play a role in the regulation of LH secretion [335]. EGF has been localized in the pituitary within cells that produce glycoprotein hormones. EGF-receptor is expressed by normal human anterior pituitary and is upregulated in some adenomas, usually recurrent somatotroph tumors [336]. It has been speculated that EGF may mediate proliferation of thyrotrophs in hypothyroidism and of lactotrophs in the lactotroph hyperplasia of pregnancy [337]. TGF-a is expressed by pituitary cells where it has a membrane-anchored localization [338,339]; by immunohistochemistry it colocalizes with PRL and possibly with GH in the bovine pituitary [340]. TGF-a interacts with the EGF receptor and inhibits replication of rat pituitary tumor cells [341]. The regulation of lactotroph growth and differentiation by this substance suggests a potential role in promotion or facilitation of pituitary tumorigenesis [339] and in transgenic mice, targeting of TGF-a overexpression to lactotrophs results in lactotroph adenoma formation [343]. Activin, a member of the TGF-b gene family, suppresses GH secretion and somatotroph replication, and stimulates FSH secretion [343–346]. The inhibin subunits which comprise activin and inhibin and their mRNAs have been localized in pituitary gonadotrophs [309]. Activin-binding protein, which shows homology to follistatin, has been isolated in the rat pituitary and appears to block the action of activin [347]. Follistatin is expressed by normal gonadotrophs and is reduced or absent in gonadotroph adenomas, suggesting a role for this growth factor in the tumorigenic process [348]. The pituitary contains high concentrations of basic FGF [349]. There are several indications that the FGF family plays an important role in the regulation of pituitary function. It may be an important paracrine regulator of PRL secretion [170]; nonmitogenic concentrations of FGF stimulate TRHinduced PRL and TSH secretion in pituitary cells. Pituitaryderived FGF stimulates the replication of human pituitary cells in vitro [350]. FGF has also been implicated in the new arteriolar vessel formation reported to accompany prolactinomas [351]. FGF expression is upregulated in aggressive pituitary adenomas and this growth factor has been shown to be released by the adenoma cells [352], indicating its potential role in the control of adenohypophysial cell proliferation. Moreover, altered FGF receptors have been implicated in the dysregulated growth of pituitary tumors [353].

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Endothelin, a powerful vasoconstrictor, is expressed in the pituitary and stimulates FSH and LH secretion [354]. Pituitary-derived endothelin-3 is stimulated by IGF-I [355]. IGF-I mediates most of the peripheral growth promoting actions of GH [356]. GH-dependent IGF-I is secreted predominantly by the liver, and IGF-I participates in feedback regulation of GH gene transcription and secretion [357]. Regulation of pituitary IGF-I receptors also determines the action of the growth factor on somatotroph function [356]. IGF-I also stimulates the in vitro secretion of hypothalamic SRIH, further delineating its role in feedback regulation of GH secretion [358]. Pituitary expression of GH, IGF-I and IGF-I receptors have been documented [359,360] and may therefore mutually interact by a paracrine or autocrine feedback mechanism [361]. Regulation of endogenous or circulating pituitary growth factors and their respective receptors may be important paracrine or autocrine determinants of pituitary cell function and trophic hormone secretion. The role of these growth factors in the development of pituitary tumors is being intensively studied [232].

Classification of Adenohypophysial Pathology Many diseases can affect tissues in and adjacent to the sella turcica, giving rise to a wide spectrum of clinical pathology. The clinical problems may be manifest as pituitary hormone deficiency or pituitary hormone excess. In addition, associated problems arise from compression, invasion, injury, or destruction of other tissue components; symptoms such as visual field defects, nerve palsies and headaches are characteristic of mass effects on the hypothalamus and neurohypophysis. Adenohypophysial Hormone Deficiency

The clinical problem of pituitary hormone deficiency may be due to decreased secretion or to increased degradation of hormone. Characteristic adenohypophysial changes are often associated with abnormalities of hormone secretion. Hypopituitarism involving one, two, or more adenohypophysial hormones is usually attributed to either a decreased number of hormone-secreting cells or to reduced endocrine activity. Organic lesions such as massive necrosis, inflammatory, or neoplastic processes can replace large portions of the pituitary and account for reduction of hormone-secreting parenchyma [195]. Reduced endocrine activity can result from target gland hormone excess or administration of exogenous hormones feedback negatively to suppress hypophysial function. Alternatively, it may be due to decreased hypothalamic stimulation or interference with receptors which govern secretion of hormones. Various developmental abnormalities can reduce the amount of adenohypophysial parenchyma. Some of these have been reviewed above (see embryology). It is now recognized that mutations of PROP-1 or Pit-1 result in various patterns of pituitary hormone deficiency and hypoplasia

[229,230,233,245,247]. In pituitary aplasia, there is total absence of the adenohypophysis due to a defect in the formation of Rathke’s pouch; pituitary hypoplasia is a milder variant of this disorder. In anencephaly, the brain, including the hypophysiotropic hypothalamus, is missing; due to lack of neurohumoral control, the adenohypophysis is smaller than normal and there is marked reduction in the number of corticotrophs associated with a less striking reduction of other adenohypophysial cell types [276a]. Cornelia de Lange syndrome, a rare congenital cyst of Rathke’s pouch, may compress the adenohypophysis and lead to various degrees of hypopituitarism. Pituitary dystopia or ectopia rarely affects function. Tissue destruction leads to a decrease or absence of pituitary hormone-producing parenchyma. This may be caused by tumors, inflammatory or infiltrative processes, or vascular lesions. Symptoms of hypopituitarism develop only with reduction of more than 60% of anterior lobe tissue and is clinically significant when there is more than a 90% reduction of hormone-producing cells. Hormonally inactive tumors of the adenohypophysis represent approximately 25% of surgically removed pituitary adenomas [195]. The null cell adenomas and oncocytomas fall into this category; these cell types have been discussed above. Craniopharyngiomas are less common than pituitary adenomas [195]. They represent 3–5% of intracranial neoplasms and occur usually in children or young adults. They are more frequently suprasellar than intrasellar and can cause varying degrees of hypopituitarism due to compression or destruction of the adenohypophysis, pituitary stalk, or hypophysiotropic hypothalamus. Other primary neoplasms in and around the sella turcica include fibromas, angiomas, gliomas, meningiomas, granular cell tumors, paragangliomas, chordomas, and many others (see Chapter 15) [195]. These tumors produce no hormones. The majority are benign and may be discovered incidentally at postmortem examination. Occasionally they cause hypopituitarism and local symptoms. Primary sarcomas have been reported in patients who have previously received irradiation for the treatment of pituitary adenomas [363]. Metastatic malignancies are found in patients with widely disseminated neoplasms; reported incidences vary from 1 to 14% [47,362]; however, the true incidence of adenohypophysial involvement is not known, since small deposits are easily overlooked. Pituitary involvement is rarely manifest before patients are overwhelmed by the malignancy. Inflammatory conditions in the sella turcica may occur as acute processes, with purulent hypophysitis and abscess formation, due to severe septicemia or direct extension from adjacent tissues. Granulomatous inflammation may be seen in tuberculosis, syphilis, sarcoidosis, and giant-cell granuloma. The latter is an uncommon disorder of unknown etiology which may involve the pituitary gland selectively; it may represent localized sarcoidosis [364]. Lymphocytic hypophysitis is an autoimmune disorder which may cause

Chapter 1

extensive destruction of the adenohypophysis and subsequent hypopituitarism [365,366]. Vascular lesions such as hemorrhages may occur as complications of traumatic head injuries or in tumors. Infarction is seen focally as an incidental autopsy finding but significant lesions may be associated with diabetes mellitus, generalized carcinomas, cranio-cerebral trauma, increased intracranial pressure, infection, and in patients maintained on mechanical ventilators. Postpartum pituitary necrosis, known as Sheehan’s syndrome [367], occurs in pregnancy, during which time the pituitary is predisposed to vasospasm and infarction. When damage is significant, hypopituitarism is proportional to the degree of tissue destruction. Infiltrative disorders such as amyloidosis, hemochromatosis, and mucopolysaccharidosis, may impair adenohypophysial cell function. Hemochromatosis can give rise to selective hypogonadism due to preferential deposition of iron in pituitary gonadotrophs [368]. Feedback inhibition may cause cytologic alterations in the adenohypophysis. These changes have been described above. Selective deficiencies of adenohypophysial hormones may result from inherited genetic abnormalities or selective damage to one cell type. Isolated GH deficiencies are a genetically heterogeneous group of disorders that cause dwarfism. In most cases, there is a normal pituitary with normal numbers of granulated somatotrophs; these are attributed to GHRH deficiency or abnormality [172–175]. Selective deficiency of a specific pituitary transcription factor, Pit-1, causes selective congenital GH and PRL deficiency associated with TSH deficiency [369–371]; several animal models of pituitary dwarfism, the Snell, Jackson and Ames dwarf mice, have also been shown to have specific abnormalities of the Pit-1 gene [372]. Congenital isolated ACTH deficiency has been attributed to T pit mutations. Lymphocytic hypophysitis has been reported to cause selective destruction of corticotrophs; antibodies to other pituitary cell types are also detectable in patients with endocrine autoimmune diseases and may give rise to isolated pituitary hormone deficiency [365,366]. Short stature with features of isolated GH deficiency but elevated GH blood levels was found to be due to a deficiency of GH-binding protein, the extracellular domain of the GH receptor [373,374]. Adenohypophysial Hormone Excess

Excess hormone production by the pituitary is usually due to a pituitary tumor [195]. The most common lesion is adenoma; carcinoma occurs exceedingly rarely and may be associated with hormone excess. Hyperplasia and hypertrophy of hormone-secreting cells may result from increased stimulation by hypothalamic releasing hormones, or from loss of inhibition by hypothalamic-inhibiting hormones, or excess target organ hormones. The cytologic features of each adenoma type have been described above. The features of hyperplastic adenohypophysial cells have also been provided. Tumor-like lesions may also be associated with hypersecretion of adenohypophysial hormones. Lymphocytic

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hypophysitis may give rise to a mass lesion of the sella turcica associated with hyperprolactinemia [365,366]. The elevated PRL levels may be due to inflammation, injury of the stalk or hypothalamus or compression of those structures by the enlarged, inflamed gland. The disorder is frequently associated with pregnancy and it has been suggested that antibodies directed against hyperplastic lactotrophs may stimulate PRL release, interfere with dopamine receptors, or damage PRL cells causing release of stored PRL. Rarely, pituitary hormone excess has been associated with normal pituitary morphology [195]. The hyperfunction may be caused by intrinsic abnormalities of the cells which produce subtle changes that may not be detectable by conventional morphologic techniques.

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Functional Anatomy of the Hypothalamic Pituitary Axis

41

213 Cox BM, Baizman ER, Su T-P et al. Further studies on the nature and function of pituitary endorphins. Adv Biochem Psychopharmacol 1978;18: 183–189. 214 Ferrand R, Hraoui S. Origine exlusivement ectodermique de l’adénohypophyse chez la caille et le poulet; demonstration par la méthode des associations tissulaires interspécifiques. C R Soc Biol 1973;167:740–743. 215 Ferrand R, Pearse AGE, Polak JM, Le Douarin NM. Immunohistochemical studies on the development of avian embryo pituitary corticotrophs under normal and experimental conditions. Histochemistry 1974;38:133–141. 216 LeDouarin N. Particularités du noyau interphasique chez la caille japonaise (Coturnix coturnix japonica). Utilisation de ces particularités comme “marque biologique” dans les recherches sur les interactions tissulaires et les migrations cellulaires au cours de l’ontogénèse. Bull Biol Fr Belg 1969;103: 435–452. 217 Takor Takor T, Pearse AGE. Neuroectodermal origin of avian hypothalamohypophyseal complex: the role of the ventral neural ridge. J Embryol Exp Morphol 1975;34:311–325. 218 Daikoku S. Studies on the human foetal pituitary. 1. Quantitative observations. Tokushima J Exp Med 1958;5:200–213. 219 Baker BL, Jaffe RB. The genesis of cell types in the adenohypophysis of the human fetus as observed by immunocytochemistry. Am J Anat 1975;143: 137–162. 220 Asa SL, Kovacs K, Laszlo FA et al. Human fetal adenohypophysis. Histologic and immunocytochemical analysis. Neuroendocrinology 1986;43:308–316. 221 Asa SL, Kovacs K, Horvath E et al. Human fetal adenohypophysis. Electron microscopic and ultrastructural immunocytochemical analysis. Neuroendocrinology 1988;48:423–431. 222 Tremblay JJ, Lanctot C, Drouin J. The pan-pituitary activator of transcription, Ptxl (pituitary homeobox 1) acts in synergy with SF-1 and Pit-1 and is an upstream regulator of the Lim-homeodomain gene Lim3/Lhx3. Mol Endocrinol 1998;12:428–441. 223 Gage PJ, Camper SA. Pituitary Homeobox 2, a novel member of the bicoidrelated family of homeobox genes, is a potential regulator of anterior structure formation. Hum Mol Genet 1997;6:457–464. 224 Sheng HZ, Moriyama K, Yamashita T et al. Multistep control of pituitary organogenesis. Science 1997;278:1809–1812. 225 Bach I, Rhodes SJ, Pearse RV et al. P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc Natl Acad Sci USA 1995;92:2720–2724. 226 Hermesz E, Machem S, Mahon KA. Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke’s pouch of the mouse embryo. Develop 1996;122:41–52. 227 Sornson MW, Wu W, Dasen JS et al. Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 1996;384:327–333. 228 Gage PJ, Brinkmeier MLSLM, Knapp LT. The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation. Mol Endocrinol 1996;10: 1570–1581. 229 Wu W, Cogan JD, Pfäffle RW et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nature Genet 1998;18:147–149. 230 Fofanova O, Takmura N, Kinoshita E. Compound heterozygous deletion of the prop-1 gene in children with combined pituitary hormone deficiency. J Clin Endocrinol Metab 1998;83:2601–2604. 231 Jackson SM, Barnhart KM, Mellon P et al. Helix-loop proteins are present and differentially expressed in different cell lines from the anterior pituitary. Mol Cell Endocrinol 1993;96:167–176. 232 Asa SL, Ezzat S. The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 1998;19:798–827. 233 Asa SL, Ezzat S. Molecular determinants of pituitary cytodifferentiation. Pituitary 1999;1:159–168. 234 Lamolet B, Pulichino AM, Lamonerie T et al. A pituitary cell-restricted T box factor, T pit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 2001;104:849–859. 235 Poulin G, Turgeon B, Drouin J. NeuroD1/beta2 contributes to cell-specific transcription of the proopiomelanocortin gene. Mol Cell Biol 1997;17: 6673–6682. 236 Ingraham HA, Lala DS, Ikeda Y et al. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev 1994;8:2302–2312. 237 Asa SL, Bamberger A-M, Cao B et al. The transcription activator steroidogenic factor-1 is preferentially expressed in the human pituitary gonadotroph. J Clin Endocrinol Metab 1996;81:2165–2170.

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SECTION 1

Hypothalamic–Pituitary Function

238 Rosenfeld MG. POU-domain transcription factors: pou-er-ful developmental regulators. Genes Dev 1991;5:897–907. 239 Asa SL, Puy LA, Lew AM et al. Cell type-specific expression of the pituitary transcription activator Pit-1 in the human pituitary and pituitary adenomas. J Clin Endocrinol Metab 1993;77:1275–1280. 240 Friend KE, Chiou Y-K, Laws ER Jr et al. Pit-1 messenger ribonucleic acid is differentially expressed in human pituitary adenomas. J Clin Endocrinol Metab 1993;77:1281–1286. 241 Pellegrini I, Barlier A, Gunz G et al. Pit-1 gene expression in the human pituitary and pituitary adenomas. J Clin Endocrinol Metab 1994;79:189–196. 242 Day RN, Koike S, Sakai M et al. Both Pit-1 and the estrogen receptor are required for estrogen responsiveness of the rat prolactin gene. Mol Endocrinol 1990;4:1964–1971. 243 Drolet DW, Scully KM, Simmons DM et al. TEF, a transcription factor expressed specifically in the anterior pituitary during embryogenesis, defines a new class of leucine zipper proteins. Genes Dev 1991;5:1739–1753. 244 Li S, Crenshaw EB III, Rawson EJ et al. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 1990;347:528–533. 245 Tatsumi K, Miyai K, Notomi T et al. Cretinism with combined hormone deficiency caused by a mutation in the Pit-1 gene. Nature Genet 1992;1:56–58. 246 Pfäffle RW, DiMattia GE, Parks JS et al. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 1992;257:1118–1121. 247 Radovick S, Nations M, Du Y et al. A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science 1992;257:1115–1118. 248 Puy LA, Asa SL. The ontogeny of pit-1 expression in the human fetal pituitary gland. Neuroendocrinology 1996;63:349–355. 249 Ikeda Y, Luo X, Abbud R et al. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol Endocrinol 1995;9:478–486. 250 Yang H-J, Ozawa H, Kurosumi K. Ultrastructural changes in growth hormone cells in the rat anterior pituitary after thyroidectomy as studied by immunoelectron microscopy and enzyme nistochemistry. J Clin Electr Microsc 1989;22:269–283. 251 Ezzat S, Kontogeorgos G, Redelmeier DA et al. In vitro responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide. Eur J Endocrinol 1995;133:686–690. 252 Horvath E, Kovacs K. The adenohypophysis. In: Kovacs K, Asa SL, eds. Functional Endocrine Pathology 2nd ed. Boston: Blackwell Science, 1998; 247–281. 253 Sano T, Ohshima T, Yanad S. Expression of glycoprotein hormones and intracytoplasmic distribution of cytokeratin on growth hormone-producing pituitary adenomas. Pathol Res Pract 1991;187:530–533. 254 Neumann PE, Goldman JE, Horoupian DS, Hess MA. Fibrous bodies in growth hormone-secreting adenomas contain cytokeratin filaments. Arch Pathol Lab Med 1985;109:505–508. 255 Billestrup N, Swanson L, Vale W. Growth hormone-releasing factor stimulates proliferation of somatotrophs in vitro. Proc Natl Acad Sci USA 1986;83: 6854–6857. 256 Richardson SB, Twente S. Evidence that diminished pituitary responsitivity to GHRF is secondary to intracellular GH pool depletion. Am J Physiol 1988;254:E358–364. 257 Loras B, Yi JY, Durand A et al. GRF et adénomes somatotropes humains. Correlations in vivo et in vitro entre la libération de GH et les aspects morphologiques et immunocytochimiques. Ann Endocrinol 1985;46: 373–382. 258 Kawakita S, Asa SL, Kovacs K. Effects of growth hormone-releasing hormone (GHRH) on densely granulated somatotroph adenomas and sparsely granulated somatotroph adenomas in vitro: a morphological and functional investigation. J Endocrinol Invest 1989;12:443–448. 259 Beckers A, Stevenaert A, Kovacs K et al. The treatment of acromegaly with SMS 201–995. Advanc Biosci 1988;69:227–228. 260 Barkan AL, Lloyd RV, Chandler WF et al. Preoperative treatment of acromegaly with long-acting somatostatin analog SMS 201–995: shrinkage of invasive pituitary macroadenomas and improved surgical remission rate. J Clin Endocrinol Metab 1988;67:1040–1048. 261 Ezzat S, Snyder PJ, Young WF et al. Octreotide treatment of acromegaly. A randomized, multicenter study. Ann Intern Med 1992;117:711–718. 262 Asa SL, Felix I, Kovacs K, Ramyar L. Effects of somatostatin on somatotroph adenomas of the human pituitary: an in vitro functional and morphological study. Endocr Pathol 1990;1:228–235.

263 Baringa M, Bilezikjian LM, Vale WW, Rosenfeld MG, Evans RM. Independent effects of growth hormone releasing factor on growth hormone release and gene transcription. Nature 1985;314:279–281. 264 Herman V, Weiss M, Becker D, Melmed S. Hypothalamic hormonal regulation of human growth hormone gene expression in somatotroph adenoma cell cultures. Endocr Pathol 1990;1:236–244. 265a Zafar M, Ezzat S, Ramyar L et al. Cell specific expression of estrogen receptor in the human pituitary and its adenomas. J Clin Endocrinol Metab 1995;80:3621–3627. 265b Friend KE, Chiou TK, Lopes MBS et al. Estrogen receptor expression in human pituitary. J Clin Endocrinol Metab 1994;78:1497–1504. 266 Asa SL, Penz G, Kovacs K, Ezrin C. Prolactin cells in the human pituitary: a quantitative immunocytochemical analysis. Arch Pathol Lab Med 1982;106: 360–363. 267 Scheithauer BW, Sano T, Kovacs K et al. The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 1990;65:461–474. 268a Scheithauer BW, Kovacs K, Randall RV, Ryan N. Effects of estrogen on the human pituitary: a clinicopathologic study. Mayo Clin Proc 1989;64: 1077–1084. 268b Asa SL, Kelly MA, Grandy DK, Low MJ. Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptordeficient mice. Endocrinology 1999;140:5348–5355. 269 Tindall GT, Kovacs K, Horvath E, Thorner MO. Human prolactin-producing adenomas and bromocriptine: a histological, immunocytochemical, ultrastructural, and morphometric study. J Clin Endocrinol Metab 1982;55: 1178–1183. 270 Esiri MM, Bevan JS, Burke CW, Adams CBI. Effect of bromocriptine treatment on the fibrous tissue component of prolactin-secreting and nonfunctioning macroadenomas of the pituitary gland. J Clin Endocrinol Metab 1986;63:383–388. 271 Felix IA, Horvath E, Kovacs K et al. Mammosomatotroph adenoma of the pituitary associated with gigantism and hyperprolactinemia. Acta Neuropathol 1986;71:76–82. 272 Asa SL, Kovacs K, Stefaneanu L et al. Pituitary adenomas in mice transgenic for growth hormone-releasing hormone. Endocrinology 1992;131:2083–2089. 273 Lewis ME, Sherman TG, Burke S et al. Detection of proopiomelanocortin mRNA by in situ hybridization with an oligonucleotide probe. Proc Natl Acad Sci USA 1986;83:5419–5423. 274 Horvath E, Ilse G, Kovacs K. Enigmatic bodies in human corticotroph cells. Acta Anat 1977;98:427–433. 275 Neumann PE, Horoupian DS, Goldman JE, Hess MA. Cytoplasmic filaments of Crooke’s hyaline change belong to the cytokeratin class. An immunocytochemical and ultrastructural study. Am J Pathol 1984;116:214–222. 276a Asa SL, Kovacs K. Functional morphology of the human fetal pituitary. Pathol Annu 1984;19(1):275–315. 276b Pilardzic D, Kovacs K, Asa SL. Pituitary morphology in human anencephalic fetuses. Neuroendocrinology 1997;65:164–172. 277 Scheithauer BW, Kovacs K, Randall RV. The pituitary gland in untreated Addison’s disease. A histologic and immunocytologic study of 18 adenohypophyses. Arch Pathol Lab Med 1983;107:484–487. 278 Siperstein ER, Allison VF. Fine structures of the cells responsible for secretion of adrenocorticotropin in the adrenalectomized rat. Endocrinology 1965;76: 70–79. 279 Asa SL, Kovacs K, Hammer GD et al. Pituitary corticotroph hyperplasia in rats implanted with a medullary thyroid carcinoma cell line transfected with a corticotropin-releasing hormone complementary deoxyribonucleic acid expression vector. Endocrinology 1992;131:715–720. 280 Coates PJ, Doniach I, Hale AC, Rees LH. The distribution of immunoreactive a-melanocyte-stimulating hormone cells in the adult human pituitary gland. J Endocrinol 1986;111:335–342. 281 McNicol AM. A study of intermediate lobe differentiation in the human pituitary gland. J Pathol 1986;150:169–173. 282 Horvath SE, Asa SL, Kovacs K et al. Human pituitary corticotroph adenomas in vitro: morphologic and functional reponses to corticotropin-releasing hormone and cortisol. Neuroendocrinology 1990;51:241–248. 283 Horvath E, Lloyd RV, Kovacs K. Propylthiouracyl-induced hypothyroidism results in reversible transdifferentiation of somatotrophs into thyroidectomy cells: a morphologic study of the rat pituitary including immunoelectron microscopy. Lab Invest 1990;63:511–520. 284 Asa SL, Kovacs K, Bilbao JM. The pars tuberalis of the human pituitary: a histologic immunohistochemical, ultrastructural and immunoelectron microscopic analysis. Virchows Archiv (Pathol Anat) 1983;399:49–59.

Chapter 1 285 Horvath E, Kovacs K. Gonadotroph adenomas of the human pituitary: sexrelated fine structural dichotomy. A histologic, immunocytochemical and electron microscopic study of 30 tumors. Am J Pathol 1984;117:429–440. 286 Denef C. Paracrine interactions in the anterior pituitary. Clin Endocrinol Metab 1986;15:1–32. 287 Kovacs K, Horvath E. Gonadotrophs following removal of the ovaries: a fine structural study of human pituitary glands. Endokrinologie 1975;66:1–8. 288 Horvath E, Kovacs K, Penz G, Ezrin C. Origin, possible function and fate of “follicular cells” in the anterior lobe of the human pituitary. Am J Pathol 1974;77:199–212. 289 Girod C, Trouillas J, Dubois MP. Immunocytochemical localization of S-100 protein in stellate cells (folliculo-stellate cells) of the anterior lobe of the normal human pituitary. Cell Tissue Res 1985;241:505–511. 290 Höfler H, Walter GF, Denk H. Immunohistochemistry of folliculo-stellate cells in normal human adenohypophyses and in pituitary adenomas. Acta Neuropathol 1984;65:35–40. 291 Baes M, Allaerts W, Denef C. Evidence for functional communication between folliculo-stellate cells and hormone-secreting cells in perifused anterior pituitary aggregates. Endocrinology 1987;120:685–691. 292 Vankelecom A, Carmeliet P, Van Damme J et al. Production of interleukin-6 by folliculo-stellate cells of the anterior pituitary gland in a histiotypic cell aggregate culture system. Neuroendocrinology 1989;49:102–106. 293 Ferrara N, Schweigerer L, Neufeld G et al. Pituitary follicular cells produce basic fibroblast growth factor. Proc Natl Acad Sci USA 1987;84: 5773–5777. 294 Coates PJ, Doniach I. Development of folliculo-stellate cells in the human pituitary. Acta Endocrinol 1988;119:16–20. 295 Lauriola L, Cocchia D, Sentinelli S et al. Immunohistochemical detection of folliculo-stellate cells in human pituitary adenomas. Virchows Archiv (Cell Pathol) 1984;47:189–197. 296 Nishioka H, Llena JF, Hirano A. Immunohistochemical study of folliculostellate cells in pituitary lesions. Endocr Pathol 1991;2:155–160. 297 Kovacs K, Horvath E, Ryan N, Ezrin C. Null cell adenomas of the human pituitary. Virchows Archiv (Pathol Anat) 1980;387:165–174. 298 Asa SL, Cheng Z, Ramyar L et al. Human pituitary null cell adenomas and oncocytomas in vitro: effects of adenohypophysiotropic hormones and gonadal steroids on hormone secretion and tumor cell morphology. J Clin Endocrinol Metab 1992;74:1128–1134. 299 Yamada S, Asa SL, Kovacs K et al. Analysis of hormone secretion by clinically nonfunctioning human pituitary adenomas using the reverse hemolytic plaque assay. J Clin Endocrinol Metab 1989;68:73–80. 300 Jameson JL, Klibanski A, Black PMcL et al. Glycoprotein hormone genes are expressed in clinically nonfunctioning pituitary adenomas. J Clin Invest 1987;80:1472–1478. 301 Kontogeorgos G, Horvath E, Kovacs K et al. Null cell adenoma of the pituitary with features of plurihormonality and plurimorphous differentiation. Arch Pathol Lab Med 1991;115:61–64. 302 Kovacs K, Asa SL, Horvath E et al. Null cell adenomas of the pituitary: attempts to resolve their cytogenesis. In: Lechago J, Kameya T, eds. Endocrine Pathology Update. Philadelphia: Field and Wood, 1990;17–31. 303 Kovacs K, Horvath E, Bilbao JM. Oncocytes in the anterior lobe of the human pituitary gland. A light and electron microscopic study. Acta Neuropathol 1974;27:43–54. 304 Carafoli E. Mitochondrial pathology: an overview. Ann NY Acad Sci 1986; 488:1–18. 305 Horvath E, Kovacs K, Singer W et al. Acidophil stem cell adenoma of the human pituitary: clinicopathological analysis of 15 cases. Cancer 1981;47: 761–771. 306 Sano T, Kovacs K, Asa SL, Smyth HS. Immunoreactive luteinizing hormone in functioning corticotroph adenomas of the pituitary. Immunohistochemical and tissue culture studies of two cases. Virchows Archiv (Pathol Anat) 1990;471: 361–367. 307 Moriarty GC, Garner LL. Immunocytochemical studies of cells in the rat adenohypophysis containing both ACTH and FSH. Nature 1977;265:356–358. 308 May V, Wilber JF, U’Prichard DC, Childs GV. Persistence of immunoreactive TRH and GnRH in long-term primary anterior pituitary cultures. Peptides 1987;8:543–558. 309 Joubert (Bression) D, Benlot C, Lagoguey A et al. Normal and growth hormone (GH)-secreting adenomatous pituitaries release somatostatin and GH-releasing hormone. J Clin Endocrinol Metab 1989;68:572–577. 310 Pagesy P, Li JY, Rentier-Delrue F et al. Evidence of pre-prosomatostatin mRNA in human normal and tumoral anterior pituitary gland. Mol Endocrinol 1989;3:1289–1294.

Functional Anatomy of the Hypothalamic Pituitary Axis

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311 Duello TM, Nett TM, Farquhar MG. Fate of a gonadotropin releasing hormone agonist internalized by rat pituitary gonadotrophs. Endocrinology 1983;112:1–10. 312 Deschepper CF, Crumrine DA, Ganong WF. Evidence that the gonadotrophs are the likely site of production of angiotensin II in the anterior pituitary of the rat. Endocrinology 1986;119:36–43. 313 Major J, Ghatei MA, Bloom SR. Bombesin-like immunoreactivity in the pituitary gland. Experientia 1983;39:1158–1159. 314 Zaidi M, Abeyasekera G, MacIntyre I. Calcitonin gene-related peptide: endocrine distribution and characterization of circulating forms. J Endocrinol Invest 1989;12:699–704. 315 Rehfeld JF. Preprocholecystokinin processing in the normal human anterior pituitary. Proc Natl Acad Sci USA 1987;84:3019–3023. 316 Rehfeld JF, Lindholm J, Andersen BN et al. Pituitary tumors containing cholecystokinin. N Engl J Med 1987;316:1244–1247. 317 Vrontakis ME, Sano T, Kovacs K, Friesen HG. Presence of galanin-like immunoreactivity in nontumorous corticotrophs and corticotroph adenomas of the human pituitary. J Clin Endocrinol Metab 1990;70:747–751. 318 Vrontakis ME, Peden LM, Duckorth MC, Friesen HG. Isolation and characterization of a complementary DNA (galanin) clone from estrogeninduced pituitary tumor messenger RNA. J Biol Chem 1987;262: 16755–16758. 319 O’Halloran DJ, Jones PM, Steel JH et al. Effect of endocrine manipulation on anterior pituitary galanin in the rat. Endocrinology 1990;127: 467–475. 320 Kaplan LM. Gabriel SM, Koenig JI et al. Galanin is an estrogen-inducible, secretory product of the rat anterior pituitary. Proc Natl Acad Sci USA 1988;85:7408–7412. 321 Larson LI, Rehfeld JF. Pituitary gastrins occur in corticotrophs and melanotrophs. Science 1981;213:768–770. 322 Bardram L, Lindholm J, Rehfeld JF. Gastrin in pituitary tumors. Acta Endocrinol 1987;115:419–422. 323 Jones PM, Ghatei MA, Steel J et al. Evidence for neuropeptide-Y synthesis in the rat anterior pituitary and the influence of thyroid hormone status: comparison with vasoactive intestinal peptide, substance P, and neurotensin. Endocrinology 1989;125:334–341. 324 Goedert M, Lightman SL, Nagy IT et al. Neurotensin in the rat anterior pituitary gland. Nature 1982;298:163–165. 325 Morel G, Chayvialle JA, Kerdelhue B, Dubois PM. Ultrastructural evidence for endogenous substance P-like immunoreactivity in the rat pituitary gland. Neuroendocrinology 1982;35:86–92. 326 de Palatis LR, Fiorindo RP, Ho RH. Substance P immunoreactivity in the anterior pituitary gland of the guinea pig. Endocrinology 1982;110: 282–284. 327 Arnaout MA, Garthwaite TL, Martinson DR, Hagen TC. Vasoactive intestinal polypeptide is synthesized in anterior pituitary tissue. Endocrinology 1986;119: 2052–2057. 328 Steel JH, Gon G, O’Halloran DJ et al. Galanin and vasoactive intestinal polypeptide are colocalised with classical pituitary hormones and show plasticity of expression. Histochemistry 1989;93:183–189. 329 Lam SK, Reichlin S. Pituitary vasoactive intestinal peptide regulates prolactin secretion in the hypothyroid rat. Neuroendocrinology 1989;50: 524–528. 330 Webster J, Ham J, Bevan JS, Scanlon MF. Growth factors and pituitary tumors. Trends Endocrinol Metab 1989;1:95–98. 331 Ezzat S, Melmed S. The role of growth factors in the pituitary. J Endocrinol Invest 1990;13:691–698. 332 White BA, Bancroft FC. Epidermal growth factor and thyrotropin-releasing hormone interact synergistically with calcium to regulate prolactin mRNA levels. J Biol Chem 1983;258:4618–4622. 333 Murdoch GH, Potter E, Nicolaisen AK et al. Epidermal growth factor rapidly stimulates prolactin gene transcription. Nature 1982;300:192–194. 334 Polk DH, Ervin MG, Padbury JF et al. Epidermal growth factor acts as a corticotropin-releasing factor in chronically catheterized fetal lambs. J Clin Invest 1987;79:984–988. 335 Miyake A, Tasaka K, Otsuka S et al. Epidermal growth factor stimulates secretion of rat pituitary luteinizing hormone in vitro. Acta Endocrinol 1985;108:175–178. 336 Leriche VK, Asa SL, Ezzat S. Epidermal growth factor and its receptor (EGFR) in human pituitary adenomas: EGF-R correlates with tumor aggressiveness. J Clin Endocrinol Metab 1996;81:656–662. 337 Kasselberg AG, Orth DN, Gray ME, Stahlman MT. Immunocytochemical localization of human epidermal growth factor/urogastrone in several human tissues. J Histochem Cytochem 1985;33:315–322.

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338 Mueller SG, Kobrin MS, Paterson AJ, Kudlow JE. Transforming growth factor-a expression in the anterior pituitary gland: regulation by epidermal growth factor and phorbol ester in dispersed cells. Mol Endocrinol 1989;3:976–983. 339 Ezzat S, Walpola IA, Ramyar L et al. Membrane-anchored expression of transforming growth factor-≤ in human pituitary adenoma cells. J Clin Endocrinol Metab 1995;80:534–539. 340 Kobrin MS, Asa SL, Samoondar J, Kudlow JE. a-Transforming growth factor in the bovine anterior pituitary gland: secretion by dispersed cells and immunohistochemical localization. Endocrinology 1987;121:1412–1416. 341 Ramsdell JS. Transforming growth factor-a and -b are potent and effective inhibitors of GH4 pituitary tumor cell proliferation. Endocrinology 1991;128: 1981–1990. 342 McAndrew J, Paterson AJ, Asa SL et al. Targeting of transforming growth factor-a expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas. Endocrinology 1995;136: 4479–4488. 343 Ying S-Y. Inhibins, activins, and follistatins: gonadal proteins modulating the secretion of follicle-stimulating hormone. Endocr Rev 1988;9:267–293. 344 Roberts V, Meunier H, Vaughan J et al. Production and regulation of inhibin subunits in pituitary gonadotropes. Endocrinology 1989;124:552–554. 345 Billestrup N, González-Manchón C, Potter E, Vale W. Inhibition of somatotroph growth and growth hormone biosynthesis by activin in vitro. Mol Endocrinol 1990;4:356–362. 346 Corrigan AZ, Bilezikjian LM, Carroll RS et al. Evidence for an autocrine role of activin B within rat anterior pituitary cultures. Endocrinology 1991;128:1682–1684. 347 Kogawa K, Nakamura T, Sugino K et al. Activin-binding protein is present in pituitary. Endocrinology 1991;128:1434–1440. 348 Penabad JL, Bashey HM, Asa SL et al. Decreased follistatin gene expression in gonadotroph adenomas. J Clin Endocrinol Metab 1996;81:3397–3403. 349 Gospodarowicz D, Ferrara N, Schweigener L, Neufeld G. Structural characterization and biological functions of fibroblast growth factor. Endocr Rev 1987;8:95–114. 350 Prysor-Jones RA, Silverlight JJ, Jenkins JS. Oestradiol, vasoactive intestinal peptide and fibroblast growth factor in the growth of human pituitary tumour cells in vitro. J Endocrinol 1989;120:171–177. 351 Elias KA, Weiner RI. Direct arterial vascularization of estrogen-induced prolactin-secreting anterior pituitary tumors. Proc Natl Acad Sci USA 1984;81:4549–4553. 352 Ezzat S, Smyth HS, Ramyar L, Asa SL. Heterogeneous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas. J Clin Endocrinol Metab 1995;80:878–884. 353 Ezzat S, Zheng L, Zhu XF, Wu GE, Asa SL. Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. J Clin Invest 2002;109:69–78. 354 Stojlkovic SS, Merelli F, Iida T et al. Endothelin stimulation of cystolic calcium and gonadotropin secretion in anterior pituitary cells. Science 1990;248:1663–1666. 355 Matsumoto H, Suzuki N, Shiota K et al. Insulin-like growth factor-I stimulates endothelin-3 secretion from rat anterior pituitary cells in primary culture. Biochem Biophys Res Commun 1990;172:661–668.

356 Prager D, Melmed S, Fagin J. Feedback regulation of growth hormone gene expression by insulin-like growth factor I. In: LeRoith D, Raizada MK, eds. Molecular and Cellular Biology of Insulin-like Growth Factors and Their Receptors. New York: Plenum Press, 1989:57–71. 357 Yamashita S, Melmed S. Insulin-like growth factor I regulation of growth hormone gene transcription in primary rat pituitary cells. J Clin Invest 1987;79:449–452. 358 Berelowitz M, Szabo M, Frohman LA et al. Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary. Science 1982;212:1279. 359 Han VKM, Lund PK, Lee DC, D’Ercole AJ. Expression of somatomedin/ insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution. J Clin Endocrinol Metab 1998;66:422–429. 360 Yamashita S, Weiss M, Melmed S. Insulin-like growth factor I regulates GH secretion and mRNA levels in human pituitary tumor cells. J Clin Endocrinol Metab 1986;63:730–735. 361 Asa SL, Coschigano KT, Bellush L et al. Evidence for growth hormone (GH) autoregulation in pituitary somatotrophs in GH antagonist-transgenic and GH receptor-deficient mice. Am J Pathol 2000;156:1009–1015. 362 Asa SL, Kovacs K. Histological classification of pituitary disease. J Clin Endocrinol Metab 1983;12:567–596. 363 Shi T, Farrel MA, Kaufmann JCL. Fibrosarcoma Complicating irradiated pituitary adenoma. Surg Neurol 1984;22:277–283. 364 Del Pozo JM, Roda JE, Montoya JG et al. Intrasellar granuloma. Case Report. J Neurosurg 1980;53:717–719. 365 Asa SL, Bilbao JM, Kovacs K et al. Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism. A distinct clinicopathologic entity. Ann Intern Med 1981;95:166–171. 366 Thodou E, Asa SL, Kontogeorgos G et al. Lymphocytic hypophysitis: Clinicopathologic findings. J Clin Endocrinol Metab 1995;80:2302–2311. 367 Sheehan HL, Stanfield JR. The pathogenesis of post-partum necrosis of the anterior lobe of the pituitary gland. Acta Endocrinol 1961;37:479–510. 368 Bergeron C, Kovacs K. Pituitary siderosis. A histologic and immunocytologic study. Arch Intern Med 1979;139:248-249. 369 Pfäffle RW, DiMattia GE, Parks JS et al. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 1992;257:1118–1121. 370 Radovick S, Nations M, Du Y et al. A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science 1992;257:1115–1118. 371 Tatsumi K, Miyai K, Notomi T et al. Cretinism with a combined hormone deficiency caused by a mutation in the Pit-1 gene. Nature Gen 1992;1:56–58. 372 Li S, Crenshaw EB III, Rawson EJ et al. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 1990;347:528–533. 373 Daughaday WH, Trivedi B. Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism). Proc Natl Acad Sci USA 1987;84:4636–4640. 374 Baumann G, Shaw MA, Winter RJ. Absence of the plasma growth hormonebinding protein in Laron-type dwarfism. J Clin Endocrinol Metab 1987;65: 814–816.

C h a p t e r

2 Adrenocorticotropin Mark A. Herman Joseph A. Majzoub

The anterior pituitary forms via invagination of the pharyngeal stomodeum in the region of contact with the diencephalon. By week 5 of human gestation, this invagination, termed Rathke’s diverticulum, has formed, but the downward migration of the diencephalic diverticulum, destined to be the neurophypophysis, has not yet commenced. It is at this time that adrenocorticotropin (ACTH) is first detectable by immunocytochemistry in the collection of cells within Rathke’s diverticulum which are furthest from contact with the diencephalon [1]. By 8 weeks of gestation, ACTH is detectable by radioimmunoassay of both fetal pituitary tissue and fetal blood [1]. The hypophyseal–portal vascular system forms between 8 and 14 weeks gestation, dating the earliest time after which hypothalamic corticotropin releasing factors may function to regulate fetal pituitary ACTH [1]. By 14 weeks gestation, release of ACTH from human fetal corticotrophs is highly responsive to exposure to corticotropin releasing hormone (CRH) in vitro [2]. The intensity of immunohistochemical ACTH staining in the anterior pituitary increases progressively from the mid-first through the end of the second trimester. In contrast, it is only after 21 weeks gestation that ACTH-positive cells begin to appear in the pars intermedia of the human fetal pituitary, defined as that region between Rathke’s cleft anteriorly and the neurohypophysis posteriorly. The ACTHcontaining cells in this region are epithelial-like, in contrast to the more angular, ovoid appearance of corticotrophs in the anterior pituitary [1].

those containing a-L-fucose and complex N-glyosylprotein, as well as terminal b-galactose. Corticotrophs constitute between 10 and 20% of the cell population of the anterior pituitary [3]. They are large cells with an ovoid or angular shape. They occur either singly or in clumps. They are most numerous in the midsagittal region of the pituitary (median wedge) but also occur in the lateral wings of the gland. Although the adult human pituitary does not contain an intermediate lobe, the junctional zone between the anterior and posterior lobes is known as the zona intermedia. This region, derived from the portion of Rathke’s diverticulum posterior to Rathke’s cleft, contains scattered cells immunopositive for ACTH. Some of these ACTHcontaining cells appear to extend into the posterior pituitary, a feature known as basophilic invasion [3]. These areas of apparent migration of corticotrophs from the zona intermedia into the posterior pituitary occur focally along the border between these two regions. In humans, in addition to the sellar pituitary, a pharyngeal pituitary exists which is located in either the sphenoid sinus or within the sphenoid bone. It consists of pituitarylike tissue approximately 2 to 5 mm by 0.2 mm in size. It is connected to the sellar gland by transsphenoidal vessels [4]. Only 1% to 2% of the cells in the pharyngeal pituitary contain immunoreactive ACTH, in contrast to approximately 14% of the cells in the sellar pituitary [4]. The pharyngeal pituitary is thought to arise as a rest of tissue resulting from the normal migration of cells from Rathke’s pouch to the sella turcica. There have been several reports of Cushing’s disease due to corticotroph adenomas arising in the pharyngeal pituitary [4,5].

Adult Anatomy

Molecular Embryology

Corticotrophs were initially identified by their basophilic staining. This has been subsequently found to be due to the presence of complex sugars in corticotrophs, principally

Tremendous progress has been made in recent years concerning the molecular mechanisms controlling pituitary organogenesis and pituitary cell-lineage specification in

CELLS OF ORIGIN

Fetal Anatomy

45

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animal models. A complex network of transcriptional events mediated by extrinsic and intrinsic signals has been implicated in the determination and a stereotypical spatiotemporal differentiation of the five trophic cell types of the mature anterior pituitary gland. Intrinsic Signals

RPX (for Rathke’s pouch homeobox), also known as HESX1 (for homeobox gene expression in embryonic stem cells) is the earliest known marker for the pituitary primordium [6]. HESX1/RPX is a member of the paired-like class of homeobox genes. Early HESX1/RPX expression occurs in the anterior midline endoderm and prechordal plate precursor, followed by expression in the cephalic neural plate [6]. Expression becomes progressively restricted anteriorly in the cephalic neural plate in a distribution consistent with tissue known by fate mapping studies to form the primordium of the anterior pituitary [7–10]. HESX1/RPX expression ultimately becomes restricted to Rathke’s pouch, and down regulation of HESX1/RPX in the pouch coincides with the differentiation of pituitary-specific cell types [6]. Embryonic mice lacking Rpx demonstrate variable abnormalities of hypothalamic and pituitary morphogenesis, reduced prosencephalon, anophthalmia or microophthalmia, and defective olfactory development. Neonatal mice have abnormalities in the corpus callosum, the anterior and hippocampal commisures, and the septum pellucidum [11]. These abnormalities are reminiscent of defects seen in a heterogeneous group of human disorders known as septooptic dysplasia (SOD). Deficits in SOD include optic nerve hypoplasia, abnormalities of the midline brain structures, and abnormalities of the hypothalamic-pituitary axis. Patients commonly present with endocrinopathies including hypoglycemia and adrenal crisis, which may signal growth hormone, ACTH, or thryoid-stimulating hormone deficiency [12]. Dattani and colleagues have identified two siblings with SOD who are homozygous for missense mutations within the HESX1 homeodomain which prevents it from binding target DNA [11]. The siblings identified with HESX1 mutations presented with hypoglycemia hours after birth and demonstrated hypopituitarism, substantiating a role for HESX1 in human pituitary development [11,13]. The corticotroph lineage appears to diverge relatively early from the other cell types of the anterior pituitary. LHX3, a LIM-type homeodomain protein, is essential for growth of Rathke’s pouch and determination of pituitary cell lineages [14]. In Lhx3-deficient mice, proopiomelanocortin (Pomc) was detected in a small cohort of cells at the ventral base of the pouch remnant which roughly corresponds to the position of the first presumptive corticotroph cells to differentiate in the wild-type pouch [14]. Although some pouch cells were able to differentiate and express Pomc, these cells failed to proliferate. An insufficient or non-functional corticotroph cell mass may have caused the hypoplastic adrenal cortices noted in these animals [14].

Ptx1 is a bicoid-related homeobox transcription factor identified based upon its ability to activate transcription of Pomc in the corticotroph derived AtT-20 cell line [15] and its ability to interact with the transactivation domain of Pit-1 [16]. It is expressed in the primordial Rathke’s pouch, oral epithelium, first branchial arch, the duodenum, and hindlimb [16]. Ptx1 is expressed in all mature pituitary cells, but is differentially expressed during pituitary development in different cell types [17]. In the mature pituitary, the highest levels of expression are found within corticotrophs [15]. In addition to activating transcription of Pomc, Ptx1 is required for sustained expression of Lhx3 [18], directly activates transcription of the common a-glycoprotein subunit (a-GSU) [16], synergizes with Pit-1 on the growth hormone and prolactin promoter [18], and synergizes with SF-1 on the promoter of the lutenizing hormone b (LH-b) gene [18]. Ptx2, also known as RIEG, is an additional bicoid-related homeobox gene 97% identical to Ptx1 [19]. Ptx2 is also differentially expressed in the pituitary and is excluded from corticotrophs [20], suggesting that some of the functions ascribed to Ptx1 may be performed by Ptx2. Expression of Pit-1, a POU domain transcription factor, is restricted to the anterior pituitary and required for the development of thyrotophs, lactotrophs, and somatotrophs [21]. Consistent with this, patients with mutations in PIT-1 have normal hypothalamic-pituitary-advanced (HPA) axis function [22]. Prophet of PIT-1 (PROP-1) is required for PIT-1 expression, and mutation of its gene is also associated with deficiencies in the development of thyrotrophs, lactotrophs, and somatotrophs in the Ames dwarf mouse and in humans. In a small number of patients with mutations in PROP1, modest impairment of ACTH secretion has been reported [23]. Developmentally essential, cell line-restricted factors have been identified for a number of different pituitary cell types. SF-1, an orphan nuclear receptor, is necessary for the development of gonadotrophs [24]. However, no essential corticotroph specific factor has yet been clearly identified. NeuroD, also known as Beta2, is a cell-restricted basic helixloop-helix (bHLH) transcription factor implicated in late neuronal differentiation [25] which has also been isolated as a cell-specific transcription factor of the insulin gene [26]. NeuroD is expressed in a number of tissues including pancreatic endocrine cells, the intestine, and brain including the mouse corticotroph AtT-20 cell line, but not the rat somatotroph pituitary cell line (GH3) [26]. Drouin and colleagues have recently demonstrated that NeuroD expression does appear to be restricted to corticotrophs in the mouse pituitary, and that NeuroD, in association with ubiquitous bHLH dimerization partners, specifically recognizes and activates transcription from the POMC promoter E box that confers transcriptional specificity of POMC to corticotrophs [27,28]. However, the necessity of this transcription factor for corticotroph specification or differentiation is still undetermined. Recently, a corticotroph-restricted transcription factor. TPIT, has been identified, which interacts with PTX1 and is required for POMC transcription, as discussed subse-

Chapter 2

quently. However, its role in corticotroph development is not known, and awaits further study. Because no instrinsic factor has yet been identified that is absolutely required for the development of corticotrophs in situ, it is possible that they arise elsewhere during fetal life and migrate into the anterior pituitary. One possible source could be neural crest, as this is the origin of POMC-producing melanocytes which migrate to the skin [29]. Extrinsic Signals

The oral ectoderm, from which Rathke’s pouch forms, and the neural ectoderm of the ventral diencephalon, from which the hypothalamus arises, are in direct contact at the time of the formation of Rathke’s pouch [30]. Classical explant experiments have indicated that inductive signals arising from mesenchyme and neural ectoderm adjacent to Rathke’s pouch are required for pituitary organogenesis and cell line specification [31]. The necessity for extrinsic signals for development of corticotrophs is supported by the demonstration that the expression of POMC in ectoderm explants requires coculture with mesoderm [32]. Direct evidence confirming the necessity of the ventral diencephalon for proper pituitary organogenesis has recently been obtained from examination of mice bearing null mutations in the Nkx2.1 homeobox gene, also known as T/EBP or TTF1 [33]. This gene is not expressed in the oral ectoderm or in the developing pituitary at any time during embryogenesis [34], but Nkx2.1-null mice demonstrate severe defects in the development of the diencephalon and also fail to develop a pituitary gland [33]. The nature of the extrinsic signals that promote pituitary organogenesis and cause cell-line specification is an area of active investigation. A number of secreted factors have been implicated in pituitary development and cell-line specification including bone morphogenic proteins (BMP4, BMP2), fibroblast growth factor 8 (FGF8), Sonic hedgehog (Shh) and Wnt5a [35–37]. A model of coordinate control of anterior pituitary progenitor cell identity, proliferation and differentiation imposed by FGF8 secreted from the dorsally located infundibulum and BMP2 from ventrally located mesenchyme has been proposed [37]. It has been suggested that corticotroph progenitors progress to a definitive corticotroph state only after escaping both FGF8 and BMP2 signaling [37]. While the precise signals and interactions required for pituitary organogenesis and corticotroph specification are incompletely understood, it is clear that signals from the mature hypothalamus like corticotropin releasing hormone (CRH) and vasopressin (AVP) are not required for corticotroph specification. The anterior pituitary appears to develop normally in a Crh-null mouse [38]. Furthermore, deletion of the class III POU transcription Brn-2 results in failed maturation of Avp-, Crh-, and oxytocin producing neurons of the hypothalamus and failed maturation of the posterior pituitary with no apparent defect in the maturation of any anterior pituitary cell type [39].

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Localization of Non-ACTH Peptides with Corticotrophs Many other neuropeptides have been found to be colocalized with ACTH within corticotrophs, although in most cases it is not clear whether this is due to synthesis or binding of the peptide within the cell. Neurophysin (but not vasopressin) colocalizes with ACTH in both normal and adenomatous corticotrophs [40]. Neurophysin immunocytochemical staining is especially prominent in corticotrophs in the zona intermedia which appear to project into the posterior pituitary. Chromogranin A has been described in the majority of corticotroph adenomas, although only a fraction of these patients have elevations of circulating plasma chromogranin A levels [41]. Galanin is present in all normal corticotrophs as well as in the majority of corticotroph adenomas which have been examined [42]. Galanin has also been found in those corticotrophs in the zona intermedia which appear to be migrating into the posterior pituitary. It has also been described in corticotrophs which have undergone Crooke’s hyalinization. Calpastatin, an inhibitor of the calcium-dependent cysteine proteases, calpain I, and calpain II, has been found in all ACTH-containing cells of the anterior pituitary, including those in the median wedge as well as those extending into the posterior pituitary [43]. Vasoactive intestinal peptide has been found in corticotroph adenomas, but only rarely in normal corticotrophs [44]. Normal corticotrophs contain small amounts of cytokeratin, whereas corticotrophs which have undergone Crooke’s hyalinization are markedly positive for this protein [45]. Corticotrophs appear to have few structural characteristics associated with neuronal cell types, for they are negative for neurofilament, vimentin, glial fibrillary acidic protein and desmon [45,46]. Likewise, corticotrophs in the zona intermedia, unlike those in the pars intermedia of rodents, appear not to be innervated by neurons, since they do not stain with any of these neuron-specific markers [47]. Similarly, synaptophysin, a 38 kD integral membrane glycoprotein found in presynaptic vesicles of neurons stains only weakly in corticotrophs [48]. These findings, together with a lack in humans of an anatomically discrete intermediate lobe with large numbers of a-MSH-containing cells, has led most investigators to conclude that there is no functional counterpart of the rodent pituitary intermediate lobe in humans.

Extra-pituitary Localization of ACTH and Related Peptides Although the vast majority of ACTH is synthesized in anterior pituitary corticotrophs, it is also expressed in several nonpituitary human tissues, both within and outside of the central nervous system. Within the central nervous system, ACTH and its related peptides are expressed to the greatest degree in cell bodies of the infundibular nucleus of the basal hypothalamus (analogous to the rodent arcuate nucleus) [49–51]. (See POMC Biosynthesis and Processing,

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pp. 52–53.) The cell bodies of these hypothalamic ACTH neurons are located at the base of the third ventricle, adjacent to the median eminence and pituitary stalk. These neurons project to limbic, diencephalic, mesencephalic, and amygdaloid sites [52]. Lesser amounts of ACTH and related peptides are found in substantia nigra, periventricular grey matter, and hippocampus [53]. Interestingly, POMC expression in the hypothalamus occurs in areas also known to express the orexigenic neuropeptides NPY and AGRP and project to many of the same hypothalamic targets [54,55]. The rodent arcuate nucleus prominently expresses the leptin receptor, implicating Pomc products in the regulation of appetite and energy homeostasis (see Melanocortin Receptor 4, p. 60) [56,57]. The brain areas containing ACTH also coincide with areas mediating stimulation analgesia, suggesting that expression of ACTH, or another product of the POMC gene (such as b-endorphin) in these sites may regulate pain perception [52]. Outside of the central nervous system, ACTH and other POMC gene products, including a-MSH and b-endorphin, are synthesized in a large number of human tissues, including in descending order of abundance, adrenal, testis, peripheral mononuclear cells, spleen, kidney, ovary, lung, thyroid, liver, colon, and duodenum [58,59]. In most of these tissues, POMC peptides are translated from truncated messenger RNAs lacking signal peptide sequences, suggesting that they cannot be secreted extracellularly [60,61], raising the question of their functional significance. However, adrenal and testis in addition express full length POMC mRNA, suggesting that these tissues may also secrete POMC-related peptides [58]. Recently, several additional cell types have been shown to produce POMC peptides including monocytes [62], astrocytes [63], gastrin-producing cells of the gastrointestinal tract [64], keratinocytes [65], skin melanocytes [66], and atrial myocytes [67]. GENE STRUCTURE ACTH is derived from a 266 amino acid precursor, proopiomelanocortin (POMC), so named because it encodes opioid, melanotropic, and corticotropic activities [68]. The human POMC gene is a single copy gene located on chromosome 2p23 [69]. It and the highly homologous opioid peptides, preproenkephalin A and preproenkephalin B (dynorphin), are all located on different chromosomes [70]. The human POMC gene is 8 kilobases (kb) long (Fig. 2.1). It consists of a promoter of at least 400 basepairs (bp) at the 5¢ end of the gene, followed by three exons, 86 (exon 1), 152 (exon 2), and 833 (exon 3) bp long, and two introns, 3708 (intron 1) and 2886 (intron 2) bp in length [69]. Exon 1 is not translated. Perhaps because of this, exon 1 of the human and other mammalian POMC genes are less than 50% identical. The initiator methionine is located 20 bp into exon 2, and is followed by a 26 amino acid hydrophobic signal peptide. Except for the signal peptide and 18 amino acids of the amino-terminal glycopeptide, the majority of

the POMC precursor is encoded by exon 3 [71]. Exon 2 is close to 90% identical between the POMC genes of humans and other mammals. Within exon 3 of POMC are located all known peptide products of the gene, including N-terminal glycopeptide, gamma-melanotropin (gammaMSH), joining peptide, a-MSH, ACTH, corticotropin-like intermediate lobe peptide (CLIP), b-lipotropin (b-LPH), b-MSH, and b-endorphin. Within exon 3, the regions encoding the N-terminal glycopeptide, a-MSH, ACTH, and b-endorphin, are greater than 95% identical between the human and other mammals [71]. In contrast, joining peptide, the region between the N-terminal glycopeptide and ACTH, is very poorly conserved among mammals [72], which has suggested to some workers that it does not encode a biologically important function [73].

POMC Gene Promoter Structure The promoter of the human POMC gene contains typical TATA and CAAT boxes 28 and 62 bp, respectively, upstream from the transcription start site. Using in vitro transcription [74] and transfection of the human POMC gene into heterologous cells [75], the POMC gene promoter has been shown to contain DNA elements which mediate increased transcription by cyclic AMP and decreased transcription by glucocorticoids. Although these DNA elements have not been precisely localized in the human POMC gene promoter, they are present with in the 700 bp 5¢ to the transcription start site [75]. The rat Pomc gene promoter has been studied more extensively. Drouin and coworkers, using DNA-mediated gene transfer into transgenic mice and tissue culture cells, found that the DNA sequences needed for corticotroph-specific expression and negative transcriptional regulation by glucocorticoid are contained within 543 bp of the transcription start site. These workers have reported the presence of a DNA sequence which mediates negative regulation by glucocorticoids (nGRE), located in the region of the CAAT box, which also binds nuclear proteins of the chicken ovalbumin upstream promoter (COUP) family. Using DNAase footprint and gel retardation analysis of the rat Pomc gene promoter, multiple synergistic DNA elements have been reported to be necessary for correct pituitaryspecific expression of the gene [76]. Recently, these workers have identified NeuroD, Ptx1, and Tpit as transcription factors which cooperate to cause corticotroph-specific expression of POMC [77].

POMC mRNA Transcription, Splicing, and Polyadenylation In addition to the major transcriptional initiation site present in corticotrophs, at least six other start sites have been found in several non-pituitary tissues (Fig. 2.1), including adrenal, thymus, and testes of the human [60] and rat [78]. These sites are all between 41 and 162 nucleotides downstream from the 5¢ and of exon 3. The mRNAs transcribed from

Chapter 2

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FIGURE 2.1. Structure of pro-opiomelanocortin (POMC) gene, messenger RNA (mRNA), and peptide products. (a) schematic diagram of gene (top), mRNA (middle) and POMC peptide (bottom). The gene consists of the promoter, 3 exons (thick bar, 1–3) separated by two exons (thin broken lines). Translated regions are stippled. The mRNA consists of 3 exons and the polyadenylate (AAAA) tail. The POMC precursor can be divided into 3 domains: I (N-terminal glycopeptide, joining peptide), II (adrenocorticotropic hormone; ACTH); and III (b-lipotropin; b-LPH). (b) Structure of individual products of POMC. Individual peptides are enclosed in different boxes depending on proteolytic cleavage specificities: = similar processing in pituitary and brain; = pituitary pattern of processing; = brain pattern of processing. = dibasic amino acids at proteolytic cleave sites. = glycosylation sites. = N-terminal acetylation sites. CLIP, corticotropin-like intermediate lobe peptide; a-MSH, a-melanocyte stimulating hormone.

these sites thus would be intronless, and the only truncated molecules that might be translated would be devoid of a signal peptide, and therefore could not be secreted [78]. Tissues containing these shorter forms of POMC mRNA, including adrenal, testis, spleen, kidney, ovary, lung, thyroid, and gastrointestinal tract, express ACTH, N-terminal glycopeptide1–61, and b-endorphin [58]. These truncated mRNAs are capable of being translated both in cell-free translation systems and in heterologous cells transfected with the appropriate fragment of the human POMC gene, although the peptide products are not secreted [61]. The significance of the expression of these truncated forms of POMC mRNA and their translated peptide products in human nonpituitary tissue is not clear.

A canonical polyadenylation signal is present in human POMC mRNA 23 bases upstream from the poly (A) addition site [79]. The length of the polyadenylate tail, attached to the 3¢ end of POMC mRNA and believed to play a role in translational efficiency of mRNA stability, is much longer in hypothalamic compared with pituitary cells in the rat [78], although this has not been studied in the human. GENE REGULATION In human anterior pituitary corticotrophs, POMC mRNA levels are increased by CRH and inhibited by glucocorticoids [80]. Similar results are seen in normal and adenoma-

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tous corticotrophs, although the glucocorticoid inhibition of POMC mRNA expression is less in the latter cells [80]. The same results are seen in rat anterior pituitary corticotrophs, where the opposing effects of CRH and glucocorticoids are due to their opposite influence on the transcription rate of the POMC gene [81]. Of interest, glucocorticoids have no effect on the POMC mRNA content of rat intermediate pituitary lobe corticotrophs [81]. CRH, acting via the type 1 CRH receptor [82] increases cAMP content in anterior pituitary corticotrophs [83]. CRH, vasopressin, and glucocotricoids all inhibit expression of CRH receptor 1 mRNA [84], which may limit the effect of these agents during the stress response, as discussed subsequently. The CRH-induced rise in cAMP is responsible for both the increase in POMC transcription and peptide synthesis as well as for the rise in intracellular calcium which results in ACTH secretion [85]. CRH mediates its stimulation of POMC transcription via the POMC CRH responsive element (PCRH-RE), which binds PCRH-RE binding protein [86]. The negative effect of glucocorticoids upon POMC gene transcription is thought to be mediated by a glucocorticoid–glucocorticoid receptor complex binding to cis-acting DNA sequences within the POMC promoter, although definitive evidence for this is lacking. The possibility exists that the glucocorticoid receptor complex does not bind directly to the POMC gene, but instead to another protein such as a positive transcription factor, and in this way mediates its negative effect on POMC gene expression [87]. Glucocorticoid stimulates, rather than inhibits, POMC gene expression [88] in the arcuate nucleus of the hypothalamus, the site of alphaMSH production. The significance of this is not clear, but could be involved in the inhibition of appetite by glucocorticoids in the postabsorptive state, when glucocorticoid levels are high. Recently, new insights into the development and regulation of the HPA axis have come from the discovery that leukemia-inhibitory factor (LIF) has an important role in these events [89]. LIF is a cytokine expressed in corticotrophs and folliculostellate cells beginning as early as 14 weeks gestation [90]. LIF stimulates transcription of POMC and expression of ACTH [90]. In many tissues, including pituitary, LIF expression is unregulated by inflammatory stimuli. The LIF receptor is a member of the class I cytokine receptor superfamily which heterodimerizes with gp130. In common with other family members, the LIF receptor signals through the Jak-STAT pathway, particularly utilizing Jak1 and STAT-3 [91]. As with other receptors coupled via these mediators, SOCS-3 inhibits POMC expression following its simulation by LIF [92]. Mice which overexpress a LIF transgene develop Cushing’s syndrome [93]. Their pituitary glands have corticotroph hyperplasia and multiple Rathke-like cysts lined by ciliated cells. Mice with targeted deletion of LIF have secondary adrenal insufficiency [94]. All of these data point towards LIF playing an important role in the regulation of ACTH secretion, perhaps most

importantly by immune and inflammatory stimuli [95]. In addition, the data suggest that LIF might be involved in the pathogenesis of Rathke-cleft tumors. Vasopressin potentiates the action of CRH on ACTH secretion, both in vitro [96] and in vivo [97]. Vasopressin’s effect is mediated by the vasopressin V1b (or V3) receptor and protein kinase C [98]. Despite this positive effect on ACTH secretion, vasopressin has been reported to decrease both basal and CRH-stimulated POMC mRNA levels in anterior pituitary cells [99]. b-adrenergic catecholamines, like CRH, also increase POMC mRNA levels in corticotrophs via a cAMP mechanism [100]. Insulin-induced hypoglycemia also causes an increase in POMC mRNA content in rat anterior pituitary corticotrophs [101,102], but whether this is secondary to an increase in hypothalamic CRH [101], vasopressin [103], or catecholamines [104] is not known. The inhibitory neurotransmitter GABA causes a decrease in POMC mRNA levels in intermediate, but not anterior pituitary corticotrophs [105]. POMC BIOSYNTHESIS AND PROCESSING The human POMC precursor has the potential to encode several overlapping peptides of biological importance (Fig. 2.1). Within the precursor, these peptides are separated from one another by two or more basic amino acids which serve as recognition sites for prohormone cleavage enzymes. In addition, POMC-derived peptides contain potential signals for amidation, glycosylation, acetylation and phosphorylation. Because the nomenclature of the various proteolytic products of POMC has been derived from both peptidemapping studies as well as molecular biological studies in which putative peptides had been predicted from inspection of nucleotide sequences [72], the terminology can be confusing. To avoid confusion, amino acid (aa) positions in this chapter are numbered as superscripts with reference to the 240 aa-long human POMC precursor, formed after removal of the 26 aa-long signal peptide. The 240 aa POMC precursor can be considered to be composed of three domains (Fig. 2.1). Domain I (aa 1–111), the N-terminal domain, encodes the 76 aa long Nterminal glycopeptide1–76 within its first 78 aa, and the 30 aa long C-terminal joining, or hinge, peptide ( JP79–108) within its last 33 aa. The middle Domain II (aa 112–152), 41 aa long, encodes the 39 aa ACTH112–150 peptide, which may be further processed to a-melanocyte stimulating hormone (MSH)112–124. The C-terminal Domain III, termed b-LPH153–240, is 88 aa long. It contains within it the 31 aa long b-endorphin210–240. Besides these peptides, several other products have been identified, although evidence for their existence and/or biological importance in man is not clear [106]. These include gamma1-MSH51–61, gamma2-MSH51–62, and gamma3-MSH51–76 in Domain I, corticotropin-like intermediate lobe peptide (CLIP)130–150 in Domain II, and gamma-LPH153–206 and b-MSH191–206 in Domain III (Fig. 2.1).

Chapter 2

Glycosylation of POMC Within the endoplasmic reticulum (ER), POMC undergoes initial glycosylation. Human POMC is glycosylated solely at two sites in the N-terminal glycopeptide1–76 of Domain I. Carbohydrate is added via an O-linked glycosylation to Thr45 and via an N-linked glycosylation to Asn65.

C-terminal Amidation of POMC Three human POMC products undergo C-terminal amidation [107]. These include N-terminal glycopeptide1–61, JP79–108, and -MSH112–124. In addition, these three products are also present in their Gly-extended forms, which may be incompletely-processed intermediates. C-terminal amidation is common among neuropeptides, and is usually essential for bioactivity [108]. This reaction is mediated by a bifunctional enzyme consisting of peptidylglycinea-amidating monooxygenese (PAM) and peptidly-ahydroxyglycine a-amidating lyase (PAL) activities, which transfer the amino group of a C-terminal Gly to the carboxyl group of the adjacent amino acid. Human PAM/ PAL exists in both a membrane-bound and free cytoplasmic form [109].

N-terminal Acetylation of POMC Two human POMC products undergo N-terminal acetylation. These are (as described below) a-MSH and bendorphin. In humans a-MSH exists predominantly in the nonacetylated form [110]. N-terminal acetylation of ACTH1–13-amide to form a-MSH results in increased melanotrophic activity [111] and decreased corticotrophic activity.

Proteolytic Processing of POMC POMC gives rise to several smaller, biologically active peptide products. These are generated by posttranslational cleavage of POMC by trypsin-like prohormone convertase endopeptidase enzymes which cleave the precursor on the C-terminal side of regions of two or more basic amino acid residues [112]. These basic amino acids are subsequently removed by a carboxypeptidase activity. Some POMC proteolytic products subsequently undergo amidation at their C-terminus or acetylation at their N-terminus, as described above. The posttranslational processing of POMC exhibits a remarkable degree of tissue-specificity, which recently has been postulated to be due to the differential distribution of processing enzymes in the various tissues which synthesize POMC (see below). Proteolytic Processing Enzymes

All proteolytic processing of human POMC occurs at either lys–arg or arg–arg residues (Fig. 2.1). Every lys–arg and arg– arg site within the human precursor is capable of being cleaved in vivo [106], whereas in the mouse and rat, additional arg–lys and lys–lys sequences at the N-termini of

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gamma1-MSH and b-MSH, respectively, appear to be utilized [106]. It is likely that the proteolytic digestion of human POMC at all sites is mediated by either of two structurally related endopeptidases, prohormone convertase 1 (PC1) [113] or prohormone convertase 2 (PC2) [113]. These enzymes, best studied in rodents thus far, are part of a seven member family of subtilisin/kexin-like mammalian proteinases [114], and are distributed specifically within endocrine cells and neurons. Both enzymes are capable of cleaving neuropeptide precursors, including POMC, proinsulin, and proglucagon, at dibasic sites, and each appears to manifest distinct preferences for different sites within the same precursor prohormone, with PC2 able to cleave at a wider selection of available dibasic sites than PC1 [115]. The tissue distributions of PC1 and PC2 mRNAs are distinctly different. PC1 is abundant in approximately 20% of anterior pituitary cells (presumably including corticotrophs), in all intermediate lobe pituitary cells (of the rodent), and in the supraoptic nucleus of the hypothalamus [116]. In contrast, PC2 is absent from the anterior pituitary, but is highly expressed in rodent pituitary intermediate lobe, multiple sites within the central nervous system, including cerebral cortex, hippocampus, and thalamus, and in pancreatic islet cells [116]. The differential tissue-specific distribution of these enzymes matches nicely with the known tissue-specific differences in POMC proteolytic processing (see below), suggesting that PC1 is responsible for the POMC cleavage products found in anterior pituitary corticotrophs, whereas PC2 cleaves POMC in pituitary intermediate lobe (of lower mammals) and in the brain. This suggestion is supported by studies of the differential processing of POMC by PC1 and PC2 [115,116]. Recently, a patient with severe childhood obesity and hyperproinsulinemia with postprandial hypoglycemia has been identified with compound heterozygous mutations in the PC1 gene [117]. The patient presented with multiple endocrine abnormalities including impaired glucose tolerance and postprandial hypoglycemia which has been attributed to the secretion of large amounts of proinsulin given its partial insulin-like action and long biological half-life. She also suffered from hypogonadotropic hypogonadism with primary amenorrhea, but otherwise normal development of secondary sexual characteristics. Ovulation was induced with exogenous gonadotropins, and the patient delivered healthy quadruplets. The pregnancy was complicated by gestational diabetes requiring insulin treatment. She also suffered from mild adrenal cortical insufficiency with complaints of fatigue and excessive daytime somnolence reversed by glucocorticoid administration. The adrenal cortical insufficiency was attributed to defective POMC processing with elevated levels of serum ACTH precursors confirming a role for PC1 in human POMC processing [117]. Following the generation of peptide products by prohormone convertase enzymes, the C-terminal basic amino acids are removed by carboxypeptidase activities. Carboxypeptidase E (Cpe) is required for the excision of paired

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dibasic residues of various peptide prohormone intermediates, including those derived from proinsulin and POMC [118]. The mutation in a strain of hyperproinsulinemic, late-onset obese mouse, the fat/fat mouse, has recently been mapped to the carboxypeptidase E gene [118]. A missense mutation has been identified in the Cpefat allele and these mice demonstrated a 20-fold decrease in Cpe enzymatic activity in pituitaries and isolated islets. The sorting of POMC into secretory granules is probably mediated by a signal “patch” [119], located within the tertiary structure of the molecule, which directs it to the granules. The presence of all POMC processed products in equimolar amounts within secretory granules suggests that this sorting precedes proteolytic cleavage of POMC. This suggestion is supported by data which demonstrates that initiation of proteolytic processing of POMC begins in the trans-Golgi system and continues in secretory vesicles, and is also consistent with data demonstrating localization of PC1 and PC2 within the TGN and/or dense core secretory granules [120]. Since POMC as well as PC1 and PC2 all contain signal peptides and are presumably colocalized throughout the endoplasmic reticulum, prohormone convertase activity must be inhibited in the endoplasmic reticulum and cis-Golgi regions. Proconvertase activity may be regulated by the local intracellular environment of these compartments and/or by control of catalytic activation of prohormone convertase. 7B2 is a small, hydrophobic acidic protein originally isolated from porcine and human anterior pituitary glands [121] that is widely distributed in neuroendocrine tissues [122] and found to associate specifically with PC2 [123]. The 27-kDa 7B2 precursor protein is cleaved to a 21-kDa protein and a small carboxy-terminal peptide (CT peptide) [124]. Interaction of 7B2, particularly the 21-kDa fragment, with proPC2 appears necessary for the generation of mature and active PC2 in the trans-Golgi region [125]. The 7B2 CT peptide is a nanomolar inhibitor of PC2 in vitro, but its role in vivo has not been defined. The role of 7B2 in activating proPC2 has been confirmed in vivo in 7B2-null mice [126]. 7B2-null mice are devoid of PC2 activity and deficiently process islet hormones and Pomc. The mice are hypoglycemic and demonstrate hyperproinsulinemia and hypoglucagonemia. These mice also demonstrate profound intermediate lobe ACTH hypersecretion with minimal conversion of this peptide to a-MSH, resulting in a severe Cushing’s syndrome that causes death by 9 weeks of age [126]. Curiously, PC2 null mice demonstrate similar islet cell dysfunction resulting in hypoglycemia, but do not abnormally produce a Cushingnoid syndrome [127]. This discrepancy suggests additional functional roles for 7B2, which are further suggested by the localization of 7B2 in regions of the brain lacking PC2 [128]. Recently, the suggestion that 7B2 may represent one member of a family of related convertase inhibitor proteins has been proposed with the identification of the protein proSAAS [129]. ProSAAS is a 26 kDa granin-like neuroen-

docrine peptide precursor isolated from rodents and humans with structural similarity to 7B2, including a proline-rich sequence in the first half of the molecule and a C-terminal peptide (SAAS CT peptide) following a dibasic cleavage sequence [129]. Overexpression of proSAAS in AtT-20 cells reduces the rate of Pomc processing and the SAAS CT peptide is a nanomolar competitive inhibitor of PC1, but not PC2 [129]. Tissue Specificity of POMC Processing

In human corticotrophs, POMC is processed predominantly into N-terminal glycopeptide1–76, joining peptide ( JP)79–108, ACTH112–150, and b-LPH153–240 (Fig. 2.1) [130]. Much smaller amounts of a-MSH112–124, CLIP130–150, bendorphin210–240, and a truncated form of N-terminal glycopeptide1–61, also known as “big” gamma-MSH, are also present [107]. There is no evidence for cleavage after arg50, and therefore no evidence for the presence of gamma1MSH51–61 in the human pituitary. JP79–108 exists as both a monomer and homodimer, most likely joined via disulfide bonding between the single Cys87 of two molecules [73]. Although JP79–108 has been postulated to stimulate adrenal androgen steroidogenesis [131], some studies do not support this hypothesis [73]. A function for N-terminal glycopeptide has also not been assigned, although one intriguing study reported that it is capable of stimulating aldosterone release from adrenal cells [130]. Whereas the production of distinct POMC peptide derivatives is clearly segregated between the anterior and intermediate lobes of the rodent, in the human, small, acetylated POMC peptide derivatives colocalize with larger desacetylated POMC peptides in corticotrophs of the anterior pituitary, suggesting that the strict dichotomy between corticotrope and melanotrope POMC processing observed in rodents and other species does not extend to human pituitaries [132]. Levels of desacetyl-a-MSH are elevated in pituitary corticotrophs [133] and plasma [134] of patients with Addison’s disease, Cushing’s disease, and Nelson’s syndrome. Desacetyla-MSH has approximately 75% of the melanotrophic activity as does a-MSH [111], whereas ACTH is only 5% as potent as a-MSH in this regard [111,135]. Because the serum levels of ACTH are 50- to 100-fold higher than levels of desacetyl-a-MSH in patients with Cushing’s disease, Addison’s disease, and Nelson’s syndrome, it is likely that the hyperpigmentation associated with these disorders is largely due to the melanotrophic effect of ACTH, and not MSH. Thus, in human anterior pituitary corticotrophs, the POMC precursor is predominantly cleaved at limited lys–arg sites into two peptides in Domain I (N-terminal glycopeptide1–76 and JP79–108), one peptide in Domain II (ACTH112–150) and one peptide in Domain III (b-LPH153–240) (see Fig. 2.1). As discussed above, human POMC is also expressed in several brain sites outside of the anterior pituitary, predominantly in the arcuate nucleus of the anterior hypothalamus. In these extra-pituitary locations, POMC is

Chapter 2

processed to a greater extent than in anterior pituitary. In brain, ACTH112–150 is cleaved to a-MSH112–124 and CLIP130–150 such that the amount of a-MSH relative to ACTH is 300-fold higher in hypothalamus, telencephalon, and mesencephalon than it is in anterior pituitary [136]. As in anterior pituitary, a-MSH is almost exclusively present in the desacetyl form [50]. Adding additional levels of complexity to the issue of tissue specificity of POMC processing are results from a dopamine D2 receptor (D2R) deficient mouse. Similar to dopaminergic tonic inhibitory control of prolactin expression in lactotrophs, POMC expression in the rodent intermediate lobe is under inhibitory dopaminergic control mediated via D2 receptors [137]. D2R-deficient mice demonstrate mild intermediate lobe hyperplasia accompanied by upregulation of both PC1 and PC2 [138]. These mice present with unexpectedly high levels of ACTH with corresponding adrenal hypertrophy and increases in corticosteroid secretion [138]. The altered prohormone convertase levels in these mice suggest the possibility of dynamic regulation of prohormone processing within specific tissues. HORMONE MEASUREMENT ACTH was one of the first substances to be measured by radioimmunoassay (RIA) [139]. In pioneering work using polyclonal antisera, Berson and Yalow described the measurement of ACTH and related peptides in normal persons and those with ectopic ACTH production by lung cancer [140]. These studies provided among the first data that ACTH was synthesized from larger precursors, which were termed “big” and “big–big” ACTH. The ACTH RIA can be performed on unextracted plasma, but suffers from a limit of sensitivity of approximately 25 pg/ml, and is therefore often unable to detect levels of plasma ACTH in the normal basal range. Radioimmunoassay remained the standard method for the measurement of plasma ACTH until the development of the immunoradiometric assay (IRMA). ACTH IRMAs employ two antibodies, one or both monoclonal, against ACTH. The solution-phase antibody is radiolabeled, and the solid-phase antibody is linked to a bead or other solid support. In general, the ACTH IRMA on unextracted plasma compares very favorably with RIA [141], being more sensitive, more reproducible, and more rapid [142]. Most IRMAs have lower limits of detection of 3–5 pg/ml and coefficients of variation of less than 10% up to 5000 pg/ml [141,142]. Depending on the antigenic specificity of the chosen antibodies, the ACTH IRMA may detect only intact ACTH [141], both ACTH and POMC precursor peptides [143,144], or only POMC precursors [145]. It is essential to know the sequence specificity of any IRMA in clinical use, for some, unlike most polyclonal RIAs, are incapable of detecting ACTH precursors which may be secreted by lung carcinomas [143]. Despite the wide availability of the ACTH IRMA, results from different laboratories are diffi-

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cult to compare because of lack of agreement on a suitable ACTH reference standard. An immunofluorometric assay (IFMA) for ACTH has also been developed [146]. Its sensitivity and accuracy are similar to those of the IRMA. Its principal advantage is its speed and the use of a nonradioactive label which is stable for over 1 year. Plasma assay of POMC products other than ACTH, including b-endorphin [147] and N-terminal glycopeptide, has been suggested as an adjunct in the evaluation of the hypothalamic-pituitary-adrenal (HPA) axis. In general, the levels of these hormones parallel that of ACTH in various HPA axis abnormalities [148]. However, except for use as a screening test for lung carcinoma associated with preferential secretion of N-terminal glycopeptide1–61 or proACTH1–150 [148], such tests are much less helpful than the ACTH IRMA because of the low concentration of other POMC peptide fragments compared with ACTH in most physiologic and pathologic settings. SECRETION OF ACTH: BIOCHEMISTRY AND PHARMACOLOGY Secretion of ACTH from the corticotrophs of the anterior pituitary is mediated by several factors (Fig. 2.2). CRH and vasopressin are the primary secretagogues for ACTH, although a number of other agents may also affect its release, and glucocorticoids are the major negative regulators of ACTH secretion. Once a ligand has bound to its receptor, release of ACTH from the corticortroph is mediated by second messengers through one of four signal transduction pathways, involving either protein kinase A, protein kinase C, glucocorticoids, or the Janus kinase/STAT system. (This

–

CRH

AVP

Catecholamines IL1β IL-6 TNFα

+

–

Cortisol

ACTH

Adrenal

+

+

LIF IL-6 IL1β TNFα

CRH IL1β IL-6 TNFα

FIGURE 2.2. Control of adrenocorticotropic hormone synthesis and secretion.

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last pathway, regulated by LIF, was described in a previous section, p. 50.) These pathways result in changes in the phosphorylation pattern of specific cellular proteins, and/ or in intracellular calcium levels, impacting on ACTH synthesis and release. Circulating ACTH then binds to receptors, primarily in the adrenal gland, leading to steroid biosynthesis.

Second Messenger Regulation of ACTH Secretion Protein Kinase A Pathway

CRH stimulates ACTH release via the cAMP-protein kinase A pathway. CRH stimulates adenylate cyclase activity, which then increases cAMP [83]. Forskolin, a direct stimulator of adenylate cyclase activity, and 8-bromo-cAMP, a cAMP analog, both markedly stimulate ACTH release, and increase CRH-stimulated ACTH release, but do not potentiate ACTH release from cells maximally stimulated by CRH [149]. The CRH-stimulated increase in cAMP activates cAMP-dependent protein kinase A [83]. Protein Kinase C Pathway

AVP V1b and V2 receptors are coupled to different second messenger systems. V1 receptors in the pituitary mobilize calcium through activation of phospholipase C, whereas V2 receptors activate adenylate cyclase, increasing cAMP [150]. AVP-stimulated ACTH release is mediated via the protein kinase C pathway [151]. Evidence that AVP acts through the protein kinase C pathway in the anterior pituitary includes the finding that AVP stimulates accumulation of inositol phosphates in rat anterior pituitary cells [152]. Phorbol esters, which activate protein kinase C directly by substituting for diacylglycerol and binding to protein kinase, induce ACTH release in rat pituitary cell cultures. Activation of protein kinase C appears more important in the sustained phase of AVP-stimulated ACTH release, not in the initial phase [153].

CRH CRH Stimulation of ACTH Secretion

Perfused human fetal pituitaries and cultured human fetal pituitary cells in culture secrete ACTH in response to CRH [2]. Rats have been used extensively in the study of ACTH secretion, as it is difficult to culture human corticotroph cells in vitro. In dispersed rat anterior pituitary cells, CRH stimulates a ninefold increase in ACTH release that is sustained for as long as the cells are exposed to CRH [83]. Even with maximal CRH stimulation, only 6% of cultured pituitary cells release ACTH [154]. CRH stimulates ACTH synthesis as well as release. In humans, the biphasic response may reflect secretion of a ready pool of ACTH, followed by later release of newly synthesized protein [155]. Exposing cells to CRH for a long period of time results in an increase in ACTH in the cell and in the medium. Thus, the sustained phase of ACTH

secretion may represent later release of newly synthesized ACTH peptide. Most of the CRH released into the hypophyseal blood is derived from the PVN [156]. Concentrations of oCRH that are similar to the concentrations of CRH found in rat portal plasma have been shown to increase secretion of ACTH in human fetal hemipituitaries in vitro [157]. The CRH content in the hypophyseal portal blood of anesthetized male rats is about 100 pM [158], which exceeds the in vitro threshold of 10–20 pM CRH to stimulate ACTH release [159]. In addition to stimulating ACTH expression and release, CRH can also directly stimulate secretion of glucocorticoids from the adrenal gland [160]. CRH Receptors

In human pituitaries, CRH has been shown to bind to sites in the anterior lobe [161]. The distribution of binding sites in human pituitary correlates with the distribution of corticotrophs [161]. CRH receptors in the anterior pituitary gland are low capacity, high affinity receptors, with a Kd for CRH binding of about 1 nM [162]. To date, two CRH receptor genes have been identified in humans and other mammals [163–165], with a third additional one being described in the catfish [166]. The type 1 receptor [163,165] is expressed predominantly in anterior pituitary corticotroph cells, whereas the type 2 receptor [164] is more widely distributed in the brain and periphery, particularly in cardiovascular tissue. The type 1 receptor binds and is activated by both CRH as well as the CRH-like peptide, urocortin [167]. This receptor mediates the actions of CRH at the corticoctroph. In addition, the type 1 receptor mediates fear and anxiety behaviors following stressors, even in CRHdeficient mice [168]. Mice with deletion of the CRH type 1 receptor gene show reduced fear and anxiety [169]. These data suggest that a CRH-related peptide, possibly urocortin or another unknown member of the CRH family, mediates fear responses via the CRH type 1 receptor. The CRH type 2 receptor binds urocortin with over 20-fold higher affinity compared to CRH. Its distribution, along with the hypotensive cardiovascular response to infused urocortin which is abolished in CRH type 2 receptor-deficient mice [170], suggests that the receptor may be involved in blood pressure control. This may underlie the hypotension observed during the CRH stimulation test. Recently, a nonpeptide, type 1-specific CRH antagonist has been developed which is orally active [171,172]. It should help to elucidate the role of CRH in ACTH regulation and other pathways.

AVP AVP Stimulation of ACTH Secretion

In rat anterior pituitary cells, AVP causes a twofold increase in ACTH release [173]. AVP elicits an initial rapid release of ACTH, observable within 5 seconds, reaching a maximum in less than 1 to 2 minutes, and lasting less than 3 to 6 minutes. This is followed by a second phase lasting

Chapter 2

for several hours. In humans, AVP infusion by itself has only a small effect on ACTH release. AVP is synthesized in the same parvocellular hypothalamic paraventricular nuclear neurons which express CRH, and appears to be coreleased with CRH at the median eminence into the portal hypophyseal system [174]. However, a substantial amount of AVP in the portal blood is released from projections from the supraoptic nuclei in the median eminence [156]. AVP from the posterior pituitary may also reach the anterior pituitary through portal vessels that connect the two [175]. This raises the possibility that increased vasopressin secretion from the posterior pituitary, in response to hyperosmolality, may also stimulate ACTH secretion. AVP Receptors

A single population of specific AVP receptors have been identified in rat anterior pituitaries, which are distinct from CRH receptors [176]. Most corticotrophs have AVP receptors, since 80% of the ACTH-secreting cells in the pituitary bind AVP [176]. The anterior pituitary AVP receptors are distinct from the V2 renal receptors and the V1 hepatic/pressor receptors [150]. This has led to the classification of hepatic/pressor receptors as V1a receptors and anterior pituitary receptors as V1b [150], or V3, receptors. V1a, V1b, and V2 receptors can be distinguished by their patterns of recognition of AVP analogues [177]. V1a binding sites in the rat anterior pituitary have a Kd of about 1 nM, and the minimal effective dose of AVP is 0.1 nM [173]. dDAVP (desmopressin), an AVP analog with V2 receptor affinity, has an insignificant effect on plasma ACTH levels, though it does increase, but is not additive to, CRHstimulated ACTH release [178]. During the past 6 years, the genes for all three vasopressin receptors (V1a, V2, and V1b) have been identified [179]. They are highly related members of the 7 transmembrane, G protein coupled, receptor family. As anticipated, V1b receptor mRNA is highly expressed in anterior pituitary corticotrophs, and is coupled to stimulation of POMC gene expression and ACTH secretion via the protein kinase C pathway [180,181].

Modulators of CRH and AVP Release CRH is the most important physiologic ACTH secretagogue [182]. Stressors, endogenous circadiam rhythms, and glucocorticoids influence CRH release [183]. In the rat, afferent inputs to the PVN may mediate the action of stressors by controlling the release of CRH [183]. Sources of neuronal afferents to the hypothalamus include the amygdala and hippocampus of the limbic system, and brainstem regions involved in autonomic functions [184]. In rats, acetylcholine, norepinephrine, angiotensin II, and possibly CRH itself, increase CRH concentrations in the hypophyseal portal plasma. On the other hand, AVP, b-endorphin, and GABA inhibit the ACTH response to stress [182,185–187].

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In rodents, central catecholamines stimulate ACTH release, and the effects of catecholamines on ACTH secretion appear to be mediated via secretion of CRH, and possibly AVP, into the hypophyseal portal circulation [188]. However, in humans, catecholamines have little direct effect on ACTH secretion from the pituitary. Peripheral catecholamines, increased by a variety of stresses, do not cross the blood–brain barrier to reach the hypothalamus, but do reach the pituitary, yet do not increase basal or CRHstimulated plasma ACTH levels. This suggests that the increased peripheral levels of epinephrine and norepinephrine generated during stress are probably not responsible for the increase in ACTH, and that catecholamines do not act directly on the pituitary to stimulate ACTH release [189]. In humans and other intact mammals, the impact of angiotensin II on basal or CRH-stimulated ACTH release is unclear. In humans, infusion of angiotensin II alone does not increase ACTH release [178]. However, in dispersed rat anterior pituitary cells, angiotensin II does stimulate release of ACTH [190]. Angiotensin II has a synergistic effect with CRH in stimulating ACTH release in humans in vivo [178]. Angiotensin II potentiates CRH-stimulate ACTH release from cultured anterior pituitary cells [191], although it is less effective than AVP, and potentiates the CRH-stimulated increase in cAMP. Angiotensin II and AVP do not potentiate each other’s effect on ACTH release, suggesting that they act via the same mechanism. Interleukin-1 beta stimulates ACTH release in conscious rats by acting on the hypothalamus [192] to induce secretion of CRH [193,194]. Interleukin-1 does not cross the blood–brain barrier [195], but activates noradrenergic neurons in the brainstem and hypothalamus, which may stimulate CRH secretion, especially in the median eminence. Prostaglandins may be involved in the response to interleukin-1, since ibuprofen, which blocks the formation of prostaglandins, blocks endotoxin-induced ACTH release in humans [196]. Tumor necrosis factor is a potent secretagogue for ACTH, and when administered to human subjects, leads to an increase in ACTH, cortisol, and AVP [197], but inhibits CRH-, AVP-, and angiotensin II-stimulated ACTH secretion [198]. Tumor necrosis factor may stimulate ACTH secretion by stimulating CRH release from the hypothalamus [199]. However, there is evidence that the site of action of tumor necrosis factor is peripheral to the pituitary and hypothalamus [199]. Bacterial endotoxin, when administered to human subjects, increases ACTH, cortisol, and AVP release [196]. Tumor necrosis factor may mediate the hormonal responses to endotoxin, since tumor necrosis factor levels increase after endotoxin administration [200]. Endotoxin does not increase ACTH release from cultured rat adenohypophyseal cells [201]. In rats and humans, interleukin-6 leads to ACTH secretion via CRH-dependent [202] and CRH-independent pathways, most likely via a prostaglandin-dependent pathway [203]. GABA inhibits the secretion ACTH by inhibiting

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the release of CRH and possibly AVP [184]. GABAnergic inputs into the PVN of the hypothalamus have been characterized in animals, including inputs from the hippocampus [184]. Opiates and opiate agonists decrease ACTH secretion, and may tonically inhibit ACTH secretion [204–211], although some studies demonstrate no effect of naloxone, an opiate antagonist, on the basal levels of cortisol [212,213]. Opiates inhibit CRH- and AVP-stimulated ACTH release, and different opiate agonists differentially effect CRH- versus AVP-stimulated release [214]. In humans, morphine blunts CRH-stimulated ACTH release without decreasing AVP or catecholamine levels [214]. Modulation of CRH-stimulated ACTH secretion by opiates most likely occurs at a level above the corticotroph [214]. Met-enkephalin analogs inhibit ACTH secretion, and controversy exists as to whether inhibition occurs at the hypothalamus or pituitary. In humans CRH-induced ACTH release is almost completely abolished with pretreatment with a met-enkephalin analog [215].

Synergism Between CRH and AVP Alone, AVP is a less important physiologic ACTH secretagogue than CRH [182]. AVP potentiates CRH-stimulated release of ACTH from cultivated rat anterior pituitary cells by twofold. When cells are first exposed to CRH, reaching the sustained phase of CRH-stimulated ACTH release, and AVP is then added, the usual initial spike of AVP-stimulated ACTH secretion is superimposed on top of the CRHinduced plateau of secretion. Despite continued exposure to AVP, ACTH secretion decreases down to the level of the plateau phase of CRH-stimulated secretion [216]. In cells exposed to AVP before CRH, CRH does not potentiate AVP-stimulated ACTH secretion [216]. This, together with the presence of AVP and CRH in the same parvocellular neurons of the PVN, suggests that the two neuropeptides cooperate to regulate ACTH release. However, this remains to be proven in humans, as there are no examples of persons with defects in AVP synthesis or release who have impaired ACTH secretion.

Oxytocin In humans, low-dose oxytocin perfusion decreases plasma ACTH and cortisol levels [217], and infusion of oxytocin completely inhibits CRH-stimulated ACTH release [218]. Oxytocin acts via a similar mechanism as AVP. Oxytocin binds competitively to AVP receptors in the anterior pituitary [219], but is much weaker than AVP at stimulating ACTH release [220]. Like AVP, oxytocin stimulates ACTH secretion through the protein kinase C pathway.

Glucocorticoids Glucocorticoids are the primary negative regulators of ACTH secretion. Glucocorticoids act on corticotrophs to

inhibit the secretion of ACTH induced by AVP and CRH, the synergism between CRH and AVP, and substances that provoke production of inositol phosphates and cAMP. Glucocorticoids’ negative impact on ACTH regulation is also due to their inhibition of the principal stimulators of ACTH, CRH and AVP. In the rat, glucocorticoid receptors are widely distributed in the brain, including the PVN. The PVN is a site for glucocorticoid negative feedback, since dexamethasone decreases the amount of basal CRH in the hypothalami explant and in the PVN, and the CRH response to secretagogues like serotonin and to stress. Glucocorticoids inhibit CRH release and decrease intracellular CRH in the rat PVN [182], and dexamethasone has a local effect on the hypothalamus, decreasing CRH mRNA expression [221], and preventing the rise in intracellular of CRH and AVP usually seen after adrenalectomy [183]. Glucocorticoids increase, and adrenalectomy decreases, the amount of GABA in the hypothalamus and the hippocampus [222]. Glucocorticoids appear to feedback to increase the GABA activity of the hippocampus and hypothalamus, and thus inhibiting CRH release [222]. In the anterior pituitary, glucocorticoid inhibition of ACTH secretion in vitro is mediated via glucocorticoid receptors, and lack of glucocorticoid effect in the intermediate lobe of the pituitary is most likely because functional receptors are not present in these cells. The negative effect of glucocorticoids on CRH-, AVP-, angiotensin II-, and norepinephrinestimulated ACTH release [223] is biphasic, which may reflect an initial inhibition of ACTH release, followed by an inhibition of POMC biosynthesis. Glucocorticoids inhibit POMC secretion, gene transcription and mRNA levels in the anterior pituitary. EFFECTS OF POMC-DERIVED PEPTIDES IN SKIN AND ADRENAL The melanocortin receptors are a family of seven transmembrane-spanning, G-protein coupled receptors that are activated by melanocortin derivatives of POMC including a-MSH and ACTH. Activation of all five receptors results in adenylate cyclase activity and cAMP production. Cloning of the melanocyte MSH receptor (melanocortin 1 receptor–MC1R) [224,225] and the adrenal ACTH receptor (melanocortin 2 receptor–MC2R) [225] were quickly followed by the cloning of three additional family members. The five known melanocortin receptors show distinct tissue distributions throughout the nervous system and periphery and distinct selectivities for the various melanocortin peptides. Prior to the cloning of this receptor family, the actions of melanocortins were primarily known through the effects of MSH on pigmentation and the effects of ACTH on glucocorticoid secretion from the adrenals. However, many additional roles including cognitive and behavioral effects, effects on the immune system, and effects on the cardiovascular system have also been attributed to the melanocortins.

Chapter 2

With the cloning of this family of receptors, the physiologic roles of ACTH, MSH and other melanocortin derivatives are beginning to be elucidated.

Ligand Specificity The pharmacology of melanocortin receptor activation with a large number of natural and synthetic melanocortin peptides is the subject of extensive investigation. All five melanocortin receptors are activated by ACTH. However, MC2R binds only ACTH and is not activated by other melanocortin peptides [226]. The synthetic agonist 4norleucine, 7-D-phenylalanine-a-MSH (NDP-MSH) is the most potent agonist of MC1R, MC3R, MC4R, and MC5R [227,228]. The endogenous non-ACTH melanocortin peptides generally bind the melanocortin receptors with an order of potency MC1R > MC3R > MC4R > MC5R when expressed in COS cells and measurements are obtained in competition with NDP-MSH [228–232]. g-MSH is relatively selective for MC3R over MC4R and MC5R [228,233]. Whether the differences in melanocortin receptor specificity for different melanocortin ligands are physiologically relevant are unknown. Interestingly, Org 2766 and BIM 22015, two ACTH4-10 analogs, have no activity at any of the cloned MCRs, but have potent effects on central and peripheral nervous systems suggesting the possibility of undiscovered melanocortin receptors [234,235].

Melanocortin 1 Receptor The MC1R was initially cloned from primary melanoma tumors [224,236]. MC1R gene expression has also been confirmed in primary human melanocytes by northern blotting [236]. Other cutaneous cells including keratinocytes [237] and dermal fibroblasts [238] have also been reported to express MC1R, although the presence of MC1R mRNA [239] and MC1R protein [240] in keratinocytes could not be confirmed in other studies. Recent evidence demonstrates that the MC1R is expressed in keratinocytes and that its expression is induced by calcium and UV light treatments [241]. Corresponding to its expression in the skin, its function is perhaps most fully understood with respect to its role in cutaneous pigmentation (for review see [242]). Activation of melanocyte MC1R, via activation of adenylate cyclase, stimulates tyrosinase activity, the rate-limiting enzyme in melanogenesis [239]. The activation of tyrosinase results in an increased proportion of eumelanin (brown–black pigment) formation over pheomelanin (red–yellow pigment) formation resulting in increased pigmentation [243]. Mutations and variant alleles in the MC1R gene have been linked to variation in mammalian pigmentation. The extension locus has long been known to regulate pigmentation in mammalian species. The extension locus has been shown to encode the mouse MC1R [244]. The recessive yellow allele (e) at this locus results from a frameshift that produces a prematurely terminated, nonfunctioning recep-

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tor [244]. The sombre (Eso and Eso–3j) alleles and tobacco darkening (Etob) alleles, which have dominant melanizing effects, result from point mutations that produce constitutively active or hyperactive receptors [244]. The human MC1R is highly polymorphic, and mutant alleles have been associated with fair skin and blond or red hair [245–247]. Analysis of five naturally occurring common variants of MC1R associated with fair skin and red hair have revealed decreased stimulation of cAMP synthesis with no changes in or only slightly reduced aMSH binding [248]. In addition, MC1R variants have recently been shown to determine sun-sensitivity in humans with dark hair [249]. Melanocytes, which express POMC and several of its processed peptides [250,251], are derived from the neural crest [29]. It is likely that a-MSH produced via POMC expression in melanocytes is responsible for the pigmenting effects of ultraviolet light, and together with variations in MC1R discussed above, for the different degrees of skin pigmentation observed among ethnic groups. MC1R mRNA [252] and protein [253] have been detected in Leydig cells of the testis, luteal cells of the corpus luteum, and in the placenta. In the central nervous system, detection of MC1R mRNA and protein has been confined to a few scattered neurons of the periaqueductal grey in rat and human brains [254]. With the cloning of the melanocortin receptors, the role of melanocortins as anti-inflammatory agents has gained renewed interest [255–257]. Systemic administration of a-MSH has been shown to be beneficial in animal models of arthritis [258], adult respiratory distress syndrome (ARDS) [259], and septic shock [260]. Consistent with this role, MC1R expression has been documented on macrophages and monocytes [261,262]. Treatment of activated macrophages with a-MSH resulted in decreased nitric oxide production by inhibiting the induction of nitric oxide synthase II [262]. Lipopolysaccharides (LPS) and interferon treatments of neutrophils induced increases in neutrophil MC1R mRNA and treatment with a-MSH inhibited neutrophil chemotaxis by a cAMP dependent process [263]. Constitutive expression of MC1R has also been found on dermal microvascular endothelial cells where its expression can be increased by stimulation with IL-1b or a-MSH itself [264]. A potential role for melanocortins to regulate local inflammation in the brain has been proposed based on the evidence that tumor necrosis factor (TNF)-alpha secretion by an anaplastic astrocytoma cell line (A-172) is decreased by aMSH and that these cells express MC1R [63].

Melanocortin 2 Receptor—the ACTH Receptor Eary in the study of receptor biology, Haynes demonstrated the action of ACTH in generating cyclic adenosine monophosphate (cAMP) in adrenal cells [265]. The ACTH receptor was the first receptor that was shown to bind its ligand with high affinity and specificity [266]. In human adrenal glands, the ACTH receptor has a Kd of 1.6 nmol/l

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and about 3500 sites/cell [267]. The ED50 of ACTH for cAMP production is 0.11 nmol/l, 20-fold less than the Kd for binding [267]. The ED50 of ACTH for cortisol production is 2 pmol/l, 720-fold less than the Kd for ACTH binding, and 35-fold less than the concentration of ACTH needed to obtain a half-maximal increase in cAMP production [267]. Only a small percentage of ACTH receptors need to be occupied to achieve a maximal effect on steroidogenesis, which occurs at an ACTH concentration of 0.01 nmol/l [268,269]. Because the adrenal gland may express more than one of the five melanocortin receptors (see below) it is not possible to assign the biochemical characterizations to a specific melanocortin receptor. The human ACTH receptor (MC2R) was cloned based on its homology to MC1R [225]. In situ hybridization with the adrenal gland of the rhesus monkey demonstrated the presence of messenger RNA in the zona glomerulosa and fasciculata cells, and a weaker signal in the zona reticularis [225]. Initial attempts at characterizing the ligand specificity and cAMP signal generation in response to ACTH and other melanocortins was confounded by either poor levels of expression or the presence of endogenous melanocortin receptors in transfected cells [225,270,271]. Recently, the human MC2R has been stably transfected into the Y6 cell line, a mutant derived from the mouse Y1 adrenocortical cell line, that fails to express any endogenous MC2R [272]. Y6 cells alone demonstrated no cAMP response to micromolar ACTH, and MC2R transfected cells displayed an EC50 of 6.8 nmol/l [272].

Adrenal Actions of Acth The critical role of ACTH in regulating the synthesis and secretion of steroids from the adrenal gland has long been recognized. In adrenocortical cells, ACTH regulates lipoprotein uptake by receptor-mediated endocytosis from the plasma to lipid droplets by stimulation of lipoprotein receptors [273]. Within the lipid droplets, ACTH regulates hydrolysis of cholesterol esters by activation of cholesterol esterases or suppression of cholesterol acyltransferase, through cAMP-dependent protein kinase [274]. ACTH stimulates the transport of cholesterol to the mitochondria [275–277], principally via stimulation of steroidogenic acute regulatory protein (StAR) [278]. The rate-limiting step in steroidogenesis is the side-chain cleavage of cholesterol to pregnenolone, and is catalyzed by cytochrome P450-side chain cleavage enzyme [279] in the inner membrane of mitochondria of the adrenal [280], probably on the matrix side [281]. ACTH stimulation results in long-term and short-term effects on steroid hormone biosynthesis in the mitochondria [282]. The long-term effect of ACTH leads to an increase in the amounts of steroid hormone enzymes by increasing transcription of these genes [282]. StAR is the key protein which regulates cholesterol transport into the mitochondion [278]. Mutations in this protein result in defects in adrenal and gonadal steroidogenesis, which had been previously attributed to defects in side chain cleavage

enzyme activity [278]. Beginning several hours after ACTH administration, ACTH increases the levels of steroidogenic enzyme mRNAs in primary cultures of human adrenals by several-fold, including cholesterol side chain cleavage enzyme, 17-a-hydroxylase/17,20-lyase, 11-b-hydroxylase/ 18-hydroxylase/18-methyl-oxidase, and 21-hydroxylase cytochrome P-450 enzyme [283]. ACTH has a positive regulatory effect on its own receptors, and on the cAMP response to binding of ACTH to the receptor [284]. With sustained stimulation, down-regulation does occur, but physiologically this effect is minor since ACTH causes proliferation as well as steroid secretion. In addition to its prominent role in regulating adrenal steroidogenesis, ACTH exerts profound trophic effects upon the adrenal. Hypophysectomy results in adrenal atrophy and ACTH replacement restores adrenal gland weight in a dosedependent manner [285–288]. While the role of ACTH in adrenal hypertrophy is well established, its role in adrenocortical mitogenesis and hyperplasia is incompletely understood. The absence of ACTH induces apoptotic cell death in the adrenal cortex [289]. Prolonged ACTH administration not only blocks apoptosis, but also increases the adrenal DNA content in the rat [290], ACTH increases mRNA levels for c-fos and b-actin, proteins involved in cellular proliferation [291]. However, ACTH paradoxically inhibits mitosis of adrenocortical cells in culture [292–294]. ACTH antiserum administered to intact rats caused a highly significant decrease in corticosterone levels, but had no effect on adrenal weight [295]. Furthermore, ACTH inhibits the rapid compensatory proliferation of the remaining adrenal that normally occurs after unilateral adrenalectomy [296]. Another anterior pituitary-derived candidate for the stimulation of adrenal proliferation is the 28 amino acid Nterminal pro-opiomelanocortin peptide (N-POMC). This peptide is mitogenic in vitro and in vivo for the adrenal cortex, and N-POMC antiserum significantly diminishes adrenal mitotic activity after enucleation [297,298]. The compensatory adrenal growth that occurs after unilateral adrenalectomy may be mediated by a neural reflex that includes afferent neurons originating from the disrupted adrenal gland, the ventromedial nuclei of the hypothalamus, and efferent neurons innervating the remaining gland [299,300]. In 1947, Albright coined the term adrenarche to denote the developmental increase in adrenal androgens that occurs several years before the onset of gonadal maturation [301]. Adrenal androgen secretion may be sufficient for the development of some secondary sexual changes, including the development of pubic and axillary hair [302] and the maturation of sebaceous glands [303]. A condition in which axillary and pubic hair develop prematurely as a result of early adrenal androgen secretion has been termed premature adrenarche [304–309]. The mechanisms controlling adrenarche have remained obscure. Many hypotheses have been advanced, and many factors including ACTH, estrogens, prolactin, gonadotropins, growth hormone, glucocorticoids, androgens, and other POMC-derived products have been

Chapter 2

suggested as modulators of adrenal androgen secretion (for review see [310]). ACTH is widely accepted as a modulator of adrenal androgen secretion although, after administration of corticotropin, increases in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) tend to be small [311–313]. Furthermore, the increase in adrenal androgens that occurs in adrenarche is not accompanied by an increase in serum cortisol levels, leading to the suggestion that factors other than ACTH are responsible for adrenarche [307,309,314,315]. However, cortisol production rates do increase at the same time as does the increase in adrenal androgen secretion, suggesting a possible common link that could be due to ACTH stimulation of both steroid pathways [316]. Dissection of the physiology of adrenarche has proven difficult as the only animal showing an adrenarche similar to that of humans is the chimpanzee [317]. Recent data from patients with genetic defects in MC2R provide definitive evidence of the participation of this receptor in the process of adrenarche, as discussed subsequently. Familial Glucocorticoid Deficiency Syndrome

The familial glucocorticoid deficiency (FGD) syndrome is a rare autosomal recessive syndrome originally described by Shepard et al. in 1959 [318]. Patients typically present with symptoms resulting from their glucocorticoid insufficiency including hyperpigmentation, hypoglycemia, lethargy, and weakness [318–321]. The clinical course may be complicated by frequent infections [318,319]. Patients with FGD do not present with symptoms related to salt wasting, dehydration, or electrolyte disturbances, as the renin-aldosterone axis is preserved. The preservation of the renin-aldosterone axis clearly distinguishes this syndrome from childhood Addison’s disease. An unexplained feature of the syndrome is that many of the patients are reported to be unusually tall [318,319,321–325]. Patients with FGD typically have low or undetectable cortisol concentrations, but occasionally low, normal cortisol values, which respond subnormally to exogenous corticotropin [318,319,321–325]. Plasma ACTH levels are markedly elevated, often greater than 1000 pg/ml. The adrenal glands are atrophic, and only occasional cortical cells remained in the zona glomerulosa with no remnants of the zona fasciculata or reticularis, but the adrenal medulla appears normal [318,319,323]. This adrenal atrophy substantiates the physiologic relevance of ACTH’s trophic action on the adrenal gland. Recently, an examination of 11 patients with FGD revealed a discrepancy between partial glucocorticoid deficiency and significantly diminished DHEAS secretion confirming a significant contribution for ACTH (or at least for MC2R) in the onset of adrenarche [326]. A number of different homozygous or compound heterozygous missense and nonsense mutations in MC2R have been reported in patients with FGD, and in all cases, these mutations cosegregate with disease in the affected families [322,327–331]. Transient expression of the S741 mutant MC2R (ser74 Æ ile) in COS-7 cells resulted in a EC50 for cAMP production of 67 nmol/l, approximately 12-fold

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higher than the EC50 of the normal MC2R of 5.5 nmol/l. Expression of a Asp107 Æ Asn mutation in Cloudman S91 melanoma cells resulted in a six- to ninefold increase in the EC50 for cAMP generation. These results were confounded by endogenous melanocortin receptors making it difficult to determine whether the mutant receptor demonstrated defective ligand binding or defective coupling to adenylate cyclase [328]. Not all cases of the FGD syndrome can be accounted for by mutations in MC2R. Several families exhibiting the classic FGD signs and symptoms have no mutations in the coding regions of the MC2R gene [322,328,332,333]. These patients are clinically indistinguishable from patients with MC2R mutations except that they do not demonstrate increased height [334]. Recently, linkage of this form of FGD to a 12-cM region surrounding MC2R has been excluded in six families [332]. FGD, with ACTH resistance, also occurs in the Allgrove, also known as triple A (adrenal insufficiency, achalasia, and alacrima) syndrome [335]. Mutations in MC2R do not cause the resistance to ACTH. Recently, a novel gene, AAAS, has been identified on chromosome 12q13 in which several homozygous or compound heterozygous loss-of-function mutations are associated with this syndrome, in nine unrelated families [336,337]. This protein must in some way interfere with the expression or function of MC2R. ACTH-independent Activation of ACTH Receptor Pathways

Several rare causes of ACTH-independent Cushing’s syndrome are due to ACTH-independent pathological activation of ACTH receptor pathways. In the McCune-Albright syndrome, a mutation in the GTPase region of the stimulatory alpha subunit G protein, Gsa, can result in constitutive activation of protein kinase A in the adrenal cortex, leading to hypersecretion of cortisol and adrenal adenoma formation [338,339]. Ectopic expression of several other transmembrane G protein-coupled receptors, including those which bind gastric inhibitory polypeptide, luteinizing hormone, vasopressin, and catecholamines, in the adrenal cortex, may occur [340]. In this situation, Cushing’s syndrome results from the cognate hormone binding to the ectopically expressed receptor, leading to stimulation of adenylate cylase, activation of cyclic AMP, and cortisol hypersecretion [340]. Finally, patients with mutations in the regulatory subunit of protein kinase A, R1a, may develop Cushing’s syndrome secondary to micronodular adrenocortical hyperplasia [341,342]. This disorder, termed Carney complex, may be associated with myxomas of the cardiac atria and other tissues, and freckling of the skin [343]. EFFECTS OF POMC-DERIVED PEPTIDES OUTSIDE OF ADRENAL ACTH binds with high affinity to rat adipocytes and has potent lipolytic effects [344–347]. High levels of MC2R mRNA expression have been demonstrated in all murine

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adipose tissues examined, but MC5R mRNA expression was also found in a subset of these tissues [348]. Both MC2R and MC5R mRNA were identified in the 3T3-L1 cell line after these cells were induced to differentiate into adipocytes. The physiologic importance of the actions of melanocortins on adipose tissue is unclear. Primate adipose tissues have been reported to be insensitive to the lipolytic actions of ACTH [349]. MC2R mRNA expression was not detected in human adipose tissue [252]. In order to examine whether the MC2R might play roles in the hypothalamic–pituitary–adrenal axis in sites other than the adrenal gland, MC2R expression has been examined in the hypothalamus and the pituitary. MC2R mRNA could not be detected in the hypothalamus or the pituitary [350]. The expression of an ACTH receptor on human mononuclear leukocytes was suggested after a finding that high-affinity ACTH binding did not occur in a patient with FGD [351]. However, this finding is puzzling in retrospect as MC2R mRNA expression has not been demonstrated in leukocytes. Human skin cells express MC2R along with mRNA for three obligatory enzymes of steroid synthesis, the cytochromes P450scc (CYP11A1), P450c17 (CYP17), and P450c21 (CYP21A2) [352]. Slominski et al. have hypothesized that an equivalent of the HPA axis composed of locally produced CRH, CRH-receptor, POMC, and cortisol operate in mammalian skin as a local response to stress [353]. Recently, it was demonstrated that ACTH can induce DNA synthesis and cell proliferation in an oral keratinocyte cell line [354].

Melanocortin 3 Receptor Expression of the third cloned melanocortin receptor, MC3R, was originally identified in the brain, placenta, and gut [355]. Subsequently, MC3R expression was also documented in the heart [252]. Detailed mapping of the MC3R in the central nervous system by in situ hybridization localized the highest densities of MC3R mRNA to the hypothalamus and limbic system [356]. MC3R mRNA was found in the arcuate nucleus [356], the site of POMC expression within the hypothalamus. An autoradiographic approach using the non-selective [125I]NDP-MSH in competition with the relatively MC3R selective g-MSH or an MC4R selective synthetic agent HS014 has been used to visualize the MC3R and MC4R distributions within the central nervous system [357]. In the nucleus accumbens shell, the medial preoptic area, and the ventromedial nucleus of the hypothalamus, the MC3R dominates. In the lateral septum and the olfactory tubercle, both MC3R and MC4R seem to be present. The lack of overlap between the autoradiographic data and the data concerning MC3R mRNA expression may indicate the presence of MC3R on nerve terminals projecting from the arcuate nucleus. A physiologic role for MC3R has not yet been identified.

Recently, in a murine model of experimental gout, systemic treatment of mice with ACTH4–10 inhibited neutrophil accumulation [358]. This effect was blocked by he melanocortin receptor type 3/4 antagonist SHU9119. MC3R, but not MC4R, mRNA was detected in murine macrophages suggesting that MC3R may play a role in modulating inflammation. Recently, a mouse with targeted deletion of the MC3R gene has been created [359]. Although this mouse has a normal body weight, it has an increased fat to lean weight ratio, which seems to be due to an increased efficiency of converting ingested food into stored fuel. Thus, a function of melanocortins acting via MC3R may be to promote the conversion of energy in food into either lean body mass or forms of energy other than fat. This raises the possibility that in humans, mutations in MC3R may contribute to the “thrifty” genotype, as is found in Pima Indians [360].

Melanocortin 4 Receptor The MC4R is localized to the brain [361] and, in contrast to the MC3R, its expression has been documented throughout the central nervous system including the cortex, thalamus, hypothalamus, brainstem, and spinal cord [362]. In humans, the MC4R has not been detected in any peripheral tissue [252], although this distribution does not hold true for all animals as the MC4R is expressed in many peripheral tissues of the chicken [363]. The MC4R has garnered considerable attention as this melanocortin receptor subtype appears to play a central role in weight regulation. Mice homozygous for an Mc4r-null allele demonstrate autosomal dominant, maturity-onset obesity, hyperphagia, hyperinsulinemia, and hyperglycemia [364]. Heterozygotes have an intermediate phenotype. The Mc4r-null mouse also demonstrates increased linear growth [364], a feature unique to agouti yellow mice (discussed subsequently) and MC4Rnull mice among rodent obesity models. The MC4R has been implicated in leptin signaling as administration of the melanocortin receptor antagonist SHU9119 can block the reduction of food intake induced by central administration of leptin [365]. Leptin receptors are found on POMC expressing neurons in the arcuate nucleus and administration of exogenous leptin does not reverse obesity in Mc4rnull mice [366]. The role of MC4R in weight regulation in humans has been confirmed with the identification of individuals with dominantly inherited obesity segregating with mutations in the MC4R gene that result in frameshift errors [367–369]. Recent studies suggest that haploinsufficiency of MC4R may be a frequent, but incompletely penetrant, cause of human obesity [370,371]. The incomplete penetrance is highlighted by the absence of obesity in individuals with large deletions of chromosome 18q, a region that spans the MC4R gene [372]. A dominant-negative effect of mutant MC4R has been proposed, but cotransfection studies of mutant and wild-type MC4R in vitro showed that mutants

Chapter 2

affected neither signaling nor cell surface expression of wildtype MC4R [373].

Melanocortin 5 Receptor Expression of the fifth melanocortin receptor was originally recognized in the brain [374]. Subsequently, MC5R expression was documented widely at low levels in tissues including the adrenal glands, skin, adipocytes, skeletal muscle, kidneys, lung, stomach, liver, spleen, thymus, lymph nodes, mammary glands, ovary, pituitary, testis, and uterus [64,374–377]. In situ hybridization studies showed that within the adrenal, MC5R is predominantly expressed in the aldosterone-producing zona glomerulosa cells [376]. High levels of MC5R mRNA expression have been documented in the secretory epithelia of a number of exocrine and endocrine glands including Harderian, preputial, lacrimal, sebaceous, and prostate glands and pancreas [378,379]. Melanocortins have been reported to affect a number of exocrine glands. Removal of the neurointermediate lobe of the pituitary reduces sebaceous lipid production, and this reduction is restored by administration of a-MSH [380–382]. Exogenous ACTH and MSH increase secretion from the lacrimal gland [383,384]. Deletion of the murine Mc5r resulted in the loss of detectable binding of [125I]NDP-MSH to Harderian, lacrimal, and preputial glands, and skeletal muscle indicating that MC5R is the predominant melanocortin receptor in these tissues [378]. Development of the Mc5r-null mouse confirmed a physiologic role for the melanocortins in regulating exocrine gland function; the mice demonstrate severe deficits in water repulsion and thermoregulation as a result of decreased sebaceous lipid production [378]. MC5R also appears to be essential for hormonally regulated release of porphyrins from the Harderian gland [378]. The preputial gland is a specialized sebaceous gland implicated in pheromone production [385]. Exogenous a-MSH stimulates the release of a preputial odorant into the urine of male mice which stimulates aggressive attacks [386]. Chen and colleagues have hypothesized the existence of a hypothalamic– pituitary–exocrine axis which might provide a mechanism by which stress could alter behavior via the regulation of olfactory cues [378].

Diseases Caused by Melanocortin Receptor Ligands POMC Deficiency

Two individuals have been identified with genetic defects in the POMC gene [387] (Fig. 2.3). The first patient was a compound heterozygote for two mutations in exon 3 which interfere with appropriate synthesis of ACTH and a-MSH. The second patient was homozygous for a mutation in exon 2 which abolishes POMC mRNA translation. Both patients presented with early-onset obesity, adrenal insufficiency, and red hair pigmentation. The brother of patient one had died at the age of 7 months of hepatic failure following severe

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cholestasis and was found to have bilateral adrenal hypoplasia in the postmortem examination. All other anterior pituitary-derived hormones were normal. No symptoms related to b-endorphin deficiency have been noted. The heterozygous parents were normal in both families. Isolated ACTH deficiency of the pituitary due to other causes is also rare. It most commonly appears to be acquired in later life, and is more common in men [388–391]. Most cases have been reported in Japan, and are often associated with other autoimmune endocrinopathies, including Hashimoto’s thyroiditis and type 1 diabetes mellitus. It is likely that only pituitary ACTH, and not hypothalamic aMSH, is affected in these patients, as they are not obese and do not have red hair, unlike patients with POMC gene mutations [387]. Recently, the gene Tpit has been identified as a transcription factor specific to pituitary corticotrophs and melanotrophs, and absent in hypothalamic neurons which also express POMC [77]. It interacts with the POMC-specific transcription factor, Ptx1, to regulated POMC transcription. Two families with recessive mutations in TPIT have been described [77]. Consistent with its sites of expression, these patients have congenital, secondary adrenal insufficiency, but not obesity or red hair. Recently, a POMC-deficient mouse has been produced whose phenotype is similar to the human POMC-deficient syndrome and confirms the known functions of melanocortins [392]. The phenotype includes obesity, increased body length, yellow pigmentation, deficits in sebaceous gland function and thermoregulation, and adrenal hypoplasia and glucocorticoid deficiency. Adrenal glands could not be identified. In addition to undetectable corticosterone levels, aldosterone levels were also undetectable. The mutant mice lost 40% of their excess weight after 2 weeks of treatment with a stable a-MSH agonist. Although some of this weight loss was clearly attributable to decreased food intake, these same authors have clearly shown that a-MSH administration has additional lipolytic effects and results in increased energy expenditure [393]. Agouti and Agouti-related Protein

The agouti gene locus was identified 45 years ago as a genetic locus that controls the amount and distribution of eumelanin (brown–black) and pheomelanin (yellow–red) pigmentation in the mammalian coat [394]. However, analysis of mutations at the agouti gene locus have occupied investigators for nearly a century. The lethal yellow mutation at the agouti locus was the first murine embryonic lethal mutation and the first murine obesity syndrome to be characterized [395,396]. Agouti is a small 131 amino acid protein that is secreted by dermal papillae cells and acts to block melanocortin action on follicular melanocytes at Mc1r in the mouse [397,398]. The recombinant murine agouti protein is a potent nanomolar competitive antagonist for melanocortin receptors at Mc1r and Mc4r, relatively weaker at Mc3r, and only a micromolar inhibitor of Mc5r [397,399,400] and

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SECTION 1

Girl's weight

Boy's weight

35

–P97 82

Patient

–P90

30

72

25

–P75 –P50 –P25 –P10 –P3

62

20

–P97 –P90 –P75 –P50 –P25 –P10 –P3

15

52

Patient

42 32

10 22 5

0

12

0

3 6 9 12 18 24 30 36 42 48 Age (months)

2

0

2

4

6

8 10 12 14 16 18

Age (years)

represents the first known endogenous antagonist for a Gprotein coupled-receptor. In wild-type rodents, agouti expression is restricted to the hair follicle [398]. The human agouti gene which is 85% identical to the mouse gene is expressed much more widely including in adipose tissue, testis, ovary, and heart, and at lower levels in liver, kidney, and foreskin [401,402]. The human agouti protein, the agouti-signaling protein (ASIP), displays a similar pharmacologic profile for antagonism of melanocortin receptors as compared to the murine agouti protein except that ASIP may display both competitive and noncompetitive antagonism at MC4R and also appears to act as a noncompetitive antagonist of MC2R [403,404]. The heterozygous lethal yellow agouti mouse is characterized by a yellow coat-color, late onset obesity associated

FIGURE 2.3. Patients and weight curves of two unrelated patients with homozygous mutations in POMC. Note the obesity coupled with fair skin and red hair, as well as early onset obesity. From reference [387] with permission.

with hyperphagia, hyperinsulinemia and hyperglycemia, increased linear growth, and susceptibility to a wide variety of epithelial and mesenchymal tumors (reviewed in [405]). This phenotype is the result of a 170 kb deletion which removes all but the promoter and noncoding first exon of the Raly gene 5¢ to the exons of the agouti gene [406] and results in ubiquitous overexpression of agouti in all tissues examined to date [398,407]. The lethal yellow phenotype is presumably the result of agouti antagonism of the widely distributed melanocortin receptors and is consistent with the known actions of melanocortin receptors described above. An agouti-related protein (AGRP) gene was recently identified based on its homology to agouti and is expressed in the hypothalamus, adrenal medulla, and at low levels

Chapter 2

in the testis, lung, and kidney [408,409]. In contrast to the divergent expression patterns of murine and human agouti, the expression pattern of murine and human AGRP appears identical [408]. Within the hypothalamus, AGRP expression is confined to the arcuate nucleus and AGRP-immunoreactive terminals paralleled POMCimmunoreactive terminals projecting from the arcuate nucleus [55]. AGRP is a selective, nanomolar competitiveantagonist of MC3R and MC4R, clearly implicating it as the endogenous melanocortin antagonist involved in energy homeostasis [410–412]. Corticostatins are a family of related low molecular weight members of the defensin family of peptides that are competitive inhibitors of ACTH-induced steroidogenesis in the adrenal cortex, which act by blocking the ACTH receptor [413]. In rats, a dose of 8 mg/kg body weight blocks the corticosterone response to stress [414]. Corticostatins and the agouti peptides are the two known endogenous competitive inhibitors of melanocortin receptors, but do not appear to be structurally related [415].

Additional Potential Melanocortin Actions Additional physiologic roles for melanocortins have been proposed that do not clearly correlate with the known functions of specific melanocortin receptors as surmised from human or mouse mutants. A multitude of behavioral and psychological effects have been attributed to melanocortins (for review see [416]). Intracerebroventricular administration of ACTH or a-MSH elicits excessive grooming behavior [417], yawning, stretching, and penile erection [418]. The grooming, stretching, and yawning behavior, but not erectile function, may be mediated by MC4R as deduced through the use of MC4R selective antagonists [233,419,420]. Recently, in a double-blind, placebo controlled crossover study, a cyclic a-MSH analogue initiated erections in men with psychogenic erectile dysfunction [421]. Roles for the actions of melanocortins in neuromuscular development, promotion of the regeneration of crushed nerves, and CNS protection from injury have also been postulated [235,422–425]. A potential role for melanocortins in fetal growth and brain development has been demonstrated [426,427]. Data indicating a role for melanocortins as modulators of inflammation have been discussed previously. Centrally administered MSH is a potent antipyretic agent and, in an endogenous pyrogen-induced fever model in rabbits, is approximately 25,000-fold more potent than acetaminophen [428]. Physiologic roles for melanocortins in maintenance of cardiovascular homeostasis have also been proposed. Peripheral or central administration of g-MSH causes tachycardia and pressor effects [429,430]. Central administration of a-MSH results in bradycardia and depressor effects [429,430]. Melanocortins may further influence cardiovascular homeostasis through their effects on electrolyte regulation. a-MSH and g-MSH are potent natriuretics [431–434].

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SECRETION OF ACTH: PHYSIOLOGY Physiologically a number of factors interact to determine the final pattern of ACTH release, including circadian rhythms, stress, and negative feedback by glucocorticoids. These factors impact on each other in an integrated fashion to control ACTH release. The stage of development, from fetal life through puberty, and pregnancy and parturition, also impact on ACTH secretion. Finally, the immune system interacts with the HPA axis, adding another facet to the complexity of ACTH release.

Secretion Dynamics of ACTH in vivo ACTH secretion is characterized by pulsatile release of ACTH from the corticotroph in a burst-like pattern, with no interpulse secretion [435]. Fifteen-minute sampling reveals approximately 12 ACTH and cortisol pulses over a 24-hour period [436], whereas more frequent 10-minute sampling reveals 40 ACTH pulses in 24 hours [435]. Blood ACTH rises by an average of 24 pg/ml per pulse [435]. bendorphin secretion parallels the pulsatile release of ACTH [437]. Spontaneous ACTH and cortisol pulses correlate highly. There is a strong relationship between the magnitude of concomitant ACTH and cortisol pulses, particularly if a 15 minute phase delay in cortisol secretion is allowed for [435,438–440]. Not all spontaneous ACTH and cortisol pulses are concomitant: approximately 50% to 75% of spontaneous ACTH pulses are followed by a cortisol pulse, whereas approximately 60% to 90% of spontaneous cortisol pulses are preceded by an ACTH pulse [436,440]. The 24-hour pattern of ACTH pulses, but not the cortisol pattern, differs between males and females. Males have more pulses, greater mean peak ACTH amplitude, greater 24-hour ACTH secretion, and higher mean ACTH levels [438]. The sensitivity of the adrenal cortex, or the availability of ACTH to the adrenal cortex, may be greater in females. Alternatively, males and females may have different set points for cortisol feedback [438]. CRH may also be secreted in a pulsatile fashion, accounting for pulsatile ACTH secretion. When exogenous CRH is given continuously, there is a progressive desensitization of the ACTH response to CRH [441]. However, when CRH is given in a prolonged pulsatile manner, it does not desensitize the corticotroph CRH receptor, and the releasable ACTH pool is not depleted [436].

Negative Regulation of ACTH Secretion Negative feedback can be defined as long, short, or ultrashort depending on the location and nature of the hormone mediating the feedback. Long Feedback by Glucocorticoids

Long feedback refers to the effects of adrenal glucocorticoids on ACTH secretion at the pituitary and in the hypo-

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thalamus. Glucocorticoid-mediated negative feedback can be subdivided into fast and delayed, which can be further subdivided into intermediate and slow feedback. In animals, the initial fast negative effect of glucocorticoids occurs within seconds to minutes [183], involves inhibition of stimulated ACTH and CRH release, not synthesis, and occurs during the period when plasma glucocorticoid levels are increasing. Cortisol given to patients at the start of surgery attenuates the surgery-induced ACTH rise [211], and may be an example of fast feedback. Delayed feedback has two components, intermediate and slow [442]. Intermediate feedback is the component of delayed feedback that is due to inhibition of ACTH release, but not synthesis, and may be important after short durations of glucocorticoid exposure, or after noncontinuous, repeated exposures [442]. Intermediate delayed feedback develops after 45 to 120 minutes, and maximal inhibition occurs 2 to 4 hours after administration of one dose of glucocorticoids. Unlike ACTH, CRH synthesis as well as release may be affected by intermediate feedback [442]. The slow component of delayed feedback is most important after long exposures to a moderately high dose of glucocorticoid, and is a function of the total dose of glucocorticoids, the glucocorticoid level achieved, and the amount of time since the steroid was given [442]. Slow feedback occurs after more than 24 hours of exposure to glucocorticoids and can persist for days. POMC biosynthesis is inhibited, leading to inhibition of basal and stimulated ACTH secretion [442], and intracellular ACTH decreases implying decreased synthesis. In humans, negative feedback by glucocorticoids takes 30 to 60 minutes to manifest. When endogenous cortisol is suppressed with metyrapone, the effects of exogenous glucocorticoids on the morning ACTH rise, or on oCRHstimulated ACTH release, are not seen initially but appears 30 minutes after glucocorticoid administration [443]. In addition, glucocorticoids have little effect on the initial CRH-induced increase in ACTH release, but decrease CRH-induced ACTH release after 60 minutes. Cortisol given to patients at the start of surgery attenuates the surgery-induced ACTH rise [211]. Cortisol modulates the responsiveness of the pituitary. The corticotroph is dependent on CRH stimulation to maintain ACTH secretion, and glucocorticoids suppress CRH-induced ACTH secretion in vivo and in vitro. On the other hand, when endogenous cortisol levels are suppressed by metyrapone, basal ACTH and CRH-induced ACTH release are increased [444]. Glucocorticoid inhibition of ACTH secretion from the corticotroph may recover more quickly than CRH secretion from the hypothalamus [445]. Secondary adrenal insufficiency due to long-term glucocorticoid therapy may in part be due to continued suppression of hypothalamic CRH secretion 184. Adrenalectomized patients on exogenous glucocorticoid therapy have a blunted ACTH response to CRH that normalizes after several CRH boluses, suggesting that lack of stimula-

tion of the corticotroph by CRH suppresses the ACTH response [446]. On the other hand, corticotrophs of patients recovering from transsphenoidal surgery for Cushing’s disease are profoundly unresponsive to CRH, which can not be attributed solely to deficient CRH priming [447]. Glucocorticoids inhibit AVP secretion [448]. In most studies, patients with hypopituitarism or primary adrenal insufficiency are unable to maximally dilute their urine in response to a water load, and this is corrected by glucocorticoid administration [449]. However, it is unclear if the elevated AVP levels, or the lack glucocorticoids, is responsible for the inability to maximally dilute the urine in the hypocortisolemic state [448]. Glucocorticoids inhibit nitric oxide synthase, and nitric oxide is capable of stimulating the insertion of the water channel, aquaporin 2, in the luminal membrane of the renal collecting cell [450]. This may provide an explanation for why glucocorticoid deficiency is associated with decreased free water clearance. Short Feedback

Short feedback refers to the effect of pituitary ACTH to inhibit CRH release. In normal subjects, the administration of ACTH does not affect CRH levels, most likely because of the negative effects of cortisol present prior to ACTH administration [451]. However, in patients with elevated CRH levels due to Addison’s disease or hypopituitarism, ACTH decreases CRH and b-endorphin levels, suggesting that ACTH inhibits CRH secretion [451]. ACTH may act in the median eminence or in the hypothalamus to inhibit CRH release [451].

Circadian Regulation of ACTH Secretion There is an endogenous circadian rhythm to the pulsatile pattern of ACTH secretion which leads to a circadian rhythm of glucocorticoid release. The function of this circadian rhythm in cortisol secretion is not known, although one hypothesis suggests that the early morning rise in cortisol causes a delayed-phase rise in insulin resistance, which may play a role in altered glucose metabolism [452]. For instance, since the brain does not require insulin for glucose uptake, peripheral insulin resistance might cause a rise in glucose levels, leading to greater uptake in the brain. The circadian rhythm is generated in the suprachiasmatic nucleus (SCN), and the signals travel via efferent inputs to the PVN to modulate CRH release [183,453]. This circadian rhythm is due to variation in ACTH pulse amplitude, not frequency [435]. The amount of ACTH secreted per pulse varies by 3.8-fold over a 24-hour period [435]. Basal ACTH and cortisol levels parallel each other and are the highest upon awakening in the morning between 0600 hours and 0900 hours, decline through the day to intermediate levels at 1600 hours, and are lowest between 2300 hours and 0300 hours [435]. From 2300 hours to 0200 hours, there is a quiescent period of minimal secretory activity, corresponding to the nadir of ACTH and cortisol levels [454]. Secretion of

Chapter 2

ACTH and cortisol abruptly increases in the early morning [454]. The diurnal secretory pattern is similar for free and total cortisol, although the relative increase in free cortisol is about 1.5 times greater than the relative increase in total cortisol [454]. Alterations in feeding and sleep impact on cortisol secretion [455]. Cortisol briefly increases postprandially, especially after the midday meal [454]. Exercise or administration of ACTH at 1000 hours leads to a rise in cortisol and blunts the midday cortisol surge, and at 1400 hours leads to a rise in cortisol [454]. Overall, the major features of the diurnal cortisol pattern persist under conditions of complete fasting, continuous feeding, or total sleep deprivation [456]. However, the circadian rhythm of cortisol secretion fully adapts to permanent changes in environmental time and the sleep–wake pattern. This adaptation takes about 3 weeks, the limiting factor being the time it takes for the quiescent period of secretion to fully adapt [456]. The acrophase adapts much more quickly and is partially synchronized after one day and totally synchronized after 10 days [456]. There is circadian regulation of the sensitivity of the response of the adrenal cortex to ACTH [457,458]. Injection of ACTH at 0700 hours, just at the time of the endogenous cortisol peak, causes a significant increase in cortisol. The absolute increment in cortisol secretion in response to an ACTH stimulation test is greater when the test is performed at circadian nadir compared to the peak, although in one study this was true in males only [459]. The incremental increase in cortisol secretion in response to a CRH stimulation test is also greatest at night when basal levels are lowest, although the total amount of cortisol released is greatest in the morning when the basal cortisol levels are highest [460]. The basal cortisol level, not the time of day, seems to be the important factor determining the cortisol response to oCRH, and the higher the basal cortisol level, the lower the peak cortisol response to oCRH [436]. On the other hand, the maximum ACTH blood level in response to oCRH occurs at 0700 hours, the time of the minimum cortisol increment to oCRH [436]. The factors governing the circadian rhythm in ACTH release in humans are not clear. On the one hand, it may be regulated by a diurnal rhythm in CRH secretion [461]. The highest CRH levels occur at 0600 hours (7.0 pg/ml) and the lowest at 1800 hours and 2200 hours (about 1.8 pg/ml), which parallels the pattern of ACTH and cortisol secretion [462]. Serotoninergic and cholinergic pathways may play a role in the CRH circadian rhythm, and display circadian periodicity in their hypothalamic concentrations [463]. On the other hand, when the pituitary is exposed to constant levels of CRH 30-fold higher than those found in portal hypophyseal blood, such as in pregnancy [464] and during CRH infusion [441], the circadian rhythms in ACTH and cortisol persist. CRH clearly plays a role in the ACTH rhythm, as CRH-deficient mice have an absent or markedly attenuated diurnal rise in ACTH [465]. However, in these mice, constant infusion of CRH restores the ACTH

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rhythm. This indicates that changes in CRH amplitude are not necessary to drive the ACTH rhythm, but that a tonic level of CRH is required to maintain ACTH responsiveness [466] to circadian cues.

Physical Stress Regulation of ACTH Secretion Glucocorticoid release mediated by ACTH, plays a major role in the response to stress. An interaction exists between stress-mediated ACTH release, which leads to glucocorticoid secretion, and glucocorticoid-mediated negative feedback, which inhibits further ACTH and glucocorticoid release. A number of stressful stimuli lead to ACTH secretion. Most physical stressors activate the HPA axis. The magnitude of the rise in ACTH and cortisol is dependent upon many factors, including the nature of the stress, its magnitude including the rapidity of its appearance, and the time of day it is experienced. In general, stressors have a larger impact on ACTH release when they develop rapidly, are of high magnitude, and occur during the circadian nadir in ACTH release. Hypoglycemia

In humans, insulin induced hypoglycemia is associated with a increase in plasma ACTH levels [467], from a basal level of about 40 pg/ml to a peak of 250 pg/ml at 45 minutes [467]. Cortisol levels increase over twofold, from a basal level of about 11 ug/dl to a peak of about 25 ug/dl at 60 to 90 minutes [467]. Insulin-induced hypoglycemia causes a four- to fivefold greater increase in ACTH secretion than oCRH alone, and a 1.3-fold greater increase than AVP plus CRH [97,468]. CRH may play a permissive rather than a dynamic role in the ACTH response to hypoglycemia [182], whereas AVP may play a more direct role [467]. AVP levels have been shown to increase 2.5- to sevenfold at 30 to 45 minutes after the insulin. When AVP levels are raised endogenously by saline infusion or lowered to undetectable levels by waterloading, the hypoglycemia-induced AVP increase is greater after saline, even though saline blunts the hypoglycemic response to insulin [469]. Catecholamines increase in response to hypoglycemia, and may act at the hypothalamus to mediate ACTH release. Epinephrine appears to play more of a role than norepinephrine, increasing at least 13fold at 30 minutes after insulin, whereas norepinephrine increases 2.4-fold at 60 minutes. Exercise

Exercise increases ACTH and b-endorphin levels, and the response is dependent on the intensity of exercise and the level of training [470]. Exercising to exhaustion, or exercise of short duration and high intensity, increases ACTH, bendorphin, and cortisol levels. Hypercortisolism is seen in highly trained athletes, who need a higher level of oxygen consumption to stimulate ACTH release, and have elevated basal ACTH levels [471]. Physical exercise and stress both

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lead to analgesia in man [472]. Naloxone reverses exerciseinduced analgesia from certain types of pain, suggesting a role for endorphins. Dexamethasone reverses exerciseinduced analgesia from other types of pain, like dental pain, that are not reversed by naloxone, suggesting a role for ACTH, although dexamethasone also suppresses bendorphin release. Lower Body Negative Pressure and Acute Hemorrhage

Lower body negative pressure in humans simulates acute hemorrhage. Lower body negative pressure increases ACTH secretion to peak values of 60–250 pg/ml at 2 to 10 minutes after cessation of the stimulus, and the increase in ACTH is reversed by dexamethasone [473]. Hypovolemia may be the physiologically important stress. In animals, hemorrhage stimulates ACTH secretion primarily mediated by CRH and, to some degree, by AVP [182]. Hypovolemia increases portal blood CRH, AVP, epinephrine, and oxytocin, whereas hypotension, also a component of hemorrhage, induced by nitroprusside, increases portal blood CRH only. Surgical Stress

Surgery induces a large increase in plasma ACTH levels [284]. Patients undergoing surgery may have increased sensitivity of the adrenal cortex to ACTH [474,475]. Fentanyl, an opiate agonist, attenuates the ACTH response to surgery [211]. Evidence in adrenalectomized primates suggests that supraphysiological doses of glucocorticoids are not necessary for the animal to withstand surgical stress, but that a minimal level is necessary [474,476].

Psychological and Emotional Stress Psychological and emotional stress play a role in the hormonal stress response. ACTH levels are high in patients awaiting an insulin-tolerance test. During physical exercise, psychological and physical stress may act synergistically to increase b-endorphin and ACTH levels [477]. With increasing experience in performing a set level of exhaustive physical exercise, plasma ACTH and cortisol levels declined [478].

Fetal and Postnatal Regulation of ACTH Secretion In utero, maternal cortisol influences alterations of fetal heart rate, movement, and behavioral states [479]. By 35 weeks of gestation, there is a circadian rhythm in fetal behavioral states that is altered if the maternal diurnal variation in ACTH and cortisol secretion are abolished by maternal administration of triamicinolone [479]. Neonates, even when born prematurely, have an endogenous cortisol rhythm. Minimally and severely stressed neonates in the neonatal intensive care unit, born between 23 and 38 weeks of gestation, have a significant diurnal rhythm in cortisol and endorphin secretion, although ACTH levels do not vary sig-

nificantly [463]. Others have suggested that diurnal rhythmicity is a function of maturation, and is not present before 6 months of age [463,480,481].

Regulation of ACTH Secretion During Puberty Normal children between the ages of 1 year and 16 years do not differ from adults in ACTH, b-endorphin, and cortisol responses to CRH, and the responses of boys do not differ from girls [482]. Some of the other adrenal steroids and adrenal androgens demonstrate basal and stimulated variation with age. The CRH-stimulated androstenedi one to 17-hydroxyprogesterone ratio increases with sexual maturation, suggesting that the 17,20-desmolase activity increases with puberty [483]. The dehydroepiandrosterone response to CRH increases as children progress from stage 1 to stage 5 of puberty, and by stage 5 of puberty, dehydroepiandrosterone levels do not differ from adults [482].

HPA-Axis-Immune Interactions The immune system and the neuroendocrine system communicate with each other, and share a common set of structurally identical hormones and receptors [484–488]. Cells of the immune system synthesize biologically active neuroendocrine peptide hormones, immune cells contain receptors for neuroendocrine hormones, neuroendocrine hormones modulate immune function, and lymphokines modulate neuroendorine function. The neuroendocrine system and the immune system work together in the regulation of both the stress and the immune response, and the components include lymphoid cells, cholinergic and adrenergic neurons, cytokines and lymphokines, hormones and neuropeptides released by the endocrine glands and the CNS, receptors, and higher CNS activity which modulates these responses [489,490]. Effect of Immune System on HPA Axis

Immune cells, particularly monocytes, macrophages, and lymphocytes, produce cytokines involved in the immune response, and these cytokines activate the HPA axis. Bacterial-derived endotoxin and lipopolysacchride stimulate the release of interleukin-1, interleukin-6, and TNF-a, which are regulated by glucocorticoid feedback. The effects of cytokines on the HPA axis at the level of the brain, pituitary, and adrenal gland, are the best examples of immune modulation of a neuroendocrine system. Interleukin-1 is produced by stimulated macrophages and monocytes, and stimulates CRH release. Interleukin-1 also directly stimulates the adrenal cortex. Tumor necrosis factor is produced primarily by activated monocytes [491], and has many of the same biological activities and responds to many of the same immune challenges as interleukin-1. Tumor necrosis factor stimulates ACTH release, most likely at an extra-pituitary site. Interleukin-6 has actions similar to interleukin-1 and

Chapter 2

TNF, and stimulates the HPA axis [202,491]. Interleukin-2 is synthesized by T cells after an antigenic challenge, and increases ACTH and cortisol levels in humans, although this may be indirect and due to the stress response generated by fever and chills. Gamma-interferon causes an increase in steroid production by adrenal cells. As discussed above, leukemia-inhibitory factor (LIF) may be a major activator of POMC gene transcription and ACTH release following immune or inflammatory stimulation. Effect of HPA Axis on Immune System

Stress suppresses immune function. Following an infection or most immunization procedures, and the presence of bacterial endotoxin, a stress-like response of the pituitary occurs leading to the release of ACTH and cortisol which tends to suppress the immune system. However, in humans, there is no clear evidence that the rise in cortisol following an immune or inflammatory stimulus plays a significant role in modulating the subsequent immune response. In fact, prior to the treatment of patients with primary adrenal insufficiency, there were no substantive reports that these patients suffered from overactivity of their immune systems. Receptors for CRH, ACTH, and glucocorticoids most likely mediate the effect of these hormones on the immune system. ACTH receptors on human peripheral monocytes have been characterized, and glucocorticoid receptors are present on human lymphocytes. Glucocorticoids inhibit many aspects of immune function, establishing a negative feedback loop between the immune and neuroendocrine systems. Glucocortiocoids block lymphocyte activation, block the production and action of interleukin-2, interleukin-1, gamma-interferon, TNF, and prostaglandins, and interfer with the interaction of certain effector molecules with target cells. HPA Axis Within Immune System

Cells of the immune system produce CRH, ACTH and endorphins. Human peripheral mononuclear leukocytes synthesize three molecular forms of immunoreactiveACTH, and lymphocytes produce b-endorphins. Mouse spleen macrophages and virally infected mouse splenocytes contain b-endorphin and POMC mRNA [492–494]. CRH mRNA and peptide are found in monocytes in acute inflammatory reactions [495] and in T cell lymphocytes [496]. Releasing hormones and cytokines interact to stimulate ACTH production from immune cells. CRH and AVP stimulate a dramatic increase in biologically active ACTH and b-endorphin from human peripheral leukocytes in some studies. Unstimulated leukocytes produce little ACTH. In humans, only B lymphocytes secrete b-endorphin in response to CRH and AVP, and monocyte-secreted interleukin-1 mediates the effect. A feedback loop exists between the immune and neuroendocrine systems [490]. Cytokines released by immune cells stimulate secretion of ACTH and glucocorticoids which are active in the fight

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against infection. Subsequently, these hormones suppress the further synthesis of cytokines. SECRETION OF ACTH: PATHOPHYSIOLOGY Abnormal secretion of ACTH occurs in ACTH-secreting pituitary adenomas responsible for Cushing’s disease or Nelson’s syndrome, and in Cushing’s syndrome due to an ectopic pituitary adenoma or an ectopic ACTH-secreting tumor. Decreased or absent ACTH secretion due to genetic or autoimmune causes has been discussed in the above section on melanocortin actions.

Pituitary Adenomas ACTH immunoreactivity in an abnormal pituitary is usually due to a single functional adenoma, but can be associated with nodular hyperplasia or a silent cortiocotropic adenoma. Diffuse or nodular corticotroph hyperplasia, which could result from an ectopic or hypothalmic CRH-producing tumor, or Addison’s disease, is a rare cause of a pituitary adenoma or ACTH hyperfunction. Pituitary adenomas constitute about 15% of intracranial tumors [3]. Approximately 56% of pituitary adenomas are active, and about one third of active pituitary adenomas produce ACTH. Ten to 15% of pituitary adenomas are pleurihormonal, some of which secrete ACTH. When discovered, ACTH-producing adenomas are often functional, small, highly vascular, and prone to hemorrhage [497]. Corticotroph adenomas tend to be located in the central portion of the adenohypophysis, in the “mucoid wedge,” and form micronodular aggregates [497]. Invasive adenomas are more frequently found among undifferentiated, extermely laterally localized, or large adenomas, and recur more frequently than non-invasive tumors. There is no correlation between the size of an adenoma and the cortisol level or rate of recurrence [498]. The majority of adenomas responsible for Cushing’s disease or Nelson’s syndrome are microadenomas. ACTH-producing adenomas are usually monoclonal, but may be polyclonal [499]. Pleurihormonal adenomas are usually polyclonal [499]. The biochemical structure and ultrastructure of ACTHsecreting pituitary adenoma cells differ from nonadenomatous pituitary cells [500]. The cells may look normal, but be increased in number [497]. Cells are oval to polygonal in shape, with eccentric spherical nuclei and well-developed rough endoplasmic reticulim. Crooke’s hyaline is characteristic of ACTH-producing tumors [501], is associated with either endogenous or exogenous hypercortisolism, and is due to massive accumulation of intermediate cytoplasmic filaments that are normally present in small numbers [3]. Clinically, an increased number of Crooke’s cells is correlated with a longer postoperative replacement dose of cortisol requirement [498]. Pituitary adenomas may produce products in addition to ACTH. Some ACTH-producing corticotroph adenomas contain a form of gastrin that is smaller than gastrin found

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in the normal adenophypophysis. 7B2 is a secretory granule-associated protein, which may be involved in proconvertase activtion [502], which is sometimes secreted by ACTH-producing tumors, it is secreted in the highest levels from nonfunctional pituitary tumor. A variant of Cushing’s disease is due to ACTHproducing pituitary adenomas occurring ectopically [5], and have been described to arise in the mucosa of the sphenoid sinus [5,503], within a benign cystic ovarian teratoma [504], and intrahemispherically in a 6-year-old boy [505]. Rarely, both Cushing’s disease and Nelson’s syndrome have been preceded by generalized glucocorticoid resistance due to a mutation in the glucocorticoid receptor [506,507]. In these cases, the high rate of ACTH secretion, stimulated by the generalized glucocorticoid resistance, in some way led to adenoma formation, perhaps following a second oncogenic transformation. Pituitary carcinomas are malignant pituitary tumors associated with extracranial metastases, including liver and lung [508]. Pituitary carcinomas cannot be histologically differentiated from adenomas [3]. A large number of pituitary carcinomas produce Cushing’s disease [3]. In patients with Cushing’s disease due to a pituitary carcinoma, the primary tumor and metastases stain immunochemically for ACTH, b-LPH, b-endorphin, and a-MSH [508], and production of both CRH and ACTH from a pituitary carcinoma has been described [509].

Most nonpituitary POMC-secreting tumors do not produce CRH [515]. However, some patients with ectopic ACTH syndrome due to lung cancer have tumors that produce ACTH and CRH, and secrete ACTH in response to CRH [516]. Bronchial carcinoid tumors may contain CRH and ACTH, and be associated with high plasma ACTH and CRH levels and Cushing’s syndrome, or with normal plasma CRH levels. Cushing’s syndrome has been associated with ectopic ACTH secretion from a unilateral adrenal pheochromocytoma [517], and from bilateral pheochromocytomas in a case of multiple endocrine neoplasia type 2A [518]. A number of other ectopic tumors have been described that secrete ACTH, including an adenoid cystic carcinoma of the lung [519], a renal cell carcinoma [520], a neuroendocrine tumor of the nasal roof [521], and an ACTHproducing tumor metastatic to the liver [522]. In general, POMC mRNA from nonpituitary tumors responsible for the ectopic ACTH syndrome is identical to normal and to POMC mRNA from pituitary tumors [523]. However, some tumors contain a larger POMC mRNA species that is increased in amount from 0.3% of the overall POMC mRNA in normal pituitaries, to up to 35 to 40% in the tumor, and is transcribed from an alternative upstream promoter [523]. Pancreatic islet cell tumors responsible for Cushing’s syndrome have been demonstrated to contain ACTH and b-endorphin [524], and to express POMC mRNA [524].

Ectopic ACTH-secreting Tumors Several neuroendocrine neoplasms occur in the bronchopulmonary tract, including small-cell neuroendocrine carcinomas, carcinoids, well-differentiated neuroendocrine carcinomas, and intermediate-cell neuroendocrine carcinomas [510]. These neoplasms express neuroendocrine markers including chromogranins and synaptophysin [510]. Thirtyfour percent of small-cell carcinomas of the lung show immunoreactivity to one or more peptide hormones [511], and patients with peptide-positive small-cell lung carcinomas have a shorter mean survival than in patients with nonreactive tumors. ACTH is by far the most common hormone present, and is seen in 24% of small-cell carcinomas [511]. However, 56% of small-cell lung cancer cell lines secrete significant concentrations of ACTH precursors, with little, if any, processing to ACTH. Oat-cell lung carcinomas may also produce ACTH, leading to Cushing’s syndrome [512]. Carcinoid tumors often produce more than one hormone, and can be responsible for the ectopic ACTH syndrome [513]. Bronchial carcinoids occasionally contain ACTH and related opioid peptides, which does not alter the overall favorable prognosis of these tumors. Recently, Cushing’s syndrome caused by ACTH secretion by pulmonary tumorlets has been described [514]. Upon radiologic imaging, such tumorlets, which may be over 100 in number, present a very unusual appearance.

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187 Jones MT, Hillhouse EW, Burden J. Effect on various putative neurotransmitters on the secretion of corticotrophin-releasing hormone from the rat hypothalamus in vitro – a model of the neurotransmitters involved. J Endocrinol 1976;69:1–10. 188 Rivier C, Vale W. Effects of corticotropin-releasing factor, neurohypophyseal peptides, and catecholamines on pituitary function. Fed Proc 1985;44: 189–195. 189 al-Damluji S. Adrenergic mechanisms in the control of corticotrophin secretion. J Endocrinol 1988;119:5–14. 190 Watanabe T, Oki Y, Orth DN. Kinetic actions and interactions of arginine vasopressin, angiotensin-II, and oxytocin on adrenocorticotropin secretion by rat anterior pituitary cells in the microperifusion system. Endocrinology 1989; 125:1921–1931. 191 Schoenenberg P, Gaillard RC, Kehrer P et al. cAMP-dependent ACTH secretagogues facilitate corticotropin releasing activity of angiotensin II on rat anterior pituitary cells in vitro. Acta Endocrinol (Copenh) 1987;114:118–123. 192 McCann SM, Rettori V, Milenkovic L et al. Role of monokines in control of anterior pituitary hormone release. Adv Exp Med Biol 1990;274:315–329. 193 Berkenbosch F, van Oers J, del Rey A et al. Corticotropin-releasing factorproducing neurons in the rat activated by interleukin-1. Science 1987;238: 524–526. 194 Sapolsky R, Rivier C, Yamamoto G et al. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 1987;238:522–524. 195 Matta S, Singh J, Newton R et al. The adrenocorticotropin response to interleukin-1 beta instilled into the rat median eminence depends on the local release of catecholamines. Endocrinology 1990;127:2175–2182. 196 Michie HR, Majzoub JA, ODwyer ST et al. Both cyclooxygenase-dependent and cyclooxygenase-independent pathways mediate the neuroendocrine response in humans. Surgery 1990;108:254–259. 197 Michie HR, Spriggs DR, Manogue KR et al. Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings. Surgery 1988;104:280–286. 198 Gaillard RC, Turnill D, Sappino P et al. Tumor necrosis factor alpha inhibits the hormonal response of the pituitary gland to hypothalamic releasing factors. Endocrinology 1990;127:101–106. 199 Sharp BM, Matta SG, Peterson PK et al. Tumor necrosis factor-alpha is a potent ACTH secretagogue: comparison to interleukin-1 beta. Endocrinology 1989;124:3131–3133. 200 Michie HR, Manogue KR, Spriggs DR et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988;318: 1481–1486. 201 Yasuda N, Greer MA. Evidence that the hypothalamus mediates endotoxin stimulation of adrenocorticotropic hormone secretion. Endocrinology 1978; 102:947–953. 202 Naitoh Y, Fukata J, Tominaga T et al. Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely-moving rats. Biochem Biophys Res Commun 1988;155:1459–1463. 203 Navarra P, Tsagarakis S, Faria MS et al. Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway. Endocrinology 1991;128:37–44. 204 Bochicchio D, Ambrosi B, Faglia G. Loperamide, an opiate analog, differently modifies the adrenocorticotropin responses to corticotropin-releasing hormone and lysine vasopressin in patients with Addison’s disease. Neuroendocrinology 1988;48:611–614. 205 Atkinson RL. Endocrine and metabolic effects of opiate antagonists. J Clin Psychiatry 1984;45:20–24. 206 Gaillard RC, Grossman A, Smith R et al. The effects of a met-enkephalin analogue on ACTH, beta-LPH, beta-endorphin and MET-enkephalin in patients with adrenocortical disease. Clin Endocrinol (Oxf ) 1981;14:471–478. 207 Blankstein J, Reyes FI, Winter JS et al. Effects of naloxone upon prolactin and costisol in normal women. Proc Soc Exp Biol Med 1980;164:363–365. 208 Grossman A, Gaillard RC, McCartney P et al. Opiate modulation of the pituitary–adrenal axis: effects of stress and circadian rhythm. Clin Endocrinol (Oxf) 1982;17:279–286. 209 Morley JE, Baranetsky NG, Wingert TD et al. Endocrine effects of naloxoneinduced opiate receptor blockade. J Clin Endocrinol Metab 1980;50:251–257. 210 Volavka J, Cho D, Mallya A et al. Naloxone increases ACTH and cortisol levels in man [letter]. N Engl J Med 1979;300:1056–1057. 211 Raff H, Flemma RJ, Findling JW. Fast cortisol-induced inhibition of the adrenocorticotropin response to surgery in humans. J Clin Endocrinol Metab 1988;67:1146–1148. 212 Spiler IJ, Molitch ME. Lack of modulation of pituitary hormone stress response by neural pathways involving opiate receptors. J Clin Endocrinol Metab 1980;50:516–520.

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264 Hartmeyer M, Scholzen T, Becher E et al. Human dermal microvascular endothelial cells express the melanocortin receptor type 1 and produce increased levels of IL-8 upon stimulation with alpha-melanocyte-stimulating hormone. J Immunol 1997;159:1930–1937. 265 Haynes RC. The activation of adrenal phosphorylase by the adrenocorticotropic hormone. J Biol Chem 1958;233:1220–1222. 266 Lefkowitz RJ, Roth J, Pricer W et al. ACTH receptors in the adrenal: specific binding of ACTH-125I and its relation to adenyl cyclase. Proc Natl Acad Sci USA 1970;65:745–752. 267 Catalano RD, Stuve L, Ramachandran J. Characterization of corticotropin receptors in human adrenocortical cells. J Clin Endocrinol Metab 1986;62: 300–304. 268 Buckley DI, Ramachandran J. Characterization of corticotropin receptors on adrenocortical cells. Proc Natl Acad Sci USA 1981;78:7431–7435. 269 Dallman MF, Akana SF, Jacobson L et al. Characterization of corticosterone feedback regulation of ACTH secretion. Ann NY Acad Sci 1987;512:402–14. 270 Weber A, Kapas S, Hinson J et al. Functional characterization of the cloned human ACTH receptor: impaired responsiveness of a mutant receptor in familial glucocorticoid deficiency. Biochem Biophys Res Commun 1993;197: 172–178. 271 Naville D, Penhoat A, Barjhoux L et al. Characterization of the human ACTH receptor gene and in vitro expression. Endocr Res 1996;22:337–348. 272 Elias LL, Huebner A, Pullinger GD et al. Functional characterization of naturally occurring mutations of the human adrenocorticotropin receptor: poor correlation of phenotype and genotype. J Clin Endocrinol Metab 1999;84: 2766–2770. 273 Brown MS, Kovanen PT, Goldstein JL. Receptor-mediated uptake of lipoprotein-cholesterol and its utilization for steroid synthesis in the adrenal cortex. Recent Prog Horm Res 1979;35:215–257. 274 Pedersen RC, Brownie AC. Adrenocortical response to corticotropin is potentiated by part of the amino-terminal region of procorticotropin/endorphin. Proc Natl Acad Sci USA 1980;77:2239–2243. 275 Jefcoate CR, Simpson ER, Boyd GS. Spectral properties of rat adrenalmitochondrial cytochrome P-450. Eur J Biochem 1974;42:539–551. 276 Privalle CT, Crivello JF, Jefcoate CR. Regulation of intramitochondrial cholesterol transfer to side-chain cleavage cytochrome P-450 in rat adrenal gland. Proc Natl Acad Sci USA 1983;80:702–706. 277 Papadopoulos V, Brown AS, Hall PF. Calcium-calmodulin-dependent phosphorylation of cytoskeletal proteins from adrenal cells. Mol Cell Endocrinol 1990;74:109–123. 278 Miller WL, Strauss JF. Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR. J Steroid Biochem Mol Biol 2001; 69:131–141. 279 Simpson ER. Cholesterol side-chain cleavage, cytochrone P450, and the control of steroidogenesis. Mol Cell Endocrinol 1979;13:213–227. 280 Yago N, Ichii S. Submitochondrial distribution of components of the steroid 11 beta-hydroxylase and cholesterol sidechain-cleaving enzyme systems in hog adrenal cortex. J Biochem (Tokyo) 1969;65:215–224. 281 Churchill PF, Kimura T. Topological studies of cytochromes P-450scc and P-45011 beta in bovine adrenocortical inner mitochondrial membranes. Effects of controlled tryptic digestion. J Biol Chem 1979;254:10443–10448. 282 Orme-Johnson NR. Distinctive properties of adrenal cortex mitochondria. Biochim Biophys Acta 1990;1020:213–231. 283 Miller WL. Molecular biology of steroid hormone synthesis. [Review]. Endocrine Reviews 1988;9:295–318. 284 Saez JM, Begeot M, Durand P. [ACTH receptors]. Ann Endocrinol (Paris) 1989; 50:409–417. 285 Tepperman J, Engel FL, Long CNH. A review of adrenal cortical hypertrophy. Endocrinol 1943;32:373–402. 286 Smith PE. Hypophysectomy and a replacement therapy in the rat. Amer J Anta 1930;45:205–273. 287 Ney RL, Dexter RN, Davis WW et al. A study of mechanisms by which adrenocorticotropic hormone maintains adrenal steroidogenic responsiveness. J Clin Invest 1967;46:1916–1924. 288 Ingle DJ. The functional interrelationship of anterior pituitary and the adrenal cortex. Ann Intern Med 1951;35:652–672. 289 Wyllie AH, Kerr JF, Macaskill IA et al. Adrenocortical cell deletion: the role of ACTH. J Pathol 1973;111:85–94. 290 Farese RV, Reddy WJ. Observations on the interrelations between adrenal protein, RNA and DNA during prolonged ACTH administration. Biocem Biophys Acta 1963;76:145–148. 291 Imai T, Seo H, Murata Y et al. Adrenocorticotropin increases expression of c-fos and beta-actin genes in the rat adrenals. Endocrinology 1990;127: 1742–1747.

292 Gospodarowicz D, Ill CR, Hornsby PJ et al. Control of bovine adrenal cortical cell proliferation by fibroblast growth factor. Lack of effect of epidermal growth factor. Endocrinology 1977;100:1080–1089. 293 Masui H, Garren LD. Inhibition of replication in functional mouse adrenal tumor cells by adrenocorticotropic hormone mediated by adenosine 3¢:5¢cyclic monophosphate. Proc Natl Acad Sci USA 1971;68:3206–3210. 294 Ramachandran J, Suyama AT. Inhibition of replication of normal adrenocortical cells in culture by adrenocorticotropin. Proc Natl Acad Sci USA 1975;72:113–117. 295 Rao AJ, Long JA, Ramachandran J. Effects of antiserum to adrenocorticotropin on adrenal growth and function. Endocrinology 1978;102:371–378. 296 Dallman MF, Engeland WC, Holzwarth MA et al. Adrenocorticotropin inhibits compensatory adrenal growth after unilateral adrenalectomy. Endocrinology 1980;107:1397–1404. 297 Estivariz FE, Iturriza F, McLean C et al. Stimulation of adrenal mitogenesis by N-terminal proopiocortin peptides. Nature 1982;297:419–422. 298 Estivariz FE, Morano MI, Carino M et al. Adrenal regeneration in the rat is mediated by mitogenic N-terminal pro-opiomelanocortin peptides generated by changes in precursor processing in the anterior pituitary. J Endocrinol 1988;116:207–216. 299 Engeland WC, Shinsako J, Dallman MF. Corticosteroids and ACTH are not required for compensatory adrenal growth. Am J Physiol 1975;229: 1461–1464. 300 Dallman MF, Engelmand WC, Shinsako J. Compensatory adrenal growth: a neurally mediated reflex. Am J Physiol 1976;231:408–414. 301 Albright F. Osteoporosis. Annals of Internal Medicine 1947;27:861–882. 302 Ishihara F, Komatsu M, Yamada T et al. Role of dehydroepiandrosterone and dehydroepiandrosterone sulfate for the maintenance of axillary hair in women. Horm Metab Res 1993;25:34–36. 303 Stewart ME, Downing DT, Cook JS et al. Sebaceous gland activity and serum dehydroepiandrosterone sulfate levels in boys and girls. Archives of Dermatology 1992;128:1345–1348. 304 Rosenfield RL, Grossman BJ, Ozoa N. Plasma 17-ketosteroids and testosterone in prepubertal children before and after ACTH administration. J Clin Endocrinol Metab 1971;33:249–253. 305 Rosenfield RL. Plasma 17-ketosteroids and 17-beta hydroxysteroids in girls with premature development of sexual hair. J Pediatr 1971;79: 260–266. 306 August GP, Hung W, Mayes DM. Plasma androgens in premature pubarche: value of 17 alpha-hydroxyprogesterone in differentiation from congenital adrenal hyperplasia. J Pediatr 1975;87:246–249. 307 Korth-Schutz S, Levine LS, New MI. Serum androgens in normal prepubertal and pubertal children and in children with precocious adrenarche. J Clin Endocrinol Metab 1976;42:117–124. 308 Warne GL, Carter JN, Faiman C et al. Hormonal changes in girls with precocious adrenarche: a possible role for estradiol or prolactin. J Pediatr 1978;92:743–747. 309 Sizonenko PC, Paunier L. Hormonal changes in puberty III: Correlation of plasma dehydroepiandrosterone, testosterone, FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison’s disease or hypogonadism or with premature or late adrenarche. J Clin Endocrinol Metab 1975;41:894–904. 310 Parker LN, Odell WD. Control of adrenal androgen secretion. Endocr Rev 1980;1:392–410. 311 Vaitukaitis JL, Dale SL, Melby JC. Role of ACTH in the secretion of free dehydroepiandrosterone and its sulfate ester in man. J Clin Endocrinol Metab 1969;29:1443–1447. 312 Rosenfeld RS, Hellman L, Roffwarg H et al. Dehydroisoandrosterone is secreted episodically and synchronously with cortisol by normal man. J Clin Endocrinol Metab 1971;33:87–92. 313 Irvine WJ, Toft AD, Wilson KS et al. The effect of synthetic corticotropin analogues on adrenocortical, anterior pituitary and testicular function. J Clin Endocrinol Metab 1974;39:522–529. 314 Migeon C, Keller A, Lawrence B et al. DHA and androsterone levels in human plasma. J Clin Endocrinol Metab 1957;17:1051–1062. 315 Parker LN, Sack J, Fisher DA et al. The adrenarche: prolactin, gonadotropins, adrenal androgens, and cortisol. J Clin Endocrinol Metab 1978;46:396–401. 316 Linder BL, Esteban NV, Yergey AL et al. Cortisol production rate in childhood and adolescence [see comments]. J Pediatr 1990;117:892–896. 317 Cutler Jr GB, Glenn M, Bush M et al. Adrenarche: a survey of rodents, domestic animals, and primates. Endocrinology 1978;103:2112–2118. 318 Shepard TH, Landing BH, Mason DG. Familial Addison’s disease. Case reports of two sisters with corticoid deficiency unassociated with hypoaldosteronism. Am J Dis Child 1959;97:154–162.

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398 Bultman SJ, Michaud EJ, Woychik RP. Molecular characterization of the mouse agouti locus. Cell 1992;71:1195–1204. 399 Kiefer LL, Veal JM, Mountjoy KG et al. Melanocortin receptor binding determinants in the agouti protein. Biochemistry 1998;37:991–997. 400 Willard DH, Bodnar W, Harris C et al. Agouti structure and function: characterization of a potent alpha-melanocyte stimulating hormone receptor antagonist. Biochemistry 1995;34:12341–12346. 401 Kwon HY, Bultman SJ, Loffler C et al. Molecular structure and chromosomal mapping of the human homolog of the agouti gene. Proc Natl Acad Sci USA 1994;91:9760–9764. 402 Wilson BD, Ollmann MM, Kang L et al. Structure and function of ASP, the human homolog of the mouse agouti gene. Hum Mol Genet 1995;4:223–230. 403 Yang YK, Ollmann MM, Wilson BD et al. Effects of recombinant agoutisignaling protein on melanocortin action. Mol Endocrinol 1997;11:274–280. 404 Kiefer LL, Ittoop OR, Bunce K et al. Mutations in the carboxyl terminus of the agouti protein decrease agouti inhibition of ligand binding to the melanocortin receptors. Biochemistry 1997;36:2084–2090. 405 Yen TT, Gill AM, Frigeri LG et al. Obesity, diabetes, and neoplasia in yellow A(vy)/-mice: ectopic expression of the agouti gene. Faseb J 1994;8:479–488. 406 Michaud EJ, Bultman SJ, Klebig ML et al. A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation. Proc Natl Acad Sci USA 1994;91:2562–2566. 407 Miller MW, Duhl DM, Vrieling H et al. Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation. Genes Dev 1993;7:454–467. 408 Shutter JR, Graham M, Kinsey AC et al. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 1997;11:593–602. 409 Ollmann MM, Wilson BD, Yang YK et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein [published erratum appears in Science 1998 Sep 11;281(5383):1615]. Science 1997;278:135–138. 410 Rosenfeld RD, Zeni L, Welcher AA et al. Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein. Biochemistry 1998;37:16041–16052. 411 Yang YK, Thompson DA, Dickinson CJ et al. Characterization of Agoutirelated protein binding to melanocortin receptors. Mol Endocrinol 1999; 13:148–155. 412 Fong TM, Mao C, MacNeil T et al. ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem Biophys Res Commun 1997;237:629–631. 413 Zhu Q, Bateman A, Singh A et al. Isolation and biological activity of corticostatic peptides (anti-ACTH). Endocr Res 1989;15:129–149. 414 Cervini LA, Gray WR, Kaiser R et al. Rat corticostatin R4: synthesis, disulfide bridge assignment, and in vivo activity. Peptides 1995;16:837–842. 415 Tatro JB. Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides. [Review] [224 refs]. Neuroimmunomodulation 1996;3:259–284. 416 de Wied D, Jolles J. Neuropeptides derived from pro-opiocortin: behavioral, physiological, and neurochemical effects. Physiol Rev 1982;62:976–1059. 417 Dunn AJ. Studies on the neurochemical mechanisms and significance of ACTH-induced grooming. Ann NY Acad Sci 1988;525:150–168. 418 Bertolini A, Gessa GA, Ferrari W. Penile erection and ejaculation: a central effect of ACTH-like peptides in mammals. In: Sandler M, Gessa GA. eds. Sexual Behavior, Pharmacology and Biochemistry. NY: Raven Press, 1975: 247–257. 419 Vergoni AV, Bertolini A, Mutulis F et al. Differential influence of a selective melanocortin MC4 receptor antagonist (HS014) on melanocortin-induced behavioral effects in rats. Eur J Pharmacol 1998;362:95–101. 420 Argiolas A, Melis MR, Murgia S et al. ACTH- and alpha-MSH-induced grooming, stretching, yawning and penile erection in male rats: site of action in the brain and role of melanocortin receptors. Brain Res Bull 2000;51: 425–431. 421 Wessells H, Fuciarelli K, Hansen J et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol 1998;160:389–393. 422 Strand FL, Stoboy H, Cayer A. A possible direct action of ACTH on nerve and muscle. Neuroendocrinology 1973;13:1–20. 423 Strand FL, Kung TT. ACTH accelerates recovery of neuromuscular function following crushing of peripheral nerve. Peptides 1980;1:135–138. 424 Strand FL, Rose KJ, King JA et al. ACTH modulation of nerve development and regeneration. Prog Neurobiol 1989;33:45–85. 425 Gispen WH, Verhaagen J, Bar D. ACTH/MSH-derived peptides and peripheral nerve plasticity: neuropathies, neuroprotection and repair. Prog Brain Res 1994;100:223–229.

Chapter 2 426 Swaab DF, Visser M, Tilders FJ. Stimulation of intra-uterine growth in rat by alpha-melanocyte-stimulating hormone. J Endocrinol 1976;70:445–455. 427 Swaab DF, Martin JT. Functions of alpha-melanotropin and other opiomelanocortin peptides in labour, intrauterine growth and brain development. Ciba Found Symp 1981;81:196–217. 428 Murphy MT, Richards DB, Lipton JM. Antipyretic potency of centrally administered alpha-melanocyte stimulating hormone. Science 1983;221: 192–193. 429 Klein MC, Hutchins PM, Lymangrover JR et al. Pressor and cardioaccelerator effects of gamma MSH and related peptides. Life Sci 1985;36:769–775. 430 Li SJ, Varga K, Archer P et al. Melanocortin antagonists define two distinct pathways of cardiovascular control by alpha- and gamma-melanocytestimulating hormones. J Neurosci 1996;16:5182–5188. 431 Lymangrover JR, Buckalew VM, Harris J et al. Gamma-2MSH is natriuretic in the rat. Endocrinology 1985;116:1227–1229. 432 Orias R, McCann SM. Natriuretic effect of alpha melanocyte stimulating hormone (-MSH) in hypophysectomized or adrenalectomized rats. Proc Soc Exp Biol Med 1972;139:872–876. 433 Orias R, McCann SM. Natriuresis induced by alpha and beta melanocyte stimulating hormone (MSH) in rats. Endocrinology 1972;90:700–706. 434 Chen XW, Ying WZ, Valentin JP et al. Mechanism of the natriuretic action of gamma-melanocyte-stimulating hormone. Am J Physiol 1997;272: R1946–R1953. 435 Veldhuis JD, Iranmanesh A, Johnson ML et al. Amplitude, but not frequency, modulation of adrenocorticotropin secretory bursts gives rise to the nyctohemeral rhythm of the corticotropic axis in man. J Clin Endocrinol Metab 1990;71:452–463. 436 Desir D, Van Cauter E, Beyloos M et al. Prolonged pulsatile administration of ovine corticotropin-releasing hormone in normal man. J Clin Endocrinol Metab 1986;63:1292–1299. 437 Veldhuis JD, Iranmanesh A, Johnson ML et al. Twenty-four-hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. J Clin Endocrinol Metab 1990;71:1616–1623. 438 Horrocks PM, Jones AF, Ratcliffe WA et al. Patterns of ACTH and cortisol pulsatility over twenty-four hours in normal males and females. Clin Endocrinol (Oxf ) 1990;32:127–134. 439 Iranmanesh A, Lizarralde G, Johnson ML et al. Circadian, ultradian, and episodic release of beta-endorphin in men, and its temporal coupling with cortisol. J Clin Endocrinol Metab 1989;68:1019–1026. 440 Krishnan KR, Ritchie JC, Saunders W et al. Nocturnal and early morning secretion of ACTH and cortisol in humans. Biol Psychiatry 1990;28: 47–57. 441 Schulte HM, Chrousos GP, Gold PW et al. Continuous administration of synthetic ovine corticotropin-releasing factor in man. Physiological and pathophysiological implications. J Clin Invest 1985;75:1781–1785. 442 Keller Wood ME, Dallman MF. Corticosteroid inhibition of ACTH secretion. Endocr Rev 1984;5:1–24. 443 DeBold CR, Jackson RV, Kamilaris TC et al. Effects of ovine corticotropinreleasing hormone on adrenocorticotropin secretion in the absence of glucocorticoid feedback inhibition in man. J Clin Endocrinol Metab 1989;68:431–437. 444 Totani Y, Niinomi M, Takatsuki K et al. Effect of metyrapone pretreatment on adrenocorticotropin secretion induced by corticotropin-releasing hormone in normal subjects and patients with Cushing’s disease. J Clin Endocrinol Metab 1990;70:798–803. 445 Watson AC, Rosenfield RL, Fang VS. Recovery from glucocorticoid inhibition of the responses to corticotrophin-releasing hormone. Clin Endocrinol (Oxf ) 1988;28:471–477. 446 Schopohl J, Hauer A, Kaliebe T et al. Repetitive and continuous administration of human corticotropin releasing factor to human subjects. Acta Endocrinol (Copenh) 1986;112:157–165. 447 Avgerinos PC, Nieman LK, Oldfield EH et al. The effect of pulsatile human corticotropin-releasing hormone administration on the adrenal insufficiency that follows cure of Cushing’s disease. J Clin Endocrinol Metab 1989;68: 912–916. 448 Raff H. Glucocorticoid inhibition of neurohypophysial vasopressin secretion. Am J Physiol 1987;252:R635–R644. 449 Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism [see comments]. N Engl J Med 1989;321:492–496. 450 Bouley R, Breton S, Sun T et al. Nitric oxide and atrial natriuretic factor stimulate cGMP-dependent membrane insertion of aquaporin 2 in renal epithelial cells. J Clin Invest 2000;106:115–126.

Adrenocorticotropin

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451 Suda T, Tomori N, Yajima F et al. A short negative feedback mechanism regulating corticotropin-releasing hormone release. J Clin Endocrinol Metab 1987;64:909–913. 452 Van Cauter E, Polonsky K, Scheen AJ. Role of circadian rhythm and sleep in human glucose regulation. Endocr Rev 1997;18:716–738. 453 Moore RY, Eichler VB. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 1972;42:201–206. 454 Follenius M, Brandenberger G. Plasma free cortisol during secretory episodes. J Clin Endocrinol Metab 1986;62:609–612. 455 Dallman MF, Strack AM, Akana SF et al. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. [Review] [26 refs.] Front Neuroendocrinol 1993;14:303–347. 456 Van Cauter E, Refetoff S. Multifactorial control of the 24-hour secretory profiles of pituitary hormones. J Endocrinol Invest 1985;8:381–391. 457 Dallman MF, Engeland WC, Rose JC et al. Nycthemeral rhythm in adrenal responsiveness to ACTH. Am J Physiol 1978;235:R210–R218. 458 Dijkstra I, Binnekade R, Tilders FJ. Diurnal variation in resting levels of corticosterone is not mediated by variation in adrenal responsiveness to adrenocorticotropin but involves splanchnic nerve integrity. Endocrinology 1996;137:540–547. 459 Iannotta F, Magnoli L, Visconti G et al. Differences in cortisol, aldosterone and testosterone responses to ACTH 1–17 administered at two different times of day. Chronobiologia 1987;14:38–46. 460 Sensi S, Capani F, De Remigis P et al. Circadian time structure of pituitary and adrenal response to CRF, TRH and LHRH. Prog Clin Biol Res 1990;341:535–542. 461 Suda T, Tomori N, Yajima F et al. Immunoreactive corticotropin-releasing factor in human plasma. J Clin Invest 1985;76:2026–2029. 462 Watabe T, Tanaka K, Kumagae M et al. Diurnal rhythm of plasma immunoreactive corticotropin-releasing factor in normal subjects. Life Sci 1987;40:1651–1655. 463 Hindmarsh KW, Tan L, Sankaran K et al. Diurnal rhythms of cortisol, ACTH, and beta-endorphin levels in neonates and adults. West J Med 1989;151: 153–156. 464 Sasaki A, Shinkawa O, Yoshinaga K. Placental corticotrophin-releasing hormone may be a stimulator of maternal pituitary adrenocorticotropic hormone secretion in humans. J Clin Invest 1989;84:1997–2001. 465 Muglia LJ, Jacobson L, Weninger SC et al. Impaired diurnal adrenal rhythmicity restored by constant infusion of corticotropin-releasing hormone, in corticotropin-releasing hormone-deficient mice. Journal of Clinical Investigation 1997;99:2923–2929. 466 Muglia LJ, Jacobson L, Luedke C et al. Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency [see comments]. J Clin Invest 2000 May 2000;105:1269–1277. 467 Ellis MJ, Schmidli RS, Donald RA et al. Plasma corticotrophin-releasing factor and vasopressin responses to hypoglycaemia in normal man. Clin Endocrinol (Oxf ) 1990;32:93–100. 468 Decherney GS, DeBold CR, Jackson RV et al. Effect of ovine corticotropinreleasing hormone administered during insulin-induced hypoglycemia on plasma adrenocorticotropin and cortisol. J Clin Endocrinol Metab 1987;64: 1211–1218. 469 Adler GK, Majzoub JA. Influence of infused hypertonic saline on the response to insulin-induced hypoglycemia in man. J Clin Endocrinol Metab 1987;65: 116–121. 470 Luger A, Deuster PA, Gold PW et al. Hormonal responses to the stress of exercise. Adv Exp Med Biol 1988;245:273–280. 471 Deuster PA, Chrousos GP, Luger A et al. Hormonal and metabolic responses of untrained, moderately trained, and highly trained men to three exercise intensities. Metabolism 1989;38:141–148. 472 Janal MN, Colt EW, Clark WC et al. Pain sensitivity, mood and plasma endocrine levels in man following long-distance running: effects of naloxone. Pain 1984;19:13–25. 473 Pitts AF, Preston MA, II, Jaeckle RS et al. Simulated acute hemorrhage through lower body negative pressure as an activator of the hypothalamic–pituitary–adrenal axis. Horm Metab Res 1990;22:436–443. 474 Udelsman R, Chrousos GP. Hormonal responses to surgical stress. Adv Exp Med Biol 1988;245:265–272. 475 Udelsman R, Norton JA, Jelenich SE et al. Responses of the hypothalamic– pituitary–adrenal and renin-angiotensin axes and the sympathetic system during controlled surgical and anesthetic stress. J Clin Endocrinol Metab 1987; 64:986–994. 476 Udelsman R, Ramp J, Gallucci WT et al. Adaptation during surgical stress. A reevaluation of the role of glucocorticoids. J Clin Invest 1986;77: 1377–1381.

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Hypothalamic–Pituitary Function

477 Oltras CM, Mora F, Vives F. Beta-endorphin and ACTH in plasma: effects of physical and psychological stress. Life Sci 1987;40:1683–1686. 478 Voigt K, Ziegler M, Grunert Fuchs M et al. Hormonal responses to exhausting physical exercise: the role of predictability and controllability of the situation. Psychoneuroendocrinology 1990;15:173–184. 479 Arduini D, Rizzo G, Parlati E et al. Modifications of ultradian and circadian rhythms of fetal heart rate after fetal-maternal adrenal gland suppression: a double blind study. Prenat Diagn 1986;6:409–417. 480 Price DA, Close GC, Fielding BA. Age of appearance of circadian rhythm in salivary cortisol values in infancy. Arch Dis Child 1983;58:454–456. 481 Onishi S, Miyazawa G, Nishimura Y et al. Postnatal development of circadian rhythm in serum cortisol levels in children. Pediatrics 1983;72:399–404. 482 Attanasio A, Rosskamp R, Bernasconi S et al. Plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone response to corticotropin-releasing factor in normal children during pubertal development. Pediatr Res 1987;22:41–44. 483 Ghizzoni L, Virdis R, Ziveri M et al. Adrenal steroid, cortisol, adrenocorticotropin, and beta-endorphin responses to human corticotropinreleasing hormone stimulation test in normal children and children with premature pubarche. J Clin Endocrinol Metab 1989;69:875–880. 484 McEwen BS. The neurobiology of stress: from serendipity to clinical relevance. [Review] [157 refs]. Brain Res 2000 Dec 15 2001;886:172–189. 485 Elenkov IJ, Wilder RL, Chrousos GP et al. The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. [Review] [445 refs]. Pharmacol Rev 2000 Dec 2001;52:595–638. 486 Blalock JE. Proopiomelanocortin and the immune-neuroendocrine connection. [Review] [68 refs]. Ann NY Acad Sci 1999;885:161–172. 487 Ottaviani E, Franchini A, Genedani S. ACTH and its role in immuneneuroendocrine functions. A comparative study. Curr Pharm Des 1999;5: 673–681. 488 Elenkov IJ, Webster EL, Torpy DJ et al. Stress, corticotropin-releasing hormone, glucocorticoids, and the immune/inflammatory response: acute and chronic effects. [Review] [59 refs]. Ann NY Acad Sci 1999;876:1–11. 489 Cavagnaro J. Molecular basis for the bidirectional modulation of the neuroendocrine and the immune systems. Year Immunol 1986;2:303–322. 490 Reichlin S. Neuroendocrine-immune interactions. N Engl J Med 1993;329: 1246–1253. 491 Eskay RL, Grino M, Chen HT. Interleukins, signal transduction, and the immune system-mediated stress response. Adv Exp Med Biol 1990;274: 331–343. 492 Kavelaars A, Ballieux RE, Heijnen CJ. The role of IL-1 in the corticotropinreleasing factor and arginine- vasopressin-induced secretion of immunoreactive beta-endorphin by human peripheral blood mononuclear cells. J Immunol 1989;142:2338–2342. 493 Westly HJ, Kleiss AJ, Kelley KW et al. Newcastle disease virus-infected splenocytes express the proopiomelanocortin gene. J Exp Med 1986;163: 1589–1594. 494 Lolait SJ, Clements JA, Markwick AJ et al. Pro-opiomelanocortin messenger ribonucleic acid and posttranslational processing of beta endorphin in spleen macrophages. J Clin Invest 1986;77:1776–1779. 495 Karalis K, Sano H, Redwine J et al. Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo. Science 1991;254:421–423. 496 Muglia LJ, Jenkins NA, Gilbert DJ et al. Expression of the mouse corticotropin-releasing hormone gene in vivo and targeted inactivation in embryonic stem cells. Journal of Clinical Investigation 1994;93:2066–2072. 497 Scheithauer BW. Surgical pathology of the pituitary: the adenomas. Part II. Pathol Annu 1984;19:269–329. 498 Saeger W, Geisler F, Ludecke DK. Pituitary pathology in Cushing’s disease. Pathol Res Pract 1988;183:592–595. 499 Herman V, Fagin J, Gonsky R et al. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990;71:1427–1433. 500 Hori T, Nishiyama F, Anno Y et al. Differences in glycoconjugates of adrenocorticotropic hormone-secretory granules between nonadenomatous pituitary cells and adenoma cells as detected by double labeling. Neurosurgery 1988;23:52–57. 501 Challa VR, Marshall RB, Hopkins MB et al. Pathobiologic study of pituitary tumors: report of 62 cases with a review of the recent literature. Hum Pathol 1985;16:873–884.

502 Apletalina V, Muller L, Lindberg I. Mutations in the catalytic domain of prohormone convertase 2 result in decreased binding to 7B2 and loss of inhibition with 7B2 C-terminal peptide. J Biol Chem 2000;275:14667–14677. 503 Schteingart DE, Chandler WF, Lloyd RV et al. Cushing’s syndrome caused by an ectopic pituitary adenoma. Neurosurgery 1987;21:223–227. 504 Axiotis CA, Lippes HA, Merino MJ et al. Corticotroph cell pituitary adenoma within an ovarian teratoma: A new cause of Cushing’s syndrome. Am J Surg Pathol 1987;11:218–224. 505 Neilson K, de Chadarevian JP. Ectopic anterior pituitary corticotropic tumour in a six-year-old boy. Histological, ultrastructural and immunocytochemical study. Virchows Arch [A] 1987;411:267–273. 506 Karl M, Lamberts SW, Koper JW et al. Cushing’s disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. Proc Assoc Am Physicians 1996;108:296–307. 507 Karl M, Von Wichert G, Kempter E et al. Nelson’s syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene. J Clin Endocrinol Metab 1996;81:124–129. 508 Gabrilove JL, Anderson PJ, Halmi NS. Pituitary pro-opiomelanocortin-cell carcinoma occurring in conjunction with a glioblastoma in a patient with Cushing’s disease and subsequent Nelson’s syndrome. Clin Endocrinol (Oxf ) 1986;25:117–126. 509 Nawata H, Higuchi K, Ikuyama S et al. Corticotropin-releasing hormone- and adrenocorticotropin-producing pituitary carcinoma with metastases to the liver and lung in a patient with Cushing’s disease. J Clin Endocrinol Metab 1990;71:1068–1073. 510 Gould VE, Lee I, Warren WH. Immunohistochemical evaluation of neuroendocrine cells and neoplasms of the lung. Pathol Res Pract 1988;183:200–213. 511 Kasurinen J, Syrjanen KJ. Peptide hormone immunoreactivity and prognosis in small-cell carcinoma of the lung. Respiration 1986;49:61–67. 512 Sieber SC, Gelfman NA, Dandurand R et al. Ectopic ACTH and adrenal myelolipoma. Conn Med 1989;53:7–10. 513 Herbst WM, Kummer W, Hofmann W et al. Carcinoid tumors of the thymus. An immunohistochemical study. Cancer 1987;60:2465–2470. 514 Arioglu E, Doppman J, Gomes M et al. Cushing’s syndrome caused by corticotropin secretion by pulmonary tumorlets. N Engl J Med 1998;339:883–886. 515 Raux Demay MC, Proeschel MF, de Keyzer Y et al. Characterization of human corticotrophin-releasing hormone and pro-opiomelanocortin-related peptides in a thymic carcinoid tumour responsible for Cushing’s syndrome. Clin Endocrinol (Oxf ) 1988;29:649–657. 516 Suda T, Kondo M, Totani R et al. Ectopic adrenocorticotropin syndrome caused by lung cancer that responded to corticotropin-releasing hormone. J Clin Endocrinol Metab 1986;63:1047–1051. 517 Sakurai H, Yoshiike Y, Isahaya S et al. A case of ACTH-producing pheochromocytoma. Am J Med Sci 1987;294:258–261. 518 Mendonca BB, Arnhold IJ, Nicolau W et al. Cushing’s syndrome due to ectopic ACTH secretion by bilateral pheochromocytomas in multiple endocrine neoplasia type 2A [letter]. N Engl J Med 1988;319:1610–1611. 519 Southgate HJ, Archbold GP, el Sayed ME et al. Ectopic release of GHRH and ACTH from an adenoid cystic carcinoma resulting in acromegaly and complicated by pituitary infarction. Postgrad Med J 1988;64: 145–148. 520 Watanobe H, Yoshioka M, Takebe K. Ectopic ACTH syndrome due to Grawitz tumor. Horm Metab Res 1988;20:453–456. 521 Werner S, Jacobsson B, Bostrom L et al. Cushing’s syndrome due to an ACTH-producing neuroendocrine tumour in the nasal roof. Acta Med Scand 1985;217:235–240. 522 Long SI. ACTH-producing apudoma metastatic to the liver. J Natl Med Assoc 1987;79:122–123. 523 de Keyzer Y, Bertagna X, Luton JP et al. Variable modes of proopiomelanocortin gene transcription in human tumors. Mol Endocrinol 1989;3: 215–223. 524 Melmed S, Yamashita S, Kovacs K et al. Cushing’s syndrome due to ectopic proopiomelanocortin gene expression by islet cell carcinoma of the pancreas. Cancer 1987;59:772–778.

C h a p t e r

3 Growth Hormone Vivien S. Herman-Bonert Shlomo Melmed

GROWTH HORMONE (GH) GENE STRUCTURE

Somatotroph Development and Differentiation

The human GH genomic locus spans approximately 66 kb and contains a cluster of five highly conserved genes [1] located on the long arm of human chromosome 17 at bands q22–24 [2]. The 5¢ to 3¢ arrangement of these genes is hGHN, hCS-L, hCS-A, hGH-V, and hCS-B [1], all of which have the same basic structure consisting of five exons separated by four introns [1]. The hGH-N gene is transcribed only in somatotrophs of the anterior pituitary while the hCS-A and hCS-B genes are expressed in placental trophoblasts [3]. hGH-N codes for a 22-kDa protein consisting of 191 amino acids. Approximately 10% of pituitary GH is presented as a 20-kDa variant lacking amino acid residues 32–46 [4,5], and probably arising as a result of an alternate splicing mechanism [6]. hGH-V is expressed by the syncytiotrophoblast of the placenta during the second and third trimesters of gestation [7,8], hGH-V messenger RNA (mRNA) encodes 22kDa protein secreted form which can be detected in the maternal circulation from midpregnancy [9] and a minor form hGH-V2 which is predicted to be a 26-kDa protein product [10]. The role of hGH-V is unknown, however, the rise in hGH-V concentrations in maternal serum correlates with a fall in hGH-N concentrations, suggesting the possibility of a feedback loop on the maternal hypothalamic pituitary axis [9]. Postpartum, GH-V levels drop rapidly and are undetectable in the circulation after one hour [9]. hGH-V has a greater binding affinity than hGH-N for somatogen vs lactogen receptors [11]. hGH-V and hGH-N also differ in their ratio of somatogen to lactogen bioactivities, with hGH-V having the greater ratio [12]. In addition, hGH-V has been shown to influence carbohydrate and fat metabolism in rat adipose tissues in a manner similar to that of hGH-N [13]. The hCS-L gene is not known to yield a product [14].

GH is specifically expressed in the somatotroph cell of the anterior pituitary which develops in a time-and-space dependent manner. Expression of the a-subunit transcript in the hypophyseal placode within ectoderm of the pharynx prior to the formation of Rathke’s pouch defines the onset of pituitary organogenesis [15]. The mammalian anterior pituitary develops from Rathke’s pouch during the early stages of embryonic development [16]. Its ventral epithelium serves as the anterior pituitary anlagen while the dorsal epithelium generates the intermediate lobe of the pituitary. A process of cytodifferentiation gives rise to the different hormone-producing cells [17]. Acidophils are the progenitors for both GH-producing somatotrophs and prolactin producing lactotrophs (PRL), while basophils give rise to cells which secrete adrenocorticotrophic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) [17]. Cells of the intermediate lobe produce pro-opiomelanocortin (POMC) gene-related peptides [17]. Experimental evidence obtained from transgenic mice studies suggests that most PRL-expressing cells arose from GH-producing cells [18]. Ablation of somatotrophs by expression of GH-diphtheria toxin and GH-thymidine kinase fusion genes inserted into the germ line of transgenic mice results in the elimination of the majority of lactotrophs; however a small percentage of lactotrophs escape destruction [18,19]. This suggests that the majority of PRLproducing cells arose from postmitotic somatotrophs. The Pit-I gene transcript and POUIFI protein are found in somatotrophs, lactotrophs and thyrotrophs [15]. This suggests an mRNA-specific translational control as part of the developmental process [15]. The actions of Pit-1 protein are complemented by other factors required to achieve the 79

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physiologic patterns of cell-specific gene activation [15]. The estrogen receptor, which is activated subsequent to the appearance of Pit-1, appears to mediate in part a progressive increase in PRL gene expression characteristic of mature lactotrophs. Inherited isolated GH deficiency and short stature may be attributed to mutations of transcription factors, the GH-1 gene, the GHRH receptor, the GH receptor or rarely IGF-related molecules.

Promoter Structure The hGH promoter region contains cis-elements which mediate both pituitary-specific and hormone-specific signaling [20,21]. DNase footprinting reveals several proteinbinding sites within 300 bp of the 5¢ flanking DNA. One one of these proteins is unique to pituitary cells, suggesting that it plays a major role in tissues-specific expression of the GH gene [20,22]. This factor, alternately named Pit-1 or GHF-1 [23,24], binds to two sites centered around sequences -80 and -120. Pit-1 is a 31- or 33-kDa protein important for GH promoter activity both in vivo and in vitro [23–25]. When transferred into nonexpressing cells, Pit-1 is capable of stimulating GH-directed gene expression in nonpituitary cells [20]. In addition, Pit-1 binds to the PRL promoter [26]. Pit-1 is a member of a family of transcription factors sharing two regions of homology [27]; a highly conserved POU-specific (POUs) domain and a more divergent homeodomain (POUHD). Initial recognition of this family resulted from the cloning of complementary DNAs (cDNAs) encoding several transactivators Pit-1 [23,24], Oct1 [28,29], Oct-2 [30,31], and unc-86 [32]. The POUs domain is unique to this family of proteins but the POUHD, which is divergent, shares sequence homology and the predicted a-helical structures with classic homeodomain-containing proteins [33]. Data from mutant Pit-1 proteins suggest that while POUHD is required and sufficient for low-affinity DNA binding, the POUs domain is necessary for highaffinity binding and accurate recognition of natural Pit-1 response elements. In addition, POU domain proteins, in contrast to homeodomain proteins, require that both the POUs and POUHD contact the DNA [27]. Transcriptional activity of Pit-1 is conferred by a serine- and threoninerich N-terminal region which is different to the transcriptional contacts of other types of activation domains [27]. A variant isoform of Pit-1, Pit-1B [34], contains a 26-amino acid insertion in the transactivation domain and, like the previously described Pit-I protein, is capable of inducing both GH and PRL promoters. PROP-1, a paired homeobox protein, is required for initial commitment of Pit-1 cell lineages [35]. PROP-1 represses Rpx expression, and missense and spliced mutations of PROP-1 leading to loss of DNA-binding or transactivation leads to pituitary failure with short stature and varying degrees of thyroid failure, hypogonadism, and ACTH deficiency [36].

POUIFI [37] mutations may also lead to pituitary failure. Patients with combined pituitary hormone deficiency have predominantly GH and PRL deficiency, with variable degrees of hypothyroidism [37]. Footprinting analysis reveals the presence of a second, ubiquitous factor binding to the distal Pit-1 site [38,39]. The protected template contains a consensus sequence for the binding of Sp1, a transcription factor that recognizes the glycine-cysteine box in several viral and eukaryotic gene promoters [40–42]. Pit-1 binds to its distal site with a lower affinity [23,24], and, in addition, Pit-1 and Sp1 bind in a mutually exclusive manner to the GH promoter [38,39]. In vivo, both binding sites contribute to rat GH promoter activation [39]. Mutation of the Sp1 binding site results in a 50% reduction of promoter activity, suggesting that activation of GH by Pit-1 and Sp1 may occur through a multistage mechanism. Sequences -266/-252 of the hGH promoter contain an 8 bp recognition site for the adenoviral major late transcription factor (MLTF), also termed upstream stimulating factor (USF) [43]. A USF-like protein also binds to the upstream hGH promoter [38,43,44]. This factor contributes to one of the protected sites in the third footprint of the hGH gene promoter. USF is a basal transcription factor initially identified in Hela cell extracts [45,46]. Known targets of USF include adenovirus-2 [45,46], fibrinogen-g and the metallothionein-1 genes [47,48]. The distal part of this protected region of the hGH promoter, -290/-272, binds an insulin-inducible nuclear factor [44] that may represent an NF1 family protein [49]. A locus control region (LCR) of the hGH gene located 5¢ to the transcription start site determines somatotroph and latotroph GH expression. This genetic control also involves appropriate regulation of a chromatin domain in these pituitary cell types [50].

Hormonal Regulation of the hGH Gene Synthesis and release of GH is under control of a variety of hormonal agents, including insulin growth factor-I (IGF-I), GH-releasing hormone (GHRH), Ghrelin, somatostatin, thyroid hormone, glucocorticoids, and insulin. IGF-I inhibits GH mRNA expression as well as GH secretion in dispersed human adenoma cell cultures [51]. This effect is blocked by the monoclonal IGF-I receptor antibody a-IR3 [51]. IGF-I also attenuates basal and stimulated GH gene expression when 500 bp of the hGH gene promoter was transfected into human choriocarcinoma cells ( JEG3) or HeLa cells [52]. GHRH stimulates the release of hGH, and cyclic adenosine monophosphate (cAMP) is thought to be the second messenger for this effect. Analysis of the hGH promoter for a cAMP-responsive element (CRE) fails to reveal a consensus sequence. Two groups have reported the presence of novel CREs within -83 and -150 bp of the 5¢ flanking DNA, respectively [21,53]. CREB binding protein (CBP) is also a co-factor for Pit-1 dependent human GH

Chapter 3

activation. CBP is phosphorylateral by protein kinase A, independently of CREB [54]. The role of thyroid hormone in hGH synthesis remains unclear. Release of hGH in response to provocative stimuli is usually reduced in hypothyroid patients; however, basal GH levels and responses may be normal [55,56]. In numerous hGH gene transfer studies, absence of a T3 response has been documented [57,58]. Glucocorticoid responsiveness of the hGH gene has been demonstrated with the strongest receptor binding site being located within the first intron of the hGH gene; however, a 5¢ GRE is also present and capable of weak induction [59–61]. Insulin suppresses hGH secretion by acromegaly tumor cells in culture [62], and also attenuates basal and stimulated transient expression of a transfected hGH gene [63]. Somatostatin is synthesized in the medial preoptic area of the hypothalamus and inhibits secretion of GH from human adenoma cell cultures [64]. Thus, numerous ubiquitous factors bind to the GH promoter. In the absence of Pit-1 the promoter region is inactive, and binding of Pit-1 to the transcriptional machinery facilitates the interaction between this factor and other ubiquitous activators already bound to the promoter or subsequently activated to enhance GH transcription. This model

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81

of cooperative interaction provides an explanation for tissuespecific expression of the hGH gene by a single cell typespecific activator. CONTROL OF GH SECRETION The GH molecule, a single-chain polypeptide hormone consisting of 191 amino acids (Fig. 3.1), is synthesized, stored, and secreted by somatotroph cells. The crystal structure of human GH and GH-binding protein reveals four alpha helixes, and two identical GHBP molecules occurring within a single GH molecule [65]. Somatotrophs are located predominantly in the lateral wings of the anterior pituitary gland. Somatotrophs comprise 35% to 45% of pituitary cells and the gland contains a total of 5–15 mg of GH [66]. Circulating GH molecules are a heterogenous group of peptides [67] which comprises at least three monomeric forms and several oligomers. The monomeric moieties include a 22- and 20-kDa form, acetylated 22K, and two desamido GH’s. The 22-kDa peptide is the major physiologic GH component. The 20-kDa GH has a slower metabolic clearance than the 22-kDa form [68], which accounts for the plasma 20 : 22 ratio being higher than in the pituitary gland.

FIGURE 3.1. Amino acid structure of human growth hormone (GH). GH is a 191amino acid single-chain 21.5 kDa polypeptide with two intramolecular disulfide bonds. Fifteen percent of GH is deleted from amino acid (32–46) and is secreted as a 20 kDa protein.

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The 22-kDa peptide retains growth-promoting activity, but lacks diabetogenic effects, which are more pronounced with the 20-kDa form. The relative proportions of circulating GH molecular forms in children of various ages are quantitatively and qualitatively identical in adults. Monomeric GH forms found in the plasma of acromegalic patients are also qualitatively similar to those found in normal plasma [69].

Ontogeny of GH Levels Circulating GH is first detectable in fetal serum at the end of the first trimester, peaks at a concentration of 100 to 150 ng/ml at 20 weeks of gestation, and subsequently falls to 30 ng/ml at birth. GH levels continue to fall during infancy. During childhood, levels are similar to those in adulthood, until puberty, when circulating levels are elevated. GH levels decline after adolescent growth and remain stable until mid-adulthood, when they decline progressively through old age [70]. Decreased sensitivity of the pituitary to GHRH action with aging may contribute to these GH fluctuations with advancing age [71].

Physiologic Factors Involved in GH Secretion GH secretion is pulsatile, the anterior pituitary gland secreting bursts of GH, with almost undetectable basal levels occurring between these peaks [72]. The number of GH pulses detected depends on the frequency of blood sampling. When sampling frequency is reduced to three or fewer samples per hour, less than 0.4 GH pulses/hr are detected, and this rate increases as sampling is intensified [72]. Integrated GH levels are higher in women than in men [73], and are also enhanced in postmenopausal women following estrogen replacement [74]. In children and young adults, maximum GH secretion occurs within an hour of the onset of deep sleep (stage III or IV), with subsequent smaller peaks appearing during later sleep [75]. Effects of Sleep

A major GH secretory pulse occurs shortly after the onset of sleep, associated with the first episode of slow wave sleep [76]. Sleep stimulates GH secretion and 60% to 70% of daily GH secretion occurs during early sleep, in association with slow wave sleep [77] Rapid eye movement (REM) sleep is reduced by approximately 50% after age 50 years with significant sleep fragmentation [78]. The decline in slow wave sleep from early adulthood to midlife is paralleled by a major decline in GH secretion. This suggests that the age-related alterations in the somatotropic axis may partially reflect decreased sleep quality. Although increased PRL and ACTH concentrations occur later during sleep, their secretion is not as tightly linked to sleep patterns as is GH secretion. “Jet lag” transiently increases the height of GH peaks during the day and night, resulting in a transient increase of 24-hour

GH secretion. Jet lag also shifts the major GH secretory spike from early to late sleep [79]. Exercise

Exercise increases GH secretion probably mediated by a cholinergic mechanism [80]. Stress

GH release is stimulated by physical stress, including trauma with hypovolemic shock [81] and sepsis [82]. However, chronic debilitating diseases, including cancer, are not associated with increased GH levels [83]. Increased GHRH release, mediated by adrenergic pathways, is thought to mediate stress-induced GH secretion [84]. Emotional deprivation is associated with suppressed GH secretion [85], and subnormal GH responses to provocative stimuli have been described in endogenous depression [86]. Nutritional and Metabolic Effects

Nutritional and metabolic factors profoundly influence GH secretion. Chronic malnutrition [87] and voluntary 5-day fasting [88] are associated with elevated GH levels. Both pulse frequency and amplitude of GH secretory peaks increase with fasting [88] (Table 3.1). Obesity decreases basal and stimulated GH secretion. Insulin-induced hypoglycemia stimulates GH release 30 to 45 minutes after the glucose trough, whereas acute hyperglycemia inhibits GH secretion [89]. Diabetic patients with chronic hyperglycemia, however, do not have suppressed GH levels and in fact many poorly controlled diabetic patients have increased basal [90] and exercise-induced GH levels [91]. Central nervous system glucoreceptors appear to sense fluctuations, rather than absolute glucose levels. However, glucose homeostasis is not the major determinant of GH secretion, this being overridden by effects of sleep, exercise, stress, and by random GH bursts. A high-protein meal, and single amino acids (including arginine and leucine) administered intravenously stimulate GH secretion. Arginine may suppress endogenous somatostatin secretion and thereby stimulate GH secretion [92]. Decreased serum free fatty acid (FFA) levels cause acute GH release [93] and increased serum FFA blunt the effects of various stimuli, including arginine infusion, [94] sleep, Ldopa, and exercise [95–98] on GHRH-stimulated GH release [98].

Table 3.1. Deconvolution analysis of growth hormone (GH) secretion in adult males. From Thorner et al. [88a]

24 hr secretion Secretory bursts GH/burst

Normal

Fasting

Obesity

Middle-age

540 ± 44 12 ± 1 45 ± 4

2171 ± 333 32 ± 2 64 ± 9

77 ± 20 3 ± 0.5 24 ± 5

196 ± 65 10 ± 1 20 ± 6

Chapter 3

Growth Hormone

83

FIGURE 3.2. Schematic representation of the actions of leptin. Leptin acts either directly or by activating specific centers in the central nervous system to decrease food intake, increase energy expenditure, influence glucose and fat metabolism, and alter neuroendocrine function. From Mantzoros [100a].

FIGURE 3.3. Schematic representation of feedback loops involving leptin. Leptin, an adipocyte-derived hormone, circulates in the serum either in free form or bound to leptinbinding proteins, activates specific receptors in the hypothalamus, and alters expression of several neuropeptides; these in turn decrease appetite, increase energy expenditure by altering sympathetic and parasympathetic tone, and alter neuroendocrine function. Increasing leptin levels activate the thyroid, growth hormone, and gonadal axes and suppress the pituitary–adrenal axis. Leptin, acting directly or indirectly (by altering the levels of other hormones and neuropeptides), also influences hemopoiesis and immune function and improves glucose and fat metabolism. From Mantzoros [100a].

Leptin

Leptin, a 167 amino acid cytokine, is the product of the ob gene, expressed in white adipose tissue, stomach, placenta and possible mammary gland [99]. Leptin is thought to play a key role in the regulation of body fat mass [100]. Regulating food intake and energy expenditure (Fig. 3.2). GH has several metabolic effects, including lipolytic and anabolic effects. In turn, alterations in nutritional status, such as obesity and food deprivation, influence GH secretion. In obese subjects, GH secretion is markedly impaired. The mechanism by which metabolic status regulates GH secretion is poorly understood. As leptin receptors are present on

the hypothalamus, and leptin plays a role in hypothalamic–pituitary function in fasted animals [101], leptin may act as a metabolic signal to regulate GH secretion (Fig. 3.3). Leptin antiserum administered to normal fed rats, decreased plasma GH levels [102], implying that physiologic leptin levels may facilitate normal spontaneous GH secretion. Furthermore leptin administered to fasted rats reversed the inhibitory effect of food deprivation on in vivo GH secretion [102]. Increased SRIF release may be a factor in the suppressed GH secretion observed in fasted rats [103], possibly mediated by neuropeptide Y, as hypothalamic neuropeptide Y

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release is increased in fasted rats [104]. Leptin receptors are present in neuropeptide Y producing hypothalamic neurons [105], which synapse with somatostatin neurones [104]. Furthermore both antisera to neuropeptide Y and somatostatin reverse starvation-induced GH release [103,104]. Further studies are needed to elucidate the effects of leptin on neuropeptide Y, and somatostatin and its role as a metabolic signal in the regulation of GH secretion. In GH deficient hypopituitary adults, leptin concentrations are more elevated than would be expected from the degree of obesity [106].

Cholinergic and Serotonergic Neurotransmitters

Cholinergic and serotoninergic neurons have been implicated in the etiology of sleep-induced GH secretion [119]. Opiods

Endorphins and enkephalins stimulate GH secretion in animals [120], probably via interaction with other neurotransmitters in both the pituitary and hypothalamus. Opioids increase rat GHRH concentrations [121], and endogenous opiates probably increase GH release during severe physical stress and extreme exercise [122]. Gastrointestinal Neuropeptides

Pharmacologic Control of GH Secretion The central neurogenic control of GH is complex. Neuropeptides, neurotransmitters and opiates impinge on the hypothalamus and modulate GHRH and somatostatin (SRIF) release. The net effect of these complex influences determines the final secretory pattern of GH.

Several gastrointestinal neuropeptides stimulate GH secretion in animal models, including substance P, neurotensin, vasoactive intestinal polypeptide, peptide histidine isoleucine amide (PHI), motilin, galanin, cholecystokinin, and glucagon [123]. HYPOTHALAMIC HORMONES

Dopaminergic Neurotransmitters

Dopamine (DA) is a precursor of epinephrine and norepinephrine. Apomorphine, a central dopamine receptor agonist, stimulates GH secretion [107]. GH-deficient children have been shown to increase their growth velocity after 6 months of levodopa treatment [108]. Sixty to 90 minutes after oral l-dopa administration, adults increase their serum GH levels from 0 to 5–20 ng/ml [109]. Phentolamine, an a-adrenergic blocking agent, inhibits l-dopa-induced GH release, indicating that l-dopa may, in addition, require conversion to epinephrine or norepinephrine to exert its effect on GH secretion [110]. Catecholaminergic Neurotransmitters

Norepinephrine increases GH secretion via a-adrenergic pathways and inhibits GH release via b-adrenergic pathways [111]. Insulin-induced hypoglycemia increases GH secretion via an a2-adrenergic pathway [112], whereas clonidine acts on a1-adrenergic receptors to increase GH secretion [113]. Arginine administration, exercise, l-dopa, and antidiuretic hormone (ADH) facilitate GH secretion by a-adrenergic effects [114]. Animal studies using pharmacologic agents and passive immunization show that a-adrenergic blockade simultaneously inhibits GHRH release while stimulating SRIF release, resulting in suppressed GH secretion [115]. b2-adrenergic receptor stimulation decreases basal GH levels [116]. b-adrenergic blockade increases GHRH-induced GH release, possibly due to a b-adrenergic effect at the pituitary level or via decreased hypothalamic somatostatin release [117]. b-blockade also enhances GH release elicited by insulin-induced hypoglycemia, ADH, glucagon, and L-dopa [114]. Epinephrine may regulate GH release by decreasing somatostatin release [118], and metabolites of g-aminobutyric acid (GABA) may alter GH secretion by enhancing catecholaminergic release [110].

Thyrotropin-releasing hormone (TRH) does not stimulate GH secretion in normal subjects [124]; it does, however, induce GH secretion in about 70% of patients with acromegaly [125]. TRH also stimulates in vitro GH secretion in cultured pituitary tumor cells [126]. The discordant GH response to TRH has also been demonstrated in patients with liver disease [127], renal disease, ectopic GHRH-releasing carcinoid tumors [128], anorexia nervosa [129], and depression [130]. Administration of intravenous corticotropin-releasing hormone (CRH) increases GH secretion in a small percentage of patients with acromegaly [131] and in patients with chronic depression [132]. Gonadotropin-releasing hormone (GnRH) stimulates GH secretion in one-third of patients with acromegaly, but the mechanism is unclear [133].

Hormones Facilitating GH Secretion Physiologic glucocorticoid concentrations increase GH secretion in human pituitary cultures [134]. In acromegalic patients, dexamethasone suppresses GH secretion in vivo [135]. Supraphysiologic serum glucocorticoid concentrations retard growth in humans [136]. Cushing’s disease is also associated with growth retardation, decreased serum GH [137], and decreased pituitary GH content in the tissue surrounding the adenoma [138]. A single dose of dexamethasone administered to normal subjects suppresses GHRH-induced GH release within 12 hours. Glucocorticoids administered to normal subjects produce a dose dependent inhibition of GHRH-stimulated GH secretion, identical to that seen in Cushing’s syndrome [139,140]. Glucocorticoids have a greater inhibitory action on GHRHinduced GH secretion than clonidine or arginine [139]. In chronic hypocortisolism, GHRH-induced GH secretion is reduced [141]. To elucidate the mechanism of the blocking

Chapter 3

action of glucocorticoids on GH release, increased somatostatin secretion seems unlikely, as pyridostigmine (which blocks hypothalamic somatostatin secretion) does not increase suppressed GH levels in Cushing’s syndrome [142]; neither can IGF-I be incriminated, as IGF-I levels are normal in Cushing’s syndrome [143]. The above data exclude decreased endogenous GHRH release as the mechanism. When the glucocorticoid effect is measured acutely, i.e., at 3 hours, stimulated GH levels are measured, which remain elevated for 2 hours [144]. Acute glucocorticoidinduced GH secretion occurs with several different corticosteroid preparations including hydrocortisone, deflazacort, and dexamethasone. The short-term stimulatory effect of glucocorticoids on GH secretion is one of the most potent and also the most delayed stimulus to GH secretion, as it takes 3 hours to occur [144]. Thus glucocorticoids have short-term stimulatory effects on GH secretion and delayed inhibitory effects. Specific glucocorticoid responsive elements have been identified on the GH gene. Currently, the mechanism of action of the dual stimulation and inhibition of glucocorticoid on GH secretion has not been elucidated. Thyroid hormone increases basal and stimulated rat GH synthesis, acting directly at the level of gene expression [145]. This effect appears to be synergistic with glucocorticoids. T3 binds to nuclear receptors in rat pituitary tumor cells [146] and stimulates GH gene transcription [147]. In vitro data confirm that the hGH promoter is not thyroid hormone-responsive, while T3 strongly induces the rat GH promoter [21,148]. In hyperthyroid patients, GH secretion rate is decreased, but normalizes when patients are rendered euthyroid [149], suggesting that thyroid hormone suppresses GH secretion from the normal human somatotroph in vivo. GHRH

Hypothalamic GHRH was characterized initially by two different groups from ectopic pancreatic GHRH-secreting tumors causing acromegaly [128,150]. Analysis of one tumor revealed a 44-amino acid GHRH residue [151]; the other contained 37-, 40-, and 44-amino acid forms [152]. GHRH (1–40) and GHRH (1–44) are both found in extracts derived from the human hypothalamus. GHRH is secreted

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85

from neurons in the hypothalamic arcuate nucleus and premammillary area, with axons that project to the median eminence [153]. The hGHRH gene encodes a 108-amino acid prepro-hormone for GHRH-44 [154,155], which has a free amino terminal and amidated carboxy terminal residue. The amino terminal tyrosine appears to bestow biologic activity on the GHRH molecule (Fig. 3.4). There is considerable structural homology between GHRH and several gut peptides. The highest is between GHRH and PHI, which have 12 amino acids in common in equivalent positions [156]. Varying degrees of homology exist between GHRH and VIP, glucagon, secretin, and GIP [157]. All of these peptides stimulate GH secretion in various physiologic systems, but with lower potency than GHRH. GHRH binds to specific sites on the somatotroph membrane, resulting in increased intracellular 3¢, 5¢cAMP [158]. The GHRH receptor gene has recently been cloned and sequenced, encoding a 47-kDa protein of 423 amino acids [159]. GHRH has a selective action on GH release; it does not release other anterior pituitary or gut hormones. GHRH increases GH synthesis as well as secretion, and stimulates transcription of GH mRNA [64,160]. GHRH stimulates GH release from both stored and newly synthesized intracellular GH pools, with a greater effect on stored pools [161]. There are a number of heterogeneous GH pools, varying according to time of GH synthesis [162–164], molecular size [163], and response to provocative stimuli [163]. Somatostatin suppresses both basal and GHRHstimulated GH release, but does not affect GH biosynthesis [165]. It is thus apparent that GHRH stimulates both release and synthesis of GH independently of any effects of somatostatin. GHRH administered to normal adults elicits a prompt increase in serum GH levels, with higher levels occurring in female subjects [166]. Most acromegalic patients retain an intact GH response to administered GHRH [167]. SRIF

SRIF, a cyclic tetradecapeptide, is recognized as a heterogeneous group of molecules including quantitatively predominant, but less bioactive SRIF-14, more bioactive SRIF-28,

FIGURE 3.4. Amino acid structure of growth hormone-releasing hormone (GHRH) (1–44). GHRH (1–44) and GHRH (1–40) have similar GH-releasing potency in vivo. The tyrosine at the amino terminus confers biologic activity. Fragments as short as GHRH (1–29) exhibit full biologic activity. The carboxy terminal fragment (28–44) has no biologic activity.

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FIGURE 3.5. Amino acid structure of native somatostatin (SRIF). SRIF, a tetradecapeptide (14-amino acid peptide) designated SRIF-14, SRIF-28, which is extended at the amino terminal, and several larger forms range in size from 11.5 to 15.7 kDa.

sst

PHOSPHATASE

ADENYLCYCLASE K/Ca++ CHANNELS cAMP

Ca++

Calcineurin

Ser/Thr Phosphatase

– Exocytosis

INHIBITS SECRETION

FIGURE 3.6. SRIF receptor signaling pathway: somatostatin receptors mediate their responses via several cellular effectors such as adenylyl cyclase potassium and calcium channels and phosphatases. Adapted from Yogesh et al. [176a].

SRIF block the GH secretory response to insulin-induced hypoglycemia, exercise, arginine, morphine, levodopa, and sleep related GH release. Somatostatin exerts its biologic effects through specific membrane-bound high affinity receptors. At least five somatostatin receptor (SSTR) subtypes have been cloned [176], termed SSTRs1-5. Somatostatin receptors are coupled to guanine nucleotide protein (G), and have seven transmembrane domains. There is 42% to 60% amino acid homology among the five somatostatin receptor subtypes [177]. Somatostatin receptors mediate their responses via several cellular effectors such as adenylyl cyclase, protein phosphatases, Na+-H+ exchanger, cyclic GMP-dependent protein kinases, phospholipase C, potassium and calcium channels [176] (Fig. 3.6). The human pituitary gland expresses SSTR1, 2 and 5 [178,179], whereas human pituitary adenomas contain SSTR1, 2, 3 and [178–181]. Somatostatin analogs, octreotide and lanreotide, used to control GH hypersecretion in acromegaly, bind with high affinity to SSTR 2 and less efficiently to SSTR5 [182]. SSTR1-4 have highter affinity for SRIF-14, whereas SSTR5 bind more potently to SRIF-28 [176] (Table 3.2). GHRH and SRIF Interaction in Regulating GH Secretion

and still larger forms which range in molecular mass from 11.5 to 15.7-kDa [168] (Fig. 3.5). The SRIF precursor is a 116-amino acid prohormone consisting of a 24-amino acid signal peptide, a 64-amino acid connecting region, followed by SRIF-28 [169] which incorporates SRIF-14. Prosomatostatin is synthesized in neuronal perikarya of the anterior hypothalamic periventricular nuclei, and transported by axonal flow to the nerve terminals ending near the hypophyseal portal vessels. SRIF has also been isolated from pancreatic islets, gastrointestinal, neural and epithelial cells, and extrahypothalamic central nervous system neurons [170]. SRIF has a short plasma half-life of 2 to 3 minutes [168]. SRIF inhibits GH secretion, TSH release, TRH stimulation of TSH but not PRL [171], and pancreatic secretion of insulin and glucagon [172]. Dopamine [173], substance P, and neurotensin [174] stimulate SRIF release from the hypothalamus, while glucose inhibits SRIF secretion in cultured rat hypothalamus [174]. SRIF-28 binds to normal rat pituitary receptors with a threefold greater affinity than SRIF-14 [175]. Both SRIF14 and SRIF-28 block the effect of GHRH on GH release in vitro and in vivo in many different species. Infusions of

SRIF and GHRH secreted in independent waves from the hypothalamus interact to generate pulsatile GH release. SRIF inhibits GH secretion, while GHRH stimulates GH synthesis and secretion. GHRH stimulates pituitary GH synthesis and secretion, and also induces transcription of the GH gene [160]. SRIF suppresses GH secretion without altering GH mRNA levels [64]. GH secretion is further regulated by its target growth factor, IGF-I, which participates in a hypothalamic–pituitary–peripheral regulatory feedback system [183]. GH stimulates the liver and other peripheral tissues to produce IGF-I, which exerts a feedback effect on the hypothalamus and pituitary. IGF-I stimulates hypothalamic SRIF release [172] and inhibits pituitary GH gene transcription and GH secretion [51,184]. In vitro, IGF-I directly attenuates hGH gene expression [51]. Specific antibodies against GHRH and SRIF have been used to dissect the respective contributions of SRIF and GHRH in the generation of GH pulsatility in rats. Anti-SRIF antibody administration results in elevated baseline GH levels, with intact intervening GH pulses [185]. These studies imply that hypothalamic SRIF secretion generates GH troughs. AntiGHRH antibodies eliminate spontaneous GH surges. In humans, GH pulsatility persists when GHRH is tonically

Chapter 3 Table 3.2. receptors

Growth Hormone

87

Properties of the five cloned subtypes of human somatostatin

Properties

Somatostatin receptor Subtype 1

Subtype 2

Subtype 3

Subtype 4

Chromosomal location

14

17

22

20

16

G protein coupling

Yes

Yes

Yes

Yes

Yes

Effector system Adenylate cyclase activity Tryosine Phosphatase activity

Reduced Increased

Reduced Increased

Reduced ?

Reduced ?

Reduced ?

IC50 (nM) Somatostatin-14 Somatostatin-28 Octreotide Vapreotide (RC-160) Lanreotide (BIM-23014)

1.1 2.2 >1000 >1000 >1000

1.3 4.1 2.1 5.4 1.8

1.6 6.1 4.4–35 30.9 43

0.5 1.1 >1000 45 66

0.9 0.07 5.6 0.7 0.6

Brain, lungs, jejunum, kidneys, liver and pancreas

Brain and kidneys

Brain and pancreas

Brain and lungs

Brain, heart, adrenal glands placenta, pituitary, small intestine and skeletal muscle

Distribution in normal human tissue

Subtype 5

Adapted from Patel YC and Srikant CB [182].

elevated due to ectopic GHRH production by a tumor or during GHRH infusion [127,186], suggesting that hypothalamic SRIF is mainly responsible for GH pulsatility. The rat hypothalamus releases GHRH and SRIF 180° out of phase every 3 to 4 hours, resulting in pulsatile GH levels [185]. GHRH and SRIF also act synergistically, in that preexposure to SRIF has been shown to enhance somatotroph sensitivity to GHRH stimulation [187]. Hence, during a normal GH trough period, the high SRIF level probably primes the rat somatotroph to respond maximally to the subsequent GHRH pulse, thus optimizing GH release. In addition to exerting opposing and cooperative interactions on the pituitary somatotroph, SRIF exerts a central inhibitory effect on GHRH release via direct synaptic connections between SRIF-containing axons and GHRHcontaining perikarya in the rat hypothalamic arcuate nucleus [188]. GH Autoregulation

Chronic GHRH stimulation, either by continuous infusion or repeated bolus administration, eventually results in decreased GH release from cultured rat anterior pituitary cells [189] and in vivo [190] due to somatotroph desensitization. Loss of GH sensitivity to administered GHRH does not occur in acromegalic patients in vivo [191] or in somatotroph adenomas in vitro [192], possibly reflecting larger intracellular pools of GH or abnormal signaling. One possible mechanism of pituitary desensitization is depletion of a GHRH-sensitive pool of GH. GHRH pretreatment in

vitro also leads to a 50% decrease in somatotroph GHRH binding sites [193]. Feedback loops exist between GH and IGF-I and the release of SRIF and GHRH (Fig. 3.7). GH stimulates hypothalamic SRIF release in vitro [194], and in vivo, GH administration decreases GH responses to GHRH [195], most likely by increasing hypothalamic SRIF release [196]. GHRH and SRIF also autoregulate their own secretion. GHRH inhibits its own secretion but stimulates SRIF secretion in vitro [197], while SRIF inhibits its own secretion in vitro [198]. Growth Hormone Secretagogues (GHS) and Ghrelin

Small synthetic molecules termed growth hormone secretagogues (GHS) [199] stimulate and amplify pulsatile pituitary GH release [200], via a separate pathway distinct from GHRH/SRIF. A strategy of expression cloning was used to identify the GHS receptor, which is a heterotrimeric GTP-binding protein (G-protein)-coupled molecule [201]. This classic Gprotein coupled receptor has seven alpha helical membrane spanning domains and three intracellular and extracellular loops. The GHS receptor is most strongly expressed in the anterior pituitary and both the hypothalamic and nonhypothalamic regions of the brain. The ligand of the GHS receptor is a 28 amino acid peptide, Ghrelin isolated from stomach, with 3 serine residues and is n-octanoylated [202]. It releases GH both in vivo and in vitro and 0-n octanoylation appears to be essential for GH releasing activity. The

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FIGURE 3.7. Growth hormone (GH), insulin-like growth factor-I (IGF-I) Growth Hormone secretagogues GHS (GHRH and Ghrelin), somatostatin (SRIF) feedback loop in the control of somatic growth. A stimulatory effect of GHRH and Ghrelin and inhibitory effect of SRIF interact to result in GH secretion from the anterior pituitary. GH stimulates IGF-I production from the liver. This, in turn, has a negative feedback effect on pituitary GH secretion and a positive feedback effect on hypothalamic SRIF release. Pituitary GH secretion has a negative autoregulatory feedback effect on hypothalmic GHRH secretion. GH exerts an effect on somatic growth by a direct as well as indirectly via IGF-I.

gene encoding human Ghrelin has been isolated, and found to be expressed in the stomach and hypothalamus [202]. The isolation of Ghrelin implicates a control system in addition to GHRH/SRIF in the regulation of GH secretion. Ghrelin is analogous to GHRH/SRIF in that it is also synthesized in peripheral tissues (stomach) as well as centrally (hypothalamus). It would be anticipated that hypothalamic Ghrelin would control GH secretion, while peripheral sources may have other biological effects requiring further elucidation. Several artificial GH secretagogues (GHS) release GH in vitro [203]. GHSs, administered alone or in combination with GHRH are potent and reproducible GH releasers and are useful tools for the diagnosis of GH deficiency. GHSs act directly on the pituitary somatrophs [204], stimulating GH secretion by activating the cAmp-dependent protein kinase pathway [205]. GHRH and GHS thus act through distinct receptors, via different intracellular signaling pathways on somatotrope subpopulations. GHS increases the number of somatotropes releasing GH, without altering the amount of hormone released from each individual cell

[206]. Somatostatin too decreases the number of somatotropes that secrete GH, and it is postulated that GHS and SRIF may respectively depolarize and hyperpolarize the same somatotroph cell. GHRH, on the other hand, stimulates the amount of GH secreted per cell, as well as the number of cells secreting GH [206]. Evidence that the main action of GHS occurs at the hypothalamic level, and that the direct pituitary activity is ancillary, is supported by the fact that GHSs require the presence of a functional hypothalamus to exert their GH secreting effect. In patients with intact pituitaries, who have hypothalamic dysfunction leading to stalk section, GHSinduced GH release is blocked and the synergistic effect of GHRH and GHS is absent [207]. Current evidence suggests that the dual control of GH secretion postulated for GHRH/SRIF should be expanded to incorporate Ghrelin. If indeed Ghrelin acts at the hypothalamic level, its mechanism(s) of action could include release of endogenous GHRH. However available data seems to indicate that Ghrelin does not act via GHRH release in that the GH response to GHS is greater than that of GHRH alone [208];

Chapter 3

FIGURE 3.8. A new physiologic model of the regulation of GH secretion involving Ghrelin, GHRH and somatostatin (SRIF). From Diguez and Casanueva [218a].

GHSs potentiate GH release in response to a maximal stimulating dose of exogenous GHRH [209]. GHSs are unable to release GHRH in rat hypothalamic explants [210]; GHRH infusions block GHRH mediated GH release without altering the action of GHS [211,212]; after administration of a saturating dose of GHRh, a second dose of GHRH is ineffective, while GHS is fully effective [213]. The above evidence does not support a role of GHRH in the mechanism of action of GHS. GHSs do not seem to inhibit somatostatin release [212,214–216]. However, GHS mediated GH release is relatively insensitive to the inhibitory action of SRIF [217]. The presence of GHS in hypothalamic structures and the evidence that GHS-elicited GH secretion is not mediated by changes in endogenous GHRH or SRIF, but requires a functional hypothalamus, suggests that exogenous GHS may induce the release of another hypothalamic factor with GH-releasing capability [218] (Fig. 3.8). Release of another unknown hypothalamic factor with GH releasing capability is supposed by observations that GHSs effectively release GH when administered intravenously, subcutaneously, orally or intranasally [219]. Hypoglycemia increases GHS stimulated GH release [214] as does decreased circulating FFAs [220]. GHSs are resistant to wellknown inhibitors of GH secretion including increased FFA levels, hyperglycemia, SRIF infusion, atropine or drugs that enhance hypothalmic SRIF secretion [221]. GHS-mediated GH release is not reduced by a previous rise in GH [213], glucocorticoid treatment [222], or thyroid hormone abnormalities [223]. GHS-mediated GH release is more potent and reproducible than that elicited by GHRH alone [224].

Growth Hormone

89

GHRH-mediated GH release is more erratic and less reproducible, possibly due to the influence of metabolic and hormonal factors. Functional GHs receptors are detected in the human pituitary by the fifth week of gestation [225]. GHS mediated GH-release is demonstratable at birth [221], continues through infancy, increases at puberty and then decreases thereafter. Estrogen and testosterone increase GHS mediated GH release in childhood. When administered with GHRH, GHS has a synergistic action on GH release. As GH secretion elicited by combined GHRH and GHS administration is minimally altered by age, sex, or adiposity and is devoid of potential side effects (unlike insulin-induced hypogylcemia) this test has the potential to become a widely used diagnostic tool in the diagnosis of adult GHD. No side effects have been reported with the GHSs. Although highly specific for GH release, slight increases in prolactin and ACTH/cortisol have been reported with some GHSs [226], leading to the development of new more selective GHSs with no ACTH or PRLreleasing effects e.g. ipamorelin [227]. GHSs are being evaluated as potential therapeutic agents for enhancing circulating GH levels in patients with intact hypothalamic–pituitary axs, including children with GHD as well as adults with catabolic states, AIDS and heart failure. Long-term studies are required with a large number of subjects to determine dosage efficacy.

GH REGULATION

GH Transgenic Animals Transgenesis allows for the transfer of inheritable functional genes between animals of different species. GH transgene models of endocrine hyperfunction have also been useful in investigating regulatory factors required for tissue-specific gene targeting. When a rat or hGH reporter gene driven by a potent metallothionein-I (MT) promoter is expressed in a transgenic progeny, rat or human GH is produced by a number of tissues including the pituitary [228,229]. Circulating GH levels in these animals are several hundred times higher than normal with an increase in transgenic mouse size to twice that of normal littermates [230]. Circulating IGF-I levels are elevated two- to threefold, consistent with the notion that IGF-I mediates the allometric growth of these transgenic animals [228,229]. Interestingly, the effects of excess GH are only apparent after 3 weeks of age and no further growth occurs after 3 months. Immunocytochemical and ultrastructural study of transgenic pituitary glands revealed a marked reduction in both size and number of GH-secreting cells [229,231]. Pituitary lactotroph cells were also suppressed in male transgenic animals, but not in females. In contrast, both sexes exhibited corticotroph cell hyperplasia. Male transgenics had high levels of LH and highly active gonadotrophs, resembling “gonadectomy” pituitary cells. When ovariectomized female

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hGH transgenics were studied, adult female mice developed hypoprolactinemia, but had high levels of LH due to PRL-like activity of GH [232]. Metallothionein rat GH (MTrGH), metallothionein bovine GH (MTbGH) or metallothionein human GH (MThGH) female transgenics are sterile; however, metallothionein ovine GH (MToGH) female transgenics are fertile [233,234]. In MTrGH transgenic animals [235] both the liver and spleen undergo a threefold increase in size. Furthermore, MToGH male transgenics contain hepatic intranuclear inclusions whose presence correlates with high circulating levels of oGH [233]. The heart, lungs, kidneys, and thyroid glands of GH transgenics grew significantly larger when compared to nontransgenic control littermates. Interestingly, no increase was observed in brain or adrenal size. In contrast, methallothionein-driven IGF-I gene (MTIGF-1) transgenics [230] have an increased growth ratio of one to three times that of control littermates, which is only apparent from 6 to 8 weeks after birth. Spleen, pancreas, and kidneys increased in size in direct proportion to the increase in body weight both in IGF-I and GH transgenic models. Compared to GH transgenics, IGF-I transgenic mice show an increase in brain size but no enlargement of the liver or heart [230]. GH transgenics develop renal glomerular sclerosis, similar to abnormalities seen in diabetics, whereas this lesion is not present in IGF-I transgenics. GH transgenics also have elevated serum insulin and lipid levels [236]. Interestingly, mesangial renal proliferation followed by progressive glomerulosclerosis was also seen in transgenic GHRH animals [237], suggesting that the hypersomatotrophism associated with excess GHRH secretion is predominantly GH-mediated. While many of the sequelae of chronic GH overexpression such as increased growth and pituitary somatotroph atrophy were predictable, the abnormalities of hepatic and renal function, and the reduced fertility of female transgenics, were unexpected. These novel findings may provide useful models of human disease. Transgenesis is a useful tool to investigate ontogeny of gene expression, as well as a method of exposing animals to growth at a time when they would not usually be accessible to manipulation of factors responsible for both allometric as well as organ-specific growth. GH Binding Protein (GHBP)

Circulating GH is attached to specific binding proteins [238]. Two circulating GHBPs have been identified, one of high affinity and one of low affinity [239]. Although the site of GHBP synthesis is as yet undetermined, the liver has been postulated as the primary source [240]. The 60-kDa high-affinity BP corresponds to the extracellular domain of the hepatic GH receptor [241]. Under basal conditions, half of the circulating 22-kDa GH is bound to the highaffinity BP when GH levels are up to 10–15 ng/ml [242]. The 20-kDa GH binds preferentially to the low-affinity BP [243]. Binding to plasma GHBP prolongs GH plasma half-

life by decreasing GH metabolic clearance rate, as the GHbinding protein complex is too large for renal glomerular filtration [243]. The high-affinity BP also inhibits GH binding to surface receptors by competing for the ligand [244]. Thus GHBP dampens acute oscillations in serum GH levels caused by pulsatile pituitary GH secretion. Highaffinity BP levels are low in the fetus and neonate, rise most rapidly in the first 1 to 2 years after birth [245,246], and stay constant throughout adult life, with similar levels found in males and females [245]. GH itself does not regulate either type of BP, as evidenced by normal BP levels found in patients with either hypopituitarism or acromegaly [245]. GH resistance, as demonstrated in short stature, Laron dwarfism, and African pygmies, is characterized by decreased plasma levels of high-affinity BP [247,248]. Although these conditions provide insight into the role of GHBP in GH action, Laron dwarfs are also GH receptor-deficient, therefore, no conclusions can be drawn about GHBP function per se from these findings. In African pygmies, GHBP levels, although low, vary widely with considerable overlap with normal subjects.

Peripheral GH Action GH Receptor

GH binds to its peripheral receptor and induces intracellular signaling by a phosphorylation cascade involving the JAK/STAT pathway. GH also acts indirectly by inducing synthesis of IGF-I, the potent growth and differentiation factor [249]. The GH receptor (GHR) is a 70 kd protein member of the class I cytokine/hematopoietin receptor superfamily [250]. GHR consists of an extracellular ligandbinding domain, a single membrane-spanning domain, and a cytoplasmic signaling component. The GH ligand complexes with two GHR components leading to receptor dimerization. This sequential ligand-receptor interaction and dimerization is critical for subsequent GH signaling. GHR dimerization is followed by rapid binding and activation of JAK2 tyrosine kinase, leading to phosphorylation of cytoplasmic signaling molecules, especially the signal transducing activators of transcription proteins (STAT) which comprise the critical signaling components for GH action. These cytoplasmic proteins are phosphorylated by JAK2 and directly translocated to the cell nucleus where they elicit GH-specific target gene expression by binding to nuclear DNA [250]. In addition, STAT1 and STAT5 may in fact interact directly with the GH receptor molecule [251]. Other target actions induced by GH include c-fos induction, IRS-1 phosphorylation, and insulin synthesis. As a differentiating and growth factor, IGF-1 is a critical protein induced by GH, and is likely responsible for most of the growth-promoting activities of GH [252]. IGF-I itself may also directly regulate GH [252] and GH receptor function [253]. The liver contains the highest abundance of GH receptors, and several peripheral tissues also express modest amounts of receptor, including muscle and fat [254].

Chapter 3

Mutations of the GH receptor may be associated with partial or complete GH insensitivity and growth failure. These syndromes are associated with normal or high circulating GH levels, decreased circulating GHBP levels and low levels of circulating IGF-I. Multiple homozygous or heterozygous exonic and intronic GHR mutations have been described, most of which occur in the extracellular ligandbinding domain of the receptor. Tissue responses to GH signaling may be determined by the pattern of GH secretion, rather than the absolute amount of circulating hormone. Thus, linear growth patterns, liver enzyme induction and STAT5b activity may be phenotypically distinct for male animals due to their higher rates of GH pulse frequency [255]. STAT5b is sensitive to repeated pulses of injected GH [256], unlike other GHinduced patterns which are desensitized by repeated GH pulsing. Mice harboring a disrupted STAT5b transgene exhibit impaired male pattern body growth [257] with IGFI and testosterone levels normally seen in female mice. Thus, the sexual dimorphic pattern of GH secretion and GH tissue targeting appears to be determined by STAT5b. The requirement for appropriate GH pulsatility to determine body growth also appears to be mediated by STAT5b [258]. In contrast, STAT5 does not appear to be critical for metabolic effects of GH on carbohydrate metabolism [259]. Unraveling STAT5 regulation in disease, especially those involving GH resistance, will provide novel mechanistic insights for dysregulated GH signaling in humans. Intracellular GH signaling is also abrogated by SOCS proteins, which disrupt the JAK/STAT pathway and thus exert a further level of control over the action of GH [260] (Fig. 3.9).

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91

IGF-I and IGF-II Structure and Synthesis

IGF-I and IGF-II are single-chain polypeptide molecules with three intrachain sulfide bridges (Figs 3.10 and 3.11). IGF-I, composed of 70 amino acids, and IGF-II, consisting of 67 amino acids, have a sequence homology of 62% [261]. The IGFs consist of B and A peptide domains (structurally homologous with the insulin B and A chains), a C domain analogous to the connecting (C) peptide of proinsulin, and a D domain. IGF-I and IGF-II are single distinct gene loci, localized on chromosome 12 (12q22–q24.1) and chromosome 11 (11p15), respectively [262,263]. The IGF-I gene primary transcript can be alternately spliced to different products resulting in IGF-Ia (exons 1,2,3,5) or IGF-Ib (exons 1,2,3,4). Several IGF-I mRNA species have been isolated from adult and fetal tissues. The liver is an important source of circulating IGF-I levels [264]. The IGF-I gene is expressed in human fetal conective tissues and cells of mesenchymal origin [265]. This ubiquitous localization of IGFs favors a paracrine/autocrine function as well as an endocrine function of IGF-I. GH is the major regulator of IGF-I gene expression in adult liver, heart, lung, and pancreas [266], and acts at the level of IGF-I transcription [267]. Fetal IGF-I production is GHindependent [268], and platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) also stimulate IGF-I production from human fibroblasts in vitro [269]. ACTH, TSH, LH, and FSH stimulate the paracrine production of IGF-I in their respective target tissues. Nutritional status is also an important regulator of IGF-I production at all ages [270]. As discussed below, IGF-I and IGF-II are bound to carrier proteins in the serum. IGFs are found in lymph [271], breast milk [272], saliva [273], and amniotic fluid [274]. IGF-I levels are low before birth, rise during childhood to high levels during puberty, and decline with age [275]. IGF-binding Proteins (IGFBPs)

FIGURE 3.9. Role of STAT proteins in growth hormone signaling. From Herrington, Smith, Schwartz, Carter-Su [260a].

IGF-I and IGF-II are complexed to six specific binding proteins in biological fluids [276] (Fig. 3.12 and Table 3.3). The IGFBPs are cysteine-rich proteins, with very similar amino acid sequences. They have a unique ability to bind IGF’s with high affinity. Recently several groups of cysteine-rich proteins have been described [277] with structural and functional similarities to the IGFBP’s, called IGFBP-related proteins (IGFBP-rPs). The IGFBP-rPs bind IGFs with low affinity. The physiological role of these IGFBP-rPs in the IGF system is not known. However some of these proteins unequivocally bind IGFs [277]. An IGFBP superfamily has been proposed, composed of the IGFBPs and the IGFBPrelated proteins (IGFBP-rPs) (Fig. 3.13). The major form of binding protein present in the human circulation is IGFBPIII, a glycoprotein associated with an IGF molecule and an 80-kDa acid-labile subunit (ALS) to form a 150- to 200kDa complex [278] (Fig. 3.14).

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FIGURE 3.10. Amino acid sequence of human insulin-like growth factor I (IGF-I). The black amino acids are identical to those in human insulin. The numbering corresponds to the numbering of residues in the proinsulin molecule. IGF-I consists of a 70-amino acid single peptide chain with A, B, C, and D, domains. A and B domains are structurally homologous to the A and B chains in the insulin molecule, and the C domain is equivalent to the connecting (C peptide in proinsulin). From Humbel [261a].

FIGURE 3.11. Primary structure of human insulin-like growth factor II (IGF-II). From Sara and Hall [261b].

Actions of the IGFBPs include modulation of IGF actions, storage of IGFs in extracellular matrices, and the carrier protein function of IGFBPs. In the serum most of the IGF circulates as a 150,000 dalton complex that consists of IGF-I or IGF-II plus IGFBP-III and a nonIGF binding component, the acid labile cubunit (ALS). Binding of IGF-I or II to IGFBP-III in the presence of ALS results in the formation of an IGF-IGFBP-ALS ternary complex, which is stabilized by IGF binding [279] 75% of circulating IGF-I and IGF-II is carried in this ternary 150-kDa complex. When associated with the 150-kDa complex, the IGFs do not readily leave the vascular compartment, and have prolonged half-lives of 12 to 15 hours [280] compared to the half-life of free IGF-I which is less than 10 minutes [281]. The exact function of the large store of IGF bound

to the 150-kDa ternary serum complex is unknown. It has been hypothesized to be a functional pool of material available for organisms to use during stress. The plasma concentrations of IGFBPs are hormonally regulated. Serum IGFBP-III levels correlate with IGF-I and II levels, double in patients with acromegaly and are reduced in hypopituitarism [282]. Malnutrition, insulin-dependent diabetes mellitus, and cirrhosis are associated with decreased IGF-I levels, as well as suppressed IGFBP-III levels [283]. IGFBP-I levels are high at birth and decline until puberty [284]. There is a diurnal variation with a nocturnal peak in serum IGFBP-I levels [285]. However, IGFBP-I levels are elevated in hypopituitarism [286] and decreased in acromegaly. IGFBP-I levels are regulated by insulin. The increased IGFBP-I levels associated with insulin-dependent

FIGURE 3.12. Simplified diagram of GH-IGF-I axis involving hypophysiotropic hormones controlling pituitary GH release, circulating GH-binding protein and its GH receptor source, IGF-I and its largely GHdependent binding proteins, and cellular responsiveness to GH and IGF-I interacting with their specific receptors. IGFR, IGF-I receptor; FFA, free fatty acids. From Rosenbloom [276a].

Table 3.3.

General characteristics of the human IGF binding protein No. of amino acids

Core molecular mass (kDa)

Chromosomal localization

IGF affinity

Modulation of IGF action

Source in biological fluids

IGFBP-I

234

25.3

7

I = II

Inhibition and/or potentiation

Amniotic fluid, serum, placenta, endometrium, milk, urine, synovial fluid, interstitial fluid and seminal fluid

IGFBP-II

289

31.4

2

II > I

Inhibition

CSF, serum, milk, urine, synovial fluid, interstitial fluid, lymph follicular fluid, seminal fluid, and amniotic fluid

IGFBP-III

264

28.7

7

I = II

Inhibition and/or potentiation

Serum, follicular fluid, milk, urine, CSF, amniotic fluid, synovial fluid, interstitial fluid, and seminal fluid

IGFBP-IV

237

25.9

17

I = II

Inhibition

Serum follicular fluid, seminal fluid, interstitial fluid and synovial fluid

IGFBP-V

252

28.5

5

II > I

Potentiation

Serum and CSF

IGFBP-VI

216

22.8

12

II > I

Inhibition

CSF, serum and amniotic fluid

Modified from Rajaram S et al. [278a].

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FIGURE 3.13. The IGF system. The components of this system include the peptides IGF-I and -II, IGFBP-1 to -6, IGFBP-rPs, IGFBP proteases, type I and type II IGF receptors, and potential IGFBP(s) and IGFBP-rP(s) receptors. M6P, Mannose-6-phosphate. From Hwa, Oh, Rosenfeld [277a].

diabetes mellitus [287] are normalized by insulin, and insulinoma is associated with suppressed IGFBP-I levels. Octreotide (a long-acting somatostatin analog) has been shown to increase IGFBP-I levels in acromegalic patients [288]. When normal subjects ingest glucose, the fall in IGFBP-I levels correlates inversely with the rise in insulin levels [289]. Hypophysectomy is associated with elevated IGFBP-II levels in rats, which fall with GH administration [283]. Insulin infused into normal rats increases IGFBP-II levels [283]. PARACRINE GH ACTION GH and GH-releasing factors are also produced in tissues outside the hypothalamic pituitary axis. The extrapituitary actions of GH are likely autocrine/paracrine and complement the classic endocrine action between the GHreleasing factors, GH and target tissues. GH gene expression is not restricted to the pituitary gland. GH immunoreactivity and GH mRNA have been localized to several extrapi-

tuitary tissues [290] including placenta, mammary gland muscle, spleen lymphocyte, suggesting an extrapituitary paracrine/autocrine action for GH. Classic endocrine actions of GH include GH promoting effects on bone and several metabolic actions.

Effect on Growth Whether GH exerts its growth-promoting action on the skeleton via a direct GH effect on the growth plate, or indirectly by stimulating hepatic or local IGF-I production, remains unclear. The somatomedin hypothesis proposed an indirect effect of GH on growth mediated through plasmatransported IGF-I that is synthesized in the liver [291]. The dual effector theory postulates a direct effect of GH by stimulating epiphyseal growth plate precursor cells to differentiate and become responsive to IGF-I, and to induce local IGF-I synthesis that in turn stimulates the multiplication of differentiating chondrocytes [292]. This proposes a dual role for GH and IGF-I in the control of tissue mass. IGF-1 has

Chapter 3

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95

which is rapidly restored by GH administration [299]. Hypophysectomized rats show a progressive decline in longitudinal bone growth rate [300], finally growing at only 0 to 10% of the normal rate. GH and IGF-I Effects on Bone in vitro

FIGURE 3.14. Relative distribution of various IGF pools in human serum. The distribution of IGFs between the 50-kDa, 150kDa, and the free pool as determined before and during continuous subcutaneous infusion of 30 mg/day of rhIGF-1 in healthy men. From Rajaram, Baylink, Mohan [278a].

a potent mitogenic action, especially on immature differentiating cells (adipocytes, chondrocytes), whereas GH is not a mitogen [293]. The dual effector theory proposes that although the overall effects of GH and IGF-I on growth at the tissue level appear to be the same, at the cellular level their effects are very different; GH has both a direct action and an indirect action mediated by IGF-I. The IGFBP regulatory hypothesis proposes that GH stimulates both IGF-I and IGFBP-III [294]. Circulating IGFBP-III regulates the bioavailability of IGF-I to the growth plate, and may inhibit IGF-I action. However, recently hepatic IGF-II production in the liver of mice was completely abolished using an IGF-I knockout mouse model, with complete inactivation of the IGF-I gene in the hepatocytes [295]. Serum IGF-I concentration was reduced by 75%. However the reduction in serum IGFI concentration had no discernible effect on postnatal body growth. Role of GH in Growth and Development

Congenital absence of the human pituitary gland does not result in abnormal birth or newborn weight [296], indicating that fetal and early postnatal development may occur independently of GH. Postpubertal mammalian longitudinal bone growth results from chondrocyte proliferation and differentiation in long bone epiphyseal growth plates. The proximal zone of the epiphyseal growth plate contains stem cells and is the layer of prechondrocyte origin [292]. These cells differentiate and enter the proliferative layer, where they undergo limited clonal expansion. After maturation, the cells become calcified and are incorporated into metaphyseal bone [297]. Hypophysectomy in the growing rat results in a marked reduction in tibial epiphyseal cartilage plate width [298],

Although earlier studies failed to demonstrate in vitro stimulatory effects of GH [301], subsequent studies have demonstrated significant direct effects of GH on chondrocyte and osteoblast cultures [302]. GH increases progenitor cell thymidine incorporation, chondrocyte differentiation, and osteoclast formation. The in vitro effect of IGF-I on chondrocytes has been more consistently demonstrated. IGF-I increases thymidine and sulfate incorporation into isolated chondrocytes [303], and this effect is additive with GH [302,303] occurring at different stages of maturation [304]. Cells from the proximal growth plate (prechondrocytes and young proliferating chondrocytes) form larger colonies in vitro, whereas chondrocytes from the more distal proliferative zone form smaller colonies [305]. Both GH and IGF-I induce chondrocyte colony formation [305] but exert differential effects on colonies of different sizes. GH preferentially potentiates formation of large size colonies, suggesting that GH stimulates prechondrocyte differentiation [304], while IGF-I induces smaller colonies, implicating IGF-I in epiphyseal chrondrocyte stimulation at a more mature stage of differentiation [304]. In vivo Effects of GH and IGF on Skeletal Growth

GH administered locally at the epiphyseal growth plate [306,307] or infused into a femoral artery [308] in hypophysectomized rats results in unilateral longitudinal bone growth and an increase in growth plate width. When IGFI antiserum is infused locally with GH this growth effect is eliminated [308], suggesting that GH exerts its growth promotion via local IGF-I. Local infusion of IGF-I alone into the epiphyseal growth plate results in longitudinal bone growth [307] and increased epiphyseal width. Local GH infusion at the growth plate additionally results in increased numbers of IGF-I-containing cells in the proliferative zone, as well as producing a simultaneous increase in plasma IGFI levels [309], suggesting that the in vivo GH effect may be mediated by locally produced IGF-I in cells that have been stimulated by GH. This may explain why GH-deficient children treated with GH grow significantly, even though their plasma IGF-I levels may not change appreciably [310]. The effects of systemic GH and IGF-I administration have been compared. IGF-I increases tibial epiphyseal width [311] and total body growth in hypophysectomized rats [312], but to a lesser degree than after replacement doses of GH. In mutant GH-deficient dwarf rats, hGH infusions had a more pronounced stimulatory effect on body weight and bone growth than hIGF-I administration, while hIGF-I caused a greater increase in kidney, adrenal, and spleen size than did hGH [313]. GH and IGF-I may also have

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differential tissue effects. Some of these observations suggest that GH acts directly on tibial plate cartilage via a locally produced paracrine or autocrine IGF-I action. The somatomedin hypothesis, however, suggests that plasma IGF-I levels are much higher than tissue levels, and that plasma IGF-I is indeed biologically active. The liver synthesizes more IGF-I in response to GH stimulation than does costal cartilage. Furthermore, IGF-I increases thymidine and sulfate uptake and incorporation in bone and cartilage cultures to a far greater degree than does GH. These findings favor the liver as the predominant site of IGF-I synthesis, with subsequent plasma transport of biologically active IGF-I to its target organ, bone, where it mediates growth. A model incorporating GH, IGF and IGFBP systems in the regulation of systemic growth integrates the dual effector theory and the somatomedin hypothesis (Fig. 3.15). GH stimulates hepatic/tissue IGF-I synthesis, and it is the endocrine action of this circulating IGF-I on the growth plate which regulates skeletal growth, by stimulating cell division. Furthermore, GH induces hepatic IGFBIII and ALS production, forming the circulating 150-kDa ternary

complex that binds IGF-I, thereby increasing its half-life. GH also directly induces prechondrocyte differentiation into chondrocytes at the growth plate, in addition to stimulating local IGF-I production, which acts in an autocrine/ paracrine fashion to further stimulate cell division. Thus the endocrine actions of circulating IGF-I largely contribute to cell division which results in intrauterine and post natal growth. This mechanism is augmented by the direct actions of GH stimulating prechondrocyte/chondrocyte differentiation at the growth plate as well as the local IGF-I stimulation by GH where it acts by an autocrine/ paracrine action to stimulate cell division.

GH and Metabolism In childhood, the multiple metabolic actions of GH contribute to linear growth. GH continues to be secreted in adulthood after growth cessation, implying that GH has important metabolic functions in adult life. The metabolic actions of GH are either acute insulin-like or chronic insulin antagonism. The metabolic actions of GH may be direct or indirectly mediated by IGF-I.

FIGURE 3.15. Integrated model of the GH-IGFBP-IGF axis in the growth process. Three mechanisms are proposed: (1) GH stimulates IGF-I production; circulating IGF-I (endocrine IGF-I) acts at the growth plate; (2) GH regulates hepatic production of IGFBP-III and ALS: IGF-I binds to IGFBP-III and thereafter with ALS, forming the 150 kDa ternary complex; proteases cleave IGFBP-III into fragments that release IGF-I in the intravascular space and at the growth plate; and (3) GH induces differentiation local IGF-I production, and IGF-I acts via an autocrine and paracrine mechanism to stimulate cell division.From Spagnol and Rosenfeld [313a].

Chapter 3 Table 3.4.

Acute metabolic effects of growth hormone

Enhanced lipolysis and lipid oxidation ÆMobilization of stored triglyceride Protein synthesis stimulation Antagonism of insulin action Water and sodium retention

Acute, transient, insulin-like effects of GH can be demonstrated on carbohydrate, protein, and lipid metabolism (Table 3.4). The insulin-like effects are more easily demonstrated in tissues that have not recently been exposed to GH (for example, those derived from hypophysectomized animals, or GH-deficient humans) than in normal tissues [314]; casting doubt on the physiologic relevance of the insulin-like effects of GH, because GH is secreted endogenously in frequent bursts, resulting in significant changes in ambient GH levels. The chronic antiinsulin effects of GH result in decreased glucose utilization, increased lipolysis, and tissue refractoriness to the insulin-like effects of GH. Antiinsulin effects occur at both hepatic and peripheral sites [315]. Effects on Carbohydrate Metabolism

GH-deficient children have decreased fasting glucose levels [316,317], decreased insulin secretion [316], contradictory impairment of glucose tolerance [318–321], and increased insulin sensitivity due to increased glucose utilization and blunted hepatic glucose release. GH replacement increases fasting glucose levels [317,318], insulin levels [318], and hepatic glucose production [317]. Endogenous physiologic GH secretion antagonizes insulin action [322]. Normally, GH secretion increases 3 to 5 hours after oral glucose ingestion, resulting in decreased disposal of a second oral glucose challenge, associated with hyperinsulinemia occurring 2 hours after GH levels peak. Both intravenous and oral glucose tolerance tests are impaired if performed during periods of increased GH secretion, such as sleep onset. GH-deficient adults have elevated fasting insulin levels and a positive correlation between fasting plasma insulin and both fat mass and waist girth [323], suggesting insulin resistance, which is confirmed by hyperinsulinemic euglycemic clamp [324]. GH replacement initially further increases insulin resistance, in the first 1 to 6 weeks of therapy, but subsequently, although hyperinsulinemia persists, carbohydrate metabolism returns to baseline after 3 months of GH treatment [325]. Acromegaly is the experiment of nature for effects of excess GH secretion on carbohydrate metabolism. Several stages of impaired glucose tolerance occur in acromegaly, possibly indicative of a stepwise deterioration in carbohydrate metabolism as the disease progresses [326]. Glucose tolerance after both intravenous [326] and oral glucose administration is impaired in association with hyperinsu-

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linemia [327]. When acromegalic patients eventually manifest overt diabetes mellitus, postglucose insulin levels are depressed [327]. Effects on Protein Metabolism

Somatic growth is under the primary control of GH and, as such, GH is an anabolic hormone. GH causes urinary nitrogen retention and decreased plasma urea levels in GH deficient children [328], and in normal [329] and obese [330] adults. Furthermore, GH-deficient children increase their muscle mass following GH treatment [331]. Both insulin and IGF-I have been implicated in the anabolic effects of GH on protein metabolism, especially as insulin is a protein anabolic hormone and GH stimulates circulating insulin levels. However, GH-stimulated protein synthesis precedes the GH stimulated increase in insulin levels. Physiologically, GH may promote nitrogen retention during starvation, as GH levels rise during fasting.

Effects on Lipid Metabolism GH Effect on Adipose Tissue

GH plays an important role in fat metabolism. GHdeficient children are mildly obese [331,332], with a decreased total number of fat cells [333,334] that are larger in size, with a greater lipid content than normal. GH replacement therapy leads to a decrease in body fat and, eventually, a decrease in the size and lipid content of subcutaneous adipocytes. GH deficient adults have altered body composition, with increased fat mass and decreased lean body mass. Initial acute effects of GH on lipid metabolism are antilipolytic (insulin-like) and subsequently, GH exerts a lipolytic (antiinsulin) effect. Lipolysis

GH increases fat mobilization and decreases fat deposition, thereby decreasing body fat. GH activates hormonesensitive lipase [335], resulting in increased hydrolysis of triglycerides to free fatty acids and glycerol (lipolysis). GH also decreases fatty acid reesterification [336]. The lipolytic actions of GH can be counteracted by insulin and are additive with glucocorticoids [337], which decrease the antilipolytic effects of insulin [338]. In vivo Effects on Lipids and Lipoproteins

Physiologic doses of GH have multiple, inconsistently demonstrated effects on free fatty acids and ketones [339]. Lipolytic and ketogenic effects of GH are easily demonstrable in normal subjects with suppressed insulin levels [318] and in GH-deficient insulin-dependent diabetic patients infused with GH [340,341]. GH deficient adults have elevated total cholesterol, low density lipoprotein cholesterol (LDL) and apolipoprotein B (ApoB) [342], with low high density lipoprotein levels (HDL) and high triglyceride levels. This lipid profile is

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associated with premature atherosclerosis and cardiovascular disease. GH replacement treatment, decreases total cholesterol (342) LDL cholesterol and ApoB and increases HDL. Long term surveillance will be required to determine whether GH replacement therapy reverses premature atheroclerosis and reduces cardiovascular morbidity and mortality in GH-deficient adults.

the abdomen [323]. The reduction in abdominal fat mass is mainly due to reduced visceral fat mass [343,344]. GH therapy increases total body water [343] especially extracellular water within 3 to 5 days [345,351]. Total blood volume increases after 3 months of treatment [346]. A direct action of GH and/or IGF-I on renal tubular sodium reabsorption, as well as activation of the renin angiotensin system [345,352], contributes to the antinatiuretic GH effects.

GH Effects on Body Composition

The anabolic, lipolytic and antinatiuretic actions of GH impact body composition affecting fat mass, lean body mass and fluid volume in GH-deficient adults. Lean body mass (LBM) is reduced [323,343], and fat mass is increased in GH-deficient adults compared to predicted values for age, sex, and height matched normal controls in GH-deficient adults [323]. Excess fat accumulates mostly in the visceral component in a central distribution, mainly abdominal [343,344]. Total body water is reduced in adults with GH deficiency. Reduced plasma volume [345] and total blood volume [346], contribute to the reduced extracellular water [347,345]. GH replacement therapy reverses these effects on body composition by increasing LBM (Fig. 3.16) [343,344, 348–350]. There is a significant increase in skeletal muscle, the most important component of LBM [348]. GH replacement also reduces fat mass by 4–6 kg in GH deficient adults [343,344,348–350] with the most significant reduction in

GH Effects on Bone Metabolism and Bone Mineral Density (BMD)

GH-deficient adults have reduced bone mass, [353] measured by bone mineral density (BMD), resulting in a 2 to 3 times increased fracture rate [354]. The pathogenesis of the bone loss is unclear, with studies demonstrating unchanged [355], increased, [356] or reduced [357] bone formation as well as unchanged bone resorption [358] and delayed mineralization [359]. With GH replacement therapy there is predominant bone resorption in the first 3 to 6 months, resulting in initial reduced BMD after 6 to 12 months [360] with subsequent increased bone formation leading to a net gain in bone mass after 18 to 24 months of treatment [361]. GH Effects on Muscle Strength and Exercise Performance

GH deficiency is associated with reduced muscle strength, due to altered body composition [362]. Reduction in muscle cross-sectional area, as well as lack of conditioning and training, may contribute to the weakness. Prolonged GH replacement therapy for at least 12 months is required to significantly increase muscle strength [362] and for at least 3 years to normalize the muscle strength [363]. GH Effects on Cardiovascular Function

FIGURE 3.16. Effect of GH replacement on (a) lean body mass (LBM) and (b) fat mass in 24 adults with GHD. Reproduced with permission from Salomon et al. [347a].

Hypopituitary adults have increased vascular mortality [364] mostly attributable to cerebrovascular and cardiovascular disease [365]. GH deficiency has been implicated [366] based on the hypothesis that adult GH deficiency predisposes to the development of premature atherosclerosis, as evidenced by increased carotid artery intima-medial thickening and plaque formation [367], increased triglycerides, plasminogen activator inhibitor-1 activity and fibrinogen [368]. The role of GH in regulating cardiac structure and function has not been established. In GH-sufficient adults with dilated cardiomyopathy and congestive heart failure, GH has been shown to improve cardiac function and increase ventricular mass [369] by some workers and to have no beneficial effect by others. GH deficient adults have reduced left ventricular mass and impaired systolic function. Short term GH treatment for 6 months improves the deficits in cardiac function and structure, with a sustained effect on cardiac performance for up to 3 years of GH treatment [370]. Effects of GH excess in acromegaly manifest as left ventricular hypertrophy, hypertension, cardiac failure and increased mortality due to cardiovascular causes [371]. The long term effects of GH

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replacement on cardiac structure and function are unknown. GH replacement should aim to restore somatic deficiency, including cardiac size and function. In view of the deleterious cardiac effects of excessive GH, supraphysiological GH doses should be avoided.

surements to be consistently more reproducible and sensitive than repeated pharmacologic stimulation tests [377]. These conflicting findings may be attributable to differences in control groups in the discrepant studies.

TESTS OF GH SECRETION

An alternative approach to be assessment of spontaneous GH secretion is the measurement of GH concentrations in urine [378]. As urinary GH concentrations are very low, assays require high affinity antibodies [379]. Several different immunoassay methods for urinary GH measurement have been developed [380], none of which have the ability to reflect pharmacological GH testing or to adequately discriminate between normal and abnormal GH secretion [381–383]. Clinical utility of urinary GH measurements in the diagnosis of GH deficiency will require attainment of adequate-age-and-sex-matched controls and a decision as to whether GH excretion should be expressed relative to body weight or creatinine excretion [384]. 24-hour urinary collections have been assayed for GH in an attempt to diagnose acromegaly [385,386]. Overnight urinary GH measurements were, however, not useful in differentiating acromegalic patients from normal controls [385]. However, others have found 24-hour urine collections for GH measurement to be useful in diagnosis of acromegaly [385].

Urinary GH Measurement

Because of the pulsatile nature of pituitary GH secretion, a single random blood sample for GH measurement is not helpful in the diagnosis of GH hypersecretory or deficiency states, or GH neurosecretory disorders. Nonphysiologic provocative or suppression tests, or measurement of spontaneous GH secretion by 24-hour integrated serum GH concentration (IC-GH), are therefore employed to assess GH secretion.

Measurement of Spontaneous GH Secretion Twenty-four-hour Integrated Concentration of GH

Pituitary GH secretion occurs episodically during waking hours, as well as during sleep, necessitating continuous measurement of integrated secretion over 24 hours [372] rather than over shorter periods. Constant blood collection over a 24-hour period allows the determination of a true mean or IC-GH. Measurement of the 24-hour IC-GH concentration ideally requires a nonthrombogenic continuous withdrawal pump [373] or patent indwelling catheter from subjects whose food intake and physical activity are not limited. Sampling intervals of 20 minutes are most widely used [373], but 5-minute and 30-second sampling frequencies detect significantly more pulses per hour [374]. Samples from collection periods may be pooled, producing a combined aliquot in which the ICGH concentration is measured. The 24-hour IC-GH reflects the average GH concentration over a 24-hour period, eliminating peak or trough levels that might otherwise be obtained by single random sampling of GH when the latter is released in a pulsatile manner. The discriminating power of continuous GH measurement in the diagnosis of GH deficiency has been disputed [375,376]. Measuring spontaneous GH secretion in prepubertal short children was found to be an insensitive test, with no clear diagnostic advantage over GH stimulation tests and considerable overlap between values obtained in normal, short children and children with GHD [375]. As young normal controls have IC-GH levels which overlap with those of organic hypopituitary patients [377] measurement of spontaneous GH secretion has limitations in the diagnosis of organic GH deficiency in adults. As measurement of spontaneous GH secretion has limitations in the diagnosis of adult GH deficiency, 12-hour overnight spontaneous GH secretion has been measured. Night-to-night variation in results occurred when the test was repeated on consecutive nights, as compared with GH stimulation tests which proved to be more reproducible [376]. However, others have found 24-hour IC–GH mea-

Evaluation of GH Hypersecretion Increased serum IGF-I levels are a consistent finding in acromegaly [387]. Integrated 24-hour serum GH levels are elevated and show a log (dose) response correlation with serum IGF-I levels [388]. The currently accepted diagnostic test of GH hypersecretion is failure of GH levels to be suppressed to less than 1 ng/mL within 2 hours following a 75 g oral glucose load using an IRMA (two site immunoradiometric assay) or chemiluminescent assay [389]. In normal subjects receiving oral glucose loading, serum GH levels initially fall and then subsequently increase as plasma glucose declines. However, in acromegalic patients, oral glucose fails to suppress GH to the normal range [390]. GH levels may increase in response to an oral glucose load in acromegaly (in approximately 28%) [391], remain unchanged (in approximately 36%), or fall (in approximately 36% of patients). As GH secretion is pulsatile, random GH measurements may be misleading.

Evaluation of GH Deficiency Random GH and 1GF-I Measurements

Random GH measurements are not diagnostic of GH deficiency, as GH secretion is pulsatile and daytime levels are often low in normal subjects. Low IGF-I levels are suggestive of GH deficiency, but are also found in malnutrition [392], acute illness, celiac disease, poorly controlled diabetes mellitus, liver disease, and estrogen ingestion [393]. Fifteen

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percent of children diagnosed to be GH deficient by stimulation tests may have normal IGF-I levels [394]. IGF-I levels are normally very low before 3 years of age and highest in adolescence. Normal and GH-deficient children may have IGF-I levels which overlap with those observed in infancy [395]. Furthermore, both normal and low IGFI levels are present in children with growth delay and genetic short stature [396]. IGF-I levels do not always correlate with GH levels after provocative GH stimulation [397]. Low IGFBP-III levels are also encountered in patients with GH deficiency [398]. The diagnosis of adult GHD is more reliably established by provocative testing of GH secretion, as a single ageadjusted IGF-I level has limited diagnostic value [377]. Whereas, in acromegaly there is an excellent correlation between IC-GH and IGF-I [388], in adult GH deficiency, age-adjusted IGF-I should be regarded as a simple, low-cost screening test, because of the limitations outlined above. IGFBP-III is the major serum carrier protein for the IGF peptides, and is GH-dependent [282]. IGFBP-III assays have several advantages over IGF-I assays in that (i) they are technically simple, not requiring separation of IGF peptides from BPs; (ii) circulate in the plasma in high concentrations, so that assay sensitivity is not compromised; (iii) IGFBP-III plasma concentrations are less influenced by nutritional factors than IGF-I levels; (iv) plasma levels vary minimally with age, so that identification of abnormal concentrations in infancy or puberty is clear-cut [384,399]. IGFBP-III is a sensitive test for diagnosis of severe childhood GHD [518], with superior reproducibility to GH stimulation tests [400]. Provocative Tests

Dynamic testing of GH reserve involves stimulation of the somatotrophs to secrete GH in response to a pharmacologic stimulus. Several GH stimulatory agents have been utilized, including insulin, clonidine, arginine, L-dopa, GHRH, and propranolol. Insulin-induced Hypoglycemia (Insulin Tolerance Test, ITT)

This reliable stimulus for GH secretion is the gold standard provocative test [401]. The ITT is the best validated GH stimulation test and is recommended by the Growth Hormone Research Society as the test of choice [401]. Regular insulin 0.1 IU/kg is administered intravenously to decrease the basal glucose level by 50% to a value below 40 mg/dI. Maximal GH secretion peaks at 30 to 60 minutes. Patients may experience symptoms of hypoglycemia, including light headedness, anxiety, tremulousness, sweating, tachycardia seizures and rarely, unconsciousness. Insulin induced hypoglycemia is contraindicated in patients with a history of seizure disorder, coronary artery disease, or over the age of 55 years. The test should be performed under close supervision, and intravenous glucose (50%) should be readily at hand for rapid administration. The risk of inducing profound hypoglycemia is greater in GH-deficient patients because of their increased sensitivity to insulin.

Clonidine

This alpha-adrenergic agonist stimulates GH release via a central action [402]. Clonidine (0.15 mg/m2) is administered orally, with a maximum GH secretory peak occurring after 60 to 90 minutes. Patients may experience some drowsiness, with a decrease in systolic blood pressure in sodium depleted GH deficient adults at doses required to release GH (0.25–0.30 mg orally.) Clonidine, frequently used as a stimulus for GH release in children, is not reliable in adults [403]. L-dopa/propranolol

l-dopa, the immediate metabolic precursor of dopamine, stimulates GH release by stimulating hypothalamic dopaminergic receptors. Adrenergic blockade (propranolol) enhances the GH response to l-dopa [404]. l-dopa is administered orally according to the patient’s weight (125 mg if weighing <10 kg; 250 mg if 10–30 kg; 500 mg if >30 kg) together with propranolol 0.75 mg/kg (maximum dose 40 mg) after an overnight fast. Maximum GH secretion occurs after 60 to 90 minutes. l-dopa is very effective in stimulating GH release and rarely results in adverse effects [255]. Arginine/GHRH

Recently it has been shown that arginine potentiates maximal somatotroph responsiveness to GHRH [405]. After an overnight fast, GHRH 1 ug/kg is administered as an intravenous bolus at 0 minutes with Arginine 30 g in 100 ml infused from 0 to 30 minutes, with subsequent blood sampling for GH performed every 15 minutes for 90 minutes. Combined Arginine/GHRH responses are ageindependent and is a highly reproducible GH provocative test [405], at least as sensitive as insulin induced hypoglycemia [406]. GHRH/GHRP-6

GHRH 1 ug/kg plus GHRP-6 1 ug/kg is given intravenously at 0 minutes and blood is drawn for GH sampling at 0 and 120 minutes [407]. GH releasing peptide-6 (GHRP-6) is an artificial hexapeptide [203] that activates a hypothalmic and pituitary receptor whose natural ligand Ghrelin was recently characterized [202]. Combined administration of GHRP-6 and GHRH is the most potent stimulus to GH release, with excellent reproducibility and no side effects [203]. GHRH/GHRP-6 is a good alternative to the ITT in patients with organic pituitary disease, however there is some overlap between GH levels attained in the control group and severely GH-deficient patients. Since GHRH and GHRP act directly on the pituitary, it is possible that their administration restored GH secretion in patients who had a deficiency of these secretagogues because of hypothalamic disease [408]. Pitfalls of Provocative Testing

Provocative testing has several limitations. The diagnosis of childhood onset GH deficiency is determined by an inad-

Chapter 3

equate GH response to two distinct provocative tests. The definition of an adequate response is arbitrary. The availability of recombinant human GH in the mid-1980s resulted in a loosening of the diagnostic cut-off from 5–7 ng/ml to 10 ng/ml. Sequential tests on the same day have been attempted [409], but discordant individual results are obtained in approximately 30% of subjects. By altering the temporal relationship between the administration of provocative agents, the amount of GH released can be decreased or increased [410–412]. A combination of two provocative agents administered simultaneously has been tried, but this approach failed to identify some patients who demonstrated GH deficiency following separate testing with each agent individually [413]. The reproducibility of provocative tests has been questioned, as only a moderate correlation was found between pharmacologic tests carried out on two separate occasions, 6 weeks apart [414]. Many physical states alter stimulated GH levels. Increased GH response to various provocative stimuli during puberty [415] have been attributed to increased estrogens and androgens [416]. Sex steroid priming with either estrogens or testosterone 3 to 5 days prior to provocative testing in prepubertal children has therefore been recommended by some. Mildly impaired GH release in response to provocative stimuli in hypothyroid patients is a frequent finding [417]. Patients should thus be euthyroid at the time of provacative GH testing. Furthermore, 67% of patients with “idiopathic” GHD diagnosed in childhood normalize their GH secretion, when reevaluated after completion of treatment [418].

Variability of GH Assays The comparisons of results of various GH assays obtained in different laboratories is difficult because of differences between almost all aspects of the immunoassays. Plasma GH is usually measured by radioimmunoassay (polyclonal or monoclonal; RIA) or by immunoradiometric assay (dual monoclonal; IRMA). Comparative GH measurements are obtained using 11 commercial immunoassays varied by a factor of three [419]. As previously mentioned, there are several different circulating forms of GH, most of which are not measured in GH assays because reagents to detect all these forms do not exist. Because monomeric 22 k is the only GH form available as a standard in sufficient purity and quantity, and because monomeric 22 k is also the most abundant circulating form, it is used as the basis for GH measurement: however it accounts for only about 25% of circulating immunoreactivity [420]. The other GH forms are recognized to varying and largely unknown degrees. Thus an assay result is an averaged look at a variety of GH forms, and different antibodies or assay designs yield different answers. Polyclonal antibodies were used in the early RIAs, inducing higher estimates of GH, because they recognized several molecular forms of GH compared to newer immunometric

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assays employing highly specific monoclonal antibodies [421,422]. GH standards also affect comparison of GH values in different laboratories. In 1994, the first international standard for somatotropin, IRP 88/624 [423], was prepared by the WHO, using recombinant technology in contrast to the previous standards prepared from pituitary extracts. Use of an international standard enables uniformity of calibration between different GH kits. GH-binding proteins (GHBPs) may influence GH estimates by interfering in some of the GH assays. In the circulation, approximately 50% of GH is complexed to GHBP, which corresponds to the extracellular domain of the GH receptor. Both high affinity and low-affinity BPs are present in the serum. As the low-affinity GHBP has a greater affinity for the 20-KD GH molecule, it presumably does not interfere in GH estimates in the new GH assays specific for the 22-KD GH molecule. The influence of GHBP in noncompetitive immunometric assays could lead to too low estimates of GH if the GHBP competes with one or both antibodies. In competitive assays like the RIAs, the error in the GH estimates will depend on whether the GHBPbound 125 I-GH is in the antibody-bound or in the free fraction. In RIAs using polyethylene glycol or double antibody for separation, the GHBP-complexed GH will end up in the free fraction if the antibodies are directed against epitopes in the GHBP-binding area and thus give spuriously high values [424]. Another factor contributing to the heterogeneity of results from GH immunoassays is the antibody used. As different antibodies employed in immunoassays bind to a different spectrum of GH isoforms, GH concentrations measured by immunoassay are likely to depend on the particular antibody used. Furthermore, as the distribution of the different GH isoforms varies between individuals, results from different GH immunoassays cannot be compared. The heterogeneity of GH immunoassay results poses a major problem in the definition of standards for the diagnosis of GHD. Consensus statements including cut-off recommendations refer to the polyclonal-antibody-based RIA. However RIA is now used infrequently, therefore clinicians should be aware of the GH assay used by their laboratory and how it compares to polyconal RIA. Recently, three new GH assays have been developed, two of which, ESTA and IFA, measure GH bioactivity rather than immunoactivity as measured by convential RIA. A third, GHEA, measures the different GH isoforms in the circulation [425]. ESTA or IFA bioassays could replace RIA if they become commercially available, as they more closely reflect biologically active GH than that measured by RIA. CLINICAL USE OF GH

Recombinant hGH (rhGH) The application of recombinant DNA technology has made available a sufficient quantity of hGH for treatment of GH

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deficiency [426]. Early trials investigating the effects of recombinant human GH compared to pituitary-derived hGH in adults showed comparable kinetics in the two preparations, as well as similar ability to stimulate IGF-I levels. Both compounds resulted in a similar decrease in serum blood-urea nitrogen (BUN) and cholesterol, and increased serum triglyceride levels [427] and clinical growth-promoting effects.

GH Therapy in Childhood Classic GH Deficiency

Childhood GH deficiency ranges from complete absence of GH associated with severe growth retardation to partial GH deficiency resulting in short stature. Diagnosis is based on decreased height (more than 2.5 standard deviations (SD) below the mean height for age-matched normal children), poor growth velocity (less than the twenty-fifth percentile), delayed bone age and a predicted adult height below mean parental height [428]. GH deficiency (GHD) is usually confirmed by inadequate pituitary GH responses to standard provocative stimuli (peak serum GH value of less then 10 mg/L) [429], with values less than 5 mg/L in severe GH deficiency. Combined clinical evaluation and provocative testing are used in the assessment of childhood GH deficiency. Concomitant endocrine deficiencies, especially hypothyroidism, should be corrected to maximize the growth-promoting benefits of hGH. GH replacement should be started as early as possible before height drops below the third percentile, as total height gain is inversely proportional to the pretreatment chronologic and bone age [430], as well as severity of GH deficiency. The most pronounced acceleration in linear growth rate occurs during the first two years of treatment [431]. Dose and frequency of administration of hGH both influence height velocity [432]. Currently, the recommended weekly dose is 0.18 mg/kg (0.54 iu/kg) divided into six or seven daily subcutaneous injections or as three injections/ weekly administered on alternate days. The maximal replacement weekly dosage is 0.3 mg/kg (0.9 iu/kg) divided into equal doses given on three alternate days. Idiopathic Short Stature

Idiopathic short stature describes otherwise normal children who are at or below the fifth percentile for height, with normal growth hormone responses to provocative stimuli. In the past, scarcity of human pituitary GH limited its therapeutic uses to children with severe GH deficiency diagnosed by a decreased growth rate and inadequate GH response to two provocative stimuli. As short stature may affect psychological development, trials of GH in “slow” growing children have been initiated to determine whether GH treatment can increase final adult height in normal children without complications of treatment. GH treatment in these children is controversial. Long-term studies in short

children treated for up to ten years have shown conflicting results, some showing no significant difference in the SD score for final height [433] while others report final heights exceeding the predicted height [434]. Approximately onethird of all children on GH treatment in the USA are nonGH deficient with idiopathic short stature [435]. In view of the contradictory data on the benefical effect of GH therapy on final height, non-GH-deficient children and their families should have realistic expectations. In children with no identifiable cause of growth failure GH therapy is indicated if growth is retarded more than 2.5 SD below the mean for age and very slow growth velocity (less than the twenty-fifth percentile).

GH Neurosecretory Dysfunction (GHND) A subgroup of GH-deficient children has been described who have normal responses to GH provocative tests, low serum IGF-I levels and abnormal 24-hour GH secretory patterns [436]. This syndrome, termed “growth hormone neurosecretory dysfunction,” is characterized by height below the first percentile, bone age delayed by 2 or more years, and a growth velocity of 4 cm/year or less, in combination with the serum abnormalities described above. Classical GH deficiency, GHND, and normal children can be distinguished by assessing the number of GH pulses during a 24-hour period, mean peak GH pulse amplitude, highest nocturnal peak, and mean 24-hour GH concentration. Patients with GHND may secrete less GH than patients with classical GH deficiency, and the nocturnal GH surge is maintained but with a lower magnitude [436]. GHND has also been associated with Turner’s and Noonan’s syndrome, empty sella syndrome, and precocious puberty [437]. hGH was administered intramuscularly three times weekly for at least 6 months to children with GHND [436]. This treatment resulted in a doubling of growth velocity, comparable to that seen in children with GH deficiency receiving GH. Turner’s Syndrome

Patients with Turner’s syndrome manifest dysmorphic body features, ovarian failure, and reduced growth rate, starting during intrauterine life and continuing through childhood and puberty, resulting in reduced final adult height [438]. Earlier studies evaluating the use of hGH in Turner’s syndrome were inconclusive, possibly due to inadequate dosage regimens and short-term follow-up [439]. Recently, GH therapy in girls with Turner’s syndrome has been shown to significantly increase predicted height, with a greater increase in height in girls treated with combined GH and oxandrolone (an anabolic steroid) [440]. Turner’s syndrome is an approved FDA indication for GH use. Low Birth Weight

Children with low birth weight generally have reduced adult height [441]. An early study investigating the use of

Chapter 3

hGH in the treatment of short children with low birth weight yielded inconclusive results, probably due to the inadequate dosage regimen. Subsequent studies using higher, more frequent hGH dosages [442,443] have shown an increased growth rate for these children, but no increase in final height [444]. Chronic Diseases

hGH has been used in an attempt to increase height in children with short stature associated with a variety of chronic nonendocrine disorders. Growth retardation may be due to specific effects of the disease of may be secondary to poor nutrition or infection. Increased height velocity has been demonstrated after hGH treatment in prepubertal children and infants with chronic renal failure and following renal transplantation [445,446]. Chronic renal insufficiency prior

Table 3.5. deficiency

Causes of adult growth hormone (GH)

Presenting in childhood Congenital Idiopathic Genetic GHRH receptor defect Transcription factor defect Embryologic defects GH resistance Laron dwarfism Pygmy Neurosecretory defects Radiation for juvenile brain tumors, leukemia Head trauma Perinatal birth injury Child abuse Accidental Inflammatory diseases Viral encephalitis Meningitis, bacterial, fungal, tuberculosis Acquired in adulthood Postpituitary surgery Pituitary mass-adenoma, craniophyringioma Hematologic disorders Hemochromatosis Sickle cell disease Thalassemia Autoimmunity Lymphocytic hypophysitis Irradiation: central nervous system radiation for tumors Histiocytosis Granulomas Sarcoidosis Idiopathic Infection Tuberculosis Syphilis Vascular

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to transplantation is an FDA approved indication for GH therapy. Achondroplasia and Hypochondroplasia

Achondroplasia and hypochondroplasia result in short stature, with normal GH responses to provocative tests. GH therapy increases growth in both conditions, however there is worsening of body disproportion [447]. GH Treatment in Adults

As part of the normal aging process, adults experience loss of lean body mass, atrophy of skeletal muscle and organs, and increased adipose tissue [448]. Skeletal muscle atrophy is associated with a loss of muscle strength. These changes have been attributed to GH deficiency, as GH and IGF-I levels decline with age in healthy adults. With the increased availability of hGH, studies have been performed to evaluate the effects of rhGH on body composition in normal elderly individuals [449–451]. These studies have reported an increase in lean body mass, decreased adipose tissue content and increased retention of sodium, calcium, and nitrogen. None of these parameters translate into a measurable improvement in muscle size or strength. Adults may be truly GH-deficient due to isolated GH deficiency or to panhypopituitarism, from a number of causes (Table 3.5). GH-deficient adults have altered body composition with increased fat and decreased muscle volume and strength, lower psychosocial achievement, altered glucose and lipid metabolism, decreased bone mineral density and possibly increased mortality due to cardiovascular disease (Table 3.6). The same pharmacologic stimulating tests, used in children, have been used in adults. However, the definition of an adequate response differs. IGF-I, IGFBP-III, cholesterol and LDL levels can also be determined (Table 3.7). Mean 24-hour GH secretion sampled every 20 minutes, insulin-induced hypoglycemia and IGF-I levels have been compared to normals in the diagnosis of adult GHD [452]. IGF-I is a poor indicator of adult GHD as levels may overlap with normal. The diagnosis of adult GH deficiency is confirmed by provocative testing of GH secretion. Other hormonal deficits should be adequately replaced prior to GH provocative testing. The

Table 3.6. Physical findings in the adult growth hormone deficiency syndrome. Adapted from Cuneo et al. [451a] Truncal adiposity Waist/hip ratio increased Thin, dry, cool skin Exercise performance reduced Muscle strength reduced Reduced bone density Mood depressed Psychosocial impairment

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Table 3.7. Diagnosis of adult GH deficiency. Adapted from Cuneo et al. [451a] Stimulated GH <3 ng/mL Insulin Clonidine L-dopa Stimulated GH <9–16 ng/mL Arginine/GHRH IGF-I low or normal IGFBP-III low Hypercholesterolemia, with low HDL and often high LDL levels Reduced glomerular filtration rate Reduced lean body mass Reduced bone density

Table 3.8.

Table 3.9.

Complications of GH replacement therapy

Metabolic Glucose homeostasis Salt and fluid retention; peripheral edema Unmasking of thyroid dysfunction Joint Adults Children

Arthralgias and myalgias Carpal tunnel syndrome Slipped capital femoral epiphysis

Potential promotion of neoplastic growth Skin Pituitary adenoma Colonic polyps Other

GH therapy in adults Table 3.10.

Approved use GH Deficiency AIDS-associated muscle wasting Investigational use Frailty of aging Osteoporosis Catabolic states, cachexia Burns Postoperative recovery Wound healing Parenteral nutrition Ovulation induction Immune deficiency

insulin tolerance test is the current gold standard. Most normal subjects respond to insulin-induced hypoglycemia with a peak GH response of greater than 5 ng/mL. Severe GH deficiency is defined by a peak GH response to hypoglycemia of less than 3 ng/mL. Combined administration of arginine and GHRH is as sensitive as the insulin tolerance test. Childhood onset GH deficiency requires reconfirmation in adulthood by two GH provocative tests because growth hormone may no longer be deficient [453]. Adult patients with hypothalmic–pituitary disease and additional anterior pituitary hormone deficiencies require only one GH provocative test to confirm GH deficiency. Insulin induced hypoglycemia shows a clear separation of the peak GH response in GH-deficient adults compared to normals [454]. The scarcity of GH in the past has limited GH replacement therapy to GH-deficient children. The primary therapeutic goal has been to increase linear growth, and in the past treatment has been terminated after epiphyseal fusion occurs and a certain height has been achieved. However, GH secretion normally continues into adulthood, and GH influences many metabolic systems other than growth (Tables 3.8 and 3.9). The numerous beneficial effects of GH

Beneficial effects of GH replacement in adults

Body composition

Increased lean body mass Decreased fat mass Increased bone mass

Physical performance

Increased Max O2 uptake Increased max power

Metabolic effects

Increased IGF-I levels Increased BMR Decreased LDL with probable increased HDL Transient hyperglycemia Increased T3 levels Salt and water retention

Cardiovascular effects

Increased stroke volume Increased diastolic volume Increased LV wall mass Atherosclerosis impact

Psychological effects

Mood and energy uplift Enhanced vitality Improved physical mobility Social isolation improved

Adipose tissue effect

Decreased adipocyte size Increased lipolysis Decreased lipogenesis

replacement in adulthood have been previously described (Table 3.10). In addition, GH replacement in GH deficient adults is associated with increased energy levels, improved mood, vitality and emotional reactions and less feeling of social isolation [343]. GH replacement therapy is associated with significantly improved Nottingham Health Profile (NHP) energy scores (Fig. 3.17). GH doses in adulthood are adjusted to individual needs (Table 3.11). Elderly, male, or obese individuals require lower doses. Furthermore, the use of oral estrogen replacement effects the GH replacement dose. Premenopausal

Chapter 3

FIGURE 3.17. Effect of long term (10 years) treatment with GH on quality of life as measured by the Nottingham Health profile (Energy Level) in 21 GH deficient adults. (Note: higher scores indicate greater energy impairment). Reproduced with permission from Gibney et al. [343a].

Table 3.11. replacement

Factors determining side effects of GH

Patient age Enhanced IGF-I response Greater body weight and body mass index Adult onset vs. childhood onset of GH deficiency

women or postmenopausal women using transdermal estrogen replacement require lower doses of GH than postmenopausal women taking oral estrogen replacement [454]. Oral, but not transdermal estrogens antagonize the actions of GH and reduce IGF-I levels (Fig. 3.18). GH replacment therapy should be started at a low dose (0.15–0.30 mg/d) (GRS guidelines). GH is self-administered as a daily subcutaneous injection in the evening. Serum IGF-I levels and tolerability are used to guide dosing. IGF-I concentrations are monitored every 4 to 6 weeks, and GH doses are adjusted until levels reach mid-normal range for age and sex (Fig. 3.19). Side effects of GH replacement include edema and carpal tunnel syndrome due to fluid retention, which are usually transient, but may require dose reduction. Mild self-limiting arthralgias may also occur. As GH may reduce insulin sensitivity, glycemic control should be monitored. GH replacement therapy is contraindicated in patients with active malignancy, benign intracranial hypertension and proliferative diabetic retinopathy (Table 3.12). Changes in body composition, bone density and lipid profiles may only be observed after several months of therapy. These effects are best assessed by annual dual-energy x-ray absorptiometry
EXA and serum lipid level measurements. A baseline MRI is recommended prior to initial GH replacement. GH therapy does not impose a need for

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FIGURE 3.18. Time course of GH dose and serum IGF-I concentration in a representative patient (38-year-old woman) who was switched from oral to transdermal estrogen therapy during the course of GH replacement. Reproduced with permission from Cook et al. [454].

more frequent pituitary MRI’s than would be done for the regular clinical follow-up of residual pituitary tumor. GH Treatment in Catabolic States

The well-recognized anabolic actions of GH have tempted the use of GH in catabolic states such as surgery, trauma burns and organ failure. The negative nitrogen balance in critically ill patients is partly attributable to GH resistance as well as decreased production and action of IGF-I [455]. Postsurgical recovery is associated with hypercatabolism. GH administered to postsurgical patients as well as to normal subjects receiving hypocaloric intravenous alimentation [456], results in positive nitrogen balance [457]. Beneficial effects of GH in patients with extensive burns has been demonstrated in children [458] and adults [459]. Chronic high-dose glucocorticoid treatment is associated with protein catabolism. These effects in normal subjects may be reversed by simultaneous GH administration [459]. A potential complication of combined GH and glucocorticoid administration is resultant hyperglycemia. GH treatment improved nitrogen balance in two small studies of patients with chronic obstructive pulmonary disease [460,461], with improved respiratory muscle function only reported in one group [460]. Short-term studies of GH treatment in cancer patients suggested improvement in nitrogen balance, most pronounced in the least malnourished patients [461]. Although an uncontrolled study in critically ill patients suggested that GH treatment decreased mortality [462], a large European trial suggested increased mortality in critically ill patients treated with large doses of GH, and was terminated prematurely [463]. GH Treatment in Osteoporosis

Bone mass declines after the second decade of life in healthy men and women, with accelerated bone loss in post-

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FIGURE 3.19. Algorithm for the management of adult GH deficiency.

Table 3.12.

Contraindications to GH therapy in adults

Absolute Active neoplasm Intracranial hypertension Diabetic retinopathy Relative Uncontrolled diabetes Untreated thyroid dysfunction Cost benefit Need for injections

menopausal women. As declining GH secretion has been implicated in the pathogenesis of osteoporosis, GH has been administered to healthy men and women with idiopathic osteoporosis in an attempt to decrease bone loss [464]. Although GH therapy increased indices of bone formation and resorption [464] a small increase in only spine bone mineral density was observed in males, after 6 months [449], with an increase in spine mineral density in postmenopausal females when GH was administered with calcitonin [465]. A longer study in osteoporotic females showed increases in both spine and total hip bone mineral density [466], after 2 years of treatment with GH and calcitonin, although the response was less than with estrogen or biophosphonate therapy [467]. Limited efficacy, side effects and lack of comparative studies with beneficial therapies for osteoporosis, limit the use of GH in the treatment of osteoporosis.

[468], with an increase in extracellular water and lean body mass, a decrease in body fat and improved work output after 3 months [469]. Long term beneficial effects of GH on survival and quality of life have not been established yet. GH Therapy in Cardiac Failure

Beneficial effects of GH on cardiac function in GH deficiency led to its attempted use in congestive heart failure. GH administered for 3 months to a small group of patients with idiopathic dilated cardiomyopathy and moderate to severe congestive heart failure improved cardiac output [369] at rest and during exercise. A larger controlled study for a longer period of time did not confirm these findings [470]. Increased extracellular volume and edema, as well as the potential for cardiomyopathy as seen in acromegaly, must be considered in the use of GH in cardiac failure. GH and Wound Healing

GH treatment increases the strength and speed of collagen formation in incisional wounds in rats [471–473]. Fracture healing in rats is also facilitated by GH treatment [474]. No controlled data are yet available in human subjects. GH Treatment in Ovulation Induction

The growth hormone axis influences gonadal function [474] GH therapy reduces gonadotropin requirements in hypogonadotropic males and females [475,476]. Furthermore, improved implantation and pregnancy rates occur with the addition of GH to gonadotropin based protocols in women undergoing in vitro fertilization [477].

GH Treatment in AIDS-associated Wasting Syndrome

GH is FDA approved in adult patients with HIV associated cachexia. Short term GH administered to patients with HIV-associated cachexia results in positive nitrogen balance

GH use Competitive Sports

The ethical issues of GH abuse in sports have received much attention. GH has been used by many athletes to enhance

Chapter 3

muscle mass [478]. Whether this is accompanied by increased muscle strength is unknown. Continued pharmacologic use of GH by athletes would result in the adverse effects of acromegaly, which would decrease performance. COMPLICATIONS OF GH TREATMENT The complications of GH treatment have been described in GH-deficient patients treated with GH (see Table 3.9). Non-GH-deficient patients receiving GH can be likened to acromegalic patients, with increased GH levels. Adverse reactions, including arthralgias, myalgias, back ache, parasthesias, peripheral edema, carpel tunnel syndrome, headache, hypertension, and rhinitis are frequent, often transient or disappear with lowering of the GH dose and are more common in adult-onset than childhood-onset GH deficiency [479]. Although acromegalic patients have a potential increased risk of developing neoplasms of the gastrointestinal system, recent evidence is less compelling [480]. Colonic polyps occur more frequently, although their relationship to IGFI levels is not confirmed [481]. The true incidence of neoplasia in acromegalic patients is difficult to determine, although a potential link between GH and tumor development has been postulated in animal models. Elevated IGF-I levels in acromegaly may be responsible for cellular proliferation [482]. GH therapy in GH-deficient children has been implicated in the pathogenesis of leukemia. However, this was not confirmed in a worldwide survey [483]. Endogenous IGF-I concentrations have been epidemiologically linked to prostate cancer [484] and breast cancer risk [485]. ABNORMAL GH SECRETION GH hypersecretion, due to either excess GHRH (ectopic or eutopic) or to excess GH (ectopic or eutopic) secretion and GH deficiency (idiopathic or secondary) are documented fully in Chapter 10 (see also Table 3.13).

Table 3.13. acromegaly

Elevated GH levels not associated with

Associated decreased IGF levels Protein-calorie malnutrition Starvation Uncontrolled diabetes mellitus Anorexia nervosa GH insensitivity–Laron’s syndrome Decreased GH clearance Chronic renal failure Mucoviscidosis Physiologic (intermittent) Sleep Stress

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Decreased IGF-I Levels Protein-calorie Malnutrition, Starvation, Anorexia Nervosa

Short-term fasting in normal healthy people results in moderately elevated basal GH levels [486]. However, proteincalorie malnutrition is associated with low IGF-I levels and markedly elevated GH levels [487]. This may reflect an uncoupling of the IGF-I feedback regulation of GH secretion. Low levels of IGF-I in normal fasted volunteers were normalized on refeeding, and caloric intake normalized IGF-I levels to a greater degree than did protein intake [488]. In patients with anorexia nervosa, basal GH levels are also elevated [489]. Furthermore, GH levels rise paradoxically after a glucose load [490] and after TRH injection in these patients [491]. The abnormalities in anorexia nervosa are due not only to the weight loss, but to the concomitant psychiatric disturbance, which may influence hypothalamic– pituitary function. Diabetes Mellitus

Poorly controlled diabetes mellitus (both insulin dependent and noninsulin-dependent) is associated with elevated basal GH levels [90] and increased GH response to exercise [492] and to TRH [493]. Elevated GH levels return to normal with improved diabetic control after insulin administration [494]. IGF-I levels are low in children with poorly controlled insulin-dependent diabetes, including those entering puberty, suggesting insulin resistance. Antiinsulin actions of the increased GH may worsen the resistance. Addition of IGF-I to insulin therapy in adolescents with poorly controlled diabetes was postulated to decrease GH secretion, increase insulin sensitivity and decrease insulin requirements. Daily subcutaneous IGF-I injections for a month normalize IGF-I levels with less fluctuations in blood glucose levels, and reduced insulin doses [495]. Insulin resistance in non-insulin-dependent diabetes is associated with increased insulin secretion in an attempt to overcome putative post-receptor defects in insulin action [496]. IGF-I therapy was proposed to stimulate peripheral glucose utilization and reduce insulin resistance and secretion, and was shown to decrease fasting blood glucose by 30% with a 50% decrease in insulin secretion [497]. A high incidence of side effects with dosages used initially discouraged adjunctive IGF-I therapy [498]. Diabetes and malnutrition are both conditions of nutrient deprivation. In malnutrition, there is inadequate intake of nutrients, whereas diabetic patients are unable to utilize available nutrients appropriately. Malnutrition and diabetes both manifest retarded growth, despite elevated GH levels and decreased IGF-I generation. Laron Syndrome

Laron syndrome, an autosomal recessive disorder, is a condition of peripheral unresponsiveness to GH. Serum GH levels are normal or elevated, circulating IGF-I is absent, and

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there is no IGF-I response to exogenously administered GH [499]. Inactivating mutations of the GH receptor [500] cause insensitivity to exogenous GH. IGF-I therapy increased height velocity, with improved body composition as evidenced by loss of fat mass [501].

Decreased GH Clearance Chronic Renal Failure

Basal GH levels are high in patients with chronic renal failure [502], and GH rises paradoxically in response to a glucose load in these patients [502]. GH is degraded by the kidney. However, elevated basal GH levels imply some change in GH regulation; if the feedback loop were intact, GH levels should fall to normal. Serum IGF-I levels are reported to be elevated or variable in chronic renal failure [503–505]. As IGFs circulate bound to large carrier proteins, serum samples should be pretreated with acid-ethanol to ensure reliable quantitation of total IGFs [506]. Uremic serum may contain excess carrier protein not completely removed by acid-ethanol extraction, resulting in underestimation of immunoreactive IGF-I levels [505]. A more specific assay employs a second antibody to separate bound from free radioligand [507]. Despite high GH levels, children with renal failure are short. Following renal transplantation, return to normal growth is variable. Growth retardation can be inversely correlated with posttransplant creatinine clearance [508]. REFERENCES 1 Miller WL, Eberhardt NL. Structure and evaluation of growth hormone gene family. Endocrinol Rev 1983;4:97–130. 2 George DL, Phillips JA III, Francke U, Seeburg PH. The genes for growth hormone and chorionic somatomammotropin are on the long arm of human chromosome 17 in the region of q21-qter. Human Genet 1981;57:138–141. 3 Chen EY, Yu-Cheng L, Smith DH et al. The human growth hormone locus: nucleotide sequence, biology, and evolution. Genomics 1989;4:479–497. 4 Lewis UJ, Dunn JT, Bonewald LF et al. A naturally occurring structural variant of human growth hormone. J Biol Chem 1978;253:2679–2687. 5 Lewis UJ, Bonewald LF, Lewis VJ. The 20,000-dalton variant of human growth hormone: location of the amino acid deletions. Biochem Biophys Res Commun 1980;92:511–516. 6 DeNoto FM, Moore DD, Goodman HM. Human growth hormone DNA sequences and mRNA structure: possible alternative splicing. Nucleic Acids Res 1981;9:3719–3730. 7 Frankenne F, Rentier-Delrve F, Scippo ML et al. Expression of the growth hormone variant in human placenta. J Clin Endocrinol Metab 1987;64: 635–637. 8 Liebhaber SA, Urbanek M, Ray J et al. Characterization and histologic localization of human growth hormone—variant gene expression in the placenta. J Clin Invest 1989;83:1985–1991. 9 Frankeme F, Closset J, Gomez F et al. The physiology of growth hormone (GHs) in pregnant women and partial characterization of the placental GH variant. J Clin Endocrinol Metab 1988;66:1171–1180. 10 Cooke NE, Ray J, Watson MA et al. Human growth hormone gene and the highly homologous growth hormone variant gene display different splicing patterns. J Clin Invest 1988;82:270–275. 11 Ray J, Okamura H, Kelly PA et al. Human growth hormone-variant demonstrates a receptor binding profile distinct from that of normal pituitary growth hormone. J Biol Chem 1990;265:7939–7944. 12 MacLeod JN, Worsley I, Ray J et al. Human growth hormone-variant is a biologically active somatogen and lactogen. Endocrinology 1991;91:1290–1302.

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380 Hourd P, Edwards R. Current methods for the measurement of growth hormone in urine. Clin Endo 1994;40(2):155–170. 381 Albini CH, Quattrin T, Vandlen RL, McGillivray MH. Quantitation of urinary growth hormone in children with normal and subnormal growth. Pediatr Res 1988;23:89–92. 382 Hattori N, Shimatsu A, Yamanaka C et al. Nocturnal urinary growth hormone excretion in children with short stature. Acta Endocrinol (Copenh.) 1988;119:113–117. 383 Granada ML, Sanmarti A, Lucas A et al. Clinical usefulness of urinary growth hormone measurements in normal and short children according to different expressions of urinary growth hormone data. Pediatr Res 1992;32:73–76. 384 Rosenfeld RG, Albertsson-Wilkland K, Cassorl F et al. Diagnostic controversy: The diagnosis of childhood deficiency revisited. JCEM 1995;80:1532–1540. 385 Bercu BB, Shulman D, Root AW, Spiliotis BE. Growth hormone (GH) provocative testing frequently does not reflect endogenous GH secretion. J Clin Endocrinol Metab 1986;63:709–716. 386 Lunt H, Tucker AJ, Bullen H et al. Overnight urinary growth hormone measurement in the diagnosis of acromegaly. Clin Endocrinol 1990;33: 205–212. 387 Clemmons DR, Van Wyk JJ, Ridgway EC et al. Evaluation of acromegaly by radioimmunoassay of somatomedin-C. N Engl J Med 1979;301:1138–1142. 388 Barkan AL, Beitins IZ, Kelch RP. Plasma insulin-like growth factorI/Somatomedin-C in acromegaly: correlation with the degree of growth hormone hypersecretion. J Clin Endocrinol Metab 1988;67:69–73. 389 Melmed S, Jackson I, Kleinberg D et al. Current treatment guidelines for acromegaly. JCEM 1998;83:2646–2652. 390 Earll J, Sparks LL, Forsham PH. Glucose suppression of serum growth hormone in the diagnosis of acromegaly. JAMA 1967;201:628–630. 391 Beck P, Parker ML, Daughaday WH. Paradoxical hypersecretion of growth hormone in response to glucose. J Clin Endocrinol Metab 1966;26:463–469. 392 Phillips LS, Vassilopoulou-Sellin R. Somatomedins. Part I. N Engl J Med 1980;302:371–380. 393 Phillips LS, Vassilopoulou-Sellin R. Somatomedins. Part II. N Engl J Med 1980;302:438–446. 394 Dean HJ, Kellet JG, Bala RM et al. The effect of growth hormone treatment on somatomedin levels in growth hormone deficient children. J Clin Endocrinol Metab 1982;55:1167–1173. 395 Bala RM, Lopatka J, Leung A et al. Serum immunoreactive somatomedin-C levels in normal adults, pregnant women at term, children at various ages and children with constitutional delayed growth. J Clin Endocrinol Metab 1981;52:508–512. 396 Rubin KR, Lichtenfels JM, Ratzan SK et al. Relationship of somatomedin-C concentration to bone age in boys with constitutional delay of growth. Am J Dis Child 1986;19:975–980. 397 Reiter EO, Lovinger RD. The use of commercially available somatomedin-C radioimmunoassay in patients with disorders of growth. J Pediatr 1981;99: 720–724. 398 Blum WF, Ranke MB, Kietzmann K et al. A specific radioimmunoassay for growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 1990;70:1292–1298. 399 Hasegawa Y, Hasegawa T, Aso T et al. Usefulness and limitation of measurement of insulin-like growth factor binding protein 3 for diagnosis of GH deficiency. Endocrinol Jpn 1992;39:585–591. 400 Hasegawa Y, Hasegawa T, Kotch S, Tsuchiya Y. Reproducibility of GH stimulation tests (arginine and insulin) IGF-1 and IGFBP-3 measurements. Clin Pediatr Endocrinol 2 1993;(Suppl):75–78. 401 Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998;83:379–381. 402 Gil-Ad I, Topper E, Laron Z. Oral clonidine as a growth hormone stimulation test. Lancet 1979;2:278–279. 403 Gil-Ad I, Gurewitz R, Marcovici O et al. Effects of aging on plasma GH response to aging. Mech Aging Dec 1984;27:97–100. 404 Fass B, Lippe BM, Kaplan SA. Relative usefulness of three growth hormone stimulation screening tests. Am J Dis Child 1979;133:931–933. 405 Ghigo E, Bellone J, Mazza E et al. Arginine potentiates the GHRH but not the pyridostigmine-induced GH secretion in normal short children. Further evidence for a somatostatin suppressing effect of arginine. Clin Endocrinol (Oxf.) 1990;32:763–767. 406 Aimaretti G, Corneli G, Razzore P et al. Comparison between insulininduced hypoglycemia and GHRH plus Arginine as provocative tests for the diagnosis of GH deficiency in adults. JCEM 1998;83:1615–1619.

407 Popovic V, Leal A, Dragan M et al. Lancet 2000;356:1137–1142. 408 Ho KKY. Diagnosis of adult GH deficiency. Lancet 2000;356:1125–1126. 409 Penny R, Blizzard RM, Davis WT. Sequential arginine and insulin tolerance tests on the same day. J Clin Endocrinol Metab 1969;29:1499–1501. 410 Reiter EO, Morris AH, Biggs DE. Modulation of GHRH-induced growth hormone release by an alpha-adrenergic agonist and hypoglycemia. J Pediatr Endocrinol 1988;3:21–25. 411 Shibasaki T, Hotta M, Masuda A et al. Plasma GH response to GHRH and insulin-induced hypoglycemia in man. J Clin Endocrinol Metab 1985;60: 1265–1267. 412 Woolf PD, Lantigua R, Lee LA. Dopamine inhibition of stimulated growth hormone secretion: evidence for dopaminergic modulation of insulin and L-dopa-induced growth hormone secretion in man. J Clin Endocrinol Metab 1979;49:326–330. 413 Weldon VV, Gupta SK, Klingensmith G et al. Evaluation of growth hormone release in children using arginine and L-dopa in combination. J Pediatr 1975;87:540–544. 414 Cacciari E, Tassoni P, Cigognani A et al. Value and limits of pharmacological and physiological test to diagnose GH deficiency and predict therapy response: first and second retesting during replacement therapy of patients defined as GH deficient. JCEM 79:1663–1669. 415 Sperling MA, Kenny FM, Drash AL. Arginine-induced growth hormone responses in children: effect of age and puberty. J Pediatr 1970;77: 462–465. 416 Illig R, Bucher H. Testosterone priming of growth hormone release. In: Laron Z, Butenandt O, eds. Evaluation of Growth Hormone Secretion. Basel: Karger, 1983:75–83. 417 MacGillivray MH, Aceto T Jr, Frohman LA. Plasma growth hormone responses and growth retardation of hypothyroidism. Am J Dis Child 1968;115:273–276. 418 Tauber M, Moulin P, Pierkowski C et al. GH retesting and auxiological data in 131 GH deficient patients after completion of treatment. JCEM 1997;82: 352–356. 419 Granada ML, Sanmarti A, Lucas A et al. Assay-dependent results of immunoassayable spontaneous 24 hr GH secretion in short children. Acta Ped Scand 1990;370(suppl):63–70. 420 Baumann G, Shaw MA, Amburn K et al. Heterogeneity of circulating growth hormone. Nucl Med Biol 1994;21:369–379. 421 Reiter EO, Morris AH, MacGillivray MH, Weber D. Variable estimates of serum GH concentrations by different radioassay systems. JCEM 1988;66: 68–71. 422 Orskov H, Weeke J, Frystyk J, Kaal A, Nielsen S et al. Growth hormone determination in serum from patients with growth disorders; in Juul A, Jorgenson JOL eds. Growth Hormone in Adults: Physiological and Clinical Aspects. Cambridge: Cambridge University Press, 1996:109–121. 423 Bristow AF, Gaines Das R, Jeffcoate SL, Schulster D. The first international standard for somatotropin: Report of an international collaborative study. Growth Regul 1995;5:133–141. 424 Fisker S, Orskov H. Factors modifying GH estimates in Immunoassays. Horm Res 1996;46:183–187. 425 Strasburger CJ, Dattani MT. New growth hormone assays: potential benefits. Acta Pediatric 1997;423(Suppl):5–11. 426 Goeddel DV, Heyneker HL, Hozumi T et al. Direct expression in Escherichia coli of a DNA sequence coding for human growth hormone. Nature 1979;281:544–548. 427 Hintz RL, Rosenfeld RG, Wilson DM et al. Biosynthetic methionyl human growth hormone is biologically active in adult man. Lancet 1982;i:1276. 428 Vance ML, Mauras N. Drug therapy: growth hormone therapy in adults and children. N Engl J Med 1999;341:1206–1216. 429 Guidelines for the use of growth hormone in children with short stature; a report by the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. L Pediatr 1995;127:857–867. 430 Joss E, Zuppinger K, Schwartz HP, Roten H. Final height of patients with pituitary growth failure and changes in growth variables after long-term hormonal therapy. Pediatr Res 1983;17:676–679. 431 Maes M, Lindberg A, Price DA et al. Long term growth response to growth hormone therapy in prepubertal children with idiopathic growth hormone deficiencies: analysis of Kabi International growth study. Kabi International Growth Study Biannual Report No 11. Mannheim, Germany: J and J Verlag, 1994:15–26. 432 Preece MA, Tanner JM, Whitehouse RH, Cameron N. Dose dependence of growth response to human growth hormone in growth hormone deficiency. J Clin Endocrinol Metab 1976;42:477–483.

Chapter 3 433 Loche S, Cambiaso P, Setzu S et al. Final height after growth hormone therapy in non-growth hormone deficient children with short stature. J Pediatr 1994;125:196–200. 434 Hintz RL, Attie KM, Baptista J, Roche A. Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 1999;340:502–507. 435 Cuttler L, Silvers JB, Sing J et al. Short stature and growth hormone therapy: a national study of physician recommendation patterns. JAMA 1996; 276:531–537. 436 Spiliotis BE, August GP, Hung W et al. Growth hormone neurosecretory dysfunction: a treatable cause of short stature. JAMA 1984;251:2223–2230. 437 Bercu BB, Diamond F. Growth hormone neurosecretory dysfunction. J Clin Endocrinol Metab 1986;15:537–590. 438 Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child 1985;60:932–935. 439 Stahnke N. hGH treatment in short children without growth hormone deficiency. N Engl J Med 1984;310:925–926. 440 Rosenfeld RG, Attie KM, Frane J et al. Growth hormone therapy for Turner’s syndrome: beneficial effect on adult height. J Pediat 1998;132:319–324. 441 Davies PSW, Valley R, Preece MA. Adolescent growth and pubertal progression in the Silver-Russel syndrome. Arch Dis Child 1988;63: 130–135. 442 Lanes R, Plotnick LP, Lee PA. Sustained effect of human growth hormone therapy on children with intrauterine growth retardation. Pediatrics 1979;63:731–735. 443 Stanhope R, Ackland F, Hamill G et al. Physiological growth hormone secretion and response to growth hormone treatment in children with short stature and intrauterine growth retardation. Acta Paediatr Scand 1989;349(suppl.):47–52. 444 de Zegher F, Maes M, Gargosky SE et al. High dose growth hormone treatment of short children born small for gestational age. JCEM 1996;81:1887–1892. 445 Hokken-Koelega AC, Stijnen T, de Jong RC et al. A placebo-controlled, double-blind trial of growth hormone treatment in prepubertal children after renal transplant. Kidney Int Suppl 1996;53:S128–S134. 446 Fine RN. Recombinant human growth hormone in children with chronic renal insufficiency-clinical update: 1995. Kidney Int Suppl 1996;53: S115–S118. 447 Bridges NA, Brook CGD. Growth hormone in skeletal dysplasia. Horm Res 1994;42:231–234. 448 Rudman D. Growth hormone, body composition and aging. J Am Geriatr Soc 1985;33:800–807. 449 Rudman D, Feller AG, Nagraj HS et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990;323:1–6. 450 Binnerts A, Wilson JHP, Lamberts SWJ. The effects of human growth hormone administration in elderly adults with recent weight loss. J Clin Endocrinol Metab 1988;67:1312–1316. 451 Marcus R, Butterfield G, Holloway L et al. Effects of short-term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab 1990;70:519–527. 451a Cuneo RC, Salomon F, Macgauley GA, Sonksen PH. The growth of hormone deficiency syndrome in adults. Clin Endocrinol 1992;37:387–397. 452 Hoffman DM, O’Sullivan AJ, Baxter RC, Ho KKY. Diagnosis of GH deficiency in adults. Lancet 1994;343:1064–1068. 453 Nicolson A, Toogood AA, Rahim A, Shalet SM. The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood. Lancet 1996;44:311–316. 454 Cook DM, Ludlam WH, Cook MB. Route of estrogen administration helps to determine GH replacement dose in GH deficient adults. J Clin Endocrinol Metab 1999;84:3956–3960. 455 Jenkins RC, Ross RJM. Growth hormone therapy for protein catabolism. QJ Med 1996;89:813–819. 456 Manson JM, Wilmore DW. Positive nitrogen balance with human growth hormone and hypocaloric intravenous feeding. Surgery 1986;100:188–197. 457 Ponting GA, Halliday D, Teale JD, Sim AJW. Postoperative positive nitrogen balance with intravenous hyponutrition and growth hormone. Lancet 1988;i:438–440. 458 Herndon DN, Barrow RE, Kunkel KR et al. Effects of recombinant human growth hormone on donor-site healing in severely burned children. Ann Surg 1990;212:424–429. 459 Knox JB, Demling RH, Wilmore DW et al. Increased survival after major thermal injury: the effect of GH therapy in adults. J Trauma 1995;39:526–530.

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460 Pape GS, Friedman M, Underwood LE et al. The effect of GH on weight gain and pulmonary function in patients with chronic obstructive lung disease. Chest 1991;99:1495–1500. 461 Tayek JA, Brasel JA. Failure of anabolism in malnourished cancer patients receiving growth hormone: a clinical research center study. J Clin Endocrinol Metab 1995;80:2082–2087. 462 Knox JB, Wilmore DW, Demling RH et al. Use of GH for postoperative respiratory failure. Ann J Surg 1996;171:576–580. 463 Takada J, Ruokonen E, Webster N et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999;341:785–792. 464 Johansson AG, Lindh E, Blum WF et al. Effects of growth hormone and IGF in men with idiopathic osteoporosis. J Clin Endocrinol Metab 1996;81:44 –48. 465 Gonnelli S, Cepollaro C, Montomoli M et al. Treatment of postmenopausal osteoporosis with recombinant human growth hormone and salmon calcitonin: a placebo controlled study. Clin Endocrinol 1997;46:55–61. 466 Holloway L, Kohlmeier L, Kent K et al. Skeletal effects of cyclic recombinant human growth hormone and salmon calcitonin in osteoporotic postmenopausal women. J Clin Endocrinol Metab 1997;82:1111–1117. 467 Deal CL. Osteoporosis: prevention, diagnosis and management. Am J Med 1997;102:355–395. 468 Mulligan K, Grunfeld C, Hellerstein MK et al. Anabolic effects of recombinant human growth hormone in patients with wasting associated with HIV infection. J Clin Endocrinol Metab 1993;77:956–962. 469 Schambelan M, Mulligan K, Grunfield C et al. A controlled trial of recombinant human growth hormone in patients with HIV associated growth hormone wasting. Ann Inter Med 1996;125:873–882. 470 Osterziel KJ, Strohm O, Schuler J et al. Randomized, double-blinded, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dialated cardiomyopathy. Lancet 1998;351:1233–1237. 471 Hollander DM, Devereux DF, Marafino BJ, Hoppe H. Increased wound breaking strength in rats following treatment with synthetic human growth hormone. Surg Forum 1984;35:612–614. 472 Jorgensen PH, Andreassen TT, A dose-response study of the effects of biosynthetic human growth hormone on formation and strength of granulation tissue. Endocrinology 1987;121:1637–1641. 473 Belcher HJCR, Ellis H. Somatotropin and wound healing. J Clin Endocrinol Metab 1990;70:939–943. 474 Homburg R, Levy T, Ben-Rafael Z. Adjuvant growth hormone for induction of ovulation with GnRH agonist and gonadotropins in polycystic ovary syndrome: a randomized, doubleblind, placebo controlled trial. Hum reprod 1995;10:2550–2553. 475 Homburg R, Eshel A, Abdalla HI et al. Growth hormone facilitates ovulation induction by gonadotropins. Clin Endocrinol 1988;29:113–117. 476 Shoham Z, Conway GS, Ostergard H et al. Cotreatment with growth hormone for induction of spermatogenesis in patients with hypogonadotropic hypogonadism. Fertil Steril 1992;57:1044–1051. 477 Bergh C, Hillensjo T, Wikland M et al. Adjuvant growth hormone treatment during in vitro fertilization: a randomized, placebo controlled study. Fert Steril 1994;62:113–120. 478 Crist DM, Peake GT, Egan PA, Waters DL. Body composition response to exogenous GH during training in highly conditioned adults. J Appl Physiol 1988;65:579–584. 479 DeBoer H, Blok GJ, Van Der Veen EA. Clinical aspects of growth hormone deficiency in adults. Endo Rev 1995;16:63–86. 480 Melmed S. Acromegaly and cancer: not a problem? J Clin Endocrinol Metab 2000;86:2929–2934. 481 Shalet SM, Renehan AG, Painter JE et al. Circulating insulin-like growth factor II and colorectal adenomas. JCEM 2000;85(9):3402–3408. 482 Besser M, Jenkins PJ, Fairclough PD et al. Acromegalic, colonic polyps and carcinoma. Clinica Endocrinol 1997;47(1):17–22. 483 Daughaday WH. The possible autocrine/paracrine and endocrine roles of insulin-like growth factors of human tumors. Endocrinology 1990;127:1–4. 484 Stahnke N, Zeisel HJ. Growth hormone therapy and leukemia. Eur J Pediatr 1989;148:591–596. 485 Chan JM, Stampfer MJ, Giovannucci E et al. Circulating insulinlike growth factor I and prostate cancer risks a prospective study. Science 1998;279: 563–566. 486 Hankinson S, Pollak M, Michaud D et al. A prospective assessment of plasma insulin-like growth factor levels and breast cancer risk. Am J Epidemiol 1997;145:s72. 487 Cahill GR, Herrera MG, Morgan AP et al. Hormone-fuel interrelationships during fasting. J Clin Invest 1966;45:1751–1769.

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488 Grant DB, Hambley J, Becker D, Pimstone BL. Reduced sulfation factor in undernourished children. Arch Dis Child 1973;48:596–600. 489 Isley WL, Underwood LE, Clemmons DR. Dietary components that regulate serum somatomedin-C concentrations in humans. J Clin Invest 1983;71: 175-182. 490 Brown GM, Garfinkel PE, Jeuniewic N et al. Endocrine profiles in anorexia nervosa. In: Vigersky RA, ed. Anorexia Nervosa. New York: Raven Press, 1977:123–125. 491 Casper RC, Davis JM, Pandey GN. The effect of the nutritional status and weight changes on hypothalamic function tests in anorexia nervosa. In: Vigersky RA, ed. Anorexia Nervosa. New York: Raven Press, 1977:137–147. 492 Macaron C, Wilber JF, Green O, Freinkel N. Studies of growth hormone (GH), thyrotropin (TSH) and prolactin (PRL) secretion in anorexia nervosa. Psychoneuroendocrinology 1978;3:181–185. 493 Hansen AP. Abnormal serum growth hormone response to exercise in juvenile diabetics. J Clin Invest 1971;49;1467–1478. 494 Dasmahapatra A, Urdanivia E, Cohen MP. Growth hormone response to thyrotropin-releasing hormone in diabetes. J Clin Endocrinol Metab 1981;52:859–862. 495 Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids insulin, glucagon and growth hormone in normal and juvenile diabetics. Diabetologia 1970;6:27–33. 496 Bach MA, Chin E, Bondy CA. The effects of subcutaneous insulin-like growth factor-I infusion in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1994;79:1040–1045. 497 Moller DE, Flier JS. Insulin resistance-mechanisms, syndromes and implications. NEJM 1991;325:938–948. 498 Zenobi PD, Jaeggi-Groisman SE, Riesen WF et al. Insulin-like growth factor-I improves glucose and lipid metabolism in type 2 diabetes mellitus. J Clin Invest 1992;90:2234–2241. 499 Jabri N, Schalch DS, Schwartz SL et al. Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients. Diabetes 1994;43:369–374.

500 Laron Z, Pertzelan A, Karp M et al. Administration of growth hormone to patients with familial dwarfism with high plasma immunoreactive growth hormone measurement of sulfation factor, metabolic and linear growth response. J Clin Endocrinol Metab 1971;33:332–342. 501 Godowski PJ, Leung DW, Meacham LR et al. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. Proc Natl Acad Sci USA 1989;86:8083–8087. 502 Laron Z, Anin S, Klipper-Aurbach Y, Klinger B. Effects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfism. Lancet 1992;339:1258–1261. 503 Samaan NA, Freeman RM. Growth hormone levels in severe renal failure. Metabolism 1970;19:102–113. 504 Andress DL, Pandian MR, Endres DB, Kopp JB. Plasma insulin-like growth factors and bone formation in uremic hyperparathyroidism. Kidney Int 1989;36:471–477. 505 Goldberg A, Trivedi B, Delmez J et al. Uremia reduces insulin-like growth factor-I, increases insulin-like growth factor-II and modifies their serum protein binding. J Clin Endocrinol Metab 1982;55: 1040–1045. 506 Powell DR, Rosenfeld RG, Baker BK et al. Serum somatomedin levels in adults with chronic reneal failure: the importance of measuring insulin-like growth factor-I (IGF-I) and IGF-II in acid-chromatographed uremic serum. J Clin Endocrinol Metab 1986;63:1186–1192. 507 Daughaday WH, Mariz IK, Blethen SL. Inhibition of access of somatomedin to membrane receptor and immunobinding sites: comparison of radioreceptor and radioimmunoassay of somatomedin in native and acid-ethanol-extracted serum. J Clin Endocrinol Metab 1980;51:781–788. 508 Daughaday WH, Kapadia M, Mariz I. Serum somatomedin binding proteins: physiologic significance and interference of radioligand assay. J Lab Clin Med 1987;109:355–363. 509 Saenger P, Wiedermann E, Schwartz E et al. Somatomedin and growth after renal transplantation. Pediatr Res 1974;8:163–169.

C h a p t e r

4 Prolactin Mark E. Molitch

HISTORICAL OVERVIEW In the late 1920s and early 1930s, a number of groups found that pituitary extracts could induce milk secretion [1–3]. Riddle and coworkers found that this substance, which they named prolactin (PRL), could be differentiated from the known growth and gonad stimulating substances [3–5]. In these experiments, they showed that PRL stimulated milk production by guinea pig mammary glands and a milk-like substance from the crop sacs of pigeons and doves [3–6]. The pigeon crop sac assay for PRL [3–6] then became the standard assay procedure for PRL and was used in many experiments over the next 30 years. Over the ensuing years, PRL was characterized, sequenced and specific radioimmunoassays (RIAs) developed for PRL from a number of species [7–10]. Because of the high lactogenic activity of even very highly purified preparations of human growth hormone (GH) [11,12], however, it was impossible to separate human PRL from GH using the relatively crude pigeon crop assay and the evaluation of PRL physiology in humans proceeded slowly. Even the existence of a PRL separate from GH in humans was questioned [12]. Several experiments of nature provided strong evidence, however, that even in humans these two hormones were separate. For example, it was observed that most patients with pituitary tumors in whom galactorrhea and amenorrhea were the cardinal clinical features did not have acromegalic features [13] and patients who were known to have isolated, congenital GH deficiency were able to undergo postpartum lactation [14]. Finally, in 1970, Frantz and Kleinberg developed a sensitive in vitro bioassay which involved staining milk produced by cultured, lactating mouse mammary tissue in response to PRL that was capable of measuring ovine PRL levels as low as 5 ng/ml. In this

assay they added excess antibody to GH to neutralize any potential lactogenic effects it had and, for the first time, were able to demonstrate measurable PRL levels in women with puerperal and nonpuerperal galactorrhea but not in most normal men and women [15]. Shortly thereafter, still using the pigeon crop assay, Lewis et al. reported considerable progress in the purification of human PRL and its separation from GH via several sequential separation techniques, leading the way to the eventual development of heterologous [16] and homologous [17] RIAs for human PRL which could finally measure PRL levels in the sera of normal individuals. The RIA for human PRL finally permitted the eventual sequencing of human PRL [18] and determination of its cDNA sequence [19]. With the development of PRL RIAs, studies of PRL physiology and pathophysiology in animals and humans have progressed at an astonishing pace over the past 20 years.

CELL OF ORIGIN

Lactotroph Morphology PRL is made by the pituitary lactotrophs (also known as mammotrophs). In the normal human pituitary, the lactotrophs comprise about 15% to 25% of the total number of cells, are similar in number in both sexes and do not change significantly with age [20–22]. During pregnancy and subsequent lactation, however, considerable lactotroph hyperplasia may be found [23,24], presumably due to the stimulatory effect of the hormonal milieu of pregnancy (see below for a discussion of the effects of estrogen on PRL secretion). The hyperplastic process involutes within several months after delivery, although breast-feeding retards this process [24]. This stimulatory effect of pregnancy on the lactotrophs also holds true for prolactinomas and very 119

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significant pregnancy-induced tumor enlargement may occur (see Chapter 12, p. 483). The lactotrophs are of two types: (i) large, polyhedral elongated cells distributed throughout the gland but generally near capillaries; and (ii) small-to-medium-sized, angular or elongated cells appearing in clusters on the border between the lateral wings and the median wedge and in the posterolateral edges of the gland [25]. The larger cells correspond to the densely granulated (granules 250–800 nm in diameter) cells seen on electron microscopy that are thought to be in a resting, storing stage while the smaller cells correspond to the sparsely granulated (granules 200– 350 nm in diameter) cells seen on electron microscopy that are actively secreting hormone [22,25]. Within these cells, PRL synthesis on the ribosomes of the rough endoplasmic reticulum, packaging into secretory granules within the Golgi, and release into the perivascular space by exocytosis appears to proceed in a normal fashion similar to that of other secretory proteins [25,26], although exocytosis may also occur at the lateral cell membranes, a phenomenon referred to as “misplaced exocytosis” [25]. Although it is possible that the densely and sparsely granulated lactotrophs represent different cell types, it is more likely that they represent the same cells in different phases of storage and secretion [22]. Most PRL is secreted by lactotrophs in the normal individual; however, there is a small proportion that is secreted by mammosomatotrophs, that are also capable of secreting GH [20,22,27]. In these cells some secretory granules contain GH, some PRL and some both hormones [27]. The ability of individual adenohypophyseal cells to secrete PRL in culture can be assessed using the reverse hemolytic plaque assay (Fig. 4.1) [28]. In this assay, the PRL secreted by individual cells is ascertained by identifying zones of hemolysis (plaques) around individual lactotrophs when

incubated in a monolayer with staphylococcal protein-Acoated ovine erythrocytes in the presence of PRL antiserum and complement [28]. Initial experiments with this system revealed that stimulatory agents such as thyrotropin releasing hormone (TRH) could cause an increase in plaque number and size, and inhibitory agents such as dopamine (DA) could cause a decrease in plaque number and size [28]. Subsequent studies have shown that there is considerable heterogeneity in the responsiveness of lactotrophs to such stimuli. A subpopulation of lactotrophs, comprising about 65% of cells, forms large plaques and is readily suppressible by DA; the remaining cells form small plaques and are not suppressible by DA [29]. In other studies, only one-third of lactotrophs were shown to respond to TRH [30]. Further analysis revealed that cells taken from the peripheral rim of the pituitaries of lactating rats were greatly responsive to TRH but poorly responsive to DA, whereas cells from the central region of the pituitary were little influenced by TRH but highly suppressible by DA [31]. The reverse hemolytic plaque assay, applied in a sequential fashion to PRL and GH, reveals that in normal rats of the pituitary cells secreting both GH and PRL, about one-third secrete GH alone, one-third secrete PRL alone and onethird secrete both hormones (i.e. mammosomatotrophs) [32], although mammosomatotrophs were found in only 5% of cells in another study [33]. In neonatal rats, the proportion of these cells that secrete only PRL was only 1.7%, suggesting that PRL-secreting cells arise from GH-secreting cells, i.e. mammosomatotrophs [34]. Tissue obtained near the periphery contained a higher proportion of cells that produced both PRL and growth hormone (GH) than did tissue obtained from the central region of the pituitary [31]. Estradiol treatment causes some cells that had only secreted GH to also secrete PRL, i.e. they converted from somatotroph

FIGURE 4.1. Reverse hemolytic plaque assay. In this assay, the prolactin secreted by individual cells is ascertained by identifying these zones of hemolysis (plaques) when incubated in a monolayer with staphylococcal protein A-coated ovine erythrocytes in the presence of PRL antiserum and complement. From Neill and Frawley [28]

Chapter 4

to mammosomatotroph cells [35]. Added GH releasing hormone (GHRH) and gonadotropin releasing hormone (GnRH) caused an increase in the proportion of PRL secretors and a decrease in the proportion of GH secretors, but corticotropin releasing hormone (CRH) increased the proportion of PRL secretors and did not affect GH secretors [36]. As yet, few studies have been performed with the reverse hemolytic plaque assay with human pituitary tissue. In one study of human fetal pituitary tissue (gestational age 18 to 22 weeks), 8% of cells formed PRL plaques [37], a smaller number than would expected from studies of adult pituitaries (see above). Of cells secreting either GH or PRL, 70% secreted GH only, 9% secreted PRL only and 21% secreted both hormones [37]. If we assume that heterogeneity of basal secretion, the response to various stimulatory and suppressive substances, and the ability of the cell population to shift between GH, PRL and GH plus PRL secretion all also take place in the adult human, such findings have obvious importance with regard to the pathogenesis of prolactinomas. For example, such tumors may arise from cells that are minimally or not responsive to endogenous inhibition by DA and thus may explain the variability of suppression of PRL by tumors in response to dopaminergic agents such as bromocriptine.

Lactotroph Ontogeny Continuous hypothalamic–pituitary interaction takes place during embryologic development. During the formation of Rathke’s pouch, the primordium of the anterior pituitary, the ectodermal primordial cells of the anterior and intermediate lobes of the pituitary make contact with the neuroectoderm of the floor of the diencephalon and experimental studies have shown inductive interactions between these tissues that are necessary for their subsequent interdependent development [38]. Elegant studies using a series of targeted mutations have shown that there is a whole host of homeodomain transcription factors that are sequentially expressed in the developing hypothalamus and pituitary that lead to the final determination of the five mature pituitary cell types and the functional integration of the hypothalamic–pituitary system [38,39]. In the earliest phase, in which Rathke’s pouch first appears, the transcription factors Six-3 and Hesx1 (also known as Rpx) are necessary for the initial development of Rathke’s pouch and other midline brain structures [38,39]. In humans, mutations in the genes for these factors result in defects in the development of midline structures and failure of normal hypothalamic and pituitary development with clinical hypopituitarism [40,41]. The LIM homeobox gene Lhx3 begins to be expressed in Rathke’s pouch at the time of organ commitment, in part stimulated by bone morphogenic protein 4 (BMP4) that is expressed in the ventral diencephalon [39] and inactivation/deletion of both the BMP4 and Lhx3 genes in mice causes a failure of the pitu-

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itary to develop, with the exception of the corticotroph lineage, despite the formation of Rathke’s pouch [39,42]. Lhx3 can synergize with Pit-1 in the transcriptional activation of the gene that encodes PRL and is required for the eventual proliferation and determination of the lactotroph, thyrotroph, gonadotroph, and somatotroph lineages [43]. Another homeobox-containing transcription factor gene, PTX1/P-OTX, is expressed in Rathke’s pouch early but later is restricted to corticotrophs and its role in the development of lactotrophs is still unclear [38]. A second BMP, BMP2, is transiently expressed in Rathke’s pouch and its temporal rise and fall both seem to be necessary for terminal pituitary cell differentiation including specification of the Pit-1 lineage [39]. Fibroblast growth factor 8 (FGF8) and Wnt4 have also been determined as important in the proliferation of the various pituitary cell types [39]. The POU homeodomain transcription factor Pit-1 gene (see below) becomes activated close to the same time as the Lhx3 gene and is also necessary for the activation of the PRL, GH, GHRH receptor, and TSHb genes as well as being necessary for the differentiation and proliferation of these cell lineages. Pit-1 also activates the c-fos promoter and Fos is known to be involved in cell cycle initiation [44]. A point mutation in the POU homeodomain of Pit-1 has been found to be the cause of the GH, PRL, and TSH deficiencies found in the Snell dwarf mouse, with absence of somatotroph, lactotroph, and thyrotroph cells [45]. Similar mutations in the POU-specific domain [46] and the POU homeodomain [47] of Pit-1 have now been found to cause a similar deficiency of GH, PRL and TSH in humans. A second paired-like homeodomain factor, known as Prophet of Pit-1 (Prop-1) has also been found to be necessary for the expression of Pit-1 and mutations of the Prop-1 gene causes the dwarfism in mice known as the Ames mouse (defects of somatotrophs, lactotrophs and thyrotrophs) [48] and similar mutations in humans cause variable deficiencies of GH, PRL, TSH, LH and FSH [49–51]. Although the glycoprotein a-subunit is the first hormone transcript to be expressed during the development of the pituitary, such cells are not the precursor of subsequent lactotrophs, as found by targeted ablation of a-subunit expressing cells [52]. Most lactotrophs arise from cells that at least at some point expressed the GH gene [53]. Subsequent lactotroph proliferation occurs once estrogen receptors appear [53]. Estrogen stimulates PRL gene transcription (see below) only if Pit-1 is bound to the PRL promoter [54]. Thus, the division of corticotroph from other cell premordia occurs very early. Stimulation by Prop-1 is necessary for the subsequent development of all noncorticotroph cells and Pit-1 is then necessary for the development and proliferation of thyrotrophs and somatomammotrophs, but the separation of these two cell lines occurs before the appearance of the ability to synthesize a-subunits. The final differentiation of somatomammotrophs occurs at least in part in relationship to estrogen stimulation.

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PROLACTIN GENE STRUCTURE

Chromosome Location The PRL gene in the human is located on chromosome 6, whereas those of the related hormones GH and human placental lactogen (HPL, also known as human chorionic somatomammotropin or HCS) are located on chromosome 17 [55,56]. In the rat, PRL similarly is dispersed to a separate chromosome from its relatives, PRL being located on chromosome 17 and GH on chromosome 10 [57]. These three genes (and possibly others, see below) are thought to have derived by gene reduplication from a common ancestral gene which diverged about 400 million years ago [19,58,59]. In both the human and the rat, the PRL genes and amino acid sequences show less homology with GH than placental lactogen does, implying an earlier divergence of PRL and GH and a more recent divergence of GH and PL [59].

PRL Gene Structure The human PRL (hPRL) and rat PRL (rPRL) genes are approximately 10 kb long from the 5¢ transcription initiation site to the poly A addition site at the 3¢ end and both consist of 5 exons separated by 4 large introns [60,61] (Fig. 4.2). Exon 1 consists of 56 bp that code for a portion of the 5¢ untranslated portion of the messenger RNA (mRNA) and the initial 28 aminoacids of the signal peptide. Exon 2 comprises 56 base pairs coding for the rest of the signal peptide and 120 base pairs coding for the first 40 amino acids of PRL itself. Exons 3 and 4 code for the amino acid sequences 41–76 and 77–136 respectively. Finally, Exon 5 codes for amino acids 137–199, the termination triplet TAA

FIGURE 4.2. details, see text.

and 118 base pairs before the AATAAA polyA signal [61]. The introns have sizes of 1.3, 1.5, 1.9 and 2.0 kb for A through D respectively [44]. The TATA sequence (Goldberg–Hogness box) is located 29 bp upstream of the start site of transcription [61]. The mature PRL mRNA that results after nuclear processing of the original heteronuclear RNA is only about 1 kb long and codes for a 227 amino acid sequence which includes an initial 28 amino acid signal peptide as well as the 199 amino acid structural peptide [19,61,62]. Almost 50% of the protein has an a-helix structure and the mature protein folds in a four-helix bundle similar to GH [63]. The 5¢ flanking region of the PRL genes contains an initial 500 base pairs region with considerable sequence homology between human, rat and bovine species, indicating that possible important regulatory elements are conserved there [61,64]. In the 5¢ flanking region, five highly conserved (79–90% homology between hPRL and rPRL) sequences for PRL are not found in hGH or rGH, indicating several specific sites that might be specific for PRL gene regulation in this regard [61].

5¢ Flanking Region and Tissue Specific Enhancers Detailed analyses of the 5¢ flanking region have been confined to the rat, using such models as the GH3, GH1, and GH4C1 tumor cell lines (Fig. 4.3). Preliminary analyses of the bovine PRL gene suggest common features in the 5¢ flanking regions across species [65], so that the findings to be discussed are likely also present in the human gene, with modifications.

Processing of the human prolactin gene. The exons are denoted by the numbers (1–5) and the introns by letters (A–D). For

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FIGURE 4.3. Detailed analysis of the 5¢ flanking region of the rat prolactin gene. ERE, estrogen response element; TRE, thyroid response element. 1P, 2P, 3P, and 4P refer to proximal binding sites for Pit-1; 1D, 2D, 3D and 4D refer to distal binding sites for Pit-1. For details see text.

There are two regions responsible for tissue-specific transcription activation, i.e. that allow expression of the PRL gene solely in the pituitary lactotrophs and not in other tissues; a distal enhancer element in the -1720 to -1580 bp region accounts for 98% to 99% of this activity while 1% to 2% of this activity is located at a more proximal promoter element at -422 to +33 [66,67]. Within these elements there are A,T—rich consensus sequences with a core of T/A T/A T/A ATANCAT that is critical and serves as a binding site for a tissue-specific transcription activator protein, termed Pit-1 [66,67]. Within the proximal region there are four binding sites for Pit-1, referred to as 1P (-38 to -62), 2P (-115 to -130), 3P (-142 to -162), and 4P (-180 to -200); similarly within the distal region the four binding sites for Pit-1 are referred to as 1D (-1550 to -1578), 2D (-1619 to -1636), 3D (-1645 to -1670), and 4D (-1694 to -1718) [67]. Although the distal and proximal regions are each capable of directing cell-specific expression of the PRL gene, they also appear to act synergistically [67]. The transcription enhancement of the PRL gene by the Pit-1 activator protein can be modified by other factors, such as TRH, epidermal growth factor (EGF), cAMP [68,69], and estrogens [54]. Others have also reported similar findings with respect to these distal and proximal sites [70]. Maurer et al. [71] have also found the tissue specific factor to bind to the sequence -1666 to -1659. Lemaigre et al. [72] demonstrated three pituitary specific protein binding sites in the proximal 217 bp of the PRL promoter in the 5¢ flanking region of the human PRL gene. Pit-1 consists of 291 amino acids with a molecular mass of 32.9 kDa [67]. Human Pit-1 cDNA has 85% DNA homology and greater than 95% amino acid sequence homology with the bovine, rat and mouse sequences

[46,73]. Pit-1 is part of the POU-domain gene family in which the DNA binding domain consists of a POUspecific domain and a POU-homeodomain [74]. Pit-1 is expressed in lactotrophs, somatotrophs and thyrotrophs and is the critical cell-specific transcription factor for activating expression of the PRL, GH, and TSH-b genes and for their respective cell development and proliferation [75,76] (see above).

Estrogen Also in the distal enhancer region lies the estrogen-response element, which has been localized to the position -1582 to -1569 [75,77,78]. This region binds the estrogen receptor and is required for the enhanced transcription of the PRL gene due to estrogen stimulation. The base sequence in this region of the rPRL gene represents an imperfect palindrome similar to the perfect conserved palindrome, GGTCANNNTGACC, which has been found to be necessary for the estrogen responsiveness of the vitellogenin gene in other tissues [75,78]. A second possible estrogen response element may also exist at -1722 to -1709 [77,79]. As noted above, estrogen regulates PRL gene transcription only if the PRL promoter is bound by Pit-1 [54].

Thyroid Hormone Two areas of the 5¢ flanking region have been found to be involved in the regulation of PRL gene transcription by thyroid hormones. The region -1565 to -1530 appears to be a stimulatory thyroid hormone response element that is distinct from the estrogen response element and can bind to the thyroid hormone receptor [80]. Day and Maurer [80] demonstrated by mutation analysis that the specific sequence

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of GGTCA at position -1555 to -1551 was shown to be critical and is the only portion of this region which displays sequence identity to a portion of the consensus sequence that has been derived for thyroid hormone response sequences [81]. A proximal region, -176 to -38, is involved in the ability of thyroid hormone to inhibit PRL gene transcription, but the thyroid hormone receptor does not bind to this region and it is likely that this inhibitory activity is indirect via some other trans-acting protein [80,82].

Intracellular Calcium Changes in cytosolic free calcium concentrations mediate the lactotroph responses to a number of extracellular stimuli (see below). A calcium response element has been demonstrated to reside within the initial 174 base pairs of the 5¢ flanking sequence [83]. The effects of intracellular calcium on enhancing PRL gene transcription may, in part, be mediated by the phosphorylation of a nuclear matrix protein kinase, topoisomerase II, by a calcium-calmodulin dependent protein kinase [84]. Four topoisomerase II recognition sequences were found in the 5¢ flanking region, at regions +1500 to +1600, -42 to -63, -1200 to -1300 and -2900 to -3000 base pairs with respect to the transcription start site [84]. Site 2, at -42 to -63 base pairs upstream from the transcription start site is within the region cited above as containing a calcium responsive element. Day and Maurer [85] have also found that both the proximal and distal enhancer regions are involved in mediating the transcriptional response to calcium. As discussed below, the activation of the phosphotidyl inositol pathway is probably a major route of stimulation of PRL gene transcription via an increase in intracellular calcium and the phosphorylation of protein kinase C. Direct stimulation of protein kinase C via phorbol ester causes PRL gene transcription via a regulatory region located at -74 to -30 of the 5¢ flanking region [68].

Glucocorticosteroids The region between -200 and +75 is necessary for glucocorticoid down-regulation of PRL gene transcription in the rat [77]. Sakai et al. [86] have provided evidence in the cow that the glucocorticoid response element (GRE) is a compound element with a constitutive enhancer-like component that activates transcription when glucocorticoids are not present and a sequence in which receptor binding reverses this enhancement. This negative GRE appears to lie between -310 and -152 of the 5¢ flanking region of the bovine PRL gene.

Cyclic AMP The sequence mediating the stimulatory effect of cAMP lies between -127 and +73 [70]. The sequence CCCCTCCC

lying between -78 and -71 in the rat gene has been shown to be a cAMP responsive element which binds to a transactivating factor termed Activator Protein 2 (AP-2) [87–89]. AP-2 has a molecular mass of 50–52 kDa [88]. In addition to this AP-2 binding region, the -97 to -84 region contains the sequence TGACGAAA which is similar to a cAMP response element (CRE) and may bind a CRE binding protein (CREB) [89]. There is also evidence that cAMP induced stimulation of PRL gene transcription may actually occur via the release of an inhibitory element downstream of -127 [70] or via intracellular calcium-dependent events [90]. Stimulation of PRL transcription by cAMP may also occur by augmenting the tissue specific enhancer element, Pit-1, discussed above [88,90].

PROLACTIN GENE REGULATION PRL secretion is influenced by a number of factors. Some of these factors, such as estrogen, have a direct action on the gene to alter transcription. Others, such as TRH and DA, act by binding to specific receptors on the lactotroph membrane, thereby activating intracellular second messenger signal transduction systems. This section will review these direct acting substances and these intracellular signal transduction systems (Fig. 4.4).

Estrogen The hormonal milieu of pregnancy has long been known to be stimulatory to lactotroph growth, causing hyperplasia of the normal pituitary lactotrophs [23,24] and enlargement of prolactinomas [91]. In early animal studies, it was shown that the PRL surge that occurred during proestrus was triggered by the prior estrogen peak [92] and that estrogen administration caused an increase in PRL synthesis [93–95]. Estrogen administration in vivo or when added to cell cultures results in an increase in lactotroph mRNA levels, paralleling the increase in PRL biosynthesis [96–101]. This stimulation of PRL gene transcription is biphasic. The first phase begins within 30 minutes of exposure and peaks within 1 hour, and involves the direct binding of estradiol to the nuclear estrogen receptor and subsequent binding of the estrogen-receptor complex to the specific estrogen response element discussed above. The second phase begins within 6 hours, continues for 24 to 48 hours and is indirect, in that it involves synthesis of a protein intermediate, as shown by this effect being blocked with protein synthesis inhibitors such as cycloheximide [100,102,103]. This second phase may be due to a modulation of the inhibitory effect of DA on PRL gene transcription, which itself is mediated by a decrease in intracellular cAMP [103,104]. Estrogen administration also stimulates mitotic activity, DNA synthesis and lactotroph proliferation [105–108].

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FIGURE 4.4. Signal transduction mechanisms involved in prolactin regulation. ER, estrogen receptor; TR, thyroid hormone receptor; GR, glucocorticoid receptor. In cytoplasm: ER, endoplasmic reticulum. For details, see text.

Thyroid Hormone

Adenyl Cyclase and Cyclic AMP

Thyroid hormones have long been known to suppress PRL synthesis and secretion from pituitary cell cultures [109]. Maurer [110] demonstrated a concomitant decrease in PRL mRNA levels, indicating an effect on PRL gene transcription. The roles of direct binding of the thyroid hormonereceptor complex to the distal thyroid hormone response element vs indirect effects via trans-acting factors at the more proximal site mentioned above in this inhibitory effect of thyroid hormone still need to be established.

Increases in intracellular cAMP result in an increase in PRL gene transcription and hormone synthesis and release in some cell systems but not others [103,114–116]. Agents which directly activate adenyl cyclase, such as forskolin, stimulate PRL gene transcription [116,117]. As discussed above, there may be both proximal and distal regions of the 5¢ flanking region that are responsible for the response to cAMP. It is likely that the effects of cAMP on gene transcription occur via the activation of a cAMP-dependent protein kinase and resultant phosphorylation of a specific DNA binding protein (AP-2, see above) associated with the cAMP response element (AP-2 binding site) of the PRL gene [118] or perhaps also via modulation of the effects of Pit-1 [70]. There are likely additional enzymes and proteins similarly phosphorylated that may be involved in eventual secretion of the mature PRL molecule. Furthermore,

Glucocorticoids Glucocorticoids exert an inhibitory action on PRL synthesis [111–113] and gene transcription. As discussed above, the inhibitory action may actually be a turning off of a constitutive enhancer-like component [86].

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protein phosphatases which interrupt signal transduction by decreasing phosphorylation are also important [119]. DA, the primary PRL inhibitory factor (PIF), acts through the D2 DA receptor, in part by inhibiting adenyl cyclase and decreasing intracellular cAMP [120,121]. Maurer found that adding monobutyryl cAMP to ergocryptine-pretreated cells resulted in a stimulation of PRL gene transcription [114] and Anderson et al. [122] were able to reverse the inhibitory effect of DA by adding forskolin, which increases intracellular cAMP levels. However, other experiments have shown that maintenance of intracellular cAMP levels does not abolish the inhibitory effects of DA on PRL release [123,124], so that other pathways may also mediate some of the inhibitory effects of DA. The intracellular phosphoinositide/calcium pathways may well be more important in mediating the inhibitory effect of DA on PRL release (see below). Vasoactive intestinal peptide (VIP) stimulates PRL release primarily through stimulation of adenyl cyclase and the production of intracellular cAMP [125–127]. However, it is unlikely that other secretogogues work through this pathway [128].

Phosphoinositide/Arachidonate Pathways A number of factors affecting PRL secretion act through the phosphoinositide pathways, including TRH, angiotensin II and DA [128]. As in other systems, after hormonereceptor interaction, coupled via a G protein, the initial step is the phospholipase C hydrolysis of phophatidylinositol 4,5biphosphate to yield inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Stimulation causes an increase in IP3 which then causes a rapid release of calcium from the endoplasmic reticulum and an activation of membrane calcium channels to increase transport of extracellular calcium, resulting in a net increase in intracellular calcium content. Changes in intracellular calcium result in a number of further changes (see below), including, with DAG, activation of protein kinase C, which then acts by phosphorylating other proteins. The role of the phosphoinositide-protein kinase C pathway in the regulation of PRL secretion has been investigated in great detail. Protein kinase C is located in the normal pituitary [129], various PRL-secreting rat pituitary lines [130,131], and human pituitary tumors [132]. Activation of protein kinase C by phorbol ester results in PRL gene transcription with an increase in PRL mRNA levels and eventual PRL release from pituitary cells in vitro [133–137]. The mechanism mediating this PRL gene transcription is probably the protein kinase C phosphorylation of intracellular proteins [138,139] that, in turn, act as transacting factors on DNA regulatory elements in the proximal promoter region of the 5¢-flanking region of the PRL gene [140]. The phosphoinositide-protein kinase C pathway is a primary mediator of the stimulatory effects of TRH on PRL

gene transcription and release. TRH results in a rapid, phospholipase C-mediated hydrolysis of phosphotidylinositol with generation of DAG and IP3 [141,142]. The released DAG stimulates protein kinase C, resulting in phosphorylation of intracellular [139] and specifically nuclear, chromatin-binding proteins [138]. DAG probably mediates the second phase of the PRL response to TRH that occurs between 5 and 60 minutes after stimulation [143]. The increase in IP3 stimulates release of intracellular calcium stores [136,144], another mechanism involved in PRL gene transcription and release (see below). In various in vitro preparations, angiotensin II, neurotensin and bombesin have been found to stimulate PRL release in a similar fashion [128]. Studies of the interaction of DA with the pituitary D2 DA receptor and the phosphoinositide-protein kinase C pathway have yielded conflicting results, in part due to differences in cell preparations and experimental designs (reviewed by Lamberts and MacLeod [128]). Because chronic D2 receptor activation results in an attenuation of the phosphorylation of phosphotidylinositides [145], Lamberts and MacLeod [128] have concluded that DA’s inhibitory activity on PRL secretion occurs via this effect on phosphorylation rather than through an effect on phospholipase C. A second pathway involving membrane phospholipids is the arachidonate pathway, although the specifics of this pathway have not been fully elucidated. Stimulation of membrane-bound phospholipase A2 by TRH, angiotensin II, neurotensin and other direct stimulators results in PRL and arachidonic acid release from pituitary cells in vitro [146,147]. This effect of arachidonic acid release is blocked by inhibitors of phospholipase A2 [146] and by DA [148]. Arachidonate itself can liberate PRL in such cultures, an effect blocked by inhibitors of the conversion of arachidonate to its metabolites [149]. As only inhibitors of the lipoxygenase and epoxygenase pathways of arachidonate metabolism have an inhibitory effect of PRL release, it is likely that one or more metabolites in these pathways are the proximal effectors of PRL release [150]. The fact that arachidonate metabolism inhibitors have a much greater effect on inhibiting PRL release in basal conditions compared to the stimulated state suggests that these eicosanoids may be more likely to mediate paracrine or autocrine modulations of secretory mechanisms, rather than to function as intracellular messengers [150]. The effect of arachidonic acid in increasing PRL release is primarily via an increase in calcium influx rather than by mobilizing intracellular calcium stores [151].

Intracellular Calcium As discussed above, activation of the phosphoinositide pathway results in a mobilization of intracellular calcium stores and an influx of extracellular calcium. The resultant increase in intracellular free calcium results in PRL gene

Chapter 4

transcription, PRL synthesis and release. The mobilization of intracellular calcium is rapid but transient, resulting in a high amplitude burst of PRL release [128,152]. The stimulation of calcium uptake via calcium channels is more prolonged and proceeds at a lower rate, resulting in sustained PRL release [128,152]. As mentioned above, calcium interacts directly with DAG to activate protein kinase C. Calcium also binds to topoisomerase II which then interacts with specific DNA binding sites and to calmodulin, which binds to a number of different intracellular enzymes [84]. Preston et al. [153] demonstrated that the increase in intracellular PRL mRNA is due not only to an increase in gene transcription but also to a posttranscriptional mechanism involving the posttranslational modification of a stable protein which then regulates PRL mRNA stability. Blockade of calmodulin activity with penfluridol or selective antagonists such as W7 results in a decrease in PRL release [154,155], whereas the calcium ionophore, A23187, stimulates PRL release [155]. Furthermore, A23187 stimulates intracellular cAMP accumulation and W7 blocks both the A23187 stimulation of intracellular cAMP accumulation and PRL release [155]. Thus mobilization of intracellular calcium may have effects on both protein kinase C and cAMP. Calcium channel antagonists, such as verapamil, diltiazem, nifedipine, nimodipine, pimozide, penfluridol and the negative enantiomer of Bay K8644 inhibit, and agonists, such as the positive enantiomer of BAY K8644, stimulate PRL gene transcription, synthesis and release in in vitro preparations [156–162]. The effects of manipulation of intracellular calcium levels on the stimulatory and/or inhibitory effects of a number of physiologic PRL regulators have been assessed. Agents which mobilize intracellular calcium stores, such as A23187 and ionomycin, do not add to the PRL releasing effects of TRH, whereas BAY K8644, which stimulates calcium channels, does show an additive effect [159,163], suggesting that the effect of TRH on the first phase of PRL release is primarily through release of calcium stores rather than by stimulating calcium channels [162–166]. However, when these experiments were examined with respect to the action of TRH on PRL gene transcription and PRL synthesis, none of these agents were additive with TRH. Thus,TRH appears to cause rapid release of PRL via activation of protein kinase C and calcium store mobilization but not calcium channel transport, and its effects on PRL gene transcription and PRL synthesis involve all three processes [159]. La Verriere et al. [159] postulate that the initial steps involve activation of protein kinase C and mobilization of intracellular calcium, which in turn control the activity of calcium channels. DA inhibits the PRL release induced by activation of calcium channels by BAY K8644 [157,160] and maitotoxin [123] and by mobilization of intracellular calcium stores by A23187 [167]. Conversely, the calcium channel blockers nimodipine, verapamil and diltiazem antagonize the inhibitory effect of DA in vitro [168]. DA administration blocks

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the rise in intracellular calcium concentrations induced by TRH and angiotensin II [169], and DA withdrawal from the medium causes a rapid influx of calcium [170]. These findings are consistent with an inhibitory action of DA on calcium influx via calcium channels. Maitotoxin, which activates calcium channels, also blocks the DA induced inhibition of PRL secretion from lactotrophs in vitro [123]. Thus, at least part of the inhibitory action of DA on PRL secretion appears to be mediated by effects on intracellular calcium concentrations. In humans, administration of the calcium channel blocker verapamil causes an increase rather than a decrease in serum PRL levels [171,172] and does not inhibit the TRHinduced PRL rise [172]. This was shown to be due to a decrease in tuberoinfundibular generation of DA [173]. Because dihydropyridine and benzothiazepine calcium channel blockers had no effect on PRL levels in humans, it was hypothesized that the effect of verapamil is via action at N-type calcium channels present in neuronal tissues [173].

HORMONE BIOSYNTHESIS The primary translation product of the human PRL gene is 227 amino acids in length, consisting of a 28 amino acid signal peptide and a 199 amino acid hormone with a molecular mass of 23-kDa [19]. The structure predicted by the mRNA sequence delineated by Cook et al. [19] differs at eight positions from the early sequence of Shome and Parlow [18], which was determined by standard sequencing techniques. There are three disulfide bonds between cysteines at positions 4 and 11, 58 and 174 and 191 and 199, giving rise to small loops at the amino and carboxy terminal ends and a large loop in the middle (See Fig. 4.2). There is considerable heterogeneity in the final PRL product, depending upon variations in the degree of posttranslational modifications, which include cleavage, polymerization, glycosylation, phosphorylation and degradation (Table 4.1).

Cleavage Products Small amounts of 16 K and 8 K cleavage products are present in the normal pituitary and plasma of humans [174] as well as rats [175] and mice [176]. In the rat, the 16 K fragment has greater mitogenic activity than the intact hormone [177], but this has not yet been determined for hPRL. Several PRL-like proteins that are only a few amino acids shorter than the 23 K form and have a molecular weight of about 21 K are present in the rat pituitary. These smaller variants arise from carboxy (COOH)-terminus proteolytic clipping during storage and not from transcriptional modifications resulting from alternative splicing of the PRL pre-mRNA, as only a single 23 K band is found with in vitro translation systems [178–181]; these have not yet been described in the human.

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Table 4.1. of prolactin

Hypothalamic–Pituitary Function

Posttranslational processing and other variants

Cleavage 23K 21K (?) 16K 8K

Polymerization Monomer—80–90% Dimer—8–20% Polymer—1–5%

Glycosylation Circulating—50–100% Pituitary—13–25%

Phosphorylation

Decidual prolactin Lymphoblastoid prolactin

different types of glycosylation products have been described [197]. The glycosylated variants account for 13% to 25% of pituitary PRL and 50% to 100% of circulating PRL [196–199]. Glycosylated PRLs are less immunoreactive in the routine PRL RIA [196], bind less well to the PRL receptor [200] and are less bioactive, using a variety of bioassays [197,201,202]. On the other hand, Young et al. [203] found glycosylated porcine PRL to have greater lactogenic and binding affinity, despite decreased mitogenicity compared to nonglycosylated PRL. Interestingly, during pregnancy, subsequent lactation, and pathologic hyperprolactinemic states, when there is a high PRL secretion rate, the relative amount of nonglycosylated PRL increases compared to other times [199,201].

Placental variants

Phosphorylated Forms Larger Molecular Weight Forms About 80% to 90% of PRL extractable from pituitaries and in serum is monomeric, 8% to 20% is dimeric (molecular mass 45–50 kDa) and 1% to 5% is polymeric [182–186]. The dimeric and polymeric forms are linked by disulfide bonds [184] (see below) and can be largely dissociated under reducing conditions or with digestion with chymotrypsin [184,185]. Polymerization occurs primarily within storage granules and in stimulated lactotrophs PRL is synthesized and discharged rapidly, bypassing polymerization [187]. However, with stimulation the stored polymeric forms are released into plasma [188]. These larger molecular weight polymers have decreased binding to receptors and display decreased bioactivity in a variety of receptor assays [183,184] but have normal bioactivity in the Nb2 lymphoma cell bioassay (see below) [186]. Using highly purified, monomeric human PRL infused into normal male subjects, Molitch et al. [189] showed that some conversion of monomer to dimer also occurs in plasma. A number of patients have been described with elevated basal serum PRL levels but normal reproductive function who were found to have markedly elevated proportions of polymeric PRL, presumably thereby resulting in less PRL bioactivity [190–194]. However, in many such reported cases the proportion of monomeric PRL in the blood is still elevated. Preliminary screening of sera suspected of having a high proportion of polymers can be done by precipitating the large complexes with polyethylene glycol, but gel filtration chromatography remains the best procedure for quantitating the amount of polymers [195]. In clinical practice, screening for polymers is rarely carried out.

Glycosylated Products Glycosylation of human PRL occurs [196]. The carbohydrate unit is linked to the asparagine at position 31 and the complex has a molecular weight of about 25 K [196]. Two

PRL can be phosphorylated within secretory granules in rat and bovine lactotrophs [181,204,205]. These secretory granules appear to contain a PRL kinase, although the specifics of this remain to be determined. The role of this phosphorylation in secretion, whether phosphorylated forms circulate, and whether this process occurs in humans are unknown.

Placental Variants In mice and rats, there are a variety of PRL-like proteins produced by the placenta in addition to placental lactogen [206,207]. These PRL-like proteins are secreted at different times during gestation by the placenta and thus may have different functions, including alterations in blood vessel formation, hematopoiesis, and lymphocyte function [206,207]. No such proteins have been identified in the human and human placental lactogen is much closer in structure to GH than it is to PRL.

Decidual Prolactin PRL levels in maternal blood rise throughout gestation and are of pituitary origin [208,209]. However, PRL concentrations in amniotic fluid are 10–100 fold higher than either maternal or fetal blood levels [208]. Early biochemical studies found that amniotic fluid PRL was identical to serum PRL biologically, chemically and immunologically [210,211]. Friesen et al. [212] first showed that cultured human chorion released PRL and subsequently Riddick and Kusmik [213] found that cultured human decidual cells released it. Finally Golander et al. [214] documented that cultured human chorion-decidual explants synthesize and release a PRL that was shown to be identical to pituitary PRL. It was further documented that the decidua produced PRL [215], and that its bioactivity was equal to pituitary PRL [216]. Additional studies have shown that decidual PRL mRNA hybridizes with a pituitary PRL

Chapter 4

cDNA probe and Northern blot analysis shows that the 2 PRL mRNAs are indistinguishable, except for four silent nucleotide differences and the decidual PRL gene being about 150 nucleotides longer in the 5¢ untranslated region [217–219]. Similar to pituitary PRL, decidual PRL is also glycosylated [220] and some of the glycosylated PRL is bound to immunoglobulin by disulfide bonds in the amniotic fluid [221]. Similar rat decidual PRL-like substances have been reported that are structurally different from rat pituitary PRL but bind to PRL receptors and stimulate steroidogenesis by the corpus luteum [222–224]. The regulation of decidual PRL production differs from that of pituitary PRL (detailed below). DA agonists [225] and antagonists [226] given to the mother respectively decrease and increase maternal serum PRL levels but have no effect on amniotic fluid PRL levels. Similarly, DA, bromocriptine, and TRH have no effects on the decidual production of PRL in vitro [214]. Decidual PRL production is increased by progesterone and progesterone plus estrogen but not estrogen alone [218,227]. In 1988, Golander et al. [228] reported that a purified, 23.5-kd placental protein could stimulate the synthesis and release of PRL from decidual cultures. Insulin, through the insulin receptor, insulin-like growth factor I (IGF-I), through the IGF-I receptor and relaxin, a third peptide related to insulin and IGF-I have all been reported to stimulate synthesis and release of PRL [218,229,230]. The function of decidual PRL remains obscure, although there is some evidence that it may contribute to the osmoregulation of the amniotic fluid [231], fetal lung maturation [232] and uterine contractility [233].

Lymphoblastoid Cell Prolactin A human clonal lymphoblast cell line, IM-9-P3, has been established which produces a PRL that is identical to pituitary PRL in all aspects [234], including the sequence of their mRNA’s [235]. There are differences from pituitary but not decidual PRL, however, in the 5¢ untranslated region of the gene, suggesting that regulatory mechanisms may be different [235]. Indeed, preliminary studies have shown that PRL production by this cell line can be decreased by dexamethasone but other substances known to affect pituitary PRL secretion, such as estradiol, thyroxine, TRH and VIP, have no effect [236]. The similarities in the structure and regulation of the IM-9 and decidual PRL genes suggest that studies of the IM-9 cell line may prove fruitful in discerning the mechanisms regulating decidual PRL production, but it is doubtful that such studies will contribute much to our understanding of pituitary PRL regulation. HORMONE SECRETION—BIOCHEMISTRY Following synthesis on the rough endoplasmic reticulum, PRL is packaged into secretory granules in the Golgi and

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PRL release occurs via exocytosis [237,238]. Nicoll and Swearingen in the early 1970s [239,240] demonstrated the existence of two pools of PRL within the rat lactotroph cell, one turning over rapidly and the other turning over slowly. Newly synthesized PRL is preferentially released compared to older, stored PRL in response to some stimuli and constitutes the rapidly turning over pool [238,241–243]. However, other stimuli, such as TRH, result in a preferential release of older, stored PRL [238]. Walker and Farquhar [238] found that these two types of secretion, rapid and slow, occurred not so much due to differences in the type of stimulation for a given cell but due to functional heterogeneity of the cells, so that some cells synthesize and secrete PRL rapidly while others secrete more slowly (see also the discussion above about the hemolytic plaque assay). Much of the storage pool of PRL in the pituitary appears to exist in a high molecular weight, disulfide-bonded, poorly immunoreactive polymeric form that is converted to a releasable, immunoreactive monomeric form within the secretory granule when processed for release [244]. This conversion involves a thio-disulfide interchange mechanism and can be stimulated by reduced glutathione and decreased by aminothiols such as cysteamine [244,245]. Treatment with cysteamine, in fact, reduces the amount of PRL detectable within cells using immunoprecipitation and RIA, but not when electrophoresis alone is used for detection [246,247]. These changes appear to explain a previous finding in rats that stimulation resulted in a “depletion” of the storage form of PRL in the pituitary with its “transformation” into the readily releasable, immunoreactive PRL [248]. Cysteamine has also been shown to reduce PRL release from pituitaries in humans and its therapeutic use in patients with hyperprolactinemia has been suggested [249], although its action on disulfide bonds in other peptides, such as somatostatin, would appear to preclude such use [250].

Measurement of PRL RIA

RIAs for PRL were initially developed for the rat [6], sheep [7] and cow [8]. After studies finally showed that in humans PRL and GH were separate molecules (see above), RIAs were developed for human PRL [16,17]. Most RIAs are double antibody assays, using as standard PRL that is either of commercial origin or a preparation available from the National Hormone and Pituitary Program in the U.S.A. or the National Institute for Biological Standards and Control in the UK. Because of the above noted differences in the kinds of PRL that exist in the pituitary and serum, it is not surprising that antibodies raised against one preparation of PRL may bind PRL differently from antibodies raised against a different preparation of PRL. Furthermore, PRL preparations for iodination and standards differ from one laboratory to another and therefore some means of standardizing one assay with another is

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important. Although antibodies still differ, at least the standards used can be standardized against a reference preparation, and this is usually done. First, second and third International Reference Preparations (IRPs) have been established by the National Institute for Biological Standards and Control in London [251,252] and similar reference preparations are made available by the National Hormone and Pituitary Program in Baltimore. Unfortunately, the supply of suitable standards does not preclude considerable variation from RIA to RIA in different laboratories in the measurement of PRL levels in both research studies and clinical evaluations of patients. In a survey of 10 different laboratories, the mean intraassay coefficient of variation was 9.6% but ranged from 5.6% to 25.3% and the mean interassay coefficient of variation was 7.9% [253]. Over the past decade, two-site immunoradiometric assays (IRMA) and chemiluminometric assays (ICMA) have come into wide use because of improved sensitivity and precision and short incubation periods. However, in patients with large prolactinomas with very high PRL levels, the very high level of PRL may saturate the antibodies, preventing the formation of the PRL-antibody sandwich, leading to loss of labeled antibody and a falsely low value [254,255]. St. Jean et al. [254] noted this high end “hook effect” in 5.6% of 69 patients thought to have clinically nonfunctioning adenomas. Therefore, in patients with large macroadenomas, PRL assessments should always be performed in both undiluted and 1 : 100 diluted serum to exclude the “hook effect” when two-site assays are used. Bioassays

The pigeon crop sac assay for PRL was the first assay used and was the standard until the late 1960s [1,3,4]. Although the procedure was refined and quantified substantially by Nicoll [4], it still proved cumbersome. Kleinberg and Frantz subsequently developed a highly sensitive bioassay which involved grading histologic changes in mouse mammary tissue that had been cultured with varying concentrations of PRL or serum samples [256]. It was with this assay that Kleinberg and Frantz first demonstrated that PRL is a separate hormone from GH in human blood [15]. This assay was further refined by Turkington [257], with quantitation of casein production by the mammary tissue being the endpoint measured. A radioreceptor assay using rabbit mammary gland membranes has been developed [258] which, as with other radioreceptor assays, essentially measures receptor binding but not true bioactivity. The most commonly used bioassay now is the Nb2 node rat lymphoma cell assay. In this assay cultured lymphoma cells replicate in response to added GH and/or PRL but not other hormones, with a sensitivity down to 0.1 ng/ml [259]. Using this assay, Tanaka et al. [260] and Rowe et al. [261] found bioassay/RIA ratios with a range of 0.53– 1.56 in sera from normal and hyperprolactinemic patients. As discussed above, in some patients with high amounts of polymeric PRL circulating in their blood, this ratio is

normal, whereas it is decreased in other bioassays. Thus this bioassay measures only one aspect of PRL function and when detailed assessments of biological function are necessary, more than one bioassay may be required. Frawley et al. [262] have revived the mammary gland casein production assay, achieving much better sensitivity. In this assay, they use a monolayer dispersed cell culture of rat mammary glands and then detect PRL induced casein production by a variant of their hemolytic plaque assay using casein antibodies, protein-A coated ovine RBC’s and complement, achieving a sensitivity of <1 pg/ml [262].

Physiology Metabolic Clearance and Production Rates of Prolactin

The metabolic clearance rate (MCR) and production rate (PR) of PRL have been determined by two methods: the infusion to equilibrium method using radioactively labeled PRL, and the infusion of exogenous hPRL into individuals in whom endogenous PRL production had been suppressed with a DA infusion. In two studies using the former method, the MCRs were found to be 46 ± 4 and 40 ± 6 mL/min/m2 [263,264] and with the latter method it was found to be 71 ± 19 mL/min/m2 [189]. The calculated PRs using the labeled PRL method were 200 ± 63 and 536 ± 218 mg/day/m2 and 802 ± 377 mg/day/m2 using the hPRL infusion method. The calculated disappearance half-lives varied from 26 to 47 minutes in these three studies. In another study the disappearance half-life was estimated to be 43.6 ± 11.2 minutes as determined from the rate of fall of PRL with individual secretory episodes [265]. The fate of PRL is unclear. Studies in patients with chronic renal failure have shown the MCR to be reduced by 33% [264] but Bratusch-Marrain et al. [266] found no hepatic uptake of PRL in man, in contrast to the liver’s being responsible for about 50% of total GH clearance in man and playing a substantial role in the uptake of PRL in rabbits [267]. Hormone Secretion Patterns

PRL is secreted episodically (Fig. 4.5). There is an innate pulsatility to pituitary PRL secretion with an interpulse interval of about 8 minutes, as determined by studies of plasma samples in rats in whom pituitaries were placed under the capsule of the kidney to escape hypothalamic regulation [268] and from media obtained from primate pituitaries cultured in vitro [269]. When plasma is sampled from normal individuals in whom hypothalamic function is superimposed upon this innate pulsatility, it becomes apparent that there are 4 to 14 secretory episodes per day. In two studies that used cluster analysis, 13 to 14 peaks per day in young subjects were found with a peak duration of 67 to 76 minutes, a mean peak amplitude of 3–4 ng/ml and an interpulse interval of 93 to 95 minutes [270,271]. Disinhibition caused by hypothalamic tumors causes an increase in

Chapter 4

FIGURE 4.5. Prolactin levels throughout the day in a single individual superimposed upon the range from five normal individuals. Note the episodic nature of secretion and the nocturnal rise.

basal PRL levels due to an increase in pulse amplitude and not pulse frequency [272]. There is an increase in the amplitude of the PRL secretory pulses that begins about 60 to 90 minutes after the onset of sleep; the secretory pulses increase with non-REM sleep and fall prior the next period of REM sleep [273]. Lowest PRL concentrations are found during REM sleep and highest concentrations are found during non-REM sleep [273]. When subjects are kept awake to reverse the sleep-waking cycle, PRL levels do not rise until sleep begins [274]. Thus, the diurnal variation of PRL secretion is not an inherent rhythm but depends on the occurrence of sleep. Interestingly, the diurnal variation of PRL with the sleep-induced rise persists despite other powerful physiologic influences such as breast-feeding [275]. Studies of PRL secretory patterns in twins show that there are both genetic and environmental influences on these patterns [276]. Weitzman et al. [277] noted small rises in PRL in the afternoon and evenings and they postulated that there may be a relationship to meals. Quigley and Ropert noted an increase in circulating PRL levels of 50% to 100% within 30 minutes of meals [278]. Subsequent work by Carlson related this increase to the amino acids generated from the protein component of the meals, phenylalanine, tyrosine and glutamic acid being the most potent in this regard [279–282]. Carlson et al. [282] have provided evidence that this stimulatory action of these amino acids is centrally mediated by showing that large neutral amino acids such as valine inhibit the transport of phenylalanine across the blood–brain barrier and blunt the stimulatory action of this amino acid. Changes in Prolactin with Age

PRL levels are elevated almost 10-fold in infants following delivery but then gradually decrease so that levels are normal by three months of age [283]. These high levels of PRL at birth are probably related to the stimulatory effect of high maternal estrogen levels. PRL levels are lowest between the ages of 3 months and 9 years and then rise modestly during

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FIGURE 4.6. Serum prolactin (PRL) concentrations measured serially at weekly intervals as a function of gestation (n = 4). The dashed line represents the linear regression and the solid line represents the second order regression. NP, nonpregnant PRL values. From Rigg et al. [209]

puberty to adult levels [283]. In some studies there is a gradual fall of basal PRL levels with age, but in other studies no changes with age have been found [271,283–290]. One recent study found that PRL levels in women gradually fall by about 50% over the first 18 months following menopause, but this fall is considerably less in women treated with estrogen replacement therapy [287]. Other studies have shown no change in PRL levels with hormone replacement therapy [288]. In hyperprolactinemic women, estrogen replacement therapy causes no change in PRL levels [289]. A recent detailed study showed that mean serum PRL concentrations were decreased by 55% in older compared to younger men, and that this decrease was due to decreased basal secretion as well as the amount of PRL secreted with each secretory burst but that there was no change in pulse duration or frequency or interpulse interval [290]. Changes in Prolactin Levels during the Menstrual Cycle

A number of investigations of the changes in blood PRL levels during the menstrual cycle have revealed that some, but not all, subjects have higher levels at mid-cycle and lower levels in the follicular compared to the luteal phase [208,253,285,291–294]. In most of these studies, no correlations were found between PRL and estradiol, progesterone, LH and FSH levels. However, some studies have shown that PRL and LH secretion are often synchronous in the luteal phase and that very small doses of GnRH can cause the secretion of both PRL and LH at this time [295]. Changes in Prolactin Levels during Pregnancy

Basal PRL levels gradually increase throughout the course of pregnancy (Fig. 4.6) [208,209]. This has generally been attributed to the stimulatory effect of the hormonal milieu of pregnancy, primarily estrogenic, on the pituitary

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lactotrophs. There is a gradual increase in the number of pituitary lactotrophs during pregnancy [23,24] and by term, PRL levels may be increased 10-fold to levels over 200 ng/ml [208,209,283]. These elevated PRL levels found at term prepare the breast for lactation. Changes in Prolactin Levels with Postpartum Lactation

Within the first 4–6 weeks postpartum basal PRL levels remain elevated in lactating women and each suckling episode triggers a rapid release of pituitary PRL resulting in a 3–5 fold increase in serum PRL levels, peaking about 10 minutes after the end of suckling [208,296]. This increase in PRL secretion is accompanied by a suckling-induced increase in pituitary PRL mRNA levels which provide for increased PRL synthesis [297]. Following termination of suckling PRL levels gradually fall to reach prenursing levels by about 3 hours after the beginning of the suckling episode [296,298,299]. Over the next 4–12 weeks, basal PRL levels gradually fall to normal and the PRL increase which occurs with each suckling episode decreases [296,300]. Eventually there is little or no rise in PRL with suckling despite continued milk production [208]. The actual PRL levels achieved during suckling do not correlate with the amount of milk produced [298]. The decreases in basal and stimulated PRL levels between 3 and 6 months postpartum are largely the result of decreased breast-feeding as formula is introduced into the baby’s diet. If intense nursing behavior is maintained, basal PRL levels remain elevated and postpartum amenorrhea persists (Fig. 4.7) [301–303]. Eighty minutes of nursing per day with a minimum of six nursing episodes will usually result in persistent hyperprolactinemia and amenorrhea [303]. However, the delay in the onset of menses is more associated with high suckling duration and frequency than with a particular level of PRL [303]. High intensity lactation-induced failure to ovulate and menstruate has been used as a method of contraception in a number of developing countries for many years [304–306]. Breast stimulation may cause an increase in PRL levels in some non-breast-feeding normal women but not in men [296] except for one study showing PRL increases in men after breast stimulation by their wives [307]. Changes in Prolactin Secretion with Stress

PRL has long been known to be one of the pituitary hormones released by stress, along with adrenocorticotropic hormone (ACTH) and GH. Neill initially demonstrated the release of PRL from rats with ether stress [308] while Noel et al. initially showed a similar response to physical stress in humans [309]. The stress-induced rise in PRL generally consists of a doubling or tripling of PRL levels and lasts less than 1 hour. This rise in PRL may be limited by the concomitant release of cortisol which suppresses further PRL release, as evidenced by the fact that stress applied to adrenalectomized rats results in a PRL increase that is sustained for as long as the stressful stimulus is applied [310,311]. In

FIGURE 4.7. Mean 24-hour prolactin levels as a function of number of minutes of nursing in the same 24-hour period. Each circle represents one woman. The same amount of nursing results in higher levels of prolactin in the first year than in the second year postpartum.
= <12 months postpartum;  = >12 months postpartum. r = 0.54, P < 0.02. From Stern et al. [303]

humans, prolonged critical illness does not cause a sustained elevation of PRL; rather there is a reduction in the pulsatile secretion with an overall lowering of levels [312]. The teleologic significance for these stress-induced changes in PRL is not clear. The neuroendocrine mediation of the acute stress response is probably multifactorial but does not include a decrease in dopamine [313]. Corenblum and Taylor [314] attempted to dissect out the neurotransmitter regulation of the PRL stress response in humans by administering various blocking agents immediately prior to surgery. Blockade of histamine H1 receptors using chlorpheniramine, serotonin receptors using cyproheptadine, and dopamine receptors using pimozide had little effect on the peak PRL level reached during surgery. Blockade of opiate receptors with high dose naloxone resulted in a significant blunting, but not complete inhibition of the PRL response. These studies imply that the endogenous opiate-like peptidergic pathways may play a role in the PRL stress response. On the other hand, in humans naloxone has generally not been found to be able to block the PRL response to hypoglycemia [315]. Abe et al. found that VIP antisera inhibited the etherinduced PRL rise in rats [316] and Kaji et al. [317] found that antisera to VIP and PHI were additive in this regard. Other factors including serotonin, oxytocin and possibly unidentified posterior pituitary PRL releasing substances may also be involved, but their relative roles remain obscure [313].

Chapter 4

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Hypoglycemia has been regarded as a form of stress, but whether it acts as a nonspecific stressor or has more specific effects is not clear. Among their tests of various types of stress, Noel et al. [309] showed that PRL did indeed rise with hypoglycemia. Woolf et al. [318] evaluated this effect systematically in normal men and women, finding that PRL levels increased by at least 10 ng/ml with a doubling of baseline levels in two-thirds of normal subjects, the maximal rise occurring between 40 and 90 minutes after the injection of intravenous insulin. 2-deoxy-d-glucose, which causes intracellular glucopenia, also causes a rise in PRL levels [319]. Studies using combinations of inhibitors of dopamine, histamine and serotonin suggest that at least some of the PRL response to hypoglycemia may be mediated by serotoninergic pathways [320]. Acute exercise has also been regarded as a form of stress and results in an acute, transient increase in PRL levels [309,321]. Although chronic, high-level exercise often results in menstrual disturbance, it is not associated with sustained hyperprolactinemia [322]. Effects of Thyroid Hormone Status on Prolactin Secretion

As noted above, thyroid hormones have a direct suppressing action on PRL gene transcription and hormone synthesis, so that in hypothyroidism this effect is decreased. As discussed below, in hypothyroidism TRH synthesis is increased, pituitary TRH binding is increased and pituitary VIP levels are increased. The result is that in hypothyroidism, PRL levels may be significantly increased. NEUROENDOCRINE REGULATION The hypothalamus exerts a predominantly inhibitory influence on PRL secretion through one or more PRL inhibitory factors (PIF) that reach the pituitary via the hypothalamic–pituitary portal vessels (Fig. 4.8). There are PRL-releasing factors (PRF) as well (Table 4.2). Disruption of the pituitary stalk leads to a moderate increase in PRL secretion as well as to decreased secretion of the other pituitary hormones.

PIFs Dopamine

In 1954, Everett [323] demonstrated that the luteotropic properties of the pituitary (due to PRL) were increased when pituitaries were transplanted to beneath the renal capsule, a site away from the regulation by the hypothalamus, thus demonstrating the predominance of the inhibitory component of hypothalamic regulation of PRL secretion. Pasteels [324] and Talwalker et al. [325] subsequently showed that hypothalamic extracts suppressed PRL secretion from pituitaries in vitro. At about the same time, Sawyer’s group [326,327] demonstrated an increase in PRL secretion in rats in vivo with use of catecholamine depleting agents such as reserpine or with DA receptor blockers, such as chlorpro-

FIGURE 4.8. Neuroendocrine regulation of prolactin secretion. GAP, gonadotropin-associated peptide; PHM, peptide histidine methionine; PIF, prolactin inhibitory factor; PRF, prolactin releasing factor; TRH, thyrotropin releasing hormone; VIP, vasoactive intestinal peptide.

mazine. In 1968 van Maanen and Smelik proposed that tuberoinfundibular DA (TIDA), released into the hypothalamic–pituitary portal vessels in the median eminence, was the physiologic PIF [328]. Shortly thereafter, the direct pituitary site of action for DA was confirmed by experiments in which it was demonstrated that DA could suppress PRL release from pituitaries in vitro [329–331] and Diefenbach et al. [332] demonstrated that the DA precursor L-dopa could suppress PRL secretion in intact and stalk-sectioned monkeys. A number of experiments have now firmly established that DA is the predominant, physiologic PIF. Gibbs and Neill [333] demonstrated that the concentration of DA found in the pituitary stalk plasma (about 6 ng/ml) was sufficient to decrease PRL levels in rats and was five to 10fold higher than levels found in peripheral plasma. Stimuli

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Table 4.2.

Substances affecting prolactin release

Stimulatory Thyrotropin-releasing hormone Vasoactive intestinal peptide Peptide histidine isoleucine Serotonin Opioid peptides Growth hormone-releasing hormone Gonadotropin-releasing hormone Oxytocin Vasopressin Histamine (H1) Bradykinin Angiotensin II Neurotensin Substance P

Inhibitory Cholecystokinin Bombesin Secretin Gastrin Galanin Calcitonin Calcitonin gene-related peptide Thymosin factor 5 Melatonin Other posterior pituitary factors (?) Platelet activating factor Epidermal growth factor a-melanocyte stimulating hormone Prolactin-releasing peptide

which result in an acute release of PRL usually also result in an acute decrease in portal vessel DA levels, including such stimuli as estrogen [334], cervical stimulation [335], and mammary nerve stimulation simulating suckling [336]. However, in many experiments it was found that the PRL increase obtained by simply reducing DA was considerably less than the elevation of PRL achieved by simultaneous stimulation by a PRF; similarly, the PRL level achieved with the simultaneous stimulation by a PRF with the reduction in DA is usually greater than that achieved by a PRF alone [337–339]. It is likely that in most physiologic circumstances that cause a PRL rise, such as lactation, there is a simultaneous fall in DA along with a rise in a PRF, such as VIP [316]. However, there may well be circumstances in which various PRF’s may stimulate PRL release with no concomitant lowering of DA levels, or DA may be lowered with no concomitant increase in a PRF. Newer work with mice in which the DA D2 receptor or DA transporter have been “knocked out” (KO) with inactivating mutations has confirmed these earlier studies that employed pharmacologic methods or lesioning. Thus, mice with the DA D2 receptor KO develop lactotroph hyperplasia without adenomatous transformation and sustained hyperprolactinemia [340,341]. DA action within the synapse terminates by DA reuptake by the DA-secreting neurons via the DA transporter. In contrast to the findings with the DA receptor KO, DA transporter KO mice have increased dopaminergic tone and lactotroph hypoplasia [342]. Although such mice have normal circulating levels of PRL, they cannot increase these levels with various stimuli and are unable to lactate [342]. Interestingly, the elevated DA levels in the DA transporter KO mice also depresses hypothalamic GH releasing hormone (GHRH) content resulting in decreased GH secretion and growth [342]. Although much of the direct work demonstrating DA in hypothalamic–pituitary portal vessels and the effects of DA

Dopamine Gonadotropin-associated peptide g-aminobutyric acid Somatostatin Acetylcholine

FIGURE 4.9. Time course of the serum prolactin response to the intravenous injection of 400 mg of synthetic thyrotropinreleasing hormone (TRH) in 36 normal men and 36 normal women. From Jacobs et al. [406]

on PRL release in vitro have been done in animals, it is clear that DA is the primary PIF in humans as well. Infusion of DA causes a rapid suppression of basal PRL levels [342–346] that can be reversed by metoclopramide, a DA receptor blocker [346]. Dopamine also blocks the PRL increments induced by such stimuli as hypoglycemia [347], arginine [348] and TRH [349]. Studies with low-dose DA infusions in humans have shown that DA blood concentrations similar to those found in rat and monkey hypothalamic–pituitary portal blood [333,350] are able to suppress PRL secretion [351–353]. Blockade of endogenous DA receptors by a variety of drugs, including phenothiazines, butyrophenones, metoclopramide and domperidone causes a rise in PRL

Chapter 4

[354,355]. Furthermore, blockade of the decarboxylation of l-dopa to DA by the dopa decarboxylase inhibitor carbidopa in the peripheral blood and median eminence causes an increase in PRL [356]. The axons responsible for the release of DA into the median eminence originate in perikarya in the dorsomedial portion of the arcuate nucleus and inferior portion of the ventromedial nucleus of the hypothalamus [357–359]. This pathway is known as the tuberoinfundibular DA (TIDA) pathway and DA axon terminals comprise about a third of all axon terminals in the zona externa of the median eminence [360]. Some TIDA neurons do not terminate in the median eminence but project to the posterior and intermediate lobes where their endings are found close to pituicytes, magnocellular axon terminals and precapillary spaces [361]. In some experiments, removal of the posterior lobe results in an increase in basal PRL levels that lasts for a few days [362]. However, the precise physiologic role of the posterior pituitary in inhibiting PRL secretion in the rat remains unknown [362]. There are no data in humans regarding such a role for the posterior pituitary in PRL regulation. The DA that traverses the TIDA pathway binds to the class of DA receptors referred to as D2 receptors [363–365] on the lactotroph cell membrane [366,367]. As discussed above, activation of this receptor results in: (i) an inhibition of adenyl cyclase with lowered intracellular cAMP levels; (ii) inhibition of phosphoinositide metabolism; and (iii) decreased intracellular calcium mobilization and inhibition of calcium transport through calcium channels. Some studies have also suggested that at least some of the inhibitory action of DA may be mediated by nitric oxide [368]. It has been proposed that these different actions of DA may actually be mediated by multiple similar D2 receptors that are produced by alternative RNA splicing [369]. The functional state of the D2 receptor is the high affinity form [364,367,370]. Although binding of DA to the D2 receptor appears to be sufficient to decrease PRL secretion mediated by the above pathways, DA can also be found intracellularly in association with PRL secretory granules [371–373]. The functional significance of this association of DA with the secretory granules is unknown. The inhibitory action of DA on PRL secretion is partially blocked by estrogen administration. This may be largely due to the direct action of estrogen on the estrogen response element of the PRL gene (see above). However, there may also be other mechanisms but with considerable interspecies differences. Estradiol is able to block the inhibitory action of dopamine on PRL release from rat lactotroph cells in vitro [374–376] but not from monkey lactotrophs [377]. In studies in humans, Judd et al. [344] found that the same dose of infused DA resulted in a greater suppression of PRL during the early follicular phase, when estrogen levels are low, compared to the late follicular or periovulatory phases, when estrogen levels are higher. PRL levels are also suppressed to a greater extent in women compared to men by the same dose of estrogen [343]. Estrogens

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result in a decrease in DA receptor numbers in rats [378] but the DA receptor population showed no sex related differences in a limited number of human pituitaries [367]. Although portal vessel DA levels are higher in female rats or in male rats treated with estrogen [379], the direct effects of estrogen at the lactotroph level result in a blunting of the inhibitory effect of DA and increased PRL production [104,105]. Gonadotropin Associated Peptide (GAP)

Whether DA alone can account for all of the PIF activity of the hypothalamus has long been a question. In the mid-1970s a number of groups found considerable PIF activity in rat hypothalamic extracts in which DA had been removed [380–383]. In 1985 Nikolics et al. [384] reported the PRL inhibiting ability of a 56 amino acid polypeptide that is in the carboxyterminal region of the precursor to gonadotropin releasing hormone (GnRH) and which they termed GAP. In pituitary cultures, GAP was found to inhibit PRL secretion at concentrations of 10-11 M, whereas DA was found to inhibit PRL secretion only at much higher concentrations (10-7 M) [384]. Subsequent experiments showed a 100-fold lower potency of GAP for PRL suppression but at still lower molar levels than for DA [385,386]. Furthermore, passive immunization of rabbits against fragments of GAP resulted in marked elevations of endogenous PRL levels [384]. In these experiments, GAP was also shown to have weak gonadotropin stimulatory properties, giving rise to the concept of inverse stimulation/inhibition of these hormones in various physiologic circumstances. Antibodies raised to a synthetic peptide constituting residues 40–53 of GAP colocalized with GnRH in secretory granules of nerve terminals in the median eminence of the rat [387], and GnRH and GAP have been found to be cosecreted into the hypothalamic–pituitary portal system in sheep [388]. The gene and hypothalamic cDNA for the common precursor for GnRH and GAP were isolated from libraries derived from human and rat hypothalamic mRNA [389]. The GAP sequences in human and rat have 17 amino acid differences, of which eight are conservative in nature [389]. However, GAP had no PRL suppressing activity when tested against human prolactinomas cultured in vitro [390] and neither GAP nor fragments of GAP were able to inhibit PRL release from lactating or oophorectomized, hypothalamo–pituitary disconnected ewes [391]. At this point the physiologic significance of GAP as a PIF vis-à-vis DA is still not clear. Still less is known about its bioactivity in humans. Because of the inverse nature of its suppressing effect on PRL while having stimulating effects on gonadotropins, GAP remains an intriguing unknown. g -Aminobutyric Acid (GABA)

Schally et al. [392] initially demonstrated the inhibitory effect of GABA on PRL secretion in vivo and in vitro in rats, and Grandison and Guidotti demonstrated high-affinity

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GABA receptors on the pituitary [393]. A tuberoinfundibular GABAergic system has been described with perikarya located in the arcuate nucleus and nerve endings demonstrated in the median eminence [394]. GABA has also been demonstrated to be present in portal blood [395]. High concentrations (10-5 mol/L) of GABA and muscimol, a GABA receptor agonist, have been shown to inhibit PRL synthesis and release in vitro in rats but blockade of this inhibition with GABA receptor antagonists, such as picrotoxin and bicuculline, have given variable results [393,396,397]. Subsequent studies have shown GABA and muscimol to cause a decrease in lactotroph PRL mRNA levels with in vitro incubations [398]. Studies of the effects of GABA in vivo in rats have shown variable results, probably due to inactivation of GABA by GABA transaminase. When inhibitors of the catabolism of GABA are employed, GABA can be shown to decrease circulating PRL levels and lactotroph PRL mRNA levels [398]. Studies of the GABA system in humans have yielded conflicting results in studies of widely differing experimental designs. Bioactive metabolites of GABA, such as gammahydroxybutyric acid and gamma-amino-beta-hydroxy butyric acid, and muscimol cause modest increases in PRL levels when injected into humans [399–401]. However, GABA itself causes a modest decrease in PRL levels when given to humans for several days [402] and activation of the endogenous GABAergic system with sodium valproate causes a suppression in the PRL rise induced by mechanical breast stimulation in puerperal women [403]. The physiologic role of GABA, like that of GAP, remains to be fully elucidated in the human as well as various animal species.

PRFs TRH

Shortly after its initial isolation and characterization, TRH was demonstrated to cause a rapid release of PRL from rat pituitary cell cultures [404] and in humans after intravenous injection (Fig. 4.9) [405,406]. Release of PRL is biphasic, the initial peak being mediated by activation of intracellular phosphoinositide pathways with IP3 generation and mobilization of intracellular calcium causing release of stored hormone; the second, more sustained phase is mediated by influx of extracellular calcium through calcium channels, which causes sustained secretion and synthesis of new hormone [166,407]. However, Tashjian et al. [408] found the rise in intracellular calcium to precede the rise in intracellular IP3, so that other mediators of intracellular calcium mobilization may also be involved. TRH is also internalized within the lactotrophs [409] and can even be synthesized by lactotrophs [410] but the physiologic significance of this is not clear. A number of different experimental approaches have failed to clarify the physiologic role of TRH as a PRF. The smallest dose of TRH that releases TSH also releases PRL in humans [411]. Immunoneutralization of endogenous TRH

FIGURE 4.10. Blockade of the prolactin rise induced by ether stress in rats treated with anti-vasoactive intestinal polypeptide (VIP) antiserum or normal rabbit serum (NRS). From Abe et al. [316]

with TRH antisera causes a 50% suppression of basal PRL levels in rats in some studies [412] but not in others [413,414]. Neither did such immunization affect the PRL response to electrical stimulation of the paraventricular nucleus or suckling [414], and it delayed but did not affect the magnitude of the spontaneous surge of PRL on proestrus [415]. Active, chronic immunization of ewes with TRH conjugated to albumin resulted in only minimal decreases in PRL levels basally and after stimulation by stress, suckling and estrus although reductions in thyroid hormone levels were more marked [416]. In the mouse with targeted disruption of the TRH gene (TRH KO), mice became hypothyroid with elevated levels of TSH with reduced biological activity but had normal PRL levels [417], further casting doubt on the essential role of TRH in PRL regulation. Suckling causes an increase in hypothalamic and portal vessel TRH levels as well as a decrease in DA levels [336]. If TRH mediates the PRL response to suckling, even in part, it ought to be accompanied by an increase in TSH, unless there were a concomitant increase in somatostatin. Detailed evaluations of serum levels of PRL and TSH following suckling in rats showed elevations of TSH in some studies [418,419] but not in others [414,420]. Similar studies in humans failed to show any elevations of TSH [421,422]. Very small doses of TRH given systemically were effective in releasing PRL and TSH in lactating rats and women in those studies, however, so it is unlikely that failure to show a rise in TSH was due to an increase in somatostatin. In hypothyroidism, TRH synthesis is increased [423] and portal vessel TRH levels are increased but not statistically significantly [424]. In addition in hypothyroidism, pituitary TRH binding is increased due to an increased number of TRH receptors, but an effect on binding affinity is contro-

Chapter 4

versial [425–427]. In human hypothyroidism, basal TSH and PRL levels are increased as are their responses to injected TRH [428]. Correction of the hypothyroidism with thyroid hormone corrects both the elevated TSH and PRL levels and their responses to TRH, although the correction is more rapid for TSH [428–430]. Conversely, in hyperthyroidism in humans, PRL levels are not low basally but the PRL response to TRH is markedly blunted and returns to normal with correction of the hyperthyroidism [428–430]. The above conflicting data from passive immunization studies, TRH KO mice, observation of TSH levels during lactation and examination of PRL levels in various thyroid states support a role for TRH as a physiologic PRF, albeit not the primary one or even one of major importance. TRH is itself generated from a larger precursor with a molecular weight of 29.2-kDa [431] and other peptides generated from the precursor have been found in the brain, but their functions are unknown [432]. Although also found in other nuclei, the neuronal perikarya for TRH which project ventrally to terminate in the median eminence are located in the parvocellular division of the paraventricular nucleus [431–433]. A stable, bioactive metabolite of TRH, cyclo-His-Pro (also known as histidyl-proline-diketopiperazine), is found in rat hypothalamus and pituitary in concentrations similar to those of TRH [434]. Cyclo-His-Pro inhibits the PRL response to TRH from rat pituitaries in vitro but reports conflict as to whether it inhibits the PRL response to TRH or suckling in vivo [435–438]. In conscious monkeys it also suppresses basal and TRH stimulated PRL levels [439]. The mechanism by which cyclo-His-Pro suppresses PRL release is not clear, as it does not appear to act via the TRH receptor [436]. How cyclo-His-Pro integrates with other factors involved in the regulation of PRL in animals and humans is as yet unknown. VIP and Peptide Histidine Methionine (PHM)/PHI

VIP was initially found to stimulate PRL release in 1978 [440,441]. VIP neuronal perikarya are present in the parvocellular region of the paraventricular nucleus, with axons terminating in the external zone of the median eminence [442,443]. Its effects are selective for PRL and additive to TRH in causing PRL release [444,445] at concentrations (2–6 ¥ 10-10 M) found in hypothalamic–pituitary portal blood [446,447]. As discussed above, the effects of VIP appear to be mediated by stimulation of adenyl cyclase, although recent evidence suggests that transport of calcium through membrane calcium channels may also be important [448]. In addition to stimulating PRL release,VIP also stimulates pituitary PRL mRNA content and PRL synthesis [449]. In conditions of increased PRL synthesis, such as lactation, hypothalamic VIP mRNA levels are also increased [450]. In addition to these studies in rats, intravenously administered VIP has also been shown to increase PRL levels in monkeys [451] and humans [452–454] at serum levels similar to those demonstrated in rat portal blood.

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FIGURE 4.11. Parallel fall in prolactin and growth hormone (GH) levels following resection of a growth hormone-releasing hormone producing pancreatic tumor that had caused acromegaly. From Thorner et al. [540]

A number of experiments have been performed using passive immunoneutralization techniques to determine the physiologic role of VIP as a PRF. Anti-VIP antisera administered to rats have been shown to partially inhibit the PRL responses to suckling, ether-induced stress (Fig. 4.10) [316,317], estrogen administration [455], intraventricular 5HT [456] and proestrus [457] and to suppress PRL pulsatile secretion in dopamine receptor blocked rats [458]. Similar results for suckling have been obtained with a VIP antagonist [459]. Part of the 20-kDa 170 amino acid VIP precursor is another similarly sized peptide known as PHM [460]. VIP has 28 and PHM has 27 amino acid residues. The terminal amino acid in the porcine equivalent of PHM is isoleucine, and therefore the peptide of porcine origin is known as PHI. PHI and VIP [461] and PHM and VIP [462] colocalize in the hypothalamus and median eminence. Interestingly, PHI is of similar potency to VIP in releasing PRL from rat pituitaries in vitro and in vivo [463,464]. Furthermore, passive immunoneutralization with anti-PHI plus anti-VIP antisera causes a greater suppression of the PRL responses to the serotonin precursor 5-hydroxytryptophan [465] and ether [317] than either anti-PHI or anti-VIP antisera alone. PHM given to humans has caused a PRL increment in some experiments [462,466] and not others [454]. Further complicating the role of VIP as a PRF is the finding that VIP is actually synthesized by anterior pituitary

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tissue [467]. Antisera to VIP inhibit basal PRL secretion from dispersed pituitary cells in vitro [468,469], suggesting a local “autocrine” role for VIP in PRL regulation within the pituitary. Interestingly, pituitary VIP concentration is increased in the pituitaries of hypothyroid rats along with a decreased PRL content [470] and TRH increased VIP and PRL secretion. However, immunoneutralization of the pituitary cultures with anti-VIP antiserum did not decrease the PRL response to TRH [471]. It is not yet clear whether the VIP secreting pituitary cells are lactotrophs [469] or nonlactotroph stellate cells [470]. The physiologic role of VIP as a PRF appears to be warranted by the experimental data. The precise roles of VIP vs. PHM and hypothalamic VIP vs. pituitary VIP still are not clear. How VIP/PHM interact with other PRF’s such as TRH are additional areas requiring clarification. Serotonin

A considerable number of experiments have demonstrated a role for serotonin as a neurotransmitter involved in the release of PRL. Most serotoninergic neuronal perikarya are in the dorsal and median raphe nuclei, and their axons project forward to the hypothalamus and other limbic and cortical areas [472]. Lesions of the dorsal but not the median raphe nuclei decrease forebrain serotonin levels and basal and stimulated serum PRL levels [472–475], while stimulation of the dorsal raphe nucleus results in PRL release [473]. Serotonin and its precursor, 5-hydroxytryptophan, cause a release of PRL in rats whether injected systemically [476,477] or into the third ventricle [478]. In a variety of experiments using blockers of serotonin synthesis, such as parachlorophenylalanine, blockers of serotonin receptors, such as methysergide, or blockers of serotonin reuptake by nerve terminals, such as fluoxetine, it has been shown that serotonin mediates, in part, the PRL elevations associated with suckling and proestrus [473,475,477,479–481]. Conversely, agents which are serotonin releasers, such as fenfluramine, or agonists, such as quipazine, result in a rapid increase in serum PRL levels [481–483]. Using specific serotonin receptor blockers, it has been found that it is the S2 receptor that mediates the serotonin action on PRL secretion [483]. Studies in humans also suggest a role for serotonin in PRL secretion. Infusion of the serotonin precursor, 5hydroxytryptophan, results in a prompt increase in PRL levels [484,485]. Nocturnal PRL secretion is inhibited by cyproheptadine [486]. Fenfluramine, a serotonin releasing agent caused a fourfold rise in PRL in humans that could be partially blocked by cyproheptadine [487]. Similarly, mchlorophenylpiperazine, a metabolite of the antidepressant drug, trazadone, has agonist activity at central serotonin receptors and causes a rise in PRL levels [488]. Fluoxetine, a serotonin reuptake inhibitor, also increases PRL levels modestly but still within the normal range [489]. On the other hand, pizotifen, a specific, non-ergot serotonin antag-

onist, had no effect on the suckling-induced PRL rise in postpartum women [490]. Whether serotonin’s effects are mediated solely through brain pathways or whether it has direct effects on the pituitary is controversial. One possibility is that serotonin causes a decrease in hypothalamic DA generation. Synaptic junctions between serotoninergic nerve terminals and dopaminergic perikarya in the arcuate nucleus have been demonstrated [491]. Furthermore, Pilotte and Porter [492] showed that intraventricular injections of serotonin decreased portal vessel DA concentrations and Johnston and NegroVillar [493] demonstrated that 5-hydroxytryptophan administration to rats results in a decrease in median eminence DA synthesis. However, when DA levels were maintained by infusion, serotonin was still able to cause a release of PRL [492]. It has also been proposed that serotonin acts by increasing VIP. Shimatsu et al. demonstrated that serotonin stimulates the release of VIP into portal blood [447] and passive immunization against VIP (see above) decreases the increase in PRL induced by 5-hydroxytryptophan [465]. Electrolytic lesions which destroy the paraventricular nucleus, the site of origin of VIPergic tuberinfundibular pathways, result in a marked blunting of the PRL responses to 5-hydroxytryptophan, ether stress and restraint stress [494], further buttressing the argument for a role for VIP in mediating the serotonin stimulatory effects on PRL secretion. Serotonin [495,496] and serotoninergic nerve fibers have been found within the anterior pituitary [497,498]. Serotoninergic nerve terminals have also been demonstrated within the median eminence [499]. Tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis is present in the pituitary [496], suggesting in situ synthesis. High affinity S2 serotonin receptors have been found in the anterior pituitary [500] as well uptake of labeled serotonin into cells of the pituitary [501]. In direct tests of the effects of serotonin on pituitary PRL release, Apfelbaum [502] found serotonin to increase basal and stimulated PRL secretion from pituitaries in vitro and Stobie and Shin [503] and Wehrenberg et al. [504] found that serotonin stimulated PRL from hypophysectomized pituitary grafted rats and stalk-section monkeys, respectively. On the other hand, Birge et al. [329], Lamberts and MacLeod [505] and Delitala et al. [506] found no effect of serotonin on PRL release from rat pituitary cells in vitro. Thus, although it is possible that serotonin is a direct secretagogue for PRL, via transport from the hypothalamus by the portal vessels or through an autocrine action within the pituitary, its role in this regard is still uncertain. It likely mediates the nocturnal surge of PRL, and may well participate in the suckling-induced rise in PRL via the ascending serotoninergic pathways from the dorsal raphe nucleus and mediated by activation of VIP release. Opioid Peptides

A detailed description of the various opioid peptides, their receptors and their neuronal pathways is beyond the scope

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of this discussion. Approaches to determining the roles of the opioid peptides and pathways in the regulation of PRL secretion have focused on using opioid agonists and antagonists in experimental animals and humans. In rats, morphine, met- and leu-enkephalin, bendorphin, dynorphin and leumorphin injected systemically or intracerebroventricularly have all been shown to cause release of PRL [507–518]. More recent studies employing specific agonists and antagonists operative on the m, d and k opioid receptors and antibodies directed against several opioid peptides have shown that it is the m receptor that is the predominant one involved in PRL release, the k receptor is involved to a lesser extent and the d receptor is not at all involved [518–521]. Most evidence suggests that the opioid peptides do not have a direct effect on the pituitary [508,521,522] and stimulate PRL release by inhibiting DA turnover and release by the TIDA pathway [523–526]. The recently identified opioid peptide, orphanin FQ (also called nociceptin), which binds to an opioid-like orphan receptor, also causes an increase in PRL levels in rats when administered intracerebroventricularly [527]. In humans, morphine and morphine analogs increase PRL release acutely [528–532] and chronically [522,523]. However, blockade of the m receptor with naloxone has minimal to no effect on PRL levels either basally or with stimulation by hypoglycemia, exercise, sleep, TRH or physical stress [315,533–537]. In contrast to these findings, two groups have reported an increase in PRL levels in response to naloxone given in the late follicular and midluteal phases of the menstrual cycle [538,539]. The interpretation of these changes is not clear. Overall, it appears that the endogenous opioid pathways play at most only a minor role in the regulation of PRL secretion, especially in humans. GHRH

A number of studies have found GHRH to have PRL releasing properties. The initial clue to this effect of GHRH was the finding that many of the patients with acromegaly due to GHRH secreting tumors were hyperprolactinemic and PRL levels fell in parallel with GH following excision of the GHRH-secreting tumor [540] (Fig. 4.11). Large doses of GHRH have been reported to release PRL in vivo in normal humans in most studies [541–546]. In our own studies, GHRH was found to cause small, consistent PRL responses in addition to larger GH responses in normal individuals (Fig. 4.12) [543]. Chronic therapy with GHRH in children with GH neurosecretory dysfunction results in a sustained elevation of PRL levels [547]. In rat pituitary cell cultures, GHRH causes PRL and GH release but an increase only in GH mRNA and not PRL mRNA, indicating no stimulation of PRL synthesis [548]. The similarity of GH and PRL responses to a variety of stimuli, such as exercise, stress, hypoglycemia, arginine infusion and sleep and the pathological conditions of renal failure and hepatic cirrhosis suggest, but do not prove, that GHRH may serve as a physiologic PRF under some circumstances.

FIGURE 4.12. Prolactin secretory responses to bolus injection of growth hormone-releasing hormone (GHRH1–40) 3.3 mg/kg. Modified from Goldman et al. [543]

Posterior Pituitary, Oxytocin and Vasopressin

A number of studies in animals have shown that oxytocin, in levels found in the hypothalamic–pituitary portal vessels [549], can stimulate PRL release when added to the medium of pituitary cell cultures or incubations or when given intravenously but it lowers PRL levels when directly injected into the third ventricle [550–554]. Studies in which endogenous oxytocin was eliminated by passive immunization with oxytocin antisera or by oxytocin antagonists show a reduction and a delay in the suckling induced PRL surges in some studies [551] but not others [552] and a reduction in the PRL rise associated with proestrus [552,555] but no effect on the PRL response to ether stress [552]. Antisera to oxytocin also block the PRL surge seen in response to intracerebroventricularly administered VIP [459]. In addition, the peak phase of the PRL surge accompanying proestrus can be blocked by either posterior pituitary

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lobectomy or antisera to VIP [457]. These last findings suggest that oxytocin and/or other posterior pituitary substances may be involved in at least one of what are turning out to be multiple routes by which VIP stimulates PRL release. Very limited studies in humans suggest that oxytocin administered intravenously has no effect on basal PRL levels and causes only a minimal increase in TRH stimulated PRL levels [556]. Vasopressin also has PRL releasing properties when injected intravenously into normal rats and sheep and rats with pituitaries transplanted to the renal capsule, but not sheep with hypothalamic–pituitary disconnection [553]. The neurophysin portions of the precursors to oxytocin and vasopressin also stimulate PRL secretion in rats [557]. Schally et al. [558] have shown that a peptide identical to the sequence of 109–147 of the vasopressin–neurophysin precursor has been isolated from porcine hypothalami and has PRL inhibiting properties. Nagy et al. [559] found that the suckling induced PRL rise is absent in Brattleboro rats (which have diabetes insipidus due to a single base deletion in the vasopressin gene) and is partially restored with exogenous vasopressin. There are no studies to date of the effects of vasopressin on PRL secretion in humans. Whether there are other PRF’s in the posterior pituitary in addition to oxytocin, vasopressin and their respective neurophysins has been a matter of controversy. Rats which have had the posterior pituitary removed and replaced with vasopressin and oxytocin have a PRL response to suckling that is greatly reduced [560]. Antagonists to TRH, angiotensin II, endorphin and inactivation of vasopressin and oxytocin by disrupting disulfide bonds do not affect this posterior pituitary PRF activity [560,561] and studies of its physical characteristics suggest that it has a molecular mass of 1–5-kDa [562]. Although Mori et al. [554] could attribute posterior pituitary PRF activity only to contained oxytocin, Samson and Mogg [563] agree with Ben-Jonathan and her coworkers that the posterior pituitary PRF activity is due to some additional factor, and recently Laudon et al. [564] have localized the PRF activity to the intermediate rather than the true posterior lobe. The posterior pituitary, therefore, may play a significant role in the regulation of PRL secretion in rats. Vasopressin, oxytocin, the neurophysins and possibly an additional factor may be involved, possibly including VIP in the concatenation of neural links. How these factors interact with dopamine, TRH and other release and inhibiting substances in PRL regulation and how relevant all of this is to human PRL regulation are aspects that remain to be determined. Gonadotropin Releasing Hormone

GnRH was initially found to release PRL from rat pituitary cells in vitro [565]. Subsequently, GnRH has been found to cause a release of PRL in anovulatory women [566–568] and in women with anorexia nervosa who were gaining weight [569]. In 24% to 78% of normal women there is a PRL response to GnRH, depending upon the phase of the

menstrual cycle, the highest number of responders being in the periovulatory phase [570]. Postmenopausal women also have a PRL response to GnRH that is augmented with estrogen supplementation [571]. There is no PRL release in response to GnRH in normal, eugonadal males but such a release does occur with high doses of estrogen pretreatment (given to transsexual men) [572]. Analysis of PRL and LH secretory pulses suggests a high degree of concordance in rats and women [295,573]. This cosecretion of LH and PRL suggests that the response to GnRH is physiologic and is evidence against the inhibitory cosecreted GAP having a physiologic role. A subset of human prolactinomas that also contain the glycoprotein a subunit have been shown to bind GnRH specifically and with high affinity and to release PRL in response to GnRH in vitro [574]. Renin–angiotensin System

Angiotensin converting enzyme (ACE) and angiotensin II receptors and activity have been identified in the rat pituitary and median eminence of the hypothalamus [575–577]. In the human pituitary, renin, ACE and angiotensinogen have been detected in normal lactotroph cells and in PRLsecreting adenomas [578]. Angiotensin II incubated with rat pituitary cells stimulates release of PRL, an effect blocked by AT1 but not AT2 antagonists [579,580a]. However, in humans, blockade of ACE with enalapril results in no change in basal PRL levels [581,582a], no change in the TRH and metoclopramide induced PRL rises [581] and only a minimal decrease in the PRL response to hypoglycemia [582a]. It is unlikely, therefore, that the endogenous reninangiotensin system of the hypothalamus and pituitary have significant physiologic effects on PRL regulation. PRL-releasing Peptide

Hinuma et al. [582b] recently discovered a new, 31 amino acid peptide capable of releasing PRL, termed PrRP31, by looking for endogenous ligands for an orphan receptor present in the human pituitary termed hGR3. In pituitary cell preparations, PrRP31 released PRL with a potency equal to that of TRH [582b]. However, although PrRP31 is found in neuronal perikarya in the paraventricular and supraoptic nuclei, PrRP31-immunoreactive nerve fibers are found only in the internal zone of the median eminence and not the external zone [582c], casting uncertainty on the physiologic significance of this new peptide. Other Neuroactive Peptides and Neurotransmitters

Neurotensin This has been found to increase PRL levels when given intravenously to urethane-anesthetized intact and steroid primed male rats [508,583]. In in vivo studies, diphenhydramine, an H1 histamine receptor blocker, was able to block this stimulatory effect of neurotensin [508] but other studies have found neurotensin to release PRL directly from rat hemipituitaries in vitro [584]. When neurotensin is injected intracerebroventricularly, however, it inhibits PRL release [583,585] and the intracerebroventricular injection of

Chapter 4

antisera to neurotensin results in a rise in PRL levels, suggesting that endogenous neurotensin may be playing a physiologic role in rats [586]. In contrast to these results in rats, the administration of neurotensin to humans has no effect on PRL levels [587]. Substance P This also stimulates PRL release when given intravenously to urethane-anesthetized rats [508,588] and when given intracerebroventricularly to monkeys [589]. No such inhibition occurred when Substance P was given intracerebroventricularly to rats [585]; indeed, inhibition of PRL release was reported when it is given in this fashion [590]. Substance P also stimulates PRL release directly in vitro with pituitaries from female [585] but not male [590] rats. Cholecystokinin (CCK) This has been shown to increase PRL release from in vitro rat preparations [445,591] but not from similar human pituitary cultures [445]. The intravenous route in rats has provided both positive [591] and negative results [592] with respect to PRL stimulation. Intracerebroventricular CCK results in a marked PRL release that can be antagonized with antisera to VIP [592], implying that its action may require the activation of VIPergic systems. The intracerebroventricular or intravenous administration of proglumide, a CCK antagonist, cause a marked fall in PRL levels in male but not female rats [593]. The reason for these varying results, the discrepancy in findings between the sexes and the relevance to humans are unknown. Somatostatin Receptors for somatostatin have been found on human PRL as well as GH-secreting adenomas [594]. Somatostatin has been found to inhibit adenyl cyclase activity of rat anterior pituitary homogenates and spontaneous [595,596], TRH-induced [596], and VIP-induced [597] PRL release. Furthermore, administration of somatostatin antiserum to rats causes a rise in PRL levels, implying a physiologic inhibitory action of somatostatin basally [594]. In humans, however, somatostatin administered exogenously has no effect on the TRH-induced PRL release [598]. Other Peptides Bombesin is present in the hypothalamus and stimulates PRL secretion in vivo from steroid-primed male rats [599] and in vitro from pituitary cell cultures [600,601]. However, when bombesin is administered intracerebroventricularly, it inhibits the PRL rise induced by restraint stress [602]. No studies of its effects in humans have been reported. Secretin has been found to have both stimulating [603] and inhibiting [604] effects on PRL release in rats. Gastrin causes an increase in PRL levels when injected intravenously in rats but causes a fall in PRL levels when injected intracerebroventricularly. It has no effect on PRL secretion in vitro [605]. Galanin is expressed in the PVN and the median eminence of the hypothalamus and in pituitary lactotrophs, where it is colocalized with PRL in the same secretory granules [606]. Galanin injected intravenously

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causes an increase in PRL levels when given in high doses, but has no effect when injected intracerebroventricularly or in vitro [607]. Galanin KO mice have 30% to 40% lower PRL levels, are unable to lactate, and their lactotrophs fail to proliferate in response to estrogen [606]. Endothelin is produced by lactotrophs and also causes a release of PRL from lactotrophs, suggesting a possible autocrine regulation of PRL secretion [608]. Transforming growth factor-b1 (TGF-b1) is similarly produced by lactotrophs but inhibits PRL gene expression, synthesis and release in a paracrine rather than an autocrine manner [609,610]. Adenosine is produced by the folliculostellate cells of the pituitary and also stimulates PRL release in a paracrine fashion [611]. Several other substances have been found to increase PRL release from pituitary cell cultures, including bradykinin [612,613], calcitonin [614]; calcitonin generelated peptide (CGRP) [615]; relaxin [616], plateletactivating factor [617], and thymosin fraction 5 [618]. Melatonin has also been shown to increase PRL levels from humans when given orally [619]. On the other hand amelanocyte stimulating hormone (a-MSH), injected intracerebroventricularly causes a decrease in PRL levels and the administration of MSH antiserum causes a rise in PRL levels [620,621]. Basic fibroblast growth factor also inhibits PRL release in vitro [622]. A peptide identical to the 27–52 amino acid sequence of proopiomelanocortin has been isolated from the hypothalamus and is also inhibitory to PRL secretion [558]. Pituitary adenylate cyclase activating polypeptide (PACAP) also inhibits PRL secretion when injected intracerebroventricularly through a stimulation of DA release by TIDA neurons [623]. Histamine This neurotransmitter plays an uncertain role in PRL regulation [624]. Histamine neuronal perikarya are present in the posterior hypothalamic region and axons project to almost all of the nuclei of the hypothalamus [624]. Histamine administered systemically or intracerebroventricularly to rats causes a modest PRL rise [625–627]. H1 receptor antagonists suppress the suckling-induced PRL increment in rats [625] as well as the PRL rise caused by intravenous histamine [627], whereas H2 receptor antagonists, such as cimetidine and ranitidine, augment the intravenous histamine-induced PRL rise [628]. In contrast, intracerebroventricular histamine also increases PRL release, an effect blocked by H2 blockers but not H1 blockers [628]. These studies suggest that histamine exerts its PRLreleasing activity via H2 receptors when given intracerebroventricularly and via H1 receptors when given intravenously. However, histamine has no effect on PRL release from pituitaries in vitro or in stalk-sectioned rats [627]. Although intracerebroventricular histamine causes a 26% fall in stalk vessel dopamine levels, this is not sufficient to explain the large rise in plasma PRL levels [626]. In humans, intravenous H2 but not H1 blockers cause a rise in PRL levels [629–632] but prolonged oral administration of H2 blockers does not result in sustained PRL elevation

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[632]. Histamine alone can cause a rise in PRL secretion in man that is further augmented by H2 blockers and is blocked by H1 blockers [628]. The fact that the administration of high doses of H2 blockers causes an increase of PRL levels in humans, that histamine cannot cross the blood–brain barrier and that histamine has no effect on pituitaries in vitro suggests that histamine may play a physiologic facilitory role within the median eminence in PRL secretion. The roles of other bioamines in the regulation of PRL secretion are even less well established. Central adrenergic a2 agonists such as clonidine usually have no effect on PRL secretion although both increases and decreases have been reported, the differences possibly being due to the doses used [633–635]. The administration of a2 adrenergic antagonists such as yohimbine or piperoxan result in an increase in PRL levels that is blocked by clonidine [635,636], implying an overall inhibitory role of the a2 adrenergic system in the hypothalamus. a-methyl dopa, another central adrenergic agonist, causes a sustained elevation of PRL [637] but this may be due to inhibition of the synthesis of norepinephrine or dopamine centrally by inhibiting the enzyme l-aromatic acid decarboxylase, which is responsible for conversion of dopa to dopamine and by acting as a false neurotransmitter to decrease dopamine secretion or synthesis by a local feedback inhibitory action. However, monoamine oxidase inhibitors cause an increase in PRL levels [638]. Such an elevation is unexpected, since these drugs should increase the levels of norepinephrine and dopamine in the synapse. Acetylcholine This neurotransmitter inhibits adenyl cyclase and cAMP accumulation, lowers intracellular free calcium levels and decreases PRL release from pituitary cell cultures, acting through muscarinic and not nicotinic receptors [127,639]. In such cultures, coincubations of acetylcholine or the cholinergic agonist, carbachol, with VIP or TRH result in marked inhibition of the VIP- and TRHinduced PRL release [127,640]. Although atropine, a muscarinic receptor antagonist, blocks this acetylcholine inhibition of PRL in vitro [127,640], it had no effect on basal or TRH-induced PRL release in humans [641]. Moreover, pirenzepine, another muscarinic receptor blocker, actually caused a modest decrease of PRL levels in humans in vivo [642]. Another muscarinic receptor blocker, methscopolamine, had no effect on the sleep induced PRL rise while blocking the GH rise [643]. The widespread presence of acetylcholine as a neurotransmitter in the CNS and the possibility that pituitary tissue itself may synthesize acetylcholine [644] make interpretation of studies testing this system difficult, and the true role of acetylcholine in the regulation of PRL secretion is uncertain.

Prolactin Short Loop Feedback Considerable evidence in rats suggests that PRL is able to feed back negatively on its own secretion (short-loop feedback or autofeedback) [645–647]. Most evidence

suggests that such feedback occurs via augmentation of hypothalamic TIDA turnover [648–652], including direct measurements of dopamine in portal vessels [379]. Direct confirmation of the importance of short-loop feedback in rodents comes from recent studies using mice with targeted disruption of the PRL gene (PRL gene KO). Mice with the PRL-KO have no pituitary PRL and have markedly decreased DA in TIDA neurons along with hyperplasia of lactotrophs that do not make PRL [653–655]. Direct evidence for such PRL short-loop feedback in the human has not been demonstrated. In a number of reports, however, it has been suggested that altered regulation of gonadotropin and TSH secretion in hyperprolactinemic patients may constitute indirect evidence of PRL-induced augmented TIDA activity [656–663]. In hyperprolactinemic patients, decreases in gonadotropin pulse amplitude and frequency are usually found, being attributed to altered gonadotropin releasing hormone secretion (see below). Such an alteration of GnRH secretion has been postulated to be due, in part, to PRL-induced DA increase [656,664–667]. In a direct test of this hypothesis, however, no evidence was found of suppression of TSH, LH or FSH levels with short term administration of human PRL which resulted in a two- to threefold elevation of PRL levels [668]. However, these acute studies do not rule out the possibility that such feedback may occur with more prolonged states of hyperprolactinemia. Alternatively, such feedback might occur via other mechanisms, such as a decrease in a PRF such as VIP [669]. PRL ACTION PRL has a great diversity of actions in many species of animals from fish and birds to mammals, including osmoregulation, growth and developmental effects, metabolic effects, actions on ectodermal and integumentary structures and actions related to reproduction [670]. However, in humans it has as its primary physiologic action the preparation of the breast for lactation in the postpartum period [671]. A number of effects of increased levels of PRL may be seen on many tissues. Although the roles of physiologic levels of PRL in such tissues are quite speculative, considerable clarification of these roles has been elucidated from studies in PRL-KO and PRL receptor KO mice.

PRL Receptors The PRL and GH receptors are members of the class 1 cytokine receptor family. The human genes for the PRL and GH receptors have been localized to the short arm of chromosome 5, sublocalizing to region 5p13–p14 [672]. The human PRL receptor gene has 10 exons, with exons 3 to 10 encoding the full length of the long form of the receptor [673]. Two PRL receptor gene promoters, termed hPIII and hPN that direct alternative first exons of the HPRL receptor gene have been found in the 5¢ untranslated region [673]. The human PRL receptor is 598 amino acids long,

Chapter 4

has a theoretical, non-glycosylated molecular mass of 66.9kDa and an additional signal peptide of 24 amino acids [674]. The extracellular domain contains five cysteine residues and three potential N-linked glycosylation sites [674]. There is a hydrophobic region (amino acids 211–234) which corresponds to the single transmembrane-spanning region of the receptor [674]. The human PRL receptor has a much longer intracytoplasmic region than does the rat PRL receptor [63] but there is high sequence homology between the rat, rabbit and human PRL receptors and also between the human PRL and GH receptors [63]. Two isoforms of the PRL receptor result from alternative splicing and differ in the length and composition of the cytoplasmic tail, being referred to as the long and intermediate forms; the short form found in the mouse is not present in humans [63,633]. PRL binds to its receptor with high affinity, the dissociation constant (Kd) being 10-10 mol/L [63]. Half-saturation of the receptor occurs at a hormone concentration of 7 ng/ml [63]. Once PRL binds to the receptor there is dimerization of the receptor, a necessary step for activation of the receptor (Fig. 4.13) [63]. PRL receptors are widely distributed, being found in the breast, pituitary, liver, kidney tubules, adrenal cortex, prostate, ovary, testes, seminal vesicles, epididymis, intestine, skin, pancreatic islets, lymphocytes, lung, myocardium and brain [63]. PRL release caused by suckling increases PRL receptor levels in the breast and liver, resulting in a much greater PRL binding activity in lactating animals compared to those not lactating [63]. Hepatic PRL receptor synthesis and numbers increase with estrogen treatment in vivo, mediated by the effect of estrogen on increasing pituitary PRL secretion [675] (Table 4.3). Interaction of PRL binding site 1, encompassing several amino acids belonging to helices one and four, with one PRL receptor causes the formation of a one-hormone-onereceptor complex. This is a prerequisite for PRL binding site 2, involving helices 1 and 3, to interact with another receptor, ultimately causing the formation of the active trimeric complex [63]. Signal transduction of the activated receptor involves the JAK-Stat pathway. JAK2 is the particular Janus kinase involved and it is constitutively associated with the PRL receptor [63]. PRL-induced dimerization of the two receptor molecules brings the two associated JAK2 molecules close to each other so that they may be activated by transphosphorylation of tyrosines [63]. The two cytoplasmic domains of the receptor must be strictly identical, and the short receptor functions as a dominant negative isoform which inhibits activation of the receptor complex by heterodimerization [63]. The activated JAK2 phophorylates tyrosine residues on the receptor itself and on three members of the Stat (signal transducer and activator of transcription) family of proteins, Stat 1, Stat 3 and, particularly, Stat 5 [63]. Activation of the MAP kinase cascade has also been reported after receptor activation but whether this involves JAK2 is not known [63]. Subsequently, the hormone–receptor complex is internalized and localized in the golgi and vacuoles [676] but the physiologic

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FIGURE 4.13. (a) Ribbon representation of the predicted 3D structure of hPRL, modeled on the basis of the crystallographic structure of porcine GH. HPRL is predicted to adopt the four-helix bundle folding described for GH. Location of binding sites 1 and 2 is indicated. Side chains of amino acids involved in binding site 1, as deduced from mutational studies are represented. (b) Human prolactin receptor extracellular domain. The extracellular domain folds in a b-sandwich formed by two antiparallel b-sheets and Cterminal ends are indicated by N and C respectively. Note that the structures depicted in panels A and B are not at the same scale. (c) Prolactin receptor activation induced by PRL-induced dimerization. Hormone binding to PRL receptor is sequential. First, the hormone (H) interacts with the receptor (R) through its binding site 1 (see A), forming an inactive H1 : R1 complex. Then, the hormone binds to a second receptor through its site 2, which leads to receptor homodimerization and formation of an active H1 : R1 complex. Hormone analogs whose binding site 2 is sterically blocked are unable to induce receptor homodimerization and are thus inactive; since they still bind to the receptor through site 1, they behave as antagonists of wild-type hormones. From Bole-Feysot et al. [63]

significance of this beyond degradation and scavenging is not known.

PRL Effects on Breast PRL, GH, cortisol, insulin, estrogen, progesterone and thyroxine all contribute to breast development. The high concentrations of estrogen and progesterone produced by the placenta, coupled with the estrogen-induced high concentration of circulating PRL and the high concentrations of hPL cause development of the lobular, alveolar tissue during

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Table 4.3.

Summary of phenotypes of PRL receptor +/- and receptor -/- mice*

+/-

-/-

Reproduction Female

Normal mating, pregnancy

Male

Normal

Sterility Ovulation decreased Oocyte maturation decreased No implantation Delayed fertility

Mammary gland development

Impaired development, efficient lactation after first pregnancy

No lactation Ductal branching greatly reduced Absence of alveoli

Behavior Maternal Eating, locomotor

Reduced Normal

Absent Normal

Immunity

Normal

Normal

* Modified from Bole-Feysot et al. [63]. +/-, heterozygous PRL receptor knockout, -/-, homozygous PRL receptor knockout.

pregnancy [671]. Once the breast is fully developed and hormonally primed, PRL stimulates the production of milk proteins and other components [671]. Prior to term, the high estrogen levels suppress the effects of the high PRL levels on milk production but the rapid fall off of estrogen levels following delivery allows milk production to proceed [677]. Suppression of this physiologic hyperprolactinemia in the puerperium by bromocriptine causes a rapid cessation of milk production [678]. The key role of PRL in milk formation has been demonstrated by the finding that mice with either the PRL gene KO [653] or the PRL receptor KO [679] are unable to lactate. One intriguing finding is the production by the lactating breast of the parathyroid hormonelike protein that has been implicated in the humoral hypercalcemia of some malignancies [680]. Suckling results in an increase in serum PRL and the appearance of the mRNA for this parathyroid hormone-like protein in breast tissue, both effects being blocked by bromocriptine treatment [680]. This protein is not present in the circulation in significant amounts but is present in breast milk in high concentrations [681], suggesting that it may act within the breast to facilitate calcium transport into the milk. Galactorrhea

Clinically, nonpuerperal galactorrhea has been regarded as being a sign of possible hyperprolactinemia. The presence of even minute amounts of milk expressible from one or both breasts justifies the diagnosis of galactorrhea. Its persistence for more than 1 year after normal delivery and cessation of breast-feeding or its occurrence in the absence of pregnancy generally is taken as a definition of inappropriate lactation. If the material expressible from the nipple looks like milk, it probably is milk; if there is any question

of diagnosis, examination of the breast secretion by staining of fat globules with Sudan IV is diagnostic. The incidence of galactorrhea has been variously reported in normal women as ranging from 1% to 45% of subjects tested [682–685]. This variability is probably the result of differences in the techniques used to express milk from the breast and the way in which nonmilky secretions are classified. The volume of milk expressed does not correlate with PRL levels. However, in individuals with hyperprolactinemia, lowering the blood PRL level to normal will almost always lead to a marked decrease or abolition of lactation. Inappropriate lactation may be an important clue to the presence of pituitary–hypothalamic disease, especially if accompanied by amenorrhea. In a series of 70 women with galactorrhea studied in the author’s clinic, 19 (27%) had normal menses [686]. Of those with normal menses, only one had elevated PRL levels. Combined data from 14 published series suggest that 27.9% of galactorrheic women with normal menses have elevated PRL levels [687]. More recent experience, however, suggests that galactorrhea may be present in about 5% to 10% of normally menstruating women and basal PRL levels are normal in more than 90% of these women.

PRL Effects on Gonadotropin Secretion The effects on gonadotropin secretion by PRL levels in the normal range are not known. However, PRL gene KO and PRL receptor KO female mice are sterile. Both types have disordered estrous cycles [653,679]. Females with the PRL receptor KO had fewer primary follicles, fewer eggs ovulated, fewer eggs fertilized, those that were fertilized had

Chapter 4

poor progression to the blastocyst stage and finally the uterus was refractory to implantation by the blastocyst [679]. Furthermore, they had decreased estradiol and progesterone levels [688]. Half of the males with PRL receptor mutations were fully fertile, but the remainder were either completely or partially infertile despite normal sexual behavior and normal spermatogenesis as determined by histologic evaluation of the testes [679]. Male mice with the PRL gene KO were fully fertile and had normal plasma testosterone levels and normal testosterone release from the testes, despite decreased plasma LH levels and LH and FSH secretion from the pituitary in vitro and decreased weights of the seminal vesicles and ventral prostate [689]. In normal women treated with short-term bromocriptine to lower PRL levels to about 5 ng/ml, there was no change in the pulsatile secretion of LH and FSH, but estradiol levels were higher the last 3 days of the follicular cycle and progesterone levels were lower during the luteal phase [690]. Hyperprolactinemia has a number of effects on various steps in the reproductive axis (Fig. 4.14). Hyperprolactinemia has been found in most studies to suppress LH pulsatile secretion by decreasing pulse amplitude and frequency [664,665,693–695]. With castration in rats or menopause in humans, hyperprolactinemia can prevent the expected rise in gonadotropins [696–699]; normalization of PRL levels with bromocriptine results in elevation of gonadotropin levels and hot flashes [699]. Hyperprolactinemia inhibits pulsatile gonadotropin secretion by a number of mechanisms. It had been postulated that the pulsatile gonadotropin secretion was directed by the hypothalamic GnRH pulse generator and that alteration of pulsatile secretion necessarily meant a direct hypothalamic action. However, direct measurement of portal vessel GnRH levels in rats showed a marked inhibitory effect of hyperprolactinemia in one study [700] but not in another [701]. The pituitary gonadotroph response to GnRH in hyperprolactinemia has generally been found to be decreased in rats [695,696,701] and normal, increased and decreased in humans [702–704]. In our own series, the gonadotropin response to GnRH was normal in 22 of 25 patients and decreased in the remaining three [686]. GnRH plays a major role in the regulation of the number of its own recep-

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tors on the gonadotroph cell. The number of GnRH receptors on gonadotroph cells in hyperprolactinemic rats are reduced [705] even when endogenous GnRH is replaced with intraarterial pulses of GnRH [695,706,707]. In addition to these effects, hyperprolactinemia in women has been associated with loss of positive estrogen feedback on gonadotropin secretion [708].

PRL Effects on the Ovary PRL has long been known to be trophic to corpus luteum function in rats, giving rise to the name luteotrophic hormone [709]. As noted above, the ovaries of PRL receptor KO mice have a decreased number of primary follicles with a decrease in the number of eggs ovulated [679] and decreased estradiol and progesterone production [688]. The role of PRL in normal ovarian function in humans is less well established, however. McNatty et al. [710] demonstrated that low physiologic concentrations of PRL are necessary for progesterone synthesis by human granulosa cells but that high concentrations are inhibitory in vitro. Recent studies suggest that PRL can activate the expression of Type II 3bhydroxysteroid dehydrogenase, the final enzymatic step in progesterone biosynthesis [711]. Del Pozo et al. [712] found no effect on luteal function in women treated with bromocriptine to lower normal PRL levels. However, Schulz et al. [713], Mühlenstedt et al. [714], and Kauppila et al. [690] found that such a decrease in PRL resulted in lowered progesterone levels and short luteal phases. On the other hand, short luteal phases have also been reported in hyperprolactinemic women [715]. In humans, plasma PRL levels > 100 ng/ml have been found to cause an increase of antral fluid PRL levels and reductions in antral fluid FSH and estradiol levels along with a decrease in granulosa cells [716]. Perfusion studies of human ovaries in vitro reveal a direct suppressive effect of PRL on progesterone and estrogen secretion [717]. PRL can inhibit estrogen formation by antagonizing the stimulatory effects of FSH on aromatase activity [718,719] and direct inhibition of aromatase synthesis has recently been shown [720]. PRL also inhibits LH-stimulated androgen synthesis by ovarian interstitial cells in rats [721], thereby

FIGURE 4.14. How hyperprolactinemia produces hypogonadism. Schematic representation of sites where hyperprolactinemia interferes with the reproductive system and sex steroid action. CNS, central nervous system; FSH, folliclestimulating hormone; LH, luteinizing hormone. From Odell [691], as modified by Malarkey [692]

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depriving the ovary of the substrate for conversion to estrogen. On the other hand, no differences in the amount of exogenous gonadotropins are necessary to induce ovulation [722,723]. PRL levels have been found to be elevated in 19% to 50% of women with polycystic ovaries (PCO) [724–728]. Bromocriptine treatment of hyperprolactinemic patients with PCO usually results in a reduction of testosterone and LH levels and resumption of ovulatory cycles. Why many patients with PCO have hyperprolactinemia is not clear. Del Pozo and Falaschi [726] have hypothesized that the increased estrogen levels found in PCO stimulate increased PRL secretion; however, no correlation has been found between estrone levels and PRL levels in these patients. The increased androgen secretion associated with PCO may cause hirsutism and other excessive androgen action such as acne and seborrhea [729], although these features may also be caused by excessive androgen secretion by the adrenal (see below). Clinical Effects of Hyperprolactinemia on Menstrual Function

When amenorrhea or oligoamenorrhea is associated with galactorrhea, it is usually a manifestation of hyperprolactinemia. In our series of 51 women with galactorrhea– oligo/amenorrhea, 84% had hyperprolactinemia [686]. In combined series totaling 471 patients with galactorrhea– amenorrhea, 75.4% were found to have hyperprolactinemia III [687]. Although the amenorrhea caused by hyperprolactinemia usually is secondary, it also can be primary if the disorder begins before the usual age of puberty. Of 33 patients presenting with primary amenorrhea and low gonadotropin levels, 9 (27%) were found to have hyperprolactinemia in two series [730,731]. However, in a third series of 38 patients with primary amenorrhea, PRL levels were normal in all [732]. In patients with primary amenorrhea due to hyperprolactinemia, estrogen deficiency and failure to develop normal secondary sexual characteristics may be the presenting problem. Galactorrhea is variable in this setting because the breast may not have been exposed to appropriate priming with estrogen and progesterone. Patients with primary amenorrhea tend to have macroadenomas more commonly than those with secondary amenorrhea, for uncertain reasons (see Prolactinoma, Chapter 12, p. 470). Hyperprolactinemia has been found in many women with a short luteal phase, as noted above. It is likely that a short luteal phase is the first evidence of interference in the normal cycle by hyperprolactinemia. Three hyperprolactinemic patients with amenorrhea corrected by bromocriptine studied by Seppala et al. [733] displayed the following sequence of events when bromocriptine was discontinued: (i) as the serum PRL levels increased, the luteal phase became shorter; (ii) ovulation was missed; and (iii) amenorrhea ensued. In the initial period of shortened luteal phase, progesterone levels were subnormal, suggesting deficient corpus luteum function.

Infertility also may be a presenting symptom of patients with hyperprolactinemia and is invariable when gonadotropin levels are suppressed with anovulation. In three series of women (combined number of 367 cases) studied for infertility, one-third were found to have hyperprolactinemia [687]. Most of the women had amenorrhea and galactorrhea as well, but in one series of 113 cases of infertility, five of the 22 hyperprolactinemic women had neither amenorrhea nor galactorrhea [734]. That PRL excess may be important in this type of patient is suggested by the finding that treatment of similar patients with bromocriptine restored fertility [729]. In some of these women, transient hyperprolactinemia lasting for 1–2 days during the cycle can be documented; this subset usually responds to bromocriptine with increased progesterone during the luteal phase and improved fertility [735]. Reduced libido and orgasmic dysfunction are found in most hyperprolactinemic amenorrheic women when such complaints are specifically elicited [686,736]. Reduction of PRL levels to normal restores normal libido and sexual function in most of these women [737].

PRL Effects on the Testes The role of PRL in normal testicular function is unclear. In hypophysectomized mice, Bartke [738] found that PRL increased the testicular spermatogenic response to LH and the administration of LH and PRL to such mice increases testosterone levels more than treatment with LH alone [739]. Suppression of normal PRL levels causes a decrease in binding of LH to LH receptors in Leydig cells [740]. In animals with hereditary PRL deficiency, PRL administration increases the activities of 17-beta-hydroxysteroid dehydrogenase and 3-beta-hydroxysteroid dehydrogenase, enzymes necessary for testosterone synthesis [741,742]. However, as noted above, the PRL gene KO mice had normal fertility and normal testosterone production despite decreased LH and FSH secretion [689], and half of the males with PRL receptor mutations were fully fertile with the remainder subfertile despite normal sexual behavior and normal spermatogenesis [679]. Suppression of normal PRL levels by bromocriptine in normal men for 8 weeks results in suppression of basal and hCG-stimulated testosterone levels, implying a physiologic role for PRL in normal testosterone production in humans [743]. Although PRL is present in human semen in very high concentrations [744] and PRL has been shown to stimulate adenyl cyclase, fructose utilization and glycolysis and glucose oxidation in human spermatozoa [745], other functions have not been investigated in detail. Chronic hyperprolactinemia in males results in impotence and decreased libido in over 90% of cases [746–754]. Other findings of hypogonadism, such as decreased beard growth and strength are less common [749,754]. Galactorrhea in men has been reported in 10% to 20% of cases and is virtually pathognomonic of a prolactinoma [746,749,751,754,755].

Chapter 4

In hyperprolactinemic men there is a decrease in the pulsatile secretion of LH and FSH, as noted above, and testosterone levels are low or are in the lower part of the normal range [746–754]. The testosterone response to stimulation with hCG has been reported to be both decreased [750,756] and normal [746,757]; in those with decreased responses there is improvement in the response when PRL levels are lowered with bromocriptine [750]. If there is sufficient normal pituitary tissue, reduction of elevated PRL levels to normal usually results in a return of normal testosterone levels [752,753,758,759]. Although some studies have suggested that drug-induced elevated PRL levels cause a partial block in the enzyme 5-alpha reductase, resulting in a decrease in dihydrotestosterone levels [760] this has not been found in studies of men with prolactinomas [756]. Carter et al. [746] noted that testosterone therapy of hyperprolactinemic men does not always correct the impotence until PRL levels are brought down to normal. Whether this is due to a decrease in DHT levels has not been verified directly. Sperm counts and motility are decreased with an increase in abnormal forms [757] and histological studies reveal abnormal seminiferous tubule walls and altered Sertoli cell ultrastructure [761]. The semen analysis does not always return to normal despite a return to normal of testosterone levels with restoration of normoprolactinemia [758]. A number of surveys have attempted to assess the frequency of hyperprolactinemia among men with complaints of impotence or infertility. Between 2% and 25% of males with impotence have been found to be hyperprolactinemic in various series [729,750,752,762–764]. However, only 1% to 5% of men with infertility have been found to be hyperprolactinemic [765–768]. Thus, although these frequencies are relatively low, the cost of the test is low in terms of money and risk and the condition is generally easily treatable, so that measurement of PRL levels is worthwhile in the investigation of the man complaining of infertility or impotence, especially if there is associated loss of libido or documented low testosterone levels.

Prolactin Effects on the Adrenal Cortex Although PRL receptors are found on cells of the adrenal cortex, the physiologic role of PRL in adrenal steroidogenesis is unknown. Plasma dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) levels have been found to be mildly elevated in about 50% of women with hyperprolactinemia in most [769–771] but not all series [772–774]. In most of these studies, however, the investigators did not try to correlate the androgen levels with the presence of hirsutism or other indices of virilization. Glickman et al. [774] and Vermuelen et al. [775] found low plasma sex hormone-binding globulin and elevated free testosterone levels in 43% of hyperprolactinemic patients, but increased DHEAS levels in only 19%. When the patients studied by Glickman et al. [774] were divided into those who were hirsute and those who were not, the hirsute patients had

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higher free testosterone levels but not higher DHEAS levels, although both groups had patients with elevated levels of both hormones. The abnormal androgen levels return to normal with correction of the hyperprolactinemia by bromocriptine [776].

Effect of Prolactin on Bones PRL may have a physiologic role in calcium and bone metabolism. PRL has been shown to increase intestinal calcium absorption even in vitamin D deficient rats [777] and can stimulate 1-a hydroxylation of 25 hydroxyvitamin D in the kidney, resulting in increased plasma levels of 1,25(OH)2D [778]. In humans, however, plasma 1,25(OH)2D levels and intestinal calcium absorption are normal in hyperprolactinemic subjects [779]. The PRL receptor KO mouse has a decrease in bone formation rate and bone mineral density in association with increased parathyroid hormone (PTH) levels, but also decreased estradiol and progesterone levels [688] so that it is difficult to say how much of the effect on bone is due to the lack of PRL. 1,25(OH)2 enhances PRL gene expression with dependence on extracellular calcium [780,781] and treatment of rats with 1,25(OH)2D causes an increase in serum PRL levels [782]. Recent studies suggest that this 1,25(OH)2D mediated increase in PRL is mediated by enhancement of calcium transport through membrane calcium channels [783]. The initial observation by Klibanski et al. that hyperprolactinemic women have a decreased bone mineral density [784] was confirmed by others [785,786] but whether this effect is mediated by estrogen deficiency [784] or is a direct effect of the hyperprolactinemia [785,787] has been controversial. Correction of the hyperprolactinemia results in an increase in bone mass [788,789]. Studies of hyperprolactinemic women who were not amenorrheic and hypoestrogenemic have shown that their bone mineral density is normal [790,791], confirming the initial hypothesis that it is the estrogen deficiency that mediates the bone mineral loss. A similar, androgen-dependent loss of bone mineral is found in hyperprolactinemic men that is reversible with reversal of the hypoandrogenic state [792,793].

Effect of Prolactin on Carbohydrate Metabolism PRL receptors have been found in islet cells [794] but the role of PRL in normal carbohydrate homeostasis is not known. Patients with hyperprolactinemia with or without evidence of prolactinoma have mildly increased (still within the normal range) blood glucose levels during glucose tolerance tests compared with normal controls [795,796]. Insulin levels are also increased in these patients, indicating mild insulin resistance [795,796]. The insulin resistance is due to a decrease in the number of receptors rather than a decrease in receptor affinity [797]. Treatment with bromocriptine causes a return to normal of both glucose and insulin levels [795]. However, in normoprolactinemic

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subjects with insulin-dependent diabetes, suppression of PRL levels with bromocriptine had no effect on glucose control [798].

Effects of Prolactin on the Kidney An extensive body of literature documents the importance of PRL in osmoregulation in fish, amphibians, reptiles, birds and lower mammals [799]. PRL effects include increased tubular reabsorption of sodium, chloride and water, increased glomerular filtration rate, increased thirst, and increased intestinal absorption of sodium, chloride, calcium, water, glucose and amino acids [799]. A number of experiments in humans, however, have failed to document a significant role for PRL in fluid and electrolyte balance or of osmotic stimuli for PRL release [800–803].

Effects of Prolactin on the Immune System Normal PRL levels appear to be essential for normal immune function in rats, although the precise role of PRL in humans in this regard is not clear. In hypophysectomized rats, antibody production against sheep red blood cells, the skin response to dinitrochlorobenzene and the rejection of skin grafts are all decreased [804]. These immune responses could be restored with treatment of the hypophysectomized rats with rPRL, rGH, bPRL, bGH, hPL and hGH [805]. Hypoprolactinemia induced with bromocriptine results in impaired lymphocyte proliferation and decreased production of macrophage activating factors by lymphocytes as well as decreased tumoricidal activation of macrophages after infections; these effects could be reversed with ovine PRL administration to the rats [806]. Neutralization of PRL with anti-PRL antibodies inhibits the in vitro lymphocyte proliferative response to T and B cell mitogens in both rat and human preparations, but neutralization with antibodies to other pituitary hormones had no effect [807]. However, when the lymphocytes were cultured in serum-free medium, the anti-PRL antibodies similarly inhibited lymphocyte proliferation, implying the presence of a necessary, lymphocyte-produced PRL-like protein [807]. In other studies, in response to stimulation with conconavalin A, a PRL-like substance has been found to be produced from murine splenic mononuclear cells that reacts with anti-PRL antibodies and is mitogenic in the Nb2 node lymphoma bioassay [808] and mRNA obtained from such lymphocytes hybridizes with PRL and GH cDNA probes [809]. Furthermore, the immunosuppressive drug cyclosporin A has been found to compete with PRL for a common binding site on rat lymphocytes and stimulation of PRL secretion reverses the immunosuppression induced by cyclosporin [809]. Presumably, this rat lymphocytic PRL-like substance is analogous to the lymphoblastoid PRL produced by IM9 lymphocytes discussed above [235]. In preliminary studies with the PRL gene KO and receptor KO mice, no effects were seen on B or T lymphocyte production but more

detailed studies on immune function have not yet been carried out [63,653]. Lymphoblastoid prolactin can also be produced by conconavalin A or phytohemag-glutinin stimulated human peripheral blood mononuclear cells and has been shown to cause lymphoproliferation, a phenomenon blocked by antihuman PRL antibodies [810]. Human T lymphocytes contain the genes for hPRL and the PRL receptor, but the lymphocyte hPRL gene has an extra 5¢ noncoding exon similar to that found for decidual PRL [811]. PRL mRNA has been localized to a variety of human immune tissues, including thymus, spleen, tonsils, and lymph nodes using in situ hybridization; within these tissues the mRNA was detected in lymphocytes, epithelial cells and vascular cells [812]. PRL receptors have been found in thymus, bone marrow, spleen, lymph nodes and peripheral macrophages and B lymphocytes [813]. A variety of cytokines affect pituitary PRL secretion and may be mediators, in part, of the PRL response to stress. In various experimental paradigms, interleukin-2 (IL-2) and IL-6 have been found to increase PRL secretion, and IL-1 and interferon-gamma inhibit PRL secretion [814–816]. However, in vivo these substances have little effect on PRL secretion in rats [816]. Conversely, PRL acts synergistically with IL-2 to induce maturation of nature killer cells [813]. Prolactin may have some clinically relevant effects on the immune system as well. Hyperprolactinemia caused by injections of ovine PRL into mice caused an increase in phagocytosis, intracellular killing of salmonella typhimurium, chemotaxis and overall survival [817]. Moreover, hyperprolactinemia caused by implanting pituitaries under the renal capsule caused increased autoimmune phenomena in the b/w mouse model [818]. In human patients with prolactinomas, polymorphonuclear cells show reduced chemotaxis [819,820] but monocytes display significantly increased bactericidal activity against Mycobacterium avium [821]. Yet other studies have shown that hyperprolactinemic patients display decreased natural killer T cell function and this effect is reversed with bromocriptine treatment [822]. Data on RPL levels in patients with various autoimmune disorders are conflicting. Nagy et al. [823] found a low PRL bioactivity to immunoreactivity ratio in patients with rheumatoid arthritis due to serum factors capable of inhibiting PRL bioactivity. In other studies hyperprolactinemia has been found in substantial portions of men and women with systemic lupus erythematosus [824–831]; in some of these studies PRL levels correlated with the extent of clinical disease and antinuclear antibody activity [826,828]. In many of these studies, no information is given regarding renal function, CNS involvement or medication use, so that whether the hyperprolactinemia is truly related to autoimmune disease or other factors known to elevate PRL levels is not clear. However, in several studies [827,828,831], lupus nephritis, hypothyroidism, medications and other known causes of hyperprolactinemia were specifically excluded. In

Chapter 4

one study of lupus in children, three of 33 had elevated PRL levels but all three had evidence of CNS lupus [829]. In an interesting report, Funauchi et al. [832] describe a patient with SLE and a prolactinoma whose serum PRL levels were significantly correlated to the serum anti-DNA titers and inversely correlated to the serum complement activity and whose flares and remission clinically correlated with stopping and resuming bromocriptine treatment. In studies of another inflammatory condition, Jara et al. [833] found PRL levels to be elevated in 36% of patients with Reiter’s syndrome. Furthermore, Bravo et al. found that four patients with Reiter’s syndrome had dramatic clinical improvement when treated with bromocriptine [834]. Giasuddin et al. [835] also reported elevated levels in patients with psoriasis. The clinical relevance of lymphoblastoid PRL and changes in immune function in normal individuals and those with hyperprolactinemia is still unclear. Although there is strong evidence in rodents that PRL is important in this regard, the evidence in humans is still very preliminary and what does exist is often contradictory and suggests that these effects of PRL are relatively minor compared to those of other immune regulators [836]. Nonetheless, the intriguing finding of increased PRL levels in many patients with autoimmune rheumatologic diseases merits continued study. PATHOLOGIC STATES OF PROLACTIN SECRETION Population studies of normal individuals reveal that PRL levels are not “normally” distributed and better fit a lognormal distribution contaminated by a small number of abnormally high measurements. Several studies have suggested that “elevated” PRL levels may be found in 1% to 10% of a random sample of individuals without evidence of endocrine abnormality [837–839]. When the frequency of abnormality in such a randomly sampled population is so high, it makes it difficult to determine what indeed is the upper limit of normal for that population and a number of mathematical formulations have been tried (for more complete discussions of this problem, see [837] and [840]). As discussed previously, PRL is secreted episodically, resulting in varying blood PRL levels throughout the day. Therefore, a PRL level in a single sample that is in the upper part of the normal range should be confirmed with one or two repeated tests before considering it to be abnormal.

Hypoprolactinemia As noted above, female mice with the PRL receptor KO are infertile with a number of defects occurring, including fewer primary follicles, fewer eggs ovulated, fewer eggs fertilized, impaired progression to the blastocyst stage, poor implantation and decreased estradiol and progesterone levels [679,688]. Male mice with the PRL receptor KO had only minimally impaired fertility [679] and those with the PRL gene KO had normal fertility [689].

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Idiopathic PRL deficiency has been described in only a single human [841]. This was a 30-year-old woman who had had a minimally delayed puberty (thelarche, age 15 and menarche, age 17), regular menses and normal body hair and breast development who conceived but was unable to lactate postpartum. Her basal PRL levels were all <3 ng/ml, during pregnancy her highest PRL level was 7.8 ng/ml and during the first few days postpartum her highest PRL level was 11.7 ng/ml. After TRH stimulation her PRL levels increased from 3.8 to 13.2 ng/ml. Her pituitary function was otherwise normal. PRL levels in her two children and other family members were normal. The ability of this woman to develop primary and secondary sexual characteristics normally and then conceive and deliver a child speak to the minimal, if any, importance of PRL in normal reproductive function, save that of postpartum lactation. No cases have been described analogous to the PRL gene or receptor KO mice. PRL deficiency may occur in the setting of panhypopituitarism, generally as a result of pituitary infarction. When the cause of the hypopituitarism is hypothalamic or stalk dysfunction, PRL levels generally rise due to disinhibition of PRL secretion (see below). However, when the pituitary tissue is actually destroyed, as in Sheehan’s peripartum necrosis, PRL levels are usually low [842]. In this latter circumstance, the hypoprolactinemia is manifest as an inability to lactate postpartum along with other symptoms of hypopituitarism. A deficiency of PRL may also occur in association with deficiencies of GH and TSH due to mutations in the Pit-1 and Prop-1 transcription factors necessary for tissuespecific PRL gene activation [46,47,49–51] (see above). PRL levels are also low in the condition of hypoparathyroidism [843]. Presumably this in some way reflects the importance of calcium as an intracellular mediator of PRL secretion, but the specific details of this have not been elucidated.

Hyperprolactinemia The differential diagnosis of sustained hyperprolactinemia is broad (Table 4.4). This section discusses those causes of hyperprolactinemia other than prolactinomas, which are discussed in Chapter 12. Medications

Neuroleptics The neuroleptic agents (phenothiazines and butyrophenones) uniformly result in elevated RPL levels, generally to less than 100 ng/ml but some patients have been reported with levels as high as 365 ng/ml [844,845]. Levels begin to rise within a few hours of starting therapy, continue to rise for 6 to 9 days, and then fall to lower, though still elevated levels after long-term treatment [844,845]. Chlorpromazine, sulpiride, and metoclopramide, major tranquilizers and antiemetics with potent dopamine antagonist action, have in fact been used as diagnostic agents to evaluate PRL secretory reserve. Neuroleptic agents raise PRL levels by blocking dopamine receptors, both on the

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Table 4.4.

Hypothalamic–Pituitary Function

Etiologies of hyperprolactinemia

Pituitary disease

Medications

Prolactinomas Acromegaly “Empty sella syndrome” Lymphocytic hypophysitis Cushing’s disease

Phenothiazines Haloperidol Monoamine-oxidase inhibitors Tricyclic antidepressants Reserpine Methyldopa Metoclopramide Amoxepin Cocaine Verapamil Serotonin reuptake inhibitors

Hypothalamic disease Craniopharyngiomas Meningiomas Dysgerminomas Nonsecreting pituitary adenomas Other tumors Sarcoidosis Histiocytosis X Neuraxis irradiation Vascular Pituitary stalk section Neurogenic Chest wall lesions Spinal cord lesions Breast stimulation

Other Pregnancy Hypothyroidism Chronic renal failure Cirrhosis Adrenal insufficiency Pseudocyesis Idiopathic

pituitary lactotrophs and in the hypothalamus. PRL levels usually fall to normal within 48 to 96 hours of discontinuation of neuroleptic drug therapy [844]. Combined serotonin/dopamine receptor antagonists such as risperidol cause similar elevations of PRL [846]. Antidepressants Tricyclic antidepressants cause modest hyperprolactinemia in about 25% of patients [847]. Monoamine oxidase (MAO) inhibitors, when used chronically, may also cause a minimal elevation of PRL levels [638]. The mechanisms by which these drugs cause increased PRL levels are not certain; they probably facilitate several possible stimulatory pathways and their effects on portal vessel dopamine are uncertain. Serotonin reuptake inhibitors, by increasing synaptic serotonin levels, commonly cause a mild increase in PRL to levels still within the normal range; rarely does hyperprolactinemia occur [489,848,849]. Opiates and Cocaine Chronic opiate abuse is associated with mild hyperprolactinemia and menstrual dysfunction (see above). Cocaine abuse has also been associated with chronic, mild hyperprolactinemia [850]. Antihypertensive Drugs Alpha-methyldopa causes moderate hyperprolactinemia [639] by reducing the effect level of dopamine that reaches the pituitary by inhibiting the enzyme l-aromatic amino acid decarboxylase, which is responsible for converting l-dopa to dopamine and by acting as a false neurotransmitter to decrease dopamine synthesis. Reserpine, a little-used antihypertensive drug now,

causes hyperprolactinemia by interfering with the storage of hypothalamic catecholamines in secretory granules [851]. ACE inhibitors, such as enalapril, facilitate PRL release in some individuals [582a] but sustained hyperprolactinemia causing symptoms has not been reported with their use. Calcium Channel Blockers Verapamil acutely and chronically, in most but not all experiments, has been found to increase basal PRL secretion and the PRL response to TRH [172,852,853] and patients have been described with galactorrhea associated with sustained hyperprolactinemia due to verapamil [171] (Fig. 4.15). In a survey of patients taking verapamil in an outpatient clinic, PRL levels were found to be elevated in 8.5% of patients [854]. Verapamil does not block the PRL inhibition caused by graded lowdose dopamine infusion, thereby showing lack of effect at the lactotroph [173]. However, it does block the hypothalamic generation of dopamine, as judged by finding decreased inhibition of PRL secretion by l-dopa after pretreatment with the peripheral dopa-decarboxylase inhibitor carbidopa, a maneuver that allows the assessment of central dopamine generation [173]. Interestingly, other calcium channel blockers such as the dihydropyridines and benzothiazepines have no action on PRL secretion, implying that the action of the phenylakylamine, verapamil, likely is acting on the neuronal N-type calcium channel [173]. Protease Inhibitors A recent report has shown that some HIV positive patients treated with protease inhibitors have developed galactorrhea and hyperprolactinemia [854a]. The mechanism for this is unknown at present. Stress

As noted previously, physical stress such as physical discomfort, exercise and hypoglycemia causes an acute, transient rise in PRL levels (see above). Chronic hyperprolactinemia due to prolonged physical stress has not been reported. Psychologic stress may cause minimal elevations of PRL [855] but chronic hyperprolactinemia has not been reported with any chronic psychiatric state except that of pseudocyesis, in which PRL levels fall with psychotherapy [856]. Renal disease

Hyperprolactinemia occurs in 73% to 91% of women and 25% to 57% of men with end-stage renal disease [857–859] (Fig. 4.16). PRL suppression by dopamine infusion is decreased [857] but this may be, at least in part, the result of delayed degradation of PRL in renal failure, since longterm use of bromocriptine results in suppression of PRL levels [858]. Although metabolic breakdown of PRL is delayed in renal failure, there is also increased production [264]. Therefore, there is disordered regulation of PRL secretion and possibly short-loop feedback, although the exact nature of the defect has not been defined. About onequarter of individuals with renal insufficiency not requiring dialysis (serum creatinine 2.0–12.0 ng/ml) have PRL levels in the 25–100 ng/ml range [800] (Fig. 4.17). When such

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FIGURE 4.15. (a) Effect of verapamil on the prolactin (PRL) response to a submaximal dose (100 mg) of thyrotropinreleasing hormone given at time 0. The open boxes represent the values before verapamil and the filled boxes represent the values after 1 week of verapamil (240 mg daily, sustained release). Note the elevated basal values. (b) Effect of verapamil on the suppression of the PRL by L-dopa (500 mg). The open boxes represent the values before verapamil and the filled boxes represent the values after 1 week of verapamil (240 mg daily, sustained release). Despite the elevated basal values after verapamil, the precentage suppressions were similar. From Kamal and Molitch [172]

FIGURE 4.16. Prolactin levels in patients requiring dialysis. CAPD, continuous ambulatory peritoneal dialysis. From Hou et al. [859]

FIGURE 4.17. Prolactin levels in patients with renal insufficiency, including patients on medications (M, metoclopramide; all others designated receiving medications were taking methyldopa). From Hou et al. [859]

has occurred in some women treated with bromocriptine [858], but reports of restored ovulation are rare [857]. patients take medications known to alter hypothalamic regulation of PRL, such as methyldopa or metoclopramide, PRL levels may rise to over 2000 ng/ml [859]. Correction of the renal failure with transplantation causes a return of PRL levels to normal [857,859]. Hyperprolactinemia plays a role in the hypogonadism of chronic renal failure, but probably does not explain all of the abnormalities in every case. Return of normal menses

Cirrhosis

Basal PRL levels are increased in patients with alcoholic cirrhosis in frequencies varying from 16% to 100% [860–862] and in patients with nonalcoholic cirrhosis from 5% [863] to 13% [860]. In a study by Van Thiel et al. [861] the PRL response to TRH was normal in 75% of the hyperprolactinemic men with alcoholic cirrhosis and blunted in

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the remainder. In another study, PRL responses to TRH were greatly augmented in patients with a variety of types of cirrhosis [864]. In a third study, 50% of patients with hepatic encephalopathy were found to be hyperprolactinemic [865]. Although l-dopa caused a decrease in PRL levels in all, inhibition of peripheral decarboxylase with carbidopa resulted in an impaired PRL response to l-dopa, implying an underlying defect in hypothalamic dopamine generation as the cause of the hyperprolactinemia in these encephalopathic patients. In women without cirrhosis, acute alcohol withdrawal is associated with hyperprolactinemia in 50% [866]. Hypothyroidism

Primary hypothyroidism is associated with a modest increase in the level of PRL in 40% of patients, but levels greater than 25 ng/ml are reached in only 10% [867]. The mechanisms involved probably include increased TRH production, increased sensitivity of lactotrophs to TRH, and possibly increased pituitary VIP generation (see above). Because many patients with long-standing hypothyroidism may have evidence of pituitary enlargement on x-ray, the finding of hyperprolactinemia, galactorrhea and/or amenorrhea associated with an enlarged pituitary seen in hypothyroidism may be easily confused with a prolactinoma. Therapy with Lthyroxine will cause the PRL levels to return to normal and can even result in a regression of pituitary size [868]. Adrenal Insufficiency

As discussed above, glucocorticoids have a suppressive effect on PRL gene transcription and PRL release. Adrenalectomy has been reported to cause hyperprolactinemia in animals [869]. Rare cases in humans have been reported of hyperprolactinemia occurring in patients with adrenal insufficiency in whom the PRL levels return to normal with glucocorticoid replacement [870–874]. Neurogenic

As discussed above, sexual breast stimulation and suckling cause a reflex release of PRL that is mediated, in part, by afferent neural pathways going through the spinal cord. Chest wall and cervical cord lesions have been reported to result in elevated PRL levels and galactorrhea through stimulation of these afferent neural pathways [875,876]. Similar chronic elevations of PRL have been reported after mastectomy and thoracotomy [877] and with chronic spinal cord injuries [878]. Ectopic Prolactin Secretion

Ectopic production of PRL is exceedingly rare. In a careful evaluation of 215 patients with a variety of malignancies, PRL elevations were found in only 15 and in 12 of these the elevations could be explained by the use of phenothiazines, opiates, or prior irradiation to the chest wall or head [879]. In one of the remaining three patients subsequent samples all had normal PRL measurements and in the other two, the cancer (lung and breast) could also have caused the

modest hyperprolactinemia by stimulation of chest wall afferent nerves. However in another series of patients with uterine cervical carcinoma, 229 out of 743 patients had elevated serum PRL levels; surgery in 86 of these patients resulted in normalization of PRL levels [880]. In this same study, 22 out of 49 cervical carcinomas stained positively for PRL by immunohistochemistry and 5 out of 8 carcinomas produced PRL when cultured [880]. In none of these cases were all of these aspects put together, i.e. elevated serum levels that normalized after surgery and whose tumors both stained for PRL and produced PRL in vitro. However, symptomatic hyperprolactinemia due to well-documented PRL production from a renal cell carcinoma [881], a gonadoblastoma [882] and ectopic pituitary tissue in two ovarian teratomas [883,884] have been reported. Given the great frequency of prolactinomas, “idiopathic hyperprolactinemia” and other causes of hyperprolactinemia, a search for an ectopic source of PRL secretion is not warranted unless some other tumor shows up coincidentally. Hypothalamic/Pituitary Stalk Disease

Hyperprolactinemia caused by lesions of the hypothalamus and of the pituitary stalk is due to disturbance of the neuroendocrine mechanisms that control PRL secretion. From hypothalamic lesion work in animals, it has been assumed that this PRL elevation is due to disinhibition of the tonic PIF (dopamine) acting at the level of the pituitary lactotrophs. PRL secretory dynamics were studied systematically in a group of such patients with hypothalamic hyperprolactinemia (six with hypothalamic lesions such as craniopharyngiomas, eosinophilic granuloma), eight with large “nonfunctioning” pituitary adenomas with marked suprasellar extension, and seven with partially empty sellas [885]. Basal PRL levels were <100 ng/ml in all but 1 (Fig. 4.18). However, in one patient with a Rathke’s cleft cyst, preoperative PRL levels ranged between 93 and 148 ng/ml; she had normal TSH and ACTH function but following transsphenoidal resection she developed diabetes insipidus and panhypopituitarism, indicating high stalk section, and PRL levels fell to 25–28 ng/ml. Interestingly, of seven of these patients tested with insulin-induced hypoglycemia, three had normal PRL responses and seven out of 12 showed a significant inhibition in response to L-dopa even after peripheral conversion to dopamine was blocked by carbidopa pretreatment. Furthermore, most of these patients had normal TSH and ACTH function. These results imply that there still is significant transmission of hypothalamic releasing factors to the pituitary in most of these cases, despite increased PRL levels. The fall in PRL levels in the patient with the Rathke’s cleft cyst, along with the development of a true stalk section syndrome, implies that there is a difference in patients with total stalk section in whom the PRL rise is due solely to dopamine deficiency and those with partial stalk/hypothalamic dysfunction who have dopamine deficiency plus continued PRF activity, resulting in higher PRL levels. In addition to this case with a Rathke’s

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FIGURE 4.18. Basal prolactin levels in patients with hypothalamic disease. From Molitch and Reichlin [900]

cleft cyst with a basal PRL level of 122 ng/ml a number of cases have been reported in the literature by others with PRL levels between 104 and 219 ng/ml [886–891]. A case of a patient with a PRL of 662 ng/ml whose tumor did not stain for PRL has been well-documented [892], but cases with such high PRL levels must be extraordinarily rare. It is also possible that some cases of hyperprolactinemia due to hypothalamic disease could be due to increased PRF activity with normal PIF activity. Anterior hypothalamic lesions that are irritative could potentially stimulate PRF pathways, similar to findings in experimental animals [893,894]. The findings of a normal suppression of PRL with l-dopa alone and combined with carbidopa in two of our patients supports the concept of an intact TIDA system in these two patients [885]. Idiopathic Hyperprolactinemia

When no specific cause is found with the evaluation outlined below, the hyperprolactinemia is of uncertain etiology and has been designated to be idiopathic. It is recognized that in many such cases small prolactinomas that are too small to be detected by current radiologic techniques may be present. In other cases the hyperprolactinemia is due to presumed hypothalamic regulatory dysfunction, but no dysfunction specific to idiopathic hyperprolactinemia has been definitively elucidated. Long-term follow-up of such patients has found that in about one-third, PRL levels return to normal, in 10% to 15% there is a rise in PRL levels to >50% over baseline, and in the remaining patients prolactin levels remain stable [895,896]. Over a 2 to 6 year followup of 199 patients, only 23 developed evidence of microadenomas and none developed macroadenomas [895–899]. CLINICAL TESTING As mentioned above, PRL is secreted episodically and some PRL levels during the day may be above the upper limit of

normal established for a given laboratory. Thus the finding of minimally elevated levels in blood requires confirmation in several samples. As indicated in the previous section, there are a number of conditions that may cause moderate PRL elevations, although generally to levels <250 ng/ml. A careful history and physical examination, screening blood chemistries, thyroid function tests and a pregnancy test will exclude virtually all causes except for hypothalamic– pituitary disease. When there is no obvious cause of the hyperprolactinemia from the routine screening, a radiologic evaluation of the hypothalamic–pituitary area is mandatory to exclude a mass lesion. This includes patients with even mild PRL elevations. At present, such an evaluation is generally done using magnetic resonance imaging (MRI) with gadolinium enhancement or computed tomography (CT) with intravenous contrast enhancement (see Chapter 20). It should be emphasized here that it is very important to distinguish between a large nonsecreting tumor causing modest PRL elevations (usually <250 ng/ml, see above) from a PRL-secreting macroadenoma (PRL levels usually >>250 ng/ml), as the therapy may be quite different. PRLsecreting macroadenomas generally will respond quite readily to bromocriptine and other dopamine agonists with size reduction (see Chapter 11, p. 425) whereas only about 10% of nonsecreting pituitary tumors respond in this manner. Stimulation and suppression tests give nonspecific results. Although blunted PRL responses to TRH (Fig. 4.19) and hypoglycemia (Fig. 4.20) are characteristic of patients with prolactinomas, such blunted responses are also seen in patients with hypothalamic dysfunction and other causes of hyperprolactinemia and normal PRL responses may be seen in 10% to 15% of patients with prolactinomas [900–902]. Similar nonspecific results have been found with chlorpromazine, metoclopramide, nomifensine, and l-dopa and also carbidopa [900–902]. Thus, consensus has developed that such stimulation and suppression tests are worthless in the

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FIGURE 4.19. Prolactin responses to thyrotropin-releasing hormone in patients with hyperprolactinemia of different etiologies. Note the marked blunting of the responses of all categories of hyperprolactinemic patients in comparison to those of normal controls. From Molitch and Reichlin [900]

FIGURE 4.20. Prolactin responses to insulin-induced hypoglycemia in patients with hyperprolactinemia of different etiologies. Note the marked blunting of the responses of all categories of hyperprolactinemic patients in comparison to those of normal controls. From Molitch and Reichlin [900]

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168 Di Renzo G, Amoroso S, Maida P et al. Effect of different Ca2+ entry blockers on dopamine-induced inhibition of in vitro prolactin secretion. Eur J Pharmacol 1988;146:201–206. 169 Kuan SI, Login IS, Judd AM. A comparison of the concentration-dependent actions of thyrotropin-releasing hormone, angiotensin II, bradykinin. Endocrinology 1990;127:1841–1848. 170 Schrey MP, Clark HJ, Franks S. The dopaminergic regulation of anterior pituitary 45Ca2+ homeostasis and prolactin secretion. Endocrinology 1986;108: 423–429. 171 Gluskin LE, Strasberg B, Shah JH. Verapamil-induced hyperprolactinemia and galactorrhea. Ann of Intern Med 1981;95:66–67. 172 Kamal TJ, Molitch ME. Effects of calcium channel blockade with verapamil on the prolactin responses to TRH, L-DOPA and bromocriptine. Am J Med Sci 1992;304:289–293. 173 Kelley SR, Kamal TJ, Molitch ME. Mechanism of verapamil calcium channel blockade-induced hyperprolactinemia. Am J Physiol 1996;270:E96– E100. 174 Sinha YN, Gillian TA, Lee DW et al. Cleaved prolactin: evidence for its occurrence in human pituitary gland and plasma. J Clin Endocrinol Metab 1985;60:239–243. 175 Mittra I. A novel “cleaved prolactin” in the rat pituitary. I. Biosynthesis, characterization and regulatory control. Biochem Biophys Res Commun 1980;95:1750–1759. 176 Sinha YN, Gilligan TA. A cleaved form of prolactin in the mouse pituitary gland: identification and comparison of in vitro synthesis and release in strains with high and low incidences of mammary tumors. Endocrinology 1984;114: 2046–2050. 177 Mittra I. A novel “cleaved prolactin” in the rat pituitary. II. In vivo mammary mitogenic activity of its N-terminal 16K moiety. Biochem Biophys Res Commun 1980;95:1760–1767. 178 Oetting WS, Walker AM. Intracellular processing of prolactin. Endocrinology 1985;117:1565–1570. 179 Sinha YN, Jacobsen BP. Structural and immunologic evidence for a small molecular weight (“21K”) variant of prolactin. Endocrinology 1988;123: 1364–1370. 180 Oetting WS, Ho TWC, Greenan JR, Walker AM. Production and secretion of the 21–23.5 kDa prolactin-like molecules. Mol Cell Endocrinol 1989;61: 189–199. 181 Greenan JR, Balden E, Ho TWC, Walker AM. Biosynthesis of the secreted 24 K isoforms of prolactin. Endocrinology 1989;125:2041–2047. 182 Suh HK, Frantz AG. Size heterogeneity of human prolactin in plasma and pituitary extracts. J Clin Endocrinol Metab 1974;39:928–935. 183 Guyda HJ. Heterogeneity of human growth hormone and prolactin secreted in vitro: immunoassay and radioreceptor assay correlations. J Clin Endocrinol Metab 1975;41:953–967. 184 Garnier PE, Aubert ML, Kaplan ASL, Grumbach MM. Heterogeneity of pituitary and plasma prolactin in man: Decreased affinity of “big” prolactin in a radioreceptor assay and evidence for its secretion. Endocrinology 1978;47: 1273–1279. 185 Wallis M, Daniels M, Ellis SA. Size heterogeneity of rat pituitary prolactin. Biochem J 1980;189:605–614. 186 Whitaker MD, Klee GG, Kao PC et al. Demonstration of biological activity of prolactin molecular weight variants in human sera. J Clin Endocrinol Metab 1983;58:826–830. 187 Torres AI, Aoki A. Release of big and small molecular forms of prolactin: dependence upon dynamic state of the lactotroph. J Endocrinology 1987;114: 213–220. 188 Lawson DM, Gala RR, Chin ML, Haisenleder DH. Size heterogeneity of plasma prolactin in the rat: TRH and serotonin-induced changes. Life Sci 1980;27:1147–1151. 189 Molitch ME, Raiti S, Baumann G et al. Pharmacokinetic studies of highly purified human prolactin normal human subjects. J Clin Endocrinol Metab 1987;65:299–304. 190 Andino NA, Bidot C, Valdez M, Machado AJ. Chromatographic pattern of circulating prolactin in ovulatory hyperprolactinemia. Fertil Steril 1985;44: 600–605. 191 Larrea F, Villanueva C, Cravioto MC. Further evidence that Big, Big prolactin is preferentially secreted in women with hyperprolactinemia and normal ovarian function. Fertil Steril 1985;44:25–30. 192 Jackson RD, Wortsman J, Malarkey WB. Characterization of a large molecular weight prolactin in women with idiopathic hyperprolactinemia and normal menses. J Clin Endocrinol Metab 1985;61:258–264. 193 Wortsman J, Carlson HE, Malarkey WB. Macroprolactinemia as the cause of elevated serum prolactin in men. Am J Med 1989;86:704–706.

194 Corenblum B. Asymptomatic hyperprolactinemia resulting from macroprolactinemia. Fertil Steril 1990;53(1):165–167. 195 Vieira JGH, Tachibana TT, Obara LH, Maciel RMB. Extensive experience and validation of polyethylene glyco precipitation as a screening method for macroprolactinemia. Clin Chem 198;44:758–759. 196 Lewis UJ, Singh RNP, Sinha YN, Vanderlaan WP. Glycosylated human prolactin. Endocrinology 1985;116:359–363. 197 Lewis UJ, Singh RNP, Lewis LJ. Two forms of glycosylated human prolactin have different pigeon crop sac-stimulating activities. Endocrinology 1989;24: 1558–1563. 198 Markoff E, Lee DW. Glycosylated prolactin is a major circulating variant in human serum. Endocrinology 1987;65:1102–1106. 199 Hashim IA, Aston R, Butler J. The proportion of glycosylated prolactin in serum is decreased in hyperprolactinemic states. J Clin Endocrinol Metab 1990;71:111–115. 200 Haro LS, Lee DW, Singh RNP et al. Glycosylated human prolactin: alterations in glycosylation pattern modify affinity for lactogen receptor and values in prolactin radiommunoassay. J Clin Endocrinol Metab 1990;71:379–383. 201 Markoff E, Sigel MB, Lacour N et al. Glycosylation selectively alters the biological activity of prolactin. Endocrinology 1988;123:1303–1306. 202 Pellegrini I, Gunz G, Ronin C et al. Polymorphism of prolactin secreted by human prolactinoma cells: immunological, receptor binding and biological properties of the glycosylated and nonglycosylated forms. Endocrinology 1988;122:2667–2674. 203 Young KH, Buhi WC, Horseman N et al. Biological activities of glycosylated and nonglycosylated porcine prolactin. Mol Cell Endocrinol 1990;71:155–162. 204 Oetting WS, Tuazon PT, Traugh JA, Walker AM. Phosphorylation of prolactin. J Biol Chem 1986;261:1649–1652. 205 Brooks CL, Kim BG, Aphale P et al. Phosphorylated variant of bovine prolactin. Mol Cell Endocrinol 1990;71:117–123. 206 Soares MJ, Müller H, Orwig KE et al. The uteroplacental prolactin family and pregnancy. Biol Reprod 1998;58:273–284. 207 Linzer DIH, Fisher SJ. The placenta and the prolactin family of hormones: regulation of the physiology of pregnancy. Mol Endocrinol 1999;13:837–840. 208 Tyson JE, Friesen HG. Factors influencing the secretion of human prolactin and growth hormone in menstrual and gestational women. Am J Obstet Gynecol 1973;116:377–387. 209 Rigg LA, Lein A, Yen SSC. Pattern of increase in circulating prolactin levels during human gestation. Am J Obstet Gynecol 1977;129:454–456. 210 Ben-David M, Rodbard D, Bates RW, Bridson E, Chrambach A. Human prolactin in plasma, amniotic fluid and pituitary: identity and characterization by criteria of electrophoresis and isoelectric focusing in polyacrylamide gel. J Clin Endocrinol Metab 1973;36:951–964. 211 Rathman P, Cederqvist L, Saxena BB. Isolation of prolactin from human amniotic fluid. Biochem Biophys Acta 1977;492:186–193. 212 Friesen H, Hwang P, Guyda H et al. In: Boyns AR, Griffiths K, eds. Prolactin and Carcinogenesis. Wales: Alpha Omega Publishing, 1972:64–80. 213 Riddich DH, Kusmik WF. Decidua: a possible source of amniotic fluid prolactin. Am J Obstet Gynecol 1977;127:187–192. 214 Golander A, Hurley T, Barrett J et al. Prolactin synthesis by human choriondecidual tissue: A possible source of prolactin in the amniotic fluid. Science 1978;202:311–313. 215 De Ziegler D, Gurpide E. Production of prolactin by cultures of cells from human decidua. J Clin Endocrinol Metab 1982;55:511–515. 216 Tomita K, McCoshen JA, Friesen HG, Tyson JE. Quantitative comparison between biological and immunological activities of prolactin derived from human fetal and maternal sources. J Clin Endocrinol Metab 1982;55:269–271. 217 Takahashi H, Nabeshima Y, Nabeshima Y-I et al. Molecular cloning and nucleotide sequence of DNA complementary to human decidual prolactin mRNA. J Biol Chem 1984;95:1491–1499. 218 Huang JR, Tseng L, Bischof P, Janne OA. Regulation of prolactin production by progestin, estrogen, and relaxin in human endometrial stromal cells. Endocrinology 1987;121:2011–2017. 219 Gellersen B, DiMattia GE, Friesen HG, Bohnet HG. Prolactin (PRL) mRNA from human decidua differs from pituitary PRL mRNA but resembles the IM-9-P3 lymphoblast PRL transcript. Mol Cell Endocrinol 1989;64:127–130. 220 Lee DW, Markoff E. Synthesis and release of glycosylated prolactin by human decidua in vitro. J Clin Endocrinol Metab 1986;62:990–994. 221 Heffner LJ, Gramates LS, Yuan RW. A glycosylated prolactin species is covalently bound to immunoglobulin in human amniotic fluid. Biochem Biophys Res Comm 1989;165:299–305. 222 Jayatilak PG, Glaser LA, Busuray R et al. Identification and partial characterization of a prolactin-like hormone produced by rat decidual tissue. Proc Natl Acad Sci USA 1985;82:217–221.

Chapter 4 223 Herz Z, Khan I, Jayatilak PG, Gibori G. Evidence for the secretion of decidual luteotropin: a prolactin-like hormone produced by rat decidual cells. Endocrinology 1986;118:2203–2209. 224 Jayatilak PG, Puryear TK, Herz Z et al. Protein secretion by mesometrial and antimesometrial rat decidual tissue: Evidence for differential gene expression. Endocrinology 1989;125:659–666. 225 Bigazzi M, Ronga R, Lancranjan I et al. A pregnancy in an acromegalic woman during bromocriptine treatment: effects on growth hormone and prolactin in the maternal, fetal and amniotic compartments. J Clin Endocrinol Metab 1979;48:9–12. 226 Kubota T, Nagae M, Yoshimasa Y et al. Prolactin-releasing system in maternal, fetal and amniotic compartments during labor. Obstetrics and Gynecology 1986;68:80–86. 227 Maslar IA, Ansbacher R. Effect of short-duration progesterone treatment on decidual prolactin by cultures of proliferative human endometrium. Fertil Steril 1988;50:250–254. 228 Golander A, Richards R, Thrailkill K et al. Decidual prolactin (PRL) releasing factors stimulate the synthesis of PRL from human decidual cells. Endocrinology 1988;123:335–340. 229 Thrailkill KM, Golander A, Underwood LE, Handwerger S. Insulin-like growth factor I stimulates the synthesis and release of prolactin from human decidual cells. Endocrinology 1988;123:2930–2934. 230 Thrailkill KM, Golander A, Underwood LE et al. Insulin stimulates the synthesis and release of prolactin from human decidual cells. Endocrinology 1989;124:3010–3014. 231 Josimovich JB, Merisko K, Boccella L. Amniotic prolactin control over amniotic and fetal extracellular fluid water and electrolytes in the rhesus monkey. Endocrinology 1977;100:564–570. 232 Johnson JWC, Tyson JE, Mitzner W et al. Amniotic fluid prolactin and fetal lung maturation. Am J Obstet Gynecol 1985;153:372–375. 233 Horrobin DF. Prolactin as a regulator of fluid and electrolyte metabolism in mammals. Fed Proc 1980;39:2567–2570. 234 Di Mattia GE, Gellersen B, Duckworth ML. Human prolactin gene expression. J Biol Chem 1990;265:16412–16421. 235 Di Mattia GE, Gellersen B, Bohnet HG, Friesen HG. A human Blymphoblastoid cell line produces prolactin. Endocrinology 1988;122:2508–2517. 236 Gellersen B, Di Mattia GE, Friesen HG. Regulation of prolactin secretion in the human B-lymphoblastoid cell line IM-9-P3 by dexamethasone but not other regulators of pituitary prolactin secretion. Endocrinology 1989;125: 2853–2861. 237 Pelletier G, Lemay A, Beraud G, Labrie F. Ultrastructural changes accompanying the stimulatory effect of n-monobutyryl adenosine 3¢,5¢monophosphate on the release of growth hormone (GH), prolactin (PRL) and adrenocorticotropic hormone (ACTH) in rat anterior pituitary gland in vitro. Endocrinology 1972;91:1355–1371. 238 Walker AM, Farquhar MG. Preferential release of newly synthesized prolactin granules is the result of functional heterogeneity among mammotrophs. Endocrinology 1980;107:1095–1104. 239 Nicoll CS, Swearingen KC. Preliminary observations on prolactin and growth hormone turnover in rat adenohyphyses in vivo. In: Martin L, Motta M, Fraschini F, eds. The Hypothalamus. New York: Academic Press, 1970; 449–462. 240 Swearingen KC, Nicoll CS. Prolactin turnover in rat adenohypophyses in vivo: Its evaluation as a method for estimating secretion rates. Endocrinology 1972;53:1–15. 241 Swearingen KC. Heterogeneous turnover of adenohypophysial prolactin. Endocrinology 1971;89:1380–1388. 242 Stachura ME. Sequestration of an early-release pool of growth hormone and prolactin in GH3 rat pituitary tumor cells. Endocrinology 1982;111:1769– 1777. 243 Stachura ME, Tyler JM, Kent PG. Pituitary immediate release pools of growth hormone and prolactin are preferentially refilled by new rather stored hormone. Endocrinology 1989;125:444–449. 244 Jacobs LS, Lorenson MY. Cysteamine, zinc and thiols modify detectability of rat pituitary prolactin: a comparison with effects on bovine prolactin suggests differences in hormone storage. Metabolism 1986;35:209–215. 245 Sagar SM, Millard WJ, Martin JB, Murchison SC. The mechanism of action of cysteamine in depleting prolactin immunoreactivity. Endocrinology 1985; 117:591–600. 246 Lorenson MY, Robson DL, Jacobs LS. Detectability of pituitary PRL and GH by immunoassay is increased by thiols and suppressed by divalent cations. Endocrinology 1983;112:1880–1882. 247 Scammell JG, Dannies PS. Depletion of pituitary prolactin by cysteamine is due to loss of immunological activity. Endocrinology 1984;114:712–716.

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248 Mena F, Clapp C, Aguayo D et al. Thiol regulation of depletiontransformation and release of prolactin by the pituitary of the lactating rat. Endocrinology 1986;118:1795–1802. 249 Copeland PM, Martin JB, Ridgway EC. Cysteamine decreases prolactin responsiveness to thyrotropin-releasing hormone in normal men. Am J Med 1986;291:16–19. 250 Brown M, Fisher L, Mason RT et al. Neurobiological actions of cysteamine. Fed Proc 1985;44:2556–2560. 251 Das Gaines RE, Cotes PM. International reference preparation of human prolactin for immunoassay: definition of the international unit, report of a collaborative study and comparison of estimates of human prolactin made in various laboratories. J Endocrinol 1979;80:157–168. 252 Schulster D, Das Gaines RE, Jeffcoate SL. International standards for human prolactin: Calibration by international collaborative study. J Endocrinol 1989;121:157–166. 253 Fujimoto VY, Clifton DK, Cohen NL, Soules MR. Variability of serum prolactin and progesterone levels in normal women: The relevance of single hormone measurements in the clinical setting. Obst and Gynecol 1990;76: 71–78. 254 St-Jean E, Blain F, Comtois R. High prolactin levels may be missed by immunoradiometric assay in patients with macroprolactinomas. Clin Endocrinol 1996;44:305–309. 255 Barkan A, Chandler WF. Giant pituitary prolactinoma with falsely low serum prolactin: the pitfall of the “high-dose hook effect”: case report. Neurosurgery 1998;9:13–15. 256 Kleinberg DL, Frantz AG. Human prolactin: Measurement in plasma by in vitro bioassay. J Clin Invest 1971;50:1557–1568. 257 Turkington RW. Measurement of prolactin activity in human serum by the induction of specific milk proteins in mammary gland in vitro. J Clin Endocrinol Metab 1971;33:210–217. 258 Shiu RPC, Kelly PA, Friesen HG. Radioreceptor assay for prolactin and other lactogenic hormones. Science 1973;180:968–970. 259 Tanaka T, Shiu RPC, Gout PW et al. A new sensitive and specific bioassay for lactogenic hormones: measurement of prolactin and growth hormone in human serum. J Clin Endocrinol Metab 1980;51:1058–1063. 260 Tanaka T, Shishiba Y, Gout PW, Beer CT. Radioimmunoassay and bioassay of human growth hormone and Human prolactin. J Clin Endocrinol Metab 1983;56:18–20. 261 Rowe RC, Cowden EA, Faiman C, Friesen HG. Correlation of Nb2 bioassay and radioimmunoassay values for human serum prolactin. J Clin Endocrinol Metab 1983;57:942–946. 262 Frawley LS, Clark CL, Schoderbek WC. A novel bioassay for lactogenic activity. Demonstration that prolactin cells differ from one another in bio- and immuno-potencies of secreted hormone. Endocrinology 1986;119:2867–2869. 263 Cooper BS, Ridgway EC, Kliman B. Metabolic clearance and production rates of prolactin in man. J Clin Invest 1979;64:1669–1680. 264 Sievertsen GD, Lim VS, Nakawatase C, Frohman LA. Metabolic clearance and secretion rates of human prolactin in normal subjects and in patients with chronic renal failure. J Clin Endocrinol Metab 1980;50:846–852. 265 Kapcala LP, Molitch ME, Arno J et al. Twenty-four hour prolactin secretory patterns in women with galactorrhea, normal menses, normal random prolactin levels and abnormal sellar tomograms. J Endocrinol Invest 1984;7:455–460. 266 Bratusch-Marrain P, Bjorkman O. Hepatic disposal of endogenous growth hormone and prolactin in man. Eur J Clin Invest 1979;9:257–260. 267 Falconer IR, Vacek AT. Degradation of 125I-labeled prolactin in the rabbit: effect of nephrectomy and prolactin infusion. J Endocrinol 1983;99:369–377. 268 Shin SH, Reifel CW. Adenohypophysis has an inherent property for pulsatile prolactin secretion. Neuroendocrinology 1981;32:139–144. 269 Stewart JK, Clifton DK, Koerker DJ, Rogol AD. Pulsatile release of growth hormone and prolactin from the primate pituitary in vitro. Endocrinology 1985;116:1–5. 270 Veldhuis JD, Johnson, L. Operating characteristics of the hypothalamo–pituitary–gonadal axis in men: circadian, ultradian, and pulsatile release of prolactin and its temporal coupling with luteinizing hormone. J Clin Endocrinol Metab 1988;67:116–123. 271 Greenspan SL, Klibanski A, Rowe JW. Age alters pulsatile prolactin release: influence of dopaminergic inhibition. Am J Physiol 1990;258:E799–E804. 272 Samuels MH, Henry P, Kleinschmidt-DeMasters B et al. Pulsatile prolactin secretion in hyperprolactinemia due to presumed pituitary stalk interruption. J Clin Endocrinol Metab 1991;73:1289–1293. 273 Parker DC, Rossman LG, Vanderlaan EF. Relation of sleep-entrained human prolactin release to REM-NonREM cycles. J Clin Endocrinol Metab 1973;38: 646–651.

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274 Sassin JF, Frantz AG, Kapen S, Weitzman ED. The nocturnal rise of human prolactin is dependent upon sleep. J Clin Endocrinol Metab 1973;37:436– 440. 275 Stern JM, Reichlin S. Prolactin circadian rhythm persists throughout lactation in women. Neuroendocrinology 1990;51:31–37. 276 Linkowski P, Spiegel K, Kerkhofs M et al. Genetic and environmental influences on prolactin secretion during wake and during sleep. Am J Physiol 1998;274:E909–E919. 277 Weitzman ED, Boyar RM, Kapen S. The relationship of sleep and sleep stages of neuroendocrine secretion and biological rhythms in man. Rec Prog Horm Res 1975;31:399–446. 278 Quigley ME, Ropert JF. Acute prolactin release triggered by feeding. J Clin Endocrinol Metab 1981;52:1043–1045. 279 Carlson HE, Wasser HL, Levin SR. Prolactin stimulation by meals is related to protein content. J Clin Endocrinol Metab 1983;57:334–338. 280 Carlson HE. Prolactin stimulation by protein is mediated by amino acids in humans. J Clin Endocrinol Metab 1989;69:7–14. 281 Carlson HE, Miglietta JT, Roginsky MS. Stimulation of pituitary hormone secretion by neurotransmitter amino acids in humans. Metabolism 1989;38:1179–1182. 282 Carlson HE, Hyman DB, Blitzer MG. Evidence for an intracerebral action of phenylalanine in stimulation of prolactin secretion: Interaction of large neutral amino acids. J Clin Endocrinol Metab 1990;70:814–816. 283 Poindexter AN, Buttram VC, Besch P. Circulating prolactin levels, I. Normal females. Int J of Fertil 1977;22:1–5. 284 Vekemans M, Robyn C. Influence of age on serum prolactin levels in women and men. Brit Med J 1975;2:738–739. 285 Djursing H, Hagen C, Moller J. Short and long term fluctuations in plasma prolactin concentration in normal subjects. Acta Endocrinol 1981;97:1–6. 286 Rolandi E, Magnani G, Sannia A. Evaluation of PRL secretion in elderly subjects. Acta Endocrinol 1982;100:351–357. 287 Balint-Peric´ LA, Prelevic´ GM. Changes on prolactin levels with the menopause: the effects of estrogen/androgen and calcitonin treatment. Gynecol Endocrinol 1997;11:275–280. 288 Foth D, Römer T. Prolactin serum levels in postmenopausal women receiving long-term hormone replacement therapy. Gynecol Obstet Invest 1997;44: 124–126. 289 Touraine P, Deneux C, Plu-Bureau G et al. Hormonal replacement therapy in menopausal women with a history of hyperprolactinemia. J Endocrinol Invest 1998;21:732–736. 290 Iranmesh A, Mulligan T, Veldhuis JD. Mechanisms subserving the physiological nocturnal relative hypoprolactinemia of healthy older men: dual decline in prolactin secretory burst mass and basal release with preservation of pulse duration, frequency, and interpulse interval—a General Clinical Research Center Study. J Clin Endocrinol Metab 1999;84:1083–1090. 291 McNeilly AS, Chard T. Circulating levels of prolactin during the menstrual cycle. Clin Endocrinol 1974;3:105–112. 292 Franchimont P, Dourcy C, Legros JJ. Prolactin levels during the menstrual cycle. Clin Endocrinol 1976;5:643–650. 293 Cole EN, England PC, Sellwood RA. Serum prolactin concentrations throughout the menstrual cycle of normal women and patients with recent breast cancer. Eur J Cancer 1977;13:677–684. 294 Gordon JS, Wu CH, Mikhail G. Daily plasma prolactin in various gynecologic endocrinopathies. Fertil Steril 1979;31:385–391. 295 Braund W, Roeger DC, Judd SJ. Synchronous secretion of luteinizing hormone and prolactin in the human luteal phase: neuroendocrine mechanisms. J Clin Endocrinol Metab 1984;58:293–297. 296 Noel GL, Suh HK, Frantz AG. Prolactin release during nursing and breast stimulation in postpartum and nonpostpartum subjects. J Clin Endocrinol Metab 1974;38:413–423. 297 Lee LR, Haisenleder DJ, Marshall JC. The role of the suckling stimulus in regulating pituitary prolactin mRNA in the rat. Mol Cell Endocrinol 1989; 64:243–249. 298 Howie PW, McNeilly AS, McArdle T, Smart L. The relationship between suckling-induced prolactin response and lactogenesis. J Clin Endocrinol Metab 1980;50:670–673. 299 Weitzman RW, Leake RD, Rubin RT. The effect of nursing on neurohypophyseal hormone and prolactin secretion in human subjects. J Clin Endocrinol Metab 1980;51:836–839. 300 Johnston JM, Amico JA. A prospective longitudinal study of the release of oxytocin and prolactin in response to infant suckling in long term lactation. J Clin Endocrinol Metab 1986;62:653–657. 301 Bonnar J, Franklin M, Nott PN, McNeilly AS. Effect of breast-feeding on pituitary–ovarian function after childbirth. Brit Med J 1975;4:82–84.

302 Battin DA, Marrs RP, Fleiss PM. Effect of suckling on serum prolactin, luteinizing hormone, follicle-stimulating hormone, and estradiol during prolonged lactation. Obstet Gynecol 1985;65:785–788. 303 Stern JM, Konner M, Herman TN, Reichlin S. Nursing behavior, prolactin and postpartum amenorrhoea during prolonged lactation in American and !Kung mothers. Clin Endocrinol 1986;25:247–258. 304 Delvoye P, Demaegd M, Uwayitu-Nyampeta, Robyn C. Serum prolactin, gonadotropins, and estradiol in menstruating and amenorrheic mothers during two years’ lactation. Am J Obstet Gynecol 1978;130:635–639. 305 Prema K, Naidu AN, Kumari SN. Lactation and fertility. Am J Clin Nutr 1979;32:1298–1303. 306 Konner M, Worthman C. Nursing frequency, gonadal function, and birth spacing among !Kung hunter-gatherers. Science 1980;207:788–792. 307 Kolodny RC, Jacobs LS, Daughaday WH. Mammary stimulation causes prolactin secretion in non-lactating women. Nature 1972;238:284–286. 308 Neill JD. Effect of “stress” on serum prolactin and luteinizing hormone levels during the estrous cycle of the rat. Endocrinology 1970;87:1192–1197. 309 Noel GL, Suh HK, Stone SJG, Frantz AE. Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab 1972;35:840–851. 310 Harms PG, Langlier P, McCann SM. Modification of stress-induced prolactin release by dexamethasone or adrenalectomy. Endocrinology 1975;96:475–478. 311 Subramanian MG, Gala RR. The influence of adrenalectomy and of corticosterone administration on the ether-induced increase in plasma prolactin in ovariectomized estrogen-treated rats. Proc Soc Exp Biol Med 1978;157:415–417. 312 Van den Berghe G, de Zegher F, Bouillon R. Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998; 83:1827–1834. 313 Gala RR. The physiology and mechanisms of the stress induced changes in prolactin secretion in the rat. Life Sci 1990;46:1407–1420. 314 Corenblum B, Taylor PJ. Mechanisms of control of prolactin release in response to apprehension stress and anesthesia-surgery success. Fertil Steril 1981;36:712–715. 315 Spiler IJ, Molitch ME. Lack of modulation of pituitary hormone stress response by neural pathways involving opiate receptors. J Clin Endocrinol Metab 1980;50:516–520. 316 Abe H, Engler D, Molitch ME et al. Vasoactive intestinal peptide is a physiological mediator of prolactin release in the rat. Endocrinology 1985;116: 1383–1390. 317 Kaji H, Chihara K, Kita T et al. Administration of antisera to vasoactive intestinal polypeptide and peptide histidine isoleucine attenuates etherinduced prolactin secretion in rats. Neuroendocrinology 1985;41:529–531. 318 Woolf PD, Lee LA, Leebaw WF. Hypoglycemia as a provocative test of prolactin release. Metabolism 1978;27:869–877. 319 Woolf PD, Lee LA, Leebaw W, Thompson D. Intracellular glucopenia causes prolactin release in man. J Clinic Endocrinol Metab 1977;45:377–382. 320 Whitaker MB, Corenblum B, Taylor PJ, Control of the hypoglycemia release of prolactin. Prog Reprod Biol 1980;6:77–82. 321 Chang FE, Dodds WG, Sullivan M, Kim MH. The acute effects of exercise on prolactin and growth hormone secretion: comparison between sedentary women and women runners with normal and abnormal menstrual cycles. J Clin Endocrinol Metab 1986;62:551–556. 322 Chang FE, Richards SR, Kim MH, Malarkey WB. Twenty-four hour prolactin profiles and prolactin responses to dopamine in long distance running women. J Clin Endocrinol Metab 1984;58:631–635. 323 Everett JW. Luteotrophic function of autografts of the rat hypophysis. Endocrinology 1954;54:685–690. 324 Pasteels JL. Administration d’extraits hypothalamiques a l’hypophyse de rat in vitro dans le but d’en controler la secretion de prolactine. C R Acad Sci Paris 1962;254:2664–2666. 325 Talwalker PK, Ratner A, Meites J. In vitro inhibition of pituitary prolactin synthesis and release by hypothalamic extract. Am J Physiol 1963;205:213– 218. 326 Barraclough CA, Sawyer CH. Induction of pseudopregnancy in the rat by reserpine and chlorpromazine. Endocrinology 1959;65:563–571. 327 Kanematsu S, Hilliard J, Sawyer CH. Effect of reserpine on pituitary prolactin content and its hypothalamic site of action in the rabbit. Acta Endocrin 44;1963:467–474. 328 van Maanen JH, Smelik PG. Induction of pseudopregnancy in rats following local depletion of monamines in the median eminence of the hypothalamus. Neuroendocrinology 1968;3:177–186. 329 Birge CA, Jacobs LS, Hammer CT, Daughaday WH. Catecholamine inhibition of prolactin secretion by isolated rat adenohypophyses. Endocrinology 1970;86:120–130.

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383 Enjalbert A, Moos F, Carbonell L et al. Prolactin inhibiting activity of dopamine-free subcellular fractions from rat mediobasal hypothalamus. Neuroendocrinology 1977;24:147–161. 384 Nikolics K, Mason AJ, Szonyi E et al. A prolactin-inhibiting factor within the precursor for human gonadotropin-releasing hormone. Nature 1985;316: 511–517. 385 Wormald PJ, Abrahamson MJ, Seeburg PH et al. Prolactin-inhibiting activity of GnRH associated peptide in cultured human pituitary cells. Clin Endocrinology 1989;30:149–155. 386 Chavali GB, Nagpal S, Majumdar SS et al. Helix-loop-helix motif in GnRH associated peptide is critical for negative regulation of prolactin secretion. J Mol Biol 1997;272:731–740. 387 Phillips HS, Nikolics K, Branton D, Seeburg PH. Immunocytochemical localization in rat brain of a prolactin release-inhibiting sequence of gonadotropin-releasing hormone prohormone. Nature 1985;316:542–545. 388 Clarke IJ, Cummins JT, Karsch FJ et al. GnRH-associated peptide (GAP) is cosecreted with GnRH into the hypophyseal portal blood of ovariectomized sheep. Biochem Biophys Res Comm 1987;143:665–671. 389 Adelman JP, Mason AJ, Hayflick JS, Seeburg PH. Isolation of the gene and hypothalamic cDNA for the common precursor of gonadotropin-releasing hormone and prolactin release-inhibiting factor in human and rat. Proc Natl Acad Sci USA 1986;83:179–183. 390 Ishibashi M, Yamaji T, Takaku F et al. Effect of GnRH-associated peptide on prolactin secretion from human lactotrope adenoma cells in culture. Acta Endocrinol 1987;116:81–84. 391 Thomas GB, Cummins JT, Doughton BW et al. Gonadotropin-releasing hormone associated peptide (GAP) and putative processed GAP peptides do not release luteinizing hormone or follicle-stimulating hormone or inhibit prolactin secretion in the sheep. Neuroendocrinology 1988;48:342–350. 392 Schally AV, Redding TW, Arimura A et al. Isolation of gamma-aminobutyric acid from pig hypothalami and demonstration of its prolactin releaseinhibiting (PIF) activity in vivo and in vitro. Endocrinology 1977;100:681–691. 393 Grandison L, Guidotti A. Gamma-aminobutyric acid receptor function in rat anterior pituitary: evidence for control of prolactin release. Endocrinology 1979;105:754–759. 394 Vincent SR, Hokfelt T, Wu JY. GABA neuron systems in the hypothalamus and the pituitary gland. Neuroendocrinology 1982;34:117–125. 395 Mulcahey JJ, Neill JD. Gamma-aminobutyric acid (GABA) levels in hypophyseal stalk plasma of rats. Life Sci 1982;32:453–456. 396 Lamberts SWJ, Macleod RM. Studies on the mechanism of the GABAmediated inhibition of prolactin secretion. Proc Soc Exptl Biol Med 1978;158: 10–13. 397 Grossman A, Delitala G, Yeo T, Besser GM. GABA and muscimol inhibit the release of prolactin from dispersed rat anterior pituitary cells. Neuroendocrinology 1981;32:145–149. 398 Loeffler JP, Kley N, Pittius CW et al. In vivo and in vitro studies of GABAergic inhibition of prolactin biosynthesis. Neuroendocrinology 1986;43:504–510. 399 Takahara J, Yunoki S, Yakushiji W et al. Stimulatory effects of gammahydroxybutyric acid on growth hormone and prolactin release in humans. J Clin Endocrinol Metab 1977;44:1014–1017. 400 Fioretti P, Melis GB, Paoletti AM et al. Gamma-Amino-b-hydroxy butyric acid stimulates prolactin and growth hormone release in normal women. J Clinic Endocrinol Metab 1978;47:1336–1340. 401 Tamminga CA, Neophytides A, Chase TN, Frohman LA. Stimulation of prolactin and growth hormone secretion by muscimol, a gamma aminobutyric acid agonist. J Clin Endocrinol Metab 1978;47:1348–1351. 402 Cavagnini F, Benetti G, Invitti C et al. Effect of gamma aminobutyric acid on growth hormone and prolactin secretion in man: influence of pimozide and domperidone. J Clin Endocrinol Metab 1980;51:789–797. 403 Melis GB, Fruzzetti F, Paoletti AM et al. Pharmacological activation of gaminobutyric acid-system blunts prolactin response to mechanical breast stimulation in puerperal women. J Clin Endocrinol Metab 1984;58:201–205. 404 Tashjian Jr AH, Barowsky NJ, Jensen DK. Thyrotropin releasing hormone: direct evidence for stimulation of prolactin production by pituitary cells in culture. Biochem Biophys Res Commun 1971;43:516–523. 405 Bowers CY, Friesen HG, Hwang P et al. Prolactin and thyrotropin release in man by synthetic pyroglutamyl-histidyl-prolinamide. Biochem Biophys Res Commun 1971;45:1033–1041. 406 Jacobs LS, Snyder PJ, Wilber JF et al. Increased serum prolactin after administration of synthetic thyrotropin releasing hormone (TRH) in man. J Clin Endocrinol Metab 1971;33:996–998. 407 Ashworth R, Hinkle PM. Thyrotropin-releasing hormone-induced intracellular calcium responses in individual rat lactotrophs and thyrotrophs. Endocrinology 1996;137:5205–5212.

408 Tashjian Jr AH, Heslop JP, Berridge MJ. Subsecond and second changes in inositol polyphosphates in GH4C1 cells induced by thyrotropin-releasing hormone. Biochem J 1987;243:305–308. 409 Morel G, Gourdji D, Grouselle D et al. Immunocytochemical evidence for in vivo internalization of thyroliberin into rat pituitary target cells. Neuroendocrinology 1985;41:312–320. 410 Le Dafniet M, Lefebvre P, Barret A et al. Normal and adenomatous human pituitaries secrete thyrotropin-releasing hormone in vitro: modulation by dopamine, haloperidol, and somatostatin. J Clin Endocrinol Metab 1990;71: 480–486. 411 Noel GL, Dimond RC, Wartofsky L et al. Studies of prolactin and TSH secretion by continuous infusion of small amounts of thyrotropin-releasing hormone (TRH). J Clin Endocrinol Metab 1974;39:6–17. 412 Koch Y, Goldhaber G, Fireman I et al. Suppression of prolactin and thyrotropin secretion in the rat by anti-serum to thyrotropin-releasing hormone. Endocrinology 1977;100:1476–1478. 413 Harris ARC, Christianson D, Smith MS et al. The physiological role of thyrotropin-releasing hormone in the regulation of thyroid-stimulating hormone and prolactin secretion in the rat. J Clin Invest 1978;61:441–448. 414 Sheward WJ, Fraser HM, Fink G. Effect of immunoneutralization of thyrotrophin-releasing hormone on the release of thyrotrophin and prolactin during suckling or in response to electrical stimulation of the hypothalamus in the anaesthetized rat. J Endocrinol 1985;106:113–119. 415 Horn AM, Fraser HM, Fink G. Effects of antiserum to thyrotrophin-releasing hormone on the concentrations of plasma prolactin, thyrotrophin and LH in the pro-oestrous rat. J Endocrinol 1985;104:205–209. 416 Fraser HM, McNeilly AS. Effect of chronic immunoneutralization of thyrotropin-releasing hormone on the hypothalamic–pituitary–thyroid axis, prolactin, and reproductive function in the ewe. Endocrinology 1982;111: 1964–1973. 417 Yamada M, Saga Y, Shibusawa N et al. Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene. Proc Natl Acad Sci USA 1997;94:10862–10867. 418 Blake CA. Stimulation of pituitary prolactin and TSH release in lactating and proestrus rats. Endocrinology 1974;94:503–508. 419 Burnet FR, Wakerley JB. Plasma concentrations of prolactin and thyrotrophin during suckling in urethane-anaesthetized rats. Endocrinology 1976;70:429– 437. 420 Riskind PN, Millard WJ, Martin JB. Evidence that thyrotropin-releasing hormone is not a major prolactin-releasing factor during suckling in the rat. Endocrinology 1984;115:312–316. 421 Gautvik KM, Tashjian Jr AH, Kourides IA et al. Thyrotropin-releasing hormone is not the sole physiologic mediator of prolactin release during suckling. N Engl J Med 1974;290:1162–1165. 422 Jeppsson S, Rannevik KO, Wide L. Influence of suckling and of suckling followed by TRH or LH-RH on plasma prolactin, TSH, GH and FSH. Acta Endocrinol 1976;82:246–253. 423 Segerson TP, Kauer J, Wolfe HC et al. Thyroid hormone regulates TRH biosynthesis in the paraventricular nucleus of the rat hypothalamus. Science 1987;238:78–80. 424 Rondeel JMM, DeGreef WJ, Schoot PVD et al. Effect of thyroid status and paraventricular area lesions on the release of thyrotropin-releasing hormone and catecholamines into hypophysial portal blood. Endocrinology 1988;123: 523–527. 425 DeLean A, Ferland L, Drouin J et al. Modulation of pituitary thyrotrophin releasing hormone receptor levels by estrogens and thyroid hormone. Endocrinology 1977;100:1505–1510. 426 Perrone MH, Hinkle PM. Regulation of pituitary receptors for thyrotropin releasing hormone by thyroid hormones. J Biol Chem 1978;253:5168– 5173. 427 Mori M, Yamada M. Thyroid hormones regulate the amount of thyrotrophinreleasing hormone in the hypothalamic median eminence of the rat. J Endocrinol 1987;114:443–448. 428 Snyder PJ, Jacobs LS, Utiger RD, Daughaday WH. Thyroid hormone inhibition of the prolactin response to thyrotropin-releasing hormone. J Clin Invest 1973;52:2324–2329. 429 Hermite ML, Robyn C, Golstein J et al. Prolactin and thyrotropin in thyroid diseases: lack of evidence for a physiological role of thyrotropin-releasing hormone in the regulation of prolactin secretion. Horm Metab Res 1974;6:1 90–195. 430 Yamaji T. Modulation of prolactin release by altered levels of thyroid hormones. Metabolism 1974;23:745–751. 431 Lechan RM, Wu P, Jackson IMD et al. Thyrotropin-releasing hormone precursor: Characterization in rat brain. Science 1986;231:159–161.

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in the control of growth hormone and prolactin release. Neuroendocrinology 1990;51:688–693. Sortino MA, Cronin MJ, Wise PM. Relaxin stimulates prolactin secretion from anterior pituitary cells. Endocrinology 1989;124:2013–2015. Camoratto AM, Grandison L. Platelet-activating factor stimulates prolactin release from dispersed rat anterior pituitary cells in vitro. Endocrinology 1989;124:1502–1506. Spangelo BL, Judd AM, Ross PC et al. Thymosin fraction 5 stimulates prolactin and growth hormone release from anterior pituitary cells in vitro. Endocrinology 1987;121:2035–2043. Waldhauser F, Lieberman HR, Lynch HJ et al. A pharmacological dose of melatonin increases PRL levels in males without altering those of GH, LH, FSH, TSH, testosterone or cortisol. Neuroendocrinology 1987;46:125–130. Khorram O, Mizunuma H, McCann SM. Effect of a-melanocyte-stimulating hormone on basal and stimulated release of prolactin: Evidence for dopaminergic mediation. Neuroendocrinology 1982;34:433–437. Khorram O, Bedran de Castro JC, McCann SM. Physiological role of amelanocyte-stimulating hormone in modulating the secretion of prolactin and luteinizing hormone in the female rat. Proc Natl Acad Sci USA 1984;81: 8004–8008. Larson GH, Koos RD, Sortino MA, Wise PM. Acute effect of basic fibroblast growth factor on secretion of prolactin as assessed by the reverse hemolytic plaque assay. Endocrinology 1990;126:927–932. Anderson ST, Curlewis JD. PACAP stimulates dopamine neuronal activity in the medial basal hypothalamus and inhibits prolactin. Brain Res 1998;790: 343–346. Knigge UP. Histaminergic regulation of prolactin secretion. Danish Med Bulletin 1990;37:109–124. Arakelian MC, Libertun C. H1 and H2 histamine receptor participation in the brain control of prolactin secretion in lactating rats. Endocrinology 1977; 100:890–895. Gibbs DM, Plotsky PM, De Greef WJ, Neill JD. Effect of histamine and acetylcholine on hypophysial stalk plasma dopamine and peripheral plasma prolactin levels. Life Sci 1979;24:2063–2070. Knigge U, Matzen S, Warberg J. Histaminergic stimulation of prolactin secretion mediated via H1- or H2-receptors: Dependence on routes of administration. Neuroendocrinology 1986;44:41–48. Knigge U, Dejgaard A, Wollesen F et al. Histamine regulation of prolactin secretion through H1- and H2-receptors. J Clin Endocrinol Metab 1982;55: 118–122. Carlson HE, Ippoliti AF. Cimetidine, an H2-antihistamine, stimulates prolactin secretion in man. J Clin Endocrinol Metab 1977;45:367–370. Pontiroli AE, Pellicciotta G, Alberetto M et al. Cimetidine and L-dopa in the control of prolactin secretion in man. Horm Metab Res 1979;11:257– 258. Sharpe PC, Melvin MA, Mills JG et al. Prolactin responses to histamine H2 receptor antagonists. Acta Endocrinol 1980;95:308–313. Masala A, Alagna S, Faedda R, Satta A, Rovasio PP. Prolactin secretion in man following acute and long-term cimetidine administration. Acta Endocrinol 1980;93:392–395. Samarthji L et al. Effect of clonidine on growth hormone, prolactin, luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone in the serum of normal men. J Clin Endocrinol Metab 1975;41: 827–832. Terry C, Martin JB. Evidence of a-adrenergic regulation of episodic growth hormone and prolactin secretion in the undisturbed male rat. Endocrinology 1981;108:1869–1873. Lien EL, Morrison A, Kassarich J, Sullivan D. Alpha-2-adrenergic control of prolactin release. Neuroendocrinology 1986;44:184–189. Gold MS, Donabedian RK, Redmond DE Jr. Further evidence for alpha-2 adrenergic receptor mediated inhibition of prolactin secretion: The effect of yohimbine. Psychoneuroendocrinology 1979;3:253–260. Steiner J, Cassar J, Mashiter K et al. Effect of methyldopa on prolactin and growth hormone. Brit Med J 1976;1:1186–1188. Slater SL, Lipper S, Shiling DJ, Murphy DL. Elevation of plasma-prolactin by monoamine-oxidase inhibitors. Lancet 1977;2:275–276. Schlegel W, Wuarin F, Zbaren C, Zahnd GR. Lowering of cytosolic free CA2+ by carbachol, a muscarinic cholinergic agonist, in clonal pituitary cells (GH3 cells). Endocrinology 1985;117:976–981. Beach JE, Smallridge RC, Chiang PK, Fein HG. Reversal of inhibition of prolactin secretion in cultured pituitary cells by muscarinic antagonists. J Pharm Exper Ther 1988;246:548–552. Casanueva FF, Villanueva L, Diaz Y et al. Atropine selectively blocks GHRHinduced GH secretion without altering LH, FSH, TSH, PRL and

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ACTH/cortisol secretion elicited by their specific hypothalamic releasing factors. Clin Endocrinol 1986;25:319–323. Masala A, Alagna S, Devilla L et al. Muscarinic receptor blockade by pirenzepine: Effect on prolactin secretion in man. J Endocrinol Invest 1982;5:53–55. Mendelson WB, Sitaram N, Wyatt RJ, Gillin JC. Methscopolamine inhibition of sleep-related growth hormone secretion: Evidence for a cholinergic secretory mechanism. J Clin Invest 1978;61:1683–1690. Carmeliet P, Denef C. Immunocytochemical and pharmacological evidence for an intrinsic cholinomimetic system modulating prolactin and growth hormone release in rat pituitary. Endocrinology 1988;123:1128–1139. MacLeod RM, Smith MC, DeWitt GW. Hormonal properties of transplanted pituitary tumors and their relation to the pituitary gland. Endocrinology 1966;79:1149–1156. Chen CL, Minaguchi H, Meites J. Effects of transplanted pituitary tumors on host pituitary prolactin secretion. Proc Soc Exptl Biol Med 1967;126:317–320. Clemens JA, Meites J. Inhibition by hypothalamic prolactin implants of prolactin secretion, mammary growth and luteal function. Endocrinology 1968;82:878–881. Annunziato L, Moore KE. Prolactin in CSF selectively increases dopamine turnover in the median eminence. Life Sci 1978;22:2037–2042. Perkins NA, Westfall TC, Paul CV et al. Effect of prolactin on dopamine synthesis in medial basal hypothalamus: evidence for a short loop feedback. Brain Res 1979;160:431–444. Morgan WW, Herbert DC. Early responses of the dopaminergic tuberoinfundibular neurons to anterior pituitary homografts. Neuroendocrinology 1980;31:215–221. Selmanoff M. The lateral medial median eminence: distribution of dopamine, norepinephrine, and luteinizing hormone-releasing hormone and the effect of prolactin on catecholamine turnover. Endocrinology 1981;108:1716–1722. Bybee DE, Nakawatase C, Szabo M, Frohman LA. Inhibitory feedback effects of prolactin on its secretion involve central nervous system dopaminergic mediation. Neuroendocrinology 1983;36:27–32. Horseman ND, Zhao W, Montecino-Rodriguez E et al. Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J 1997;16:6926–6935. Shipman SL, Scheiber MD, Horseman ND. Pituitary hyperplasia in mice carrying a targeted disruption of the prolactin gene results from disordered dopaminergic control of lactotrophs. Program of the Meeting Endocrine Society, 1999, San Diego. (Abstract P2–491). Phelps CJ, Horseman ND. Hypophysiotropic dopaminergic neurons in prolactin-knockout mice. Program of the Meeting Endocrine Society, 1999, San Diego. (Abstract P2–492). Judd SJ. Autoregulation of prolactin secretion. Prog Reprod Biol 1980;6:87–91. Quigley ME, Yen SSC. Evidence for increased dopaminergic inhibition of secretion of thyroid-stimulating hormone in hyperprolactinemic patients with pituitary microadenoma. Am J Obstet Gynecol 1980;137:653–655. Scanlon MF, Rodriquez-Arnao MD, McGregor AM et al. Altered dopaminergic regulation of thyrotrophin release in patients with prolactinomas: comparison with other tests of hypothalamic-pituitary function. Clin Endocrinol 1981;14:133–143. Massara F, Camanni F, Martra M, Dolfin GC, Muller EE, Molinatti GM. Reciprocal pattern of the TSH and PRL responses to dopamine receptor blockade in women with physiological or pathological hyperprolactinemia. Clin Endocrinol 1983;18:103–110. Rodriguez-Arnao MD, Peters JR, Foord S et al. Exaggerated circadian variation in basal thyrotropin (TSH) and in the dopaminergic inhibition of TSH release in pathological hyperprolactinemia: evidence against a hypothalamic defect. J Clin Endocrinol Metab 1983;57:975–980. Holdaway IM, Evans MC, Sheehan A, Ibbertson HK. Low thyroxine levels in some hyperprolactinemic patients due to dopaminergic suppression of thyrotropin. J Clin Endocrinol Metab 1984;59:608–613. Ghigo E, Goffi S, Molinatti GM et al. Prolactin and TSH responses to both domperidone and TRH in normal and hyperprolactinaemic women after dopamine synthesis blockade. Clin Endocrinol 1985;23:155–160. Dieguez C, Peters JR, Page MD et al. Thyroid function in patients with hyperprolactinemia: relationship to dopaminergic inhibition of TSH release. Clin Endocrinol 1986;25:435–440. Winters SJ, Troen P. Altered pulsatile secretion of luteinizing hormone in hypogonadal men with hyperprolactinemia. Clin Endocrinol 1984;21:257–263. Sauder SE, Frager M, Case GD et al. Abnormal patterns of pulsatile luteinizing hormone secretion in women with hyperprolactinemia and amenorrhea: responses to bromocriptine. J Clin Endocrinol Metab 1984;59:941–948. Koizumi K, Aono T, Koike K, Kurachi K. Restoration of LH pulsatility in

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patients with prolactinomas after transsphenoidal surgery. Acta Endocrinol 1984;107:433–438. Wiebe RH, Handwerger S, Soules M. Episodic luteinizing hormone release in hyperprolactinemic women. Fertil Steril 1986;45:483–488. Molitch ME, Rebar RW, Barsano CP. Effect of human prolactin administration on gonadotropin and thyrotropin secretion in normal men. J Endocrinol Invest 1993;16:554–563. Sarkar DK. Evidence for prolactin feedback actions on hypothalamic oxytocin, vasoactive intestinal peptide and dopamine secretion. Neuroendocrinology 1989;49:520–524. Nicoll CS. Ontogeny and evolution of prolactin’s functions. Fed Proc 1980; 39:2563–2566. Whitworth NS. Lactation in humans. Psychoneuroendocrinology 1988;13: 171–188. Arden KC, Boutin J-M, Djiane J et al. The receptors for prolactin and growth hormone are localized in the same region of human chromosome 5. Cytogenet Cell Genet 1990;53:161–165. Hu Z-Z, Zhuang L, Meng J et al. The human prolactin receptor gene structure and alternative promoter utilization: the generic promoter hPIII and a novel human promoter hPn. J Clin Endocrinol Metab 1999;84:1153–1156. Boutin J-M, Edery M, Shirota M et al. Identification of a cDNA encoding a long form of prolactin receptor in human hepatoma and breast cancer cells. Mol Endocrinol 1989;3:1455–1461. Jolicoeur C, Boutin JM, Okamura H. Multiple regulators of prolactin receptor gene expression in rat liver. Mol Endocrinol 1989;3:895–900. Dunaif AE, Zimmerman EA, Friesen HG, Frantz AG. Intracellular localization of prolactin receptor and prolactin in the rat ovary by immunocytochemistry. Endocrinology 1982;110:1465–1472. Martin RH, Glass MR, Chapman C et al. Human a-lactalbumin and hormonal factors in pregnancy and lactation. Clin Endocrinol 1980;13:223– 230. Weinstein D, Ben-David M, Polishuk WZ. Serum prolactin and the suppression of lactation. Brit J of Obstet and Gynecol 1976;83:679–682. Ormandy CJ, Camus A, Barra J et al. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev 1997;11:167–178. Thiede MA. The mRNA encoding a parathyroid hormone-like peptide is produced in mammary tissue in response to elevations in serum prolactin. Mol Endocrinol 1989;3:1443–1447. Khosla S, Johansen KL, Ory SJ et al. Parathyroid hormone-related peptide in lactation and in umbilical cord blood. Mayo Clin Proc 1990;65:1408–1414. Friedman S, Goldfien A. Breast secretions in normal women. Am J Obstet and Gynecol 1969;104:846–849. Lavric MV. Breast secretion in nulligravid women. Am J Obstet Gynecol 1972;112:1139–1140. Jones JR, Gentile GP. Incidence of galactorrhea in ovulatory and anovulatory females. Am J Obstet Gynecol 1975;45:13–14. Buckman MT, Peake GT. Incidence of galactorrhea. JAMA 1976;236:2747. Biller BJ, Boyd AE III, Molitch ME et al. Galactorrhea syndromes. In: Post KD, Jackson IMD, Reichlin S, eds. The Pituitary Adenoma, New York: Plenum Medical Book Co., 1980:65–90. Molitch ME, Reichlin S. Hyperprolactinemic disorders. Disease-a-Month 1982;28(9):1–58. Clément-Lacroix P, Ormandy C, Lepescheux L et al. Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice. Endocrinology 1999;140:96–105. Steger RW, Chandrashekar V, Zhao W et al. Neuroendocrine and reproductive functions in male mice with targeted disruption of the prolactin gene. Endocrinology 1998;139:3691–3695. Kauppila A, Reinilä M, Martikainen H et al. Hypoprolactinemia and ovarian function. Fertil Steril 1988;49:437–441. Odell WD. Prolactin producing tumors (prolactinomas). In: Odell WD, Nelson D, eds. Pituitary Tumors. Mt. Kisco: Futura Publishing Co., Inc., 1984:159. Malarkey WB. Effects of hyperprolactinemia on other endocrine systems. In: Olefsky JM, Robbins RJ, eds. Prolactinomas. New York: Churchill Livingstone, 1986:21. Klibanski A, Beitins IZ, Merriam GR et al. Gonadotropin and prolactin pulsations in hyperprolactinemic women before and during bromocriptine therapy. J Clin Endocrinol Metab 1984;58:1141–1147. Ambrosi B, Giovine C, Nava C et al. Serum gonadotrophin pulsatile secretion in men with PRL-secreting and non-secreting pituitary tumours. Acta Endocrinol 1985;109:1–6. Fox SR, Hoefer MT, Bartke A, Smith MS. Suppression of pulsatile LH secretion, pituitary GnRH receptor content and pituitary responsiveness to

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GnRH by hyperprolactinemia in the male rat. Neuroendocrinology 1987;46: 350–359. Winters SJ, Loriaux DL. Suppression of plasma luteinizing hormone by prolactin in the male rat. Endocrinology 1978;102:864–868. Login IS, Krieg RJ, Kaiser DL et al. Unremitting suppression of the postovariectomy rise in plasma 1H by tumor-induced hyperprolactinemia. Neuroendocrinology 1982;35:327–332. Brar AK, McNeilly AS, Fink G. Effects of hyperprolactinaemia and testosterone on the release of LH-releasing hormone and the gonadotrophins in intact and castrated rats. J Endocrinol 1985;104:35–43. Soccia B, Schneider AB, Marut EL, Scommegna A. Pathological hyperprolactinemia suppresses hot flashes in menopausal women. J Clin Endocrinol Metab 1988;66:868–870. Sarkar DK, Yen SSC. Hyperprolactinemia decreases the luteinizing hormonereleasing hormone concentration in pituitary portal plasma: a possible role for b-endorphin as a mediator. Endocrinology 1985;116:2080–2084. Cheung CY. Prolactin suppresses luteinizing hormone secretion and pituitary responsiveness to luteinizing hormone-releasing hormone by a direct action at the anterior pituitary. Endocrinology 1983;113:632–638. Bohnet HG, Dahlen HG, Wuttke W, Schneider HPG. Hyperprolactinemia anovulatory syndrome. J Clin Endocrinol Metab 1975;42:132–137. Campenhout JV, Papas S, Blanchet P et al. Pituitary responses to synthetic luteinizing hormone-releasing hormone in thirty-four cases of amenorrhea or oligomenorrhea associated with galactorrhea. Am J Obstet Gynecol 1977;127: 723–728. Klibanski A, Beitins IZ, Zervas NT et al. a-subunit and gonadotropin responses to luteinizing hormone-releasing hormone in hyperprolactinemic women before and after bromocriptine. J Clin Endocrinol Metab 1983;56: 774–780. Marchetti B, Labrie F. Prolactin inhibits pituitary luteinizing hormonereleasing hormone receptors in the rat. Endocrinology 1982;111:1209–1216. Garcia A, Herbon L, Barkan A et al. Hyperprolactinemia inhibits gonadotropin-releasing hormone GnRH stimulation of the number of pituitary GnRH receptors. Endocrinology 1985;117:954–959. Duncan JA, Barkan A, Herbon L, Marshall JC. Regulation of pituitary gonadotropin-releasing hormone (GnRH) receptors by pulsatile GnRH in female rats: effects of estradiol and prolactin. Endocrinology 1986;118:320–327. Glass MR, Shaw RW, Butt WR et al. An abnormality of oestrogen feedback in amenorrhoea–galactorrhoea. British Medical J 1975;3:274–275. McNeilly AS, Glasier A, Jonassen J, Howie PW. Evidence for direct inhibition of ovarian function by prolactin. J Reprod Fert 1982;65:559–569. McNatty KP, Sawers RS, McNeilly AS. A possible role for prolactin in control of steroid secretion by the human Graafian follicle. Nature 1974;250:653–655. Feltus FA, Groner B, Melner MH. Stat5-mediated regulation of the human type II 3beta-hydroxysteroid dehydrogenase/delta5–delta4 isomerase gene: activation by prolactin. Mol Endocrinol 1999;13:1084–1093. Del Pozo E, Wyss H, Tolis G et al. Prolactin and deficient luteal function. Obstet Gynecol 1979;53:282–286. Schulz KD, Geiger W, Del Pozo E, Künzig HJ. Pattern of sexual steroids, prolactin, and gonadotropic hormones during prolactin inhibition in normally cycling women. Am J Obstet Gynecol 1978;132:561–566. Mühlenstedt D, Bohnet HG, Hanker JP, Schneider HPG. Short luteal phase and prolactin. Int J Fertil 1978;23:213–218. Bahamondes L, Saboya W, Tambascia M, Trevisan M. Galactorrhea, infertility, and short luteal phases in hyperprolactinemic women: early state of amenorrhea-galactorrhea? Fertil Steril 1979;32:476–477. McNatty KP. Relationship between plasma prolactin and the endocrine microenvironment of the developing human antral follicle. Fertil Steril 1979;32:433–438. Demura R, Ono M, Demura H et al. Prolactin directly inhibits basal as well as gonadotropin-stimulated secretion of progesterone and 17b-estradiol in the human ovary. J Clin Endocrinol Metab 1982;54:1246–1250. Veldhuis JD, Hammond JM. Oestrogens regulate divergent effects of prolactin in the ovary. Nature 1980;284:262–264. Dorrington JH, Gore-Langton RE. Antigonadal action of prolactin: Further studies on the mechanism of inhibition of follicle-stimulating hormoneinduced aromatase activity in rat granulosa cell cultures. Endocrinology 1982;110:1701–1707. Krasnow JS, Hickey GJ, Richards JS. Regulation of aromatase mRNA and estradiol biosynthesis in rat ovarian granulosa and luteal cells by prolactin. Mol Endocrinol 1990;4:13–21. Magoffin DA, Erickson GF. Prolactin inhibition of luteinizing hormonestimulated androgen synthesis in ovarian interstitial cells cultured in defined medium: Mechanism of action. Endocrinology 1982;111:2001–2007.

722 Fraser IS, Markham R, Shearman RP. Plasma prolactin levels and ovarian responsiveness to exogenous gonadotropins. Obstet Gynecol 1978;51:548–551. 723 McGarrigle HHG, Sarris S, Little V et al. Induction of ovulation with clomiphene and human chorionic gonadotrophin in women with hyperprolactinaemic amenorrhoea. Brit J Obstet Gynecol 1978;85:692–697. 724 Duignant NM. Polycystic ovarian disease. Brit J Obstet Gynaecol 1976;83: 593–602. 725 Futterweit W, Krieger DT. Pituitary tumors associated with hyperprolactinemia and polycystic ovarian disease. Fertil Steril 1979;31:608–613. 726 Del Pozo E, Falaschi P. Prolactin and cyclicity in polycystic ovary syndrome. Prog Reprod Biol 1980;6:252–259. 727 Buvat J, Mourot CS, Fourlinnie JC et al. Androgens and prolactin levels in hirsute women with either polycystic ovaries or “borderline ovaries”. Fertil Steril 1982;38:695–700. 728 Corenblum B, Taylor PJ. The hyperprolactinemic polycystic ovary syndrome may not be a distinct entity. Fertil Steril 1982;38:549–552. 729 Skrabanek P, McDonald D, De Valera E et al. Plasma prolactin in amenorrhoea, infertility, and other disorders: a retrospective study of 608 patients. Irish J Med Sci 1980;149:236–245. 730 Kemmann E, Jones JR. Hyperprolactinemia and primary amenorrhea. Obstet Gynecol 1979;54:692–694. 731 Mashchak CA, Kletzky OA, Davajan V, Mishell DR. Clinical and laboratory evaluation of patients with primary amenorrhea. Obstet Gynecol 1981;57: 715–721. 732 Pepperell RJ, Aust F. Prolactin and reproduction. Fertil Steril 1981;35:267–274. 733 Seppala M, Hirvonen E, Ranta T. Hyperprolactinaemia and luteal insufficiency. Lancet 1976;1:229–230. 734 Kredentser JV, Hoskins CF, Scott JZ. Hyperprolactinemia—a significant factor in female infertility. Am J Obstet Gynecol 1981;139:264–267. 735 Huang K-E, Bongiglio TA, Muschler EK. Transient hyperprolactinemia in infertile women with luteal phase deficiency. Obstet Gynecol 1991;78:651–655. 736 Fava GA, Fava M, Kellner R et al. Depression, hostility and anxiety in hyperprolactinemic amenorrhea. Psychother Psychosom 1981;36:122–128. 737 Post KD, Biller BJ, Adelman LS et al. Selective transsphenoidal adenomectomy in women with galactorrhea–amenorrhea. JAMA 1979;242:158–162. 738 Bartke A. Effects of prolactin on spermatogenesis in hypophysectomized mice. Endocrinology 1971;49:311–316. 739 Hafiez AA, Bartke A, Lloyd CW. The role of prolactin in the regulation of testis function: the synergistic effects of prolactin and luteinizing hormone on the incorporation of [1-14C] acetate into testosterone and cholesterol by testes from hypophysectomized rats in vitro. Endocrinology 1972;53:223–230. 740 Aragona C, Bohnet HG, Friesen HG. Localization of prolactin binding in prostate and testis: the role of serum prolactin concentration on the testicular LH receptor. Acta Endocrinol 1977;84:402–409. 741 Musto N, Hafiez AA, Bartke A. Prolactin increases 17b-hydroxysteroid dehydrogenase activity in the testis. Endocrinology 1972;95:1106–1108. 742 Hafriez AA, Philpott JE, Bartke A. The role of prolactin in the regulation of testicular function: the effect of prolactin and luteinizing hormone on 3bhydroxysteroid dehydrogenase activity in the testes of mice and rats. Endocrinology 1971;50:619–623. 743 Oseko F, Endo J, Nakano A et al. Effects of chronic bromocriptine-induced hypoprolactinemia on plasma testosterone responses to human chorionic gonadotropin stimulation in normal men. Fertil Steril 1991;55:355–357. 744 Sheth AR, Mugatwala PP, Shah GV, Rao SS. Occurrence of prolactin in human semen. Fertil Steril 1975;26:905–907. 745 Shah GV, Desai RB, Sheth AR. Effect of prolactin of metabolism of human spermatozoa. Fertil Steril 1976;27:1292–1294. 746 Carter JN, Tyson JE, Tolis G et al. Prolactin-secreting tumors and hypogonadism in 22 men. New Engl J Med 1978;299:847–852. 747 Nagulesparen M, Ang V, Jenkins JS. Bromocriptine treatment of males with pituitary tumours, hyperprolactinaemia, and hypogonadism. Clin Endocrinol 1978;9:73–79. 748 Franks S, Jacobs HS, Martin N, Nabarro JDN. Hyperprolactinaemia and impotence. Clin Endocrinol 1978;8:277–287. 749 Goodman RH, Molitch ME, Post KD, Jackson IMD. Prolactin-secreting adenomas in the male. In: Post KD, Jackson IMD, Reichlin S, eds. The Pituitary Adenoma. New York: Plenum Medical Book Co., 1980:91–108. 750 Ambrosi B, Gaggini M, Travaglini P et al. Hypothalamic–pituitary–testicular function in men with PRL-secreting tumors. J Endocrinol Invest 1981;4: 309–315. 751 Grisoli F, Vincentelli F, Jaquet P et al. Prolactin secreting adenoma in 22 men. Surg Neurol 1980;13:241–247. 752 Spark RF, O’Reilly G, Wills CA et al. Hyperprolactinaemia in males with and without pituitary macroadenomas. Lancet 1982;2:129–131.

Chapter 4 753 Prescott RWG, Kendall-Taylor P, Hall K et al. Hyperprolactinaemia in men— response to bromocriptine therapy. Lancet 1982;1:245–248. 754 Perryman RL, Thorner MO. The effects of hyperprolactinemia on sexual and reproductive function in men. J Androl 1981;5:233–242. 755 Dupuy M, Derome PJ, Peillon F et al. L’adenome a prolactine chez l’homme. Sem Hôp Paris 1984;60:2943–2954. 756 Heshmati HM, Turpin G, Nahoul K et al. Testicular response to human chorionic gonadotrophin in chronic hyperprolactineamia. Acta Endocrinol 1985;108:565–569. 757 Luboshitzky R, Rosen E, Trestian S, Spitz M. Hyperprolactinaemia and hypogonadism in men: Response to exogenous gonadotrophins. Clin Endocrinol 1979;11:217–223. 758 Murray FT, Cameron DF, Ketchum C. Return of gonadal function in men with prolactin-secreting pituitary tumors. J Clin Endocrinol Metab 1984;59: 79–85. 759 Molitch ME, Elton RL, Blackwell RE et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 1985;60:698–705. 760 Magrini G, Ebiner JR, Burckhardt P, Felber JP. Study on the relationship between plasma prolactin levels and androgen metabolism in man. J Clin Endocrinol Metab 1976;43:944–947. 761 Cameron DF, Murray FT, Drylie DD. Ultrastructural lesions in testes from hyperprolactinemic men. J Androl 1984;5:283–293. 762 Schwartz MF, Bauman JE, Masters WH. Hyperprolactinemia and sexual disorders in men. Biol Psych 1982;17:861–876. 763 Leonard MP, Nickel CJ, Morales A. Hyperprolactinemia and impotence: why, when and how to investigate. J Urol 1989;142:992–994. 764 Buvat J, Lemaire A. Endocrine screening in 1,022 men with erectile dysfunction: clinical significance and cost-effective strategy. J Urol 1997;158: 1764–1767. 765 Segal S, Polishuk WZ, Ben-David M. Hyperprolactinemic male infertility. Fertil Steril 1976;27:1425–1427. 766 Hargreave JB, Kyle KF, Kelly AM, England P. Prolactin and gonadotrophins in 208 men presenting with infertility. Brit J Urology 1979;49:747–750. 767 Rjosk HK, Schill WB. Serum prolactin in male infertility. Andrologia 1979;11: 297–304. 768 Hargreave TB, Richmond JD, Liakatas J et al. Searching for the infertile man with hyperprolactinemia. Fertil Steril 1981;36(5):630–632. 769 Carter JN, Tyson JE, Warne GL et al. Adrenocortical function in hyperprolactinemic women. J Clin Endocrinol Metab 1977;45:973–980. 770 Vermeulen A, Ando S. Prolactin and adrenal androgen secretion. Clin Endocrinol 1978;8:295–303. 771 Lobo RA, Kletzky OA, Kaptein EM, Goebelsmann U. Prolactin modulation of dehydroepiandrosterone sulfate secretion. Am J Obstet Gynecol 1980;138: 632–636. 772 Parker LN, Change S, Odell WD. Adrenal androgens in patients with chronic marked elevation of prolactin. Clin Endocrinol 1978;8:1–5. 773 Belisle S. Adrenal androgen production in hyperprolactinemic states. Fertil Steril 1980;33:396–400. 774 Glickman SP, Rosenfield RL, Bergenstal RM, Helke J. Multiple androgenic abnormalities, including elevated free testosterone, in hyperprolactinemic women. J Clin Endocrinol Metab 1982;55:251–257. 775 Vermeulen A, Andó, Verdonck L. Prolactinomas, testosterone-binding globulin, and androgen metabolism. J Clin Endocrinol Metab 1982;54:409–412. 776 Lobo RA, Kletzky OA. Normalization of androgen and sex hormonebinding globulin levels after treatment of hyperprolactinemia. J Clin Endocrinol Metab 1983;56:562–566. 777 Pahuja DN, DeLuca HF. Stimulation of intestinal calcium transport and bone calcium mobilization by prolactin in vitamin D-deficient rats. Science 1981;214:1038–1039. 778 Spanos E, Brown DJ, Stevenson JC, Maclntyre IM. Stimulation of 1,25dihydroxycholecalciferol production by prolactin and related peptides in intact renal cell preparations in vitro. Biochem Biophys Acta 1981;672:7–15. 779 Kumar R, Abboud CF, Riggs BL. The effect of elevated prolactin levels on plasma 1,25-dihydroxvitamin D and intestinal absorption of calcium. Mayo Clin Proc 1980;55:51–53. 780 Wark JD, Tashjian AH Jr. Vitamin D stimulates prolactin synthesis by GH4C1 cells incubated in chemically defined medium. Endocrinology 1982;111: 1755–1757. 781 Wark JD, Tashjian AH Jr. Regulation of prolactin mRNA by 1,25dihydroxyvitamin D3in GH4C1 cells. J Biol Chem 1983;258:12118–12121. 782 Tornquist K, Allardt-Lamberg C. Systemic effects of 1,25-dihydroxyvitamin D3 on the pituitary-hypothalamic axis in rats. Acta Endocrinol 1987;115:225–228. 783 Tornquist K, Tashjian AH JR. Dual actions of 1,25-dihydroxycholecalciferol

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on intracellular Ca2+ in GH4C1 cells: evidence for effects on voltage-operated Ca2+ channels and Na+/Ca2+ exchange. Endocrinology 1989;124(6):2765–2776. Klibanski A, Neer RM, Beitins IZ et al. Decreased bone density in hyperprolactinemic women. N Engl J Med 1980;303:1511–1514. Schlechte JA, Sherman B, Martin R. Bone density in amenorrheic women with and without hyperprolactinemia. J Clin Endocrinol Metab 1983;56:1120– 1123. Koppelman MCS, Kurtz DW, Morrish KA et al. Vertebral body bone mineral content in hyperprolactinemic women. J Clin Endocrinol Metab 1984;59:1050– 1053. Schlechte J, El-Khoury G, Kathol M, Walkner L. Forearm and vertebral bone mineral in treated and untreated hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1987;64:1021–1026. Klibanski A, Greenspan SL. Increase in bone mass after treatment of hyperprolactinemic amenorrhea. New Engl J Med 1986;315(9):542–546. Caraceni MP, Gorhi E, Ortolani S et al. Increased forearm bone mineral content after bromocriptine treatment in hyperprolactinemia. Calcif Tissue Int 1985;37:687–689. Ciccarelli E, Savino L, Carlevatto V et al. Vertebral bone density in nonamenorrhoeic hyperprolactinaemic women. Clin Endocrinol 1988;28:1–6. Klibanski A, Biller BMK, Rosenthal DI et al. Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 1988;67:124– 130. Greenspan SL, Neer RM, Ridgway EC, Klibanski A. Osteoporosis in men with hyperprolactinemic hypogonadism. Ann Intern Med 1986;104:777–782. Greenspan SL, Oppenheim DS, Klibanski A. Importance of gonadal steroids to bone mass in men with hyperprolactinemic hypogonadism. Ann Intern Med 1989;110:526–531. Tesone M, Filho-Oliverira RM, Charreau EH. Prolactin binding in rat Langerhans islets. J Receptor Res 1980;1:355–372. Landgraf R, Leurs-Landgraf MMC, Weissmann A et al. Prolactin: a diabetogenic hormone. Diabetologia 1977;13:99–104. Gustafson AB, Banasiak MF, Kalkhoff RK et al. Correlation of hyperprolactinemia with altered plasma insulin and glucagon: Similarity to effects of late human pregnancy. J Clin Endocrinol Metab 1980;51:242–246. Schernthaner G, Prager R, Punzengruber C, Luger A. Severe hyperprolactinaemia is associated with decreased insulin binding in vitro and insulin resistance in vivo. Diabetologia 1985;28:138–142. Scobie IN, Kesson CM, Ratcliffe JG, MacCuish AC. The effects of prolonged bromocriptine administration on PRL secretion, GH and glycaemic control in stable insulin-dependent diabetes mellitus. Clin Endocrinol 1983;18:179– 185. Loretz CA, Bern HA. Prolactin and osmoregulation in vertebrates. Neuroendocrinology 1982;35:292–304. Adler RA, Noel GL, Wartofsky L, Frantz AG. Failure of oral water loading and intravenous hypotonic saline to suppress plasma prolactin in man. J Clin Endocrinol 1975;41:383–389. Baumann G, Marynick SP, Winters SJ, Loriaux DL. The effect of osmotic stimuli on prolactin secretion and renal water excretion in normal man and in chronic hyperprolactinemia. J Clin Endocrinol Metob 1977;44:199–202. Baumann G, Loriaux L. Failure of endogenous prolactin to alter renal salt and water excretion and adrenal function in man. J Clin Endocrinol Metab 1976;43:643–649. Sowers JR, Hershman JM, Skowsky WR et al. Osmotic control of the release of prolactin and thyrotropin in euthyroid subjects and patients with pituitary tumors. Metabolism 1977;26:187–192. Nagy E, Berczi I. Immunodeficiency in hypophysectomized rats. Acta Endocrinol 1978;89:530–537. Nagy E, Berczi I, Friesen HG. Regulation of immunity in rats by lactogenic and growth hormones. Acta Endocrinol 1983;102:351–357. Bernton EW, Meltzer MS, Holaday JW. Suppression of macrophage activation and t-lymphocyte function in hypoprolactinemic mice. Science 1988;239: 401–404. Hartman DP, Holaday JW, Bernton EW. Inhibition of lymphocyte proliferation by antibodies to prolactin. FASEB 1989;3:2194–2202. Montgomery DW, Zukoski CF, Shah GN. Conconavalin A-stimulated murine splenocytes produce a factor with prolactin-like bioactivity and immunorreactivity. J Biochem and Biophy 1987;145(2):692–698. Hiestand PC, Mekler P, Nordmann R. Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosporine. Proc Natl Acad Sci USA 1986;83:2599–2603. Sabharwal P, Glaser R, Lafuse W et al. Prolactin synthesized and secreted by human peripheral blood mononuclear cells: an autocrine growth factor for lymphoproliferation. Proc Natl Acad Sci 1992;89:7713–7716.

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811 Pelligrini K, Lebrun J-J, Ali S, Kelly PA. Expression of prolactin and its receptor in human lymphoid cells. Mol Endocrinol 1992;6:1023–1031. 812 Wu H, Devi R, Malarkey WB. Expression and localization of prolactin messenger ribonucleic acid in the human immune system. Endocrinology 1996;137:349–353. 813 Matera L. Endocrine, paracrine and autocrine actions of prolactin on immune cells. Life Sci 1996;59:599–614. 814 Azad N, Agrawal L, Emanuele MA et al. Neuroimmunoendocrinology. Am J Reprod Immunol 1991;26:160–172. 815 Smith EM. Hormonal activities of cytokines. In: Blalock JE ed. Neuroimmunoendocrinology, 2nd edn. Basel: S. Karger 1992:154–169. 816 Mandrup-Poulsen T, Nerup J, Reimers JI et al. Cytokines and the endocrine system. I. The immunoendocrine network. Eur J Endocrinol 1995;133:660–671. 817 Di Carlo R, Meli R, Galdiero M et al. Prolactin protection against lethal effects of salmonella typhimurium. Life Sci 1993;53:981–989. 818 McMurray R, Keisler D, Kanuckel K et al. Prolactin influences autoimmune disease activity in the female B/W mouse. J Immunol 1991;147:3780–3787. 819 Harris RD, Kay NE, Seljeskog EL et al. Prolactin suppression of leukocyte chemotaxis in vitro. J Neurosurg 1979;50:462–465. 820 Fornari MC, Palacios MF, Diez RA, Intebi AD. Decreased chemotaxis of neutrophils in acromegaly and hyperprolactinemia. Eur J Endocrinol 1994;130:463–468. 821 Sabharwal P, Zwilling B, Glaser R, Malarkey WB. Cellular immunity in patients with acromegaly and prolactinomas. Prog Neuro Endocrin Immunology 1992;5:120–125. 822 Vidaller A, Guadarrama F, Llorente L et al. Hyperprolactinemia inhibits natural killer (NK) cell function in vivo and its bromocriptine treatment not only corrects it but makes it more efficient. J Clin Immunol 1992;12:210– 215. 823 Nagy E, Chalmers IM, Baragar FD et al. Prolactin deficiency in rheumatoid arthritis. J Rheumatol 1991;18:1662–1668. 824 Lavalle C, Loyo E, Paniagua R et al. Correlation study between prolactin and androgens in male patients with systemic lupus erythematosus. J Rheumatol 1987;14:268–272. 825 Polomeev M, Prokaeva T, Nassonova V et al. Prolactin levels in men with SLE and RA. J Rheumatol 1990;17:1569–1570. 826 Jara LJ, Gomez-Sanchez C, Silveira LH et al. Hyperprolactinemia in systemic lupus erythematosus: association with disease activity. Am J Med Sci 1992;303:222–226. 827 Pauzner R, Urowitz MB, Gladman DD, Gough JM. Prolactin in systemic lupus erythematosus. J Rheumatol 1994;21:2064–2067. 828 Neidhart M. Elevated serum prolactin or elevated Prolactin/cortisol ratio are associated with autoimmune processes in systemic lupus erythematosus and other connective tissue diseases. J Rheumatol 1996;23:476–481. 829 El-Garf A, Salah S, Shaarawy M et al. Prolactin hormone in juvenile systemic lupus erythematosus: a possible relationship to disease activity and CNS manifestations. J Rheumatol 1996;23:374–377. 830 Rovensky J, Juránková E, Rauová L et al. Relationship between endocrine, immune and clinical variables in patients with systemic lupus erythematosus. J Rheumatol 1997;24:2330–2334. 831 Mok CC, Lau CS, Lee KW, Wong RWS. Hyperprolactinemia in males with systemic lupus erythematosus. J Rheumatol 1998;25:2357–2373. 832 Funauchi M, Ikoma S, Enomoto H et al. Prolactin modulates the disease activity of systemic lupus erythematosus accompanied by prolactinoma. Clin Extpl Rheumatol 1998;16:479–482. 833 Jara LJ, Silveira LH, Cuellar ML et al. Hyper-prolactinemia in Reiter’s syndrome. J Rheumatol 1994;21:1292–1297. 834 Bravo G, Zazueta B, Lavalle C. An acute remission of Reiter’s syndrome in male patients treated with bromocriptine. J Rheumatol 1992;19:747–750. 835 Giasuddin ASM, El-Sherif AI, El-Ojali SI. Prolactin: does it have a role in the pathogenesis of psoriasis? Dermatology 1998;197:119–122. 836 Murphy WJ, Rui H, Longo DL. Effects of growth hormone and prolactin immune development and function. Life Sci 1995;57:1–14. 837 Josimovich JB, Lavenhar MA, Devanesan MM. Heterogeneous distribution of serum prolactin values in apparently healthy young women, and the effects of oral contraceptive medication. Fertil Steril 1987;47:785–791. 838 Miyai K, Ichihara K, Kondon K, Mori S. Asymptomatic hyperprolactinaemia and prolactinoma in the general population-mass screening by paired assays of serum prolactin. Clin Endocrinol 1986;25:549–554. 839 Miyake A, Ikegami M, Chen C-F. Mass screening for hyperprolactinemia and prolactinoma in men. J Endocrinol Invest 1988;11:383–384. 840 Jeffcoate SL. Diagnosis of hyperprolactinemia. Lancet 1978;2:1245–1248. 841 Kauppila A, Chatelain P, Kirkinen P. Isolated prolactin deficiency in a woman with puerperal alactogenesis. J Clin Endocrinol Metab 1987;64:309–312.

842 Shahmanesh M, Ali Z, Pourmand M et al. Pituitary function tests in Sheehan’s syndrome. Clin Endocrinol 1980;12:303–311. 843 Carlson HE, Brickman AS, Bottazzo GF. Prolactin deficiency in pseudohypoparathyroidism. N Engl J Med 1977;296:140–144. 844 De Rivera JL, Lal S, Ettigi P, Hontela S. Effect of acute and chronic neuroleptic therapy on serum prolactin levels in men and women of different age groups. Clin Endocrinology 1976;5:273–282. 845 Spitzer M, Sajjad R, Benjamin F. Pattern of development of hyperprolactinemia after initiation of haloperidol therapy. Obstet Gynecol 1998;91:693–695. 846 Kleinberg DL, Davis JM, de Coster R et al. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57–61. 847 Meltzer HY, Fang VS, Tricou BJ, Robertson A. Effect of antidepressants on neuroendocrine axis in humans. In: Costa E, Racagni G, eds. Typical and Atypical Antidepressants: Clinical Practice. New York: Raven Press, 1982:303–316. 848 Cowen PJ, Sargent PA. Changes in plasma prolactin during SSRI treatment: evidence for a delayed increase in 5-HT neurotransmission. J Psychopharmacol 1997;11:345–348. 849 Amsterdam JD, Garcia-España F, Goodman D et al. Breast enlargement during chronic antidepressant therapy. J Affect Dis 1997;46:151–156. 850 Mendelson JH, Mello NK, Teoh SK. Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones. J Clin Endocrin Metab 1989;69:1256–1260. 851 Lee PA, Kelly MR, Wallin JD. Increased prolactin levels during reserpine treatment of hypertensive patients. JAMA 1976;235:2316–2317. 852 Barbarino A, De Marinis L. Calcium antagonists and hormone release. II. Effects of verapamil on basal, gonadotropin-releasing hormone-and thyrotropin-releasing hormone-induced pituitary hormone release in normal subjects. J Clin Endocrinol Metab 1980;51:749–753. 853 Maestri E, Camellini L, Rossi G, Bordonali G. Effects of five days verapamil administration on serum GH and PRL levels. Horm Metabol Res 1985;17: 482. 854 Romeo JH, Dombrowski R, Kwak YS et al. Hyperprolactinaemia and verapamil: prevalence and potential association with hypogonadism in men. Clin Endocrinol 1996;45:571–575. 854a Hutchinson J, Murphy M, Harries R et al. Galactorrhea and hyperprolactinemia associated with protease inhibitors. Lancet 2000;356:1003–1004. 855 Miyabo S, Hisada T, Asato T et al. Growth hormone and cortisol responses to psychological stress: comparison of normal and neurotic subjects. J Clin Endocrinol Metab 1976;42:1158–1162. 856 Yen SSC, Rebar RW, Quesenberry W. Pituitary function in pseudocyesis. J Clin Endocrinol Metab 1976;43:132–136. 857 Lim VS, Kathpalia SC, Frohman LA. Hyperprolactinemia and impaired pituitary response to suppression and stimulation in chronic renal failure: reversal after transplantation. J Clin Endocrinol Metab 1979;48:101–107. 858 Gomez F, Reyes FI, Faiman C. Nonpuerperal galactorrhea and hyperprolactinemia. Am J Med 1977;62:648–660. 859 Hou SH, Grossman S, Molitch ME. Hyperprolactinemia in patients with renal insufficiency and chronic renal failure requiring hemodialysis or chronic ambulatory peritoneal dialysis. Am J Kidney Dis 1985;6:245–249. 860 Morgan MY, Jakobovits AW, Gore MB et al. Serum prolactin in liver disease and its relationship to gynecomastia. Gut 1978;19:170–174. 861 Van Thiel DH, McClain CJ, Elson MK et al. Evidence for autonomous secretion of prolactin in some alcoholic men with cirrhosis and gynecomastia. Metabolism 1978;27:1778–1784. 862 Majumdar SK. Serum prolactin in chronic alcoholics. The Practitioner 1979;222:693–695. 863 Nunziata V, Ceparano G, Mazzacca G, Budillon G. Prolactin secretion in nonalcoholic liver cirrhosis. Digestion 1978;18:157–161. 864 Panerai AE, Salerno F, Manneschi M et al. Growth hormone and prolactin responses to thyrotropin-releasing hormone in patients with severe liver disease. J Clin Endocrinol Metab 1977;45:134–140. 865 Corenblum B, Shaffer EA. Hyperprolactinemia in hepatic encephalopathy may result from impaired central dopaminergic neurotransmission. Horm Metab Res 1989;21:675–677. 866 Välimäki M, Pelkonen R, Härkonen M, Tuomala P. Pituitary-gonadal hormones and adrenal androgens in non-cirrhotic female alcoholics after cessation of alcohol intake. Eur J Clin Invest 1990;20:177–181. 867 Honbo KS, Herle AJV, Kellett KA. Serum prolactin levels in untreated primary hypothyroidism. Am J Med 1978;64:782–787. 868 Smallridge RC. Thyrotropin-secreting pituitary tumors. Endocrinol Metab Clinics N Amer 1987;16:765–792. 869 Ben-David M, Danon A, Benveniste R et al. Results of radioimmunoassays of

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871 872

873 874

875 876 877 878 879 880 881 882 883

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rat pituitary and serum prolactin after adrenalectomy and perphenazine treatment in rats. J Endocrinol 1972;50:559–606. Refetoff S, Block MB, Ehrlich EN, Friesen GH. Chiari-Frommel syndrome in a patient with primary adrenocortical insufficiency. N Engl J Med 1972; 287:1326–1328. Lever EG, McKerron CG. Auto-immune Addison’s disease associated with hyperprolactinaemia. Clin Endocrinology 1984;21:451–457. Stryker TD, Molitch ME. Reversible hyperthyrotropinemia, hyperthyroxinemia and hyperprolactinemia due to adrenal insufficiency. Am J Med 1985;79:271–276. Kelver ME, Nagamani M. Hyperprolactinemia in primary adrenocortical insufficiency. Fertil Steril 1985;44:422–425. Shibutani Y. Case report: prolactin dynamics in a patient with isolated ACTH deficiency accompanied by hyperprolactinemia. Am J Med Sci 1988;295:140– 143. Boyd AE III, Spare S, Bower B, Reichlin S. Neurogenic galactorrhea–amenorrhea. J Clin Endocrinol Metab 1978;47:1374–1377. Morley JE, Hodgkinson DH, Kalk WJ. Galactorrhea and hyperprolactinemia associated with chest wall injury. J Clin Endocrinol Metab 1977;45:931–935. Herman VS, Kalk WJ. Neurogenic prolactin release: effects of mastectomy and thoracotomy. Prog Reprod Biol 1980;6:83–86. Wang Y-H, Huang T-S, Lien I-N. Hormone changes in men with spinal cord injuries. Am J Phys Med Rehabil 1992;71:328–322. Molitch ME, Schwartz S, Mukherji B. Is prolactin secreted ectopically? Am J Med 1981;70:803–807. Hsu C-T, Yu M-H, Lee C-YG et al. Ectopic production of prolactin in uterine cervical carcinoma. Gynecol Oncol 1992;44:166–171. Stanisic TH, Donova J. Prolactin secreting renal cell carcinoma. J Urol 1986;136:85–86. Hoffman WH, Gala RR, Kovacs K, Subramanian MG. Ectopic prolactin secretion from a gonadoblastoma. Cancer 1987;60:2690–2695. Palmer PE, Bogojavlensky S, Bhan AK, Scully RE. Prolactinoma in wall of ovarian dermoid cyst with hyperprolactinemia. Obstet Gynecol 1990;75: 540–543. Kallenberg GA, Pesce CM, Norman B. Ectopic hyperprolactinemia resulting from an ovarian teratoma. JAMA 1990;263:2472–2474. Molitch ME, Reichlin S. Hypothalamic hyperprolactinemia: neuroendocrine regulation of prolactin secretion in patients with lesions of the hypothalamus and pituitary stalk. In: MacLeod RM, Thorner MO, Scapagnini U, eds. Prolactin. Basic and Clinical Correlates. Padova: Liviana Press 1985:709–719. Snyder PJ, Jacobs LS, Rabello MM, Sterling FH et al. Diagnostic value of thyrotrophin-releasing hormone in pituitary and hypothalamic diseases. Ann Intern Med 1974;81:751–757.

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887 Woolf PD, Jacobs LS, Donofrio R. Secondary hypopituitarism: Evidence for continuing regulation of hormone release. J Clin Endocrinol Metab 1974;38: 71–76. 888 Nakasu Y, Nakasu S, Handa J, Takeuchi J. Amenorrhea-galactorrhea syndrome with craniopharyngioma. Surg Neurol 1980;13:154–156. 889 Leramo OB, Booth JD, Zinman B et al. Hyperprolactinemia, hypopituitarism and chiasmal compression due to carcinoma metastatic to the pituitary. Neurosurgery 1981;8:477–480. 890 Barbieri RL, Cooper DS, Daniels GH et al. Prolactin response to thyrotropin-releasing hormone (TRH) in patients with hypothalamic–pituitary disease. Fertil Steril 1985;43:66–73. 891 Bevan JS, Burke CW, Esiri MM, Adams CBT. Misinterpretation of prolactin levels leading to management errors is patients with sellar enlargement. Am J Med 1987;82:29–32. 892 Albuquerque FC, Hinton DR, Weiss MH. Excessively high prolactin level in a patient with a nonprolactin-secreting adenoma. J Neurosurg 1998;89:1043– 1046. 893 Tindal JS, Knaggs GS. Pathways in the forebrain of the rat concerned with the release of prolactin. Brain Research 1977;119:211–221. 894 Malven PV. Prolactin release induced by electrical stimulation of the hypothalamic preoptic area in unanesthetized sheep. Neuroendocrinology 1975;18:65–71. 895 Martin TL, Kim M, Malarkey WB. The natural history of idiopathic hyperprolactinemia. J Clin Endocrinol Metab 1985;60:855–858. 896 Sluijmer AV, Lappöhn RE. Clinical history and outcome of 59 patients with idiopathic hyperprolactinemia. Fertil Steril 1992;58:72–77. 897 Pontiroli AE, Falsetti L. Development of pituitary adenoma in women with hyperprolactinaemia: clinical, endocrine, and radiological characteristics. Brit Med J 1984;288:515–518. 898 Schlechte J, Dolan K, Sherman B et al. The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 1989;68: 412–418. 899 Rjosk HK, Fahlbusch R, von Werder K. Spontaneous development of hyperprolactinaemia. Acta Endocrinol 1982;100:333–336. 900 Molitch ME, Reichlin S. Neuroendocrine studies of prolactin secretion in hyperprolactinemic states. In: Mena F, Valverde-R, C, eds. Prolactin Secretion: A Multidisciplinary Approach. New York: Academic Press, 1984:393–421. 901 Frantz AG. Endocrine diagnosis of prolactin-secreting pituitary tumors. In: Black PM, Zervas NT, Ridgway EC, Martin JB, eds. Secretory Tumors of the Pituitary Gland. New York: Raven Press, 1984:45–52. 902 Vance ML, Thorner MO. Prolactinomas. Endocrinol Metab Clinics N Amer 1987;16:731–753.

C h a p t e r

5 Thyroid-stimulating Hormone Virginia D. Sarapura Mary H. Samuels E. Chester Ridgway

TSH SUBUNIT GENES

INTRODUCTION Thyroid-stimulating hormone (TSH) is a glycoprotein produced by the thyrotrope cells of the anterior pituitary gland. TSH and two other pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the placental hormone chorionic gonadotropin (CG), consist of a heterodimer of two noncovalently linked subunits, a and b. The a-subunit is common to all four glycoproteins, whereas the b-subunit is unique to each and confers specificity of action. Each TSH subunit is encoded by a separate gene located on a different chromosome and is transcribed in a coordinated manner responsive mainly to the inhibitory effect of thyroid hormone. Production of bioactive TSH involves a process of cotranslational glycosylation and folding that enables combination between the nascent a- and b-subunits. TSH is stored in secretory granules and is released into the circulation in a regulated manner responsive mainly to the stimulatory effect of hypothalamic thyrotropin-releasing hormone (TRH). Circulating TSH binds to specific cell-surface receptors on the thyroid gland where it stimulates the production of thyroid hormones, L-thyroxine (T4) and L-triiodothyronine (T3), which act on multiple organs and tissues to modulate many metabolic processes as well as result in a feedback inhibition of TSH output. The introduction of sensitive TSH assays has allowed accurate measurement of the level of circulating TSH and has led to the recognition of abnormal production of TSH related with abnormal function of the thyroid gland reflecting in a wide spectrum of metabolic derangements.

The TSH b- and a-subunits are encoded by two separate genes located on different chromosomes. Since the first descriptions of the structures of these genes within the last decade, much information has been gained regarding the molecular events that result in the regulated production of TSH b- and a-subunit mRNAs. Most of this information has been obtained from studies performed in mouse thyrotropic tumors and rodent pituitary glands. Thyrotrope cells are believed to contain specific transcription factors that bind to the regulatory regions of the genes and interact with ubiquitous factors to initiate transcription. The identification of those specific factors is an active area of investigation. Regulation of TSH subunit gene transcription, mainly by thyroid hormone and TRH, is achieved by modulating the activity of the specific and ubiquitous factors.

Ontogeny of TSH Subunit Gene Expression TSH production is limited to the thyrotrope cells of the anterior pituitary gland. Studies performed in mice have shown that this restricted production is the result of a tightly controlled process of differentiation of pituitary cells beginning early in embryogenesis. Pluripotential cells differentiate into cells that produce specific types of pituitary hormones, including TSH, LH, FSH, adrenocorticotrophic hormone (ACTH), growth hormone (GH) and prolactin. The glycoprotein hormone a-subunit is the first pituitary hormone gene expressed [1]. This transcript is detected in the region of ectoderm that forms Rathke’s pouch, the origin of the pituitary gland, on mouse embryo day 11. The steps leading to the initiation of a-subunit expression are 172

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just beginning to be elucidated. Recent studies have shown that members of the Wnt and BMP gene families, specifically Wnt5a and BPM4, which are expressed in the adjacent neuroepithelium during the initial development of Rathke’s pouch, provide critical signals resulting in a-subunit expression throughout the developing pituitary gland [2]. In addition, the homeobox genes Rpx [3] and Ptx [4–6], as well as the LIM homeodomain factor P-LIM/Lhx3 [7–9], all of which are expressed in Rathke’s pouch before embryonic day 10, may play an activating role in the onset of a-subunit expression. The initiation of TSHb-subunit expression occurs in the rostral tip of the developing pituitary around mouse embryo day 12.5. This expression correlates temporally and spatially with thyrotrope embryonic factor (TEF), which is restricted to the pituitary at this embryonic stage, but in the mature organism it is expressed ubiquitously [10]. Expression in the rostral tip is found in the pituitary glands of both the wild type and the Snell dwarf mouse, a model of combined pituitary hormone deficiency lacking thyrotropes, lactotropes and somatotropes [11,12]. By birth, TSH b-subunit expression in the rostral tip has disappeared. However, another population of thyrotropes arises in the caudomedial region of the developing mouse anterior pituitary on embryonic day 15.5, one day after the expression of Pit-1, a pituitary-specific transcription factor, is detected in this region [13]. Pit-1 is a POU-homeodomain protein which was first described as an activator of the GH and prolactin genes [14]. Both Pit-1 and TSH b-subunit expression in the caudomedial region are present in the wild type but not in the Snell dwarf mouse, which has a mutation of the Pit-1 gene [15]. These data suggest that the second population of thyrotropes, associated with Pit-1 expression, may be the source of mature thyrotropes. Moreover, Pit-1 mutations have also been reported in humans [16–19] and are associated with a lack of thyrotropes, somatotropes and lactotropes, analogous to the Snell dwarf mouse phenotype. It has recently been shown that Pit-1 synergizes with PLIM/Lhx3, specifically the Lhx3a isoform, to activate the TSH b-subunit promoter [20]. Pit-1 expression, in turn, depends on the expression of another transcription factor, Prophet of Pit-1 (PROP-1). Mutations in this factor have been associated with many cases of combined pituitary hormone deficiency in humans, affecting not only thyrotrope, somatotrope and lactotrope but also gonadotrope expression [21] (see p. 197). Mutations in the PROP-1 gene were also found in the Ames dwarf mouse that exhibits a similar phenotype [22]. However, other factors must be involved in the initiation of thyrotrope-specific gene expression, since the presence of both Pit-1 and P-LIM/Lhx3 in somatotropes and lactotropes does not result in TSH production by these cells. Recent studies have suggested that another transcription factor, GATA-2, which has been found to synergize with Pit-1 to activate the TSH b-subunit promoter [23] (see p. 174) plays a critical role in thyrotrope differentiation [24].

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The hypothesis is that a ventral-dorsal gradient of GATA-2 occurs early in development in response to BMP-2: the intermediate cells that express both GATA-2 and Pit-1 activate the thyrotrope-specific genes, whereas the more ventral cells that express GATA-2 and not Pit-1 become gonadotropes, and the more dorsal cells that express Pit-1 and not GATA-2 become somatotropes and lactotropes (Fig. 5.1) [24].

TSH b-subunit Gene Structure The human TSH b-subunit gene has been isolated and its structure characterized [25–27]. This gene is 4.9 kilobase pairs (kb) in size, is located on chromosome 1 locus p22 [28,29] and is present as a single copy gene. The gene structure consists of three exons and two introns (Fig. 5.2). The first exon has 37 base pairs (bp) and contains the 5¢ untranslated region of the gene. It is separated from the second exon by a large first intron of 3.9 kb. The coding region of the gene is contained in the second (163 bp) and third (326 bp) exons, which are separated by a 0.45 kb intron, and the 3¢ untranslated region is contained in the third exon. This genomic organization is similar to that found in the mouse [30,31] and rat [32], with the exception that in the mouse TSH b-subunit gene the 5¢ untranslated region is contained in 3 exons resulting from additional splicing sites that are not present in the human TSH b-subunit gene [27,33]. Optional splicing of these exons in the mouse gene is a possible regulatory step that does not appear to be present in the human gene. In addition, the human exon 1 is 10 bp longer than that of the mouse and rat, presumably due to an insertion that displaces the TATA box, a sequence

Pit-1 GATA-2

S/L Tr T G

FIGURE 5.1. Thyrotrope cell origin during anterior pituitary development. Schematic representation of the regions of the pituitary where Pit-1 (hatched area) and GATA-2 (shaded area) transcripts are detected. Somatotropes and lactotropes (S/L) evolve from Pit-1(+)/GATA-2(-) cells, gonadotropes (G) from Pit-1(-)/GATA2(+) cells, and thyrotropes (T) from Pit-1(+)/GATA-2(+) cells [24]. The thyrotropes in the rostral tip (Tr) appear at an earlier stage in the region where TEF is expressed, but do not persist in the adult. From Dasen et al. [24].

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that is important for localizing RNA polymerase II activity, 9 bp further upstream relative to the TATA box in the mouse and rat genes.

TSH b-subunit Promoter As found in many other genes, sequences close to the transcriptional start site in the 5¢ flanking region of the TSH b-subunit gene contain elements responsible for initiating transcription and regulating the expression of the gene (Fig. 5.3). The transcriptional start site, defined by primer extension or S1 nuclease analysis, defines the start of the first exon [25–27]. A consensus TATA box is located 28 bp upstream of the transcriptional start site. In contrast to the human gene, both the mouse and the rat genes have two transcriptional start sites. The downstream transcriptional start site is homologous to that in the human gene and is responsible for most of the transcriptional activity (greater than 90%). The other transcriptional start site is located 40 bp

FIGURE 5.2. Schematic representation of the human thyroid-stimulating hormone (TSH) b-subunit gene. The bars indicate the three exons and the lines, which are not drawn to scale, represent intronic DNA. The solid areas represent the coding regions, the open areas represent the untranslated regions. The intronic DNA is removed by splicing to form mature mRNA. The numbers indicate the size in nucleotides of each exon or intron.

upstream and is also preceded by a TATA box. There is one bp difference between the rodent and human genes, that changes this upstream TATA box from TATATAA in the rodent to TGTATAA in the human, and it has been suggested that this difference may account for the lack of activity of the upstream transcriptional start site in the human gene [27]. Cell-specificity of TSH b-subunit Gene Expression

The lack of a reliable TSH-producing cell line has hindered investigation of the factors that determine thyrotropespecific expression. The tissues available for such studies have been limited to primary cultured cells from hypothyroid rodent pituitary glands and mouse thyrotropic tumors. Recently, the TaT-1 cell line was derived from a pituitary tumor produced by targeting T antigen expression in a transgenic mouse using the a-subunit promoter [34]. This cell line has been shown to express the TSH b-subunit and some of the other thyrotrope-specific genes, albeit at low levels [35]. More studies are needed to characterize this cell line. Using mouse thyrotropic tumors, studies have demonstrated that mouse TSH b-subunit gene region from -271 to -80 relative to the major transcriptional start site is sufficient to confer thyrotrope-specific activity [36] and that protein factors from thyrotropic tumors are able to bind to sequences within this region [37]. The pituitary transcription factor Pit-1 has been identified as one of the factors that binds to the human TSH bsubunit promoter between -128 and -58 [38] (Fig. 5.3). Pit-1 has also been found to bind to the mouse [39] and rat [40] TSH b-subunit promoters in regions important for activation. Haugen et al. had demonstrated that a thyrotrope-specific form of Pit-1, Pit-1T, is a strong transactivator of the mouse TSH b-subunit promoter [41,42], although Pit-1T is present in relatively small amounts and a human equivalent of Pit-1T has not been found. Recently, studies have shown that the transcription factor GATA-2 synergizes with Pit-1, resulting in a strong transactivation of the mouse TSH b-subunit promoter [23,43]. This synergy is mediated by partially overlapping sites located between -133 and -88.

FIGURE 5.3. Schematic representation of the human thyroid-stimulating hormone (TSH) b-subunit promoter. The transcriptional start site is indicated by the arrow and the TATA box is shown. The numbers above the line denote the position of the nucleotides relative to the transcriptional start site set at +1. The boxes under the line indicate the regions important for the responses to T3 (white boxes), Pit-1 (black boxes), thyrotropin-releasing hormone (TRH) (dotted boxes) and GATA-2 (crosshatched box). The GATA-2 binding sites have only been described in the mouse TSH b-subunit gene.

Chapter 5 Regulation of TSH b-subunit Gene Expression

Thyroid Hormone T3 inhibits TSH production primarily by its action at the transcriptional level (p. 178). T3 response elements (Fig. 5.3) are located between +3 and +37, in the first exon of the human TSH b-subunit gene [44]. There are two T3 receptor (TR) binding sites within this region, one from +3 to +13 and another from +28 to +37. Both sites are necessary for T3 inhibition of the human TSH bsubunit gene. The upstream site has a higher affinity for TR and is capable of binding TR dimers, whereas the downstream site binds only monomers with lower affinity. T3 response elements in the mouse [36] and rat [45,46] TSH b-subunit genes are also located near the transcriptional start site. The proximity of these response elements to the transcriptional start site suggests that T3 inhibition may be due to an interference with the activity of the transcriptional initiation complex. Bodenner et al. described the modulation of T3 inhibition by AP1, the dimerization product of the proto-oncogenes c-fos and c-jun [47]. These proto-oncogenes appear to interact with the sequence from -1 to +6 (TGGGTCA) that is homologous to the AP1 consensus binding site (TGAGTCA) (Fig. 5.4). Hypothalamic Factors TRH stimulates TSH production at various levels of synthesis and secretion, with a significant effect on the transcription of both TSH b- and a-subunits (see p. 179). Two TRH-response regions are located from -128 to -61 and from -28 to +8 of the human TSH bsubunit gene promoter [48] (Fig. 5.3). The upstream region contains binding sites for the pituitary-specific transcription factor Pit-1, suggesting a role for this or a similar factor in the regulation of the TSH b-subunit gene by TRH. In the rat TSH b-subunit gene, responsiveness to TRH has been localized to regions upstream of -204, where Pit-1 binding sites are also found [49,50]. Dopamine inhibits TSH b- and a-subunit gene transcription by decreasing the intracellular levels of cAMP, which acts as a stimulator (see p. 179). Studies of the TSH b-subunit gene have localized two regions of the promoter necessary for cAMP stimulation, from -128 to -61 bp and

FIGURE 5.4. Sequence comparison of the thyroidstimulating hormone (TSH) b-subunit region from -1 to +6 and consensus binding elements for thyroid hormone (T3), cAMP, phorbol esters (PhEst) and the c-jun/c-fos heterodimer (AP1). Spaces were introduced to maximize homology.

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from +3 to +8 bp [51]. The upstream region coincides with the TRH-responsive region and contains Pit-1 binding sites. The downstream region resides within the regions responsive to T3 (+3 to +37) and TRH (-28 to +8). The downstream region also overlaps with an AP1 binding site (-1 to +6). The sequence from -1 to +6 appears to cooperate with Pit-1 in mediating responses to cAMP and TRH [52]. Thus, multiple interactions between transcription factors and hormonal regulators appear to converge on the sequence from -1 to +6 (TGGGTCA), which is critically located close to the transcriptional start site, is similar to T3, cAMP, phorbol ester and AP1 response elements (Fig. 5.4), and is functionally important for the response to each of these regulators. Steroid Hormones Glucocorticoids inhibit TSH production but TSH subunit messenger RNA (mRNA) levels do not change significantly [53]. Their major effect may be at the secretory level (see p. 187). Testosterone has been shown to increase TSH b-subunit mRNA in castrate rat pituitary and mouse thyrotropic tumor [54]. Elements of the TSH b-subunit that respond to steroid hormones have not yet been described.

a-subunit Gene Structure The human glycoprotein hormone a-subunit gene is located on chromosome 6 [55] and is present as a single copy gene that is 13.5 kb in size and contains four exons and three introns [56] (Fig. 5.5). The first exon (94 bp) contains 5¢ untranslated sequences and is separated from the

FIGURE 5.5. Schematic representation of the human glycoprotein hormone a-subunit gene. The bars indicate the four exons and the lines, which are not drawn to scale, represent intronic DNA. The solid areas represent the coding regions, the open areas represent the untranslated regions. The intronic DNA is removed by splicing to form mature mRNA. The numbers indicate the size in nucleotides of each exon or intron.

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second exon by a 6.4 kilobase (kb) intron. The second exon contains 7 bp of 5¢ untranslated sequence and 88 bp of the coding region. The coding sequence continues in the third (185 bp) and fourth (75 bp) exons and the 3¢ untranslated region (220 bp) is contained in the fourth exon. The second and third introns are 1.7 kb and 0.4 kb, respectively. The genomic organization of the mouse [57], rat [58] and cow [59] a-subunit genes are similar, except that in the rat and cow the second intron is located 12 bp downstream, resulting in a peptide sequence that is 4 amino acids longer. There are also differences in the length of the 5¢ untranslated sequence, which is 10 bp longer in the mouse, apparently due to a 10 bp insertion between the TATA box and the transcriptional start site.

a-subunit Promoter The elements responsible for initiating transcription and regulating the expression are located in the 5¢ flanking region of the human a-subunit gene (Fig. 5.6). The human a-subunit gene contains a concensus TATA box located 26 bp upstream of the transcriptional start site [56]. A single transcriptional start site has been found in the glycoprotein hormone a-subunit genes of all the species that have been studied. Cell-specificity of a-subunit Gene Expression

The glycoprotein hormone a subunit gene is unique in that it is expressed in thyrotropes, gonadotropes and placental cells, and in each of these cell types it is differentially regulated. Studies from several laboratories using the human and mouse genes have demonstrated that the cell-specific expression in each cell type is dependent on vastly different regions of the promoter (Fig. 5.6). Whereas the region downstream of -200 is sufficient for placental expression [60–62], gonadotropes require sequences between -225 and -200 [63], and regions further upstream appear to be critical for thyrotrope expression [51,64–67]. The elements involved in human placental a-subunit expression extend from -177 to -84 and include the upstream regulatory element (URE) also called trophoblast-specific element (TSE) that binds the placental-specific protein TSEB

[60,62], two cAMP response elements (CREs) [60,61,68] that bind the ubiquitous protein CREB [69], the junctional regulatory element ( JRE) that binds a 50-kDa protein [70], the CCAAT-box that binds a 53-kDa a-subunit binding factor (a CBF) [71] and a GATA motif that interacts with GATA-binding proteins [72]. Some of these regions binding to similar factors may also play a role in pituitary a-subunit expression. A region from -225 to -200 that binds the orphan nuclear receptor SF-1 appears to be critical for gonadotrope expression of the a-subunit gene [63,73], but this region has no effect on thyrotrope expression [74]. Basic-helix-loop-helix E-box-binding proteins [75] and GATA-binding proteins [72] also appear to play a role in asubunit expression in gonadotropes. Transgenic mouse studies have shown that 313 bp of the bovine a-subunit 5¢ flanking DNA, which contain the SF-1-binding region, targeted expression to gonadotropes but not thyrotropes [76], suggesting that this region was sufficient for expression in gonadotropes. It was then shown that 480 bp of the mouse a-subunit 5¢ flanking DNA was able to target transgenic expression to both gonadotropes and thyrotropes [77], in agreement with in vitro transfection studies which showed that the same promoter region mediates a high level of expression in thyrotrope and gonadotrope cells [65,67]. Several sequences within the region from -480 to -300 appear to be important for mouse a-subunit expression in thryotropes but not gonadotropes [67]. Among these is the sequence from -434 to -421 that interacts with the developmental homeodomain transcription factor Msx1 [78]. This factor was found to be expressed in mature thyrotropes, but its role in a-subunit expression has not been elucidated. Another important sequence is the pituitary glycoprotein hormone basal element, or PGBE, extending from -342 to -329, that is critical for both thyrotrope and gonadotrope expression [7]. The PGBE interacts with P-LIM (also known as mLIM3 or Lhx3), a pituitary-specific LIMhomeodomain transcription factor [8], that is important not only for thyrotrope and gonadotrope cell-specification but is also important for somatotropes and lactotropes [9]. Other sequences within the 480 bp promoter have been found to interact with the pituitary-specific homeodomain factor Ptx-1 [5,67], and a synergism between Ptx-1 and P-LIM,

FIGURE 5.6. Schematic representation of the human glycoprotein hormone a-subunit promoter. The transcriptional start site is indicated by the arrow and the TATA box is shown. The numbers above the line denote the position of the nucleotides relative to the transcriptional start site set at +1. The boxes under the line indicate the regions important for the responses to T3 (TRE) and cAMP (CRE), and the placental-specific, gonadotrope-specific and thyrotrope-specific activities, as shown. The thyrotrope-specific regions other than the P-LIM binding sites have only been described in the mouse a-subunit gene.

Chapter 5

mediated by the coactivator C-LIM, has recently been described [79]. Notwithstanding the findings with the mouse a-subunit gene, other studies showed that 1.6 kb of 5¢ flanking DNA of the human a promoter expressed in gonadotropes but not in thyrotropes of transgenic mice [80], suggesting that either the mouse thyrotropic factors are unable to activate the human promoter, or else the sequences required for thyrotrope expression of the human a-subunit gene may be located further upstream than those of the mouse gene. Recent studies with the mouse promoter also showed that regions located approximately 4 kb upstream further enhanced transgenic expression in both thyrotropes and gonadotropes, by interacting with proximal sequences [74,77,81]. The active region was localized to 125 nucleotides upstream of -3700, and this same region was shown to mediate inhibition of expression in GH3 somatotropic cells [82]. In spite of significant advances in this area, thyrotrope-specific factors that determine a-subunit gene expression have not yet been described. In contrast to the TSH b-subunit gene, it has been shown that Pit-1 is not necessary for a-subunit gene expression [39]. Regulation of a-subunit Gene Expression

Thyroid Hormone T3 inhibition of a-subunit gene transcription is observed in thryotropes in coordination with that of TSH b-subunit (see p. 178). The T3 response element of the human glycoprotein hormone a-subunit gene promoter is located from -22 to -7 [83] (Fig. 5.6). Similar to the TSH b-subunit gene, the T3 response elements of the human as well as the mouse [51] and rat [58] a-subunit genes are located close to the transcriptional start site and the mechanism of inhibition is likely to involve interference with the activity of the transcriptional initiation complex. T3 inhibition may be mediated by different isoforms of the T3 receptor (TR) [84,85] in combination with the corepressors SMRT and NCoR [86]. Studies have suggested that mutations of the T3 response element of the human a-subunit promoter that eliminate TR binding do not abrogate the inhibitor effect of T3, suggesting that protein–protein interactions may be more important than protein-DNA binding [87]. Hypothalamic Factors TRH stimulates TSH production by effects at the transcriptional, posttranscriptional and secretory levels, discussed in later sections (see pp. 179 and 185). Although TRH has clearly been shown to stimulate a-subunit transcription, the TRH-responsive element of the human glycoprotein hormone a-subunit gene promoter has not yet been localized. Studies using primary cultures of rat pituitaries have shown that the human a-subunit promoter containing 846 bp of 5¢ flanking DNA responds to TRH with a 23% increase of activity [88], and that this stimulation is mediated by a region located just upstream of -200 [89]. However, this increase was not significant, at least in part due to the presence of a-subunit expressing gonadotropes in the mixed population of pituitary cells.

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Subsequent studies showed that a CRE-binding protein that binds to the region from -151 to -135 of the human asubunit promoter is important for TRH regulation, as well as a Pit-1-like protein that binds to a more distal region from -223 to -190 [90]. a-subunit gene expression in thyrotropes is inhibited by dopamine in coordination with the expression of the TSH b-subunit gene. Its action is mediated by decreases in intracellular cAMP levels. The CRE of the human glycoprotein hormone a-subunit gene promoter extends from -146 to -111 and has been well characterized by several investigators [61,68] (Fig. 5.6). The element consists of an 18 bp repeat containing a core palindrome TGACGTCA. A single bp change in this palindrome in the mouse, rat and cow genes to TGATGTCA significantly reduces cAMP responsiveness. The importance of the CRE in placental a-subunit gene expression has been established, and it is of interest in this respect that rodents and cows do not express a-subunit in the placenta. The finding that the equine a-subunit gene does express in the placenta but also lacks a competent CRE has led to the description of a GATA element located upstream of the CRE that confers both placental-specific expression and cAMP responsiveness through its interaction with a-ACT, a placental protein related to the GATAbinding factors [91]. In gonadotropes, the interaction of the CRE with the transcription factors ATF2 and c-Jun appears to be functionally important [92], as well as the GATAbinding proteins [72]. The importance of those same interactions in thyrotropes has not been established. Steroid Hormones Regulation of TSH transcription by steroid hormones is probably of limited importance. Several studies have described the steroid hormone regulation of asubunit gene transcription and have found that in general the effects are inhibitory and correlate more closely with physiologic effects seen in gonadotropes. Androgen inhibition and androgen receptor (AR) binding has been localized to a region from -120 to -100 that coincides with the JRE described above [93]. Negative regulation by estrogen was described in the gonadotropes of transgenic mice expressing the cholamphenicol acetyl-transferase gene under the control of the human (1.5 kb) and bovine (314 bp) 5¢ flanking regions, but no binding of these regions to the estrogen receptor (ER) was detected, suggesting that estrogen acts indirectly [94]. This was also suggested by transient transfection studies that failed to detect an effect of estrogen on the human a-subunit gene promoter activity in gonadotrope cells [93]. However, other studies using rat pituitary cells of somatomammotrope origin have found positive regulation by estrogen localized to the proximal 98 bp of 5¢ flanking DNA of the human a-subunit gene and binding of the ER to the T3 response element from -22 to -7 [95]. Transcriptional inhibition by glucocorticoids appears to be mediated by binding of the glucocorticoid receptor (GR) to sequences between -122 and -93 of the human a-subunit gene [96]. This region contains the JRE

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and binds to the AR, as described above. However, no direct binding was detected in other studies, suggesting that the GR inhibits transcription by interfering with other transactivating proteins [97]. BIOSYNTHESIS OF TSH The intact TSH molecule is a heterodimeric glycoprotein with a total molecular weight of 28-kDa that is composed of the noncovalently linked a- and b-subunits. TSH biosynthesis and secretion by thyrotropes of the anterior pituitary are finely regulated events. This section examines our understanding of the biosynthesis of TSH, including the processes of transcription, translation, glycosylation, folding, combination and storage. Excellent reviews on these subjects have been published [98–100].

Transcription of TSH The TSH b- and a-subunit genes are transcribed as directed by their respective promoters in the presence of both ubiquitous and specific transcription factors as described above. The transcribed RNAs undergo a process of splicing at the exon–intron junctions that leads to the production of the mature mRNAs that then exit the nucleus and are translated in the cytoplasm. Transcription of the TSH b- and a-subunit genes is coordinated under the influence of physiologic regulators, the most important of which are T3 and TRH. Thyroid Hormone Regulation

TSH b- and a-subunit gene transcription rates are markedly inhibited by T3. Studies using mouse thyrotropic tumors have demonstrated that suppression of TSH b- and asubunit mRNA transcription rates measured by nuclear run-on assays is evident by 30 minutes after treatment and is maximal by 4 hours [101] (Fig. 5.7, upper panel). This effect was seen in the presence of the protein synthesis inhibitor cycloheximide, indicating that it did not require the induction of an intermediary protein [102] (Fig. 5.7, lower panel). Other studies using mouse and rat pituitaries and mouse thyrotropic tumors have demonstrated that steadystate mRNA levels of TSH b- and a-subunit are dramatically decreased by T3 [103–106]. In the hypothyroid state, the ratio of a- to TSH b-subunit mRNA ranges from 0.35 to 1.28. In the euthyroid state, both subunits decreased, with the ratio changing from 1.1 to 1.7. In the hyperthyroid animal, inhibition by T3 was greater for the TSH b-subunit mRNA, that decreased to undetectable levels, whereas asubunit mRNA decreased to 20% to 25% of control so that the ratio of a- to TSH b-subunit mRNA increased to approximately 2–3. Some studies in humans and animals have shown that TSH paradoxically increased after T3 treatment [107–110], although other studies did not show it [104,105,111,112]. When this effect was observed, it occurred early in the treatment of a severe, prolonged

FIGURE 5.7. T3 inhibition of thyroid-stimulating hormone (TSH) subunit transcription. Upper panel, the time course of TSH b(shaded bars) and a-subunit (white bars) mRNA synthesis. Mice bearing thyrotropic tumors (2 per group) were treated for up to 5 days with daily T3 injections. Tumors were removed after the times indicated and the transcription rates were measured in isolated nuclei. From Shupnik et al. [101]. Lower panel, the effect of cycloheximide on T3 inhibition of TSH b- and a-subunit mRNA synthesis. Mouse thyrotropic tumor explants were placed in culture for up to 4 hours and treated with 5 nM T3 in the presence or absence of the protein synthesis inhibitor cycloheximide, then transcription rates were measured in isolated nuclei. The values represent the mean ± SEM of four determinations performed in duplicate. From Shupnik et al. [102].

hypothyroid state and may be due to defective synthesis in this state that is corrected by low levels of T3. The mechanism of action of T3 involves interaction with nuclear receptors that act mainly at the transcriptional level. The transcriptional response to T3 is proportional to the nuclear receptor occupancy [112], and the time course of T3 nuclear binding and transcriptional inhibition are also in agreement [102] (Fig. 5.8). It is now believed that TR are bound to the DNA response elements in the absence of ligand, and that T3 binding appears to modify the interaction between the TR and the response element as well as

Chapter 5

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FIGURE 5.8. The effect of thyroid hormone on the transcription of the thyroidstimulating hormone (TSH) b- (black circles) and a-subunit (white circles) genes. Murine thyrotropic tumor explants were incubated for up to 4 hours with 5 nmol T3 for transcription measurements or with 5 nmol [125I]T3 with or without 1,000-fold excess of unlabeled T3 for binding measurements. Transcription rates were measured in isolated nuclei. There is an inverse relationship between T3 binding and TSH b- and a-subunit mRNA synthesis. From Shupnik et al. [102].

with other transcription factors [113]. It has been shown in mouse and rat thyrotropes that there are several types of TR: TRa1, TRb1 and TRb2, as well as non-T3 binding variant a2 [114,115]. These isoforms are able to bind DNA as monomers, homodimers and heterodimers of two different TR isoforms. Recent studies demonstrated that TRb2, which is expressed predominantly in the pituitary and T3responsive TRH neurons [116], appears to be the most important for the regulation of TSH [117,118]. Moreover, TRb2 deficient mice had a phenotype consistent with pituitary resistance to thyroid hormone, with increased TSH and thyroid hormone levels, even in the presence of TRb1 and TRa1 [119,120]. However, TRb1 and TRa1 may still play a role, since they are able to form heterodimers with TRb2. Heterodimers of a TR and a TR accessory protein, such as 9-cis retinoic acid receptors (RXR), may also bind to DNA [121], constituting heterodimeric complexes that may have different affinities for specific DNA sequences and different functional actitivies. A particular RXR isoform, RXRg1, is uniquely expressed in thyrotropes and appears to mediate the inhibition by 9-cis-retinoic acid through a region extending from -200 to -149 of the mouse TSH b-subunit promoter [122]. Other proteins that interact with TR include the coactivators, such as the glucocorticoid receptor interacting protein-1 (GRIP-1) and the steroid receptor coactivator-1 (SRC-1) [123], and corepressors, such as the silencing mediator for retinoid receptors and thyroid hormone receptors (SMRT) and the nuclear receptor corepressor (NCoR) [86,124]. These coactivators and corepressors modulate the effect of many members of the steroid–thyroid hormone receptor superfamily. Their role in the regulation of the TSHb-subunit promoter by thyroid hormone remains to be elucidated.

Posttranscriptional effects of T3 have also been described. T3 decreases the half-life of TSH b-subunit mRNA and decreases the size of the poly(A) tail [125]. The shortening of the poly(A) tail is thought to cause mRNA instability. This effect of T3 was observed for TSH b- but not for a-subunit mRNA, but this may have been due to the fact that the population of gonadotropes present in the pituitary sample may have masked the effect on thyrotropic a-subunit mRNA. Leedman et al. showed that T3 increased the binding of an RNA-binding protein present in rat pituitary to the 3¢ untranslated region of the rat TSH b mRNA [126] and also induced a shortening of the poly(A) tail of the mouse TSH b mRNA from 160 to 30 nucleotides [127]. Hypothalamic Regulation

TRH A direct effect of TRH on the transcription rates of both TSH b- and a-subunit genes has been demonstrated in primary cultures of hypothyroid rat pituitary cells [128]. The maximal stimulation ranged from two- to fivefold and occurred after 30 minutes of treatment with 10-7 M TRH for both the TSH b- and a-subunit genes (Fig. 5.9). TRH acts on a cell-surface receptor [129,130]. Studies in rat pituitary somatomammotrope cells, where TRH stimulates prolactin production, have suggested that phosphatidylinositol, protein kinase C and calcium-dependent pathways may be involved [131–133] (see TSH Secretion), and as described in a previous section, TRH stimulation of the TSH b-subunit promoter may be mediated by AP1 [52] (see pp. 175 and 177). Dopamine Dopamine acts by decreasing the levels of intracellular cAMP. This effect is achieved by binding to cell-surface receptors [134] that inhibit adenylate cyclase

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Translation of TSH

FIGURE 5.9. The effect of thyrotropin-releasing hormone (TRH) on thyroid-stimulating hormone (TSH) subunit mRNA synthesis. Pituitary cells (3–5 ¥ 106 cells/60 mm plate) were treated with 100 nM TRH for up to 4 hours, then transcription rates were measured in isolated nuclei. The values represent the mean ± SEM of four determinations. From Shupnik et al. [128].

activity [135,136]. The stimulatory effect of cAMP on TSH b- and a-subunit gene transcription was demonstrated indirectly by reversal with cAMP of the 65–70% inhibition of TSH b- and a-subunit mRNA synthesis caused by dopamine [128] and directly by treatment of primary pituitary cultures with forskolin, an activator of adenylate cyclase [137]. Somatostatin (SRIH) The inhibitory effect of SRIH on TSH production occurs mainly at the secretory level (see p. 186). Studies in GH3 somatomammotrope cells have shown that SRIH inhibits the cAMP/protein kinase A pathway [138], resulting in an inhibition of transcription. However, a direct effect on TSH gene transcription has not been demonstrated. Steroid Hormone Regulation

The impact of glucocorticoids on TSH production occurs mainly at the secretory level (see p. 188) while effects on TSH subunit gene transcription have not been observed [53,139]. Androgens have been shown to increase TSH bsubunit mRNA levels in the pituitary of castrate male rats [54] and decrease these levels in intact female rats [140]. Estrogens, on the other hand, do not appear to affect TSH transcription directly, but they increase the number of pituitary nuclear receptors for T3, and augment T3 suppression of TSH subunit gene transcription [141,142]. Estrogens may also indirectly affect TSH production, by increasing the expression and stability of TRH receptors [143], but this has only been demonstrated in GH3 somatotrope cells, and has not been described in thyrotrope cells.

The next series of processes of TSH biosynthesis are summarized in Fig. 5.10 [144]. In the cytoplasm, the mRNAs for TSH b- and a-subunit are independently translated by ribosomes. The first peptide sequence produced consists of a “signal” peptide of 20 amino acids for TSH b and 24 amino acids for a [145]. This signal peptide is important for interaction of the ribosome with the rough endoplasmic reticulum and its hydrophobic nature allows insertion through the lipid bilayer of the membrane. Translation into TSH b and a presubunits continues into the lumen, where cleavage of the signal peptide occurs before translation is completed, resulting in the formation of a 118 amino acid TSH b-subunit [146] and a 92 amino acid a-subunit [56]. Cleavage of TSH b to a protein of 112 amino acids appears to be an artifact of purification. Synthesis of recombinant TSH b-subunit has resulted in two products of 112 and 118 amino acids, both of which are similarly active in vitro [147]. Mutations of the TSH b-subunit have recently been described in humans with the diagnosis of central hypothyroidism (see p. 197). In one kindred, translation of TSH is affected by a mutation that introduces a premature termination codon [148]. This results in a truncated peptide of only 11 amino acids that is biologically inactive.

Glycosylation of TSH Glycosylation of TSH is not essential for receptor binding but has a significant impact on its biological activity [149,150]. The TSH b-subunit has a single glycosylation site, the asparagine residue at position 23, whereas the a-subunit is glycosylated in two sites, the asparagine residues at positions 52 and 78 [151] (Fig. 5.11). Excess free a-subunit is glycosylated at an additional site, the threonine residue at position 39 [152]. This residue is located in a region believed to be important for combination with the TSH b-subunit. It is not known whether glycosylation at this residue is a regulated step that inhibits combination with the TSH b-subunit or it occurs in excess free a-subunits because this site is exposed. Extensive studies on the processes of TSH subunit glycosylation have been carried out. Glycosylation of the TSH b- and a-subunits begins before translation is completed (cotranslational glycosylation), while addition of the second oligosaccharide in the a-subunit occurs after translation is completed (posttranslational glycosylation). The first step in this process involves the assembly of a 14-residue oligosaccharide, (glucose)3-(mannose)9-(N-acetylglucosamine)2 on a dolichol-phosphate carrier. This oligosaccharide is then transferred to asparagine residues by the enzyme olygosaccharyl transferase that recognizes the tripeptide sequence (asparagine)-(X)-(serine or threonine) [153]. This mannoserich oligosaccharide is progressively cleaved in the rough endoplasmic reticulum and Golgi apparatus. An intermedi-

; Chapter 5

RER

Proximal golgi

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α

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α

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α

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H2N H2N

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Distal golgi

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FIGURE 5.10 . Biosynthesis of thyroid-stimulating hormone (TSH). Schematic representation of the processes of translation and glycosylation within the rough endoplasmic reticulum (RER) and golgi apparatus, divided into proximal and distal. Cleavage of the aminoterminal (H2N) signal peptide and early addition of high mannose chains (black boxes) as well as combination of a- and b-subunits occur in the RER. In the proximal golgi, oligosaccharide chains are modified (shaded boxes) and the final steps of sulfation and sialation occur in the distal golgi apparatus. From Weintraub and Gesundheit [144].

FIGURE 5.11. Oligosaccharide chains of thyroid-stimulating hormone (TSH). Schematic representation of the typical oligosaccharide chains present on the TSH heterodimer and the free a-subunit. Glycosylated asparagine (Asp) and threonine (Thr) residues are indicated. Black and white circles, half-circles and triangles represent the oligosaccharide chain residues as indicated in the key. From Weintraub and Gesundheit [144].

ate with only six residues is produced, and then other residues are added resulting in complex oligosaccharides [154]. The residues added include N-acetylglucosamine, fucose, galactose and N-acetylgalactosamine. Oligosaccharides prior to the six-residue intermediate are termed highmannose and are sensitive to endoglycosidase H, that releases the oligosaccharide from the protein, whereas the intermediate and the complex oligosaccharides are endoglycosidase H-resistant. Complex oligosaccharides usually consist of two branches (biantennary) but sometimes three or four branches are seen, as well as hybrid oligosaccharides consisting of one complex and another high-mannose branch. Sulfation and sialation occur late in the pathway, within the distal Golgi apparatus [155]. Sulfate is bound to N-acetylgalactosamine residues, and sialic acid, or its precursor N-acetylneuraminic acid, is bound to galactoside residues

[99]. Thus, the activation of the enzymes sulfotransferase and N-acetylgalactosamine transferase may be important regulatory steps that impact the ratio of sulfate to sialic acid. As demonstrated with LH, it appears that sulfation increases and sialylation decreases the bioactivity of TSH [99], since the exclusively sialylated recombinant glycoprotein produced in Chinese hamster ovary cells has been found to have attenuated activity in vitro [156,157]. Processing of complex oligosaccharides appears to occur at a slower rate for secreted glycoproteins, such as TSH, when compared to non-secreted glycoproteins. For example, after an 11-minute pulse labeling with [35S]methionine and a 30-minute chase only a few a-subunits were endoglycosidase H resistant and only 76% reached this stage after an 18-hour chase [158]. Secretion was observed after a 60-minute chase and the secreted products—TSH, free

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a-subunit but no free b-subunit—had mostly complex oligosaccharides associated to them [151]. It may be important to note that many of the studies described were carried out in thyrotropic tumor tissue obtained from hypothyroid mice, and glycosylation may differ in the euthyroid as compared to the hypothyroid state. In addition, differences between species have been noted, such as the human TSH containing more sialic acid than the bovine TSH [146].

αL3

αL1

α64-81

α11-20

Regulation of TSH Glycosylation

Glycosylation is a regulated process that is primarily modulated by TRH and thyroid hormone [159]. Primary hypothyroidism [160,161] and TRH administration [162,163] have been found to increase oligosaccharide addition that results in an increased bioactivity of TSH [164] (see p. 190). The same was noted in patients with resistance to thyroid hormone [165]. TSH glycosylation patterns were also found to differ in several pathological states, such as central hypothyroidism, TSH-producing pituitary adenomas and euthyroid sick syndrome [166,167]. Also observed were changes in the sulfation and sialylation of the oligosaccharide residues, which modulates bioactivity [155,161,168,169] (see p. 190).

α88-92

α33-38

β88-95

α52

α40-46

Folding, Combination and Storage of TSH

The recent elucidation of the crystal structure of human CG (hCG) [170] has allowed the construction of a model of human TSH (Fig. 5.12), supported by other evidence [171,172]. This model has greatly facilitated the interpretation of structure–function studies of the protein backbone. However, crystallization was only achieved with partly deglycosylated hCG, so it is likely that the conformation of the glycosylated protein may differ to some extent, although nuclear magnetic resonance studies suggest that the asubunit carbohydrate moieties project outward and may be freely mobile [173]. Nevertheless, this model predicts that the tertiary structure of each TSH subunit consists of two hairpin loops on one side of a central knot formed by three disulfide bonds and a long loop on the other side. In this tertiary structure, the glycoprotein hormones share features in common with transforming growth factor b, nerve growth factor, platelet-derived growth factor, vascular endothelial growth factor, inhibin and activin, all of which are now grouped in the family of cystine knot growth factors [174]. Folding of nascent peptides begins before translation is completed. It has been shown that proper folding is dependent on glycosylation, since the drug tunicamycin that prevents the initial oligosaccharide transfer to the asparagine residue results in a peptide that does not fold properly and is degraded intracellularly [175]. Site-directed mutagenesis of a single glycosylation site also disrupted processing and decreased TSH secretion in transfected Chinese hamster ovary cells [176]. Folding is a critical step that allows correct internal disulfide bonding that stabilizes

β96-105

βL1

β58-69

βL3

FIGURE 5.12. Human thyroid-stimulating hormone (TSH) ribbon homology model showing domains important for activity. The schematic drawing is based on a molecular homology model [171] built on the template of the human chorionic gonadotropin (hCG) model derived from crystallographic coordinates obtained from the Brookhave Data Bank [170]. The a-subunit is shown as a checkered line, and the TSH b-subunit as a solid line. The two hairpin loops (L1, L3) in each subunit are marked. The long loops (L2) in each subunit extend from the opposite side of the central cystine knot. The functionally important a-subunit domains are boxed: a11–20, a33–38, a40–46 (“a helix”), a52, a64–81 and a88–92. The functionally important b-subunit domains are indicated within the line drawing: b58–69 (crossed line), b88–95 – the “determinant loop” or N-terminal segment of the seat-belt – (beaded line), and b96–105 – C-terminal segment of the seat-belt – (dashed line). The b-subunit beyond 106 is not drawn because the corresponding region of hCG was not traceable. The oligosaccharide chains are not shown because hCG was deglycosylated before crystallization. From Grossmann et al. [100].

the tertiary structure of the protein allowing subunit combination. Combination of TSH b- and a-subunits begins soon after translation is completed in the rough endoplasmic reticulum, and continues in the Golgi apparatus [151,177]. Subunit combination then accelerates and modifies oligosaccharide processing of the a-subunit [178]. In fact, studies

Chapter 5

have suggested that the conformation of the a-subunit differs after combination with each type of b-subunit [179], and this may affect subsequent processing. The rate of combination of TSH b- and a-subunits has been examined in mouse thyrotropic tumors. After a 20-minute pulse labeling with [35S]methionine, 19% of TSH b-subunits were combined with a-subunits, and this percentage increased to 61% after an additional 60-minute chase incubation [151,177]. The sequence of the TSH b-subunit from amino acid 27 to 31 (CAGYC) is highly conserved among species and is thought to be important for combination with the asubunit. In a case of congenital hypothyroidism, a point mutation in the CAGYC region (see p. 197) results in the synthesis of altered TSH b-subunits that are unable to associate with a-subunits, with consequent lack of intact TSH production [180]. A lack of free circulating TSH b-subunit was also observed, suggesting that combination with asubunit is necessary for TSH b-subunit secretion. This phenomenon was also demonstrated in studies where synthesis of wild-type recombinant TSH b-subunit was carried out in the presence or absence of recombinant a-subunit [181]. Using site-directed mutagenesis, another study showed that a mutation at residue 25 in the glycosylation recognition site that substitutes a serine for a threonine does not alter glycosylation but decreases TSH production by 70%, possibly because of disruption of the nearby CAGYC region [182]. After TSH and free a-subunit are processed in the distal Golgi apparatus they are transported into secretory granules or vesicles [183]. The secretory granules constitute a regulated secretory pathway, mainly influenced by TRH and other hypothalamic factors. These granules contain mostly TSH, whereas free a-subunit is contained in the secretory vesicles that constitute a nonregulated secretory pathway. TSH SECRETION TSH is synthesized and secreted only by thyrotrope cells in the anterior pituitary gland. Thyrotropes comprise approximately 5% of anterior pituitary cells, and are located chiefly in the anteromedial portion of the pituitary gland [184]. In healthy human subjects, the production rate of TSH is 100–400 mU/day [185–188]. The distribution space of TSH is slightly greater than the plasma volume, and the plasma clearance rate of TSH is approximately 50 ml/min [188]. In euthyroid subjects, the half-life of TSH in plasma is approximately 50 minutes [187]. In hypothyroid subjects, secretion rates of TSH increase up to 10 to 15 times normal rates, while the metabolic clearance rate decreases slightly. In contrast, in hyperthyroid subjects, secretion of TSH is suppressed, and metabolic clearance of exogenous TSH is accelerated [188]. The oligosaccharide chains of TSH appear to play important roles in TSH assembly, secretion, and action [144]. Nonglycosylated TSH subunits are degraded intracellularly before secretion, and inhibition of oligosaccharide chain

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processing interferes with intracellular TSH transport (see p. 182). The final structure of secreted TSH oligosaccharide is important in determining the biological activity and metabolic clearance rate of the circulating hormone. After deglycosylation, TSH has markedly reduced bioactivity and a more rapid metabolic clearance rate than the native hormone [189]. Variations in the oligosaccharide chains of TSH have been described in many clinical situations, and may affect biological half-life and bioactivity. For example, subjects with primary hypothyroidism secrete highly sialylated TSH isoforms with impaired bioactivity, and Lthyroxine treatment results in improvement in these properties [190].

Ontogeny of TSH Levels Immunoreactive TSH cells have been observed in the human pituitary gland by 12 weeks of gestation [191]. At approximately the same time, TSH is first detected in the pituitary and the serum [192–196]. TRH is measurable in hypothalamic tissue at 8 to 10 weeks, and the levels increase progressively to term. Serum and pituitary TSH levels remain low until week 18. At that point,TSH levels increase dramatically, followed by increases in serum T4 and T3 concentrations [192]. It appears that this increase in TSH represents the maturation of the hypothalamic–pituitary unit and the development of TRH input to the pituitary gland. There are continued increases in fetal serum TSH and T4 concentrations between 20 and 40 weeks of gestation. Pituitary TSH responsiveness to exogenous TRH occurs early in the third trimester, while negative feedback control of TSH secretion develops during the last half of gestation and the first 1 to 2 months of life [197]. Within 30 minutes of birth in term infants, there is an abrupt rise in serum TSH levels, followed by a marked increase in T3 concentrations within 4 hours and a lesser increase in T4 levels within the first 24 to 36 hours of extrauterine life. The initial increase in serum TSH levels appears to be stimulated by cooling the extrauterine environment. Serum TSH levels fall to the normal adult range by 3 to 5 days after birth, and serum thyroid hormone levels stabilize by 1 to 2 months of postnatal life. Healthy premature infants (less than 37 weeks gestational age) tend to have lower serum TSH levels at birth compared to term infants, although there is wide variability. There is a slight decrease in TSH levels in these infants during the first week of life, followed by a gradual increase to normal term levels. Serum TSH levels are lower at birth in ill premature infants compared to healthy premature infants matched for gestational age, but rise towards normal levels during recovery [198,199].

Patterns of TSH Secretion In healthy subjects, TSH is secreted from the pituitary gland in a dual fashion, with secretory bursts (pulses) superim-

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posed upon tonic (apulsatile) secretion (Fig. 5.13, upper panel). Tonic TSH secretion accounts for 30% to 40% of the total amount of TSH released into the circulation, while secretory bursts account for the remaining 60% to 70%. TSH pusles occur on average every 2 to 3 hours, although there is considerable variability among individuals, as well as variability due to blood sampling frequency and pulse analysis techniques [200,201]. Under normal conditions, TSH is secreted in a distinct circadian pattern, with nocturnal levels increasing up to twice daytime levels [197] (Fig. 5.13, upper panel). Peak TSH levels may occur at any time between 2300 and 500 hours, depending on the individual. In some healthy subjects, nocturnal TSH levels increase to slightly above the reported normal range for TSH assays. Lowest TSH levels occur at about 1100 hours. The TSH circadian rhythm is not apparent in premature or fullterm infants less than 4 weeks old, but begins to emerge between 1 and 2 months of life, and is well established in healthy children [202,203]. The circadian variation in TSH levels is due mainly to increased nocturnal TSH pulse amplitude, with some contribution from a slight increase in nocturnal TSH pulse frequency [201]. The nocturnal increase in TSH levels can precede the onset of sleep, and sleep deprivation actually enhances TSH secretion [200,204–206]. Therefore, in contrast to other pituitary hormones with a circadian variation, such as GH, the nocturnal rise in TSH levels is not sleep entrained. Instead, there appears to be a sleep-related inhibition of TSH release that is not of sufficient magnitude to counteract the stimuli that lead to the nocturnal TSH surge. Subjects with mild primary hypothyroidism continue to show a nocturnal rise in TSH pulse amplitude, while patients with severe primary hypothyroidism have markedly increased TSH pulse amplitude throughout the day, with no nocturnal increase (Fig. 5.13, middle panel) [201,207]. The normal TSH circadian variation is reestablished in these subjects by thyroxine replacement therapy [207]. In contrast, patients with hypothalamic–pituitary diseases and central hypothyroidism continue to secrete TSH in pulses, but lose the nocturnal TSH surge in pulse amplitude, and therefore secrete less TSH over a 24-hour period [208] (Fig. 5.13, lower panel). A similar pattern of reduced 24-hour TSH secretion due to lack of the normal nocturnal TSH surge is seen in critical illness, and may contribute to the low circulating thyroid hormone levels in severely ill patients [209]. To date, the origin of pulsatile and circadian TSH secretion is unknown. Thyroid hormones alter TSH pulse amplitude, but have little effect on pulse frequency [207], and therefore are unlikely to participate in TSH pulse generation. Some investigators have hypothesized that a TSH pulse generator exists in the hypothalamus, consisting of TRH neurons acting in concert to stimulate a burst of TSH secretion from the pituitary gland. This hypothesis is supported by studies that reported disappearance of TSH pulses in

FIGURE 5.13. Serum thyroid-stimulating hormone (TSH) levels measured every 15 minutes in a healthy subject (upper panel), in two subjects with primary hypothyroidism (middle panel) and in a subject with hypothyroidism due to a craniopharyngioma (lower panel). Significant TSH pulses were located by Cluster analysis, a computerized pulse detection program, and are indicated by asterisks (unpublished observations).

hypothyroid rats following administration of TRH antiserum, although TSH levels were near the assay detection limits and therefore TSH pulses may have been obscured [210]. Preliminary data in humans showing that constant TRH infusions do not change TSH pulse frequency cast some doubt on this theory [211]. Endogenous dopamine pathways do not appear to control pulsatile or circadian TSH

Chapter 5

secretion; although dopamine suppresses TSH pulse amplitude, it does not alter TSH pulse frequency. In addition, dopaminergic tone is actually higher at night, and therefore cannot account for the nocturnal TSH surge [212,213]. An alternate explanation for circadian TSH secretion is the diurnal variation in the activity of anterior pituitary 5¢monodeiodinase noted in the rat [214]. However, this has not been confirmed in the human. Recent studies in humans suggest that physiologic serum cortisol levels may control circadian TSH secretion. Subjects with adrenal insufficiency were studied under conditions of short-term glucocorticoid withdrawal and during intravenous administration of hydrocortisone at physiologic levels given as pulses designed to mimic normal pulsatile and circadian cortisol secretion. Daytime TSH levels were higher during glucocorticoid withdrawal, and were decreased by physiologic hydrocortisone infusions, thereby reestablishing the normal TSH circadian rhythm. Twenty four-hour TSH levels were decreased to a similar extent by hydrocortisone infusions at the same dose given as pulses of constant amplitude throughout the 24-hour period, but there was no circadian variation in TSH levels [215]. In parallel studies in healthy subjects, metyrapone (an inhibitor of endogenous cortisol synthesis) decreased endogenous serum cortisol levels during the day, and increased serum daytime TSH levels, leading to abolition of the usual circadian variation in serum TSH levels [216]. These data suggest that the early morning increase in endogenous serum cortisol levels in healthy subjects contributes to the normal daytime decrease in serum TSH levels and leads to the observed normal circadian variation in TSH.

Regulation of TSH Secretion The maintenance of normal TSH secretion depends on complex interactions between central and peripheral hormones (Fig. 5.14). The dominant hypothalamic effect on TSH secretion is stimulatory, via TRH, but there are additional positive and negative hypothalamic modulators of TSH secretion. The dominant peripheral effect on TSH secretion is inhibitory, via thyroid hormone feedback, but other circulating factors modulate TSH secretion. Hypothalamic Control of TSH Secretion

TRH TRH plays a dominant role in the posttranslational processing and release of TSH from the pituitary gland [217,218]. TRH effects on TSH transcription and glycosylation are discussed above (see pp. 179 and 182). Direct TRH effects on TSH secretion occur in vivo and in vitro at concentrations that exist in the pituitary portal blood [134,218,219], and immunoneutralization of TRH in animals leads to a decline in thyroid function [220]. The effects of TRH on TSH processing and secretion are modulated by thyroid state, as discussed in other sections [218] (see p. 187). Immunoreactive TRH is widely distributed throughout the hypothalamus, but the highest concentrations occur in

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185

FIGURE 5.14. Neuroendocrine and peripheral control of thyroid-stimulating hormone (TSH) secretion. T4 , thyroxine; T3 , triiodothyronine; TRH, thyrotropin-releasing hormone; SRIH, somatostatin; DA, dopamine.

the median eminence, preoptic suprachiasmatic nuclei, and paraventricular nuclei (PVN) [221–223]. The latter region is the site of the “thyrotropic area” of the hypothalamus [218]. TRH-containing neurons arise from a group of cells located in the PVN, and project neuronal processes to the median eminence. Lesions of the PVN decrease circulating TRH and TSH levels in normal or hypothyroid animals and cause hypothyroidism [224,225], while electrical stimulation of this area causes TSH release. It is important to note that although baseline levels of TSH are reduced in animals with lesions of the PVN, TSH levels still show appropriate responses to changes in circulating thyroid hormone levels. Thus, the function of TRH in pituitary–thyroid physiology may be to determine the set point of feedback control by thyroid hormones [218]. TRH exerts its effects on TSH secretion via specific high-affinity membrane receptors present on thyrotropes [129,130]. TRH binding to the receptor initiates a cascade of intracellular events that leads to hormone secretion [226,227]. These events have been most clearly elucidated

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in cloned GH3 somatomammotrope cells that secrete prolactin in response to TRH [129], although it appears that TRH-stimulated TSH secretion has a similar mechanism of action [132]. In GH3 cells, the TRH-receptor complex interacts with a guanine nucleotide binding regulatory protein (G) that then binds GTP, causing its activation (G¢). G¢ binds to phospholipase C (C) and activates it (C¢). C¢ catalyzes the hydrolysis of phosphatidylinositol 4,5 bisphosphate (a minor lipid in the plasma membrane), which results in the formation of two intracellular “second messengers,” inositol triphosphate (InsP3) and 1,2-diacylglycerol (1,2DG). InsP3 diffuses from the cell surface membrane to the endoplasmic reticulum, where it causes the release of sequestered Ca2+. This leads to a rapid elevation in intracellular Ca2+ levels, which activates the movement of secretory granules to the cell surface and their exocytosis, either directly or via activation of protein kinase. Simultaneous with these events, there is a parallel activation of protein kinase C by 1,2-DG that also leads to phosphorylation of proteins involved in exocytosis. The prompt and direct effects of TRH on TSH secretion form the basis for the clinical use of exogenous TRH [218]. Acute intravenous administration of 15–500 mg of TRH to normal human subjects causes a dose-related release of TSH from the pituitary. This response is detectable within 5 minutes after TRH administration, and is maximal at 20 to 30 minutes. Serum TSH levels return to basal levels by 2 hours. These normal responses have been compared to TSH levels following TRH administration in patients with primary thyroid disease or hypothalamic–pituitary disease (see p. 196). In contrast to acute bolus injections of TRH, prolonged (2–4-hour) infusions of TRH lead to biphasic increases in serum TSH levels in humans and animals [228]. It is thought that the early phase reflects the release of stored TSH within the thyrotrope, while the later phase reflects release of newly synthesized TSH. Interpretation of TSH responses to more prolonged TRH infusions (24 hours or longer) is complicated by the eventual increase in serum T3 levels, which feedback to suppress further TSH release. This is illustrated by a recent study of 48-hour TRH infusions to intact and hypothyroid-replaced subjects [211]. At all doses of TRH tested, intact subjects had attenuated increases in TSH levels compared to hypothyroid-replaced subjects. However, it should be noted that continuous TRH administration in vitro also causes desensitization of TSH responses, suggesting that increased T3 feedback does not completely explain decreased TSH levels with long-term TRH exposure [229]. SRIH The neuropeptide SRIH is the major hypothalamic inhibitor of GH release. In addition, studies in humans and animals have shown that SRIH inhibits basal and TRHstimulated TSH secretion in vivo and in vitro at concentrations that exist in the pituitary portal blood [230,231]. SRIH also inhibits TRH release from hypothalamic cultures, and SRIH antibodies stimulate TRH release. Therefore,

SRIH may have additional inhibitory effects on TRH secretion at the hypothalamic level. In humans, SRIH infusions suppress TSH pulse amplitude by up to 70%, slightly decrease TSH pulse frequency, and abolish the nocturnal TSH surge [232]. Immunoneutralization of SRIH in animals increases basal TSH levels and TSH responses to TRH [233–235]. Thus, TSH secretion is probably regulated by the hypothalamus through a simultaneous dual control system of TRH stimulation and SRIH inhibition [236]. Immunoreactive SRIH is widely distributed throughout the nervous system and other body tissues, where it exerts a variety of inhibitory actions. In the hypothalamus, the highest concentrations of SRIH occur in the anterior paraventricular region, especially the preoptic, suprachiasmatic and retrochiasmatic nuclei [236]. From these areas, axonal processes of SRIH-containing neurons project to the median eminence. Animals that have undergone sectioning of these fibers have depletion of the SRIH content of the median eminence and increased serum TSH levels [237]. SRIH is secreted in two principal forms: a 14-amino acid peptide, and an N-terminal-extended 28-amino acid peptide. Both of these forms are secreted into the pituitary portal blood in physiologically relevant concentrations [238,239]. It appears that the two forms exert equipotent effects on TSH release [240]. SRIH acts by binding to specific, high-affinity receptors in the anterior pituitary gland [241]. Five subtypes of the SRIH receptor (SSTR1–5) have been identified [242] and SSTR2 and 5 have been localized to thyrotropes [243,244]. Binding of SRIH to its receptor leads to inhibition of adenylate cyclase via the inhibitory subunit of the guanine nucleotide regulatory protein [245], which in turn lowers protein kinase A activity [243] and decreases TSH secretion. SRIH may also exert some effects by cAMP-independent actions on intracellular calcium levels [246]. In addition, SRIH has an indirect suppressive effect on TSH secretion at the pituitary level by decreasing TRH receptors [247]. Other studies had shown that hypothyroidism reduced the efficacy of SRIH in decreasing TSH secretion from bovine pituitaries, and this was reversed by thyroid hormone administration [248]. This was recently explained by studies in mouse thyrotropic tumors which showed that both SSTR2 and 5 were markedly downregulated by the hypothyroid state and were induced by thyroid hormone [244]. Although short-term infusions of SRIH lead to pronounced suppression of TSH secretion, long-term treatment with SRIH or its long-acting analogue octreotide does not cause hypothyroidism [249]. This probably reflects compensatory mechanisms in the thyroid hormone feedback loop. GH deficiency is associated with increased TSH responses to TRH, while GH administration decreases basal and TRH-stimulated TSH secretion [250]. These effects are explained by either GH stimulation of hypothalamic SRIH release or GH mediated increases in peripheral T4 to T3 conversion.

Chapter 5

Dopamine The CNS catecholamine dopamine is a second hypothalamic inhibitor of TSH secretion. Studies in humans and animals have shown that dopamine inhibits basal and TRH-stimulated TSH secretion in vivo and in vitro at concentrations that exist in the pituitary portal blood [251–256]. The administration of dopamine antagonists, including those that do not penetrate the blood–brain barrier, increases TSH levels [257]. In humans, dopamine infusions rapidly suppress TSH pulse amplitude by up to 70%, do not affect TSH pulse frequency, and abolish the nocturnal TSH surge [232]. In addition to acute inhibitory effects on TSH secretion, dopamine also decreases levels of basal and TRH-stimulated TSH subunit gene transcription [131]. Dopamine also has direct effects on hypothalamic hormone secretion that may impact on TSH secretion. For example, dopamine and dopamine-agonist drugs stimulate both TRH and SRIH release from rat hypothalami [258]. However, the net effect of these neurohormone interactions on TSH secretion is unclear. The dopamine that reaches the anterior pituitary gland through the pituitary portal vessels is secreted by neurons whose cell bodies lie in the arcuate nucleus [134]. From the arcuate nucleus, neuronal processes project to the median eminence. Dopamine acts by binding to specific type 2 dopamine receptors (DA2) on thyrotrope cells [259]. This leads to inhibition of adenylate cyclase, which decreases the synthesis and secretion of TSH. In addition, in vitro studies using rat anterior pituitary cells suggest that TSH may down-regulate its own release through the induction of DA2 receptors on thyrotrope cells [260]. The inhibitory effects of dopamine on TSH secretion vary according to sex steroid and thyroid hormone status. For example, dopamine antagonist drugs cause greater increases in serum TSH levels in women than in men [256]. Similarly, dopamine inhibition of TSH release is greater in patients with mild hypothyroidism than in normal subjects, although subjects with severe hypothyroidism may be less responsive [217]. Although short-term infusions of dopamine lead to pronounced suppression of TSH secretion and measurable decreases in serum T3 levels, long-term treatment with dopamine agonists does not cause hypothyroidism. This probably reflects compensatory mechanisms in the thyroid hormone feedback loop. Adrenergic Effects a-adrenergic activation stimulates TSH release directly from the rat pituitary gland at physiologically relevant concentrations of catecholamines [261– 263]. a-adrenergic agonists injected systemically or into the third ventricle stimulate TSH release in rats, while blockade of norepinephrine synthesis or treatment with adrenergic receptor blockers decreases TSH [134,264–266]. It is unclear whether these effects are mediated via changes in TRH and/or SRIH levels, although one study reported that norepinephrine released TRH from hypothalamic cultures. In humans, there are limited data regarding adrenergic effects on TSH secretion. a-adrenergic blockade with phentolamine, which does not readily cross the blood–brain

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barrier, diminishes the serum TSH response to TRH [98]. Administration of thymoxamine, an a-adrenergic blocker that penetrates the blood–brain barrier, causes similar effects [98]. However, administration of epinephrine does not alter TRH-stimulated TSH secretion [267]. These data suggest that endogenous adrenergic pathways have a minor direct stimulatory role in TSH secretion. Noradrenergic stimulation of TSH secretion is mediated by high-affinity a1-adrenoreceptors linked to adenylate cyclase [98]. Therefore, it is likely that dopamine and epinephrine exert opposing actions on thyrotropes by opposite effects on cAMP generation. Opioids In rats, systemic opiate administration suppresses basal or stimulated TSH levels, and the opioid receptor antagonist naloxone reverses these effects [268–271]. In contrast, previous studies in humans have shown that acute opiate administration may slightly stimulate TSH levels, while acute naloxone administration has little effect [272–279]. These findings have supported the statement that opioids have little physiologic role in TSH secretion in humans. However, a recent study has cast doubt on this conclusion [280]. In this study, naloxone was given as a lowdose infusion over 24 hours, and TSH levels were measured frequently. Daytime TSH secretion was preserved, but 24hour TSH secretion decreased by 30%, primarily due to a 40% decrease in nocturnal TSH pulse amplitude. TSH responses to TRH were decreased, suggesting that endogenous opioids stimulate TSH secretion at the pituitary level. Serum T3 levels were decreased as well, suggesting that the magnitude of TSH suppression was sufficient to affect thyroid gland function. If confirmed, these findings suggest that endogenous opioids play an important role in tonic stimulation of TSH secretion. Other Neurotransmitters In addition to the neurotransmitters discussed above, serotonin, g-aminobutyric acid, adenosine, neurotensin, vasoactive intestinal peptide, bombesin, vasopressin, oxytocin, substance P, and cholecystokinin have all been reported to alter TSH secretion [134,281–288]. However, most of these studies have been carried out in animals or in vitro, and the physiologic relevance of these findings to TSH secretion in humans is unknown. Feedback Control of TSH Secretion

The thyroid hormones T4 and T3 exert powerful, dosedependent negative feedback control over TSH synthesis directly at the pituitary level, leading to decreased TSH production (see p. 178). In addition, thyroid hormones acutely block pituitary secretion of TSH [289]. Acute administration of T3 rapidly suppresses TSH levels within hours, while chronic administration leads to further suppression [290,291]. Slight changes in serum thyroid hormone levels within the normal range (induced by thyroid hormone, antithyroid drug or iodine administration) alter basal and TRH-stimulated TSH levels, confirming the sensitivity of

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the pituitary gland to minor alterations in thyroid hormone feedback. Thyroid hormones appear to alter tonic TSH secretion and TSH pulse amplitude without affecting pulse frequency, since subjects with primary hypothyroidism have a near-normal number of TSH pulses of increased amplitude, and T4 replacement in these subjects leads to a decrease in TSH pulse amplitude without much change in pulse frequency [201,207]. Both T4 and T3 function as potent feedback hormones on the thyrotrope. The intracellular monodeiodination of T4 to T3 is greater in the pituitary gland than in peripheral tissues, and contributes approximately half of the intrapituitary content of T3 [292]. Therefore, intrapituitary T4 monodeiodination to T3 may be the mechanism by which the thyrotrope responds to circulating T4 levels. Within the pituitary gland, T3 binds to specific nuclear receptors. The activated T3-receptor complex then binds to specific nucleotide sequences on the TSH subunit genes, inhibiting transcription (see p. 178). In addition to direct effects on TSH gene transcription, thyroid hormones have other actions at the pituitary level that impact on TSH secretion. For example, thyroid hormones decrease the number of TRH receptors [293–295] and stimulate the activity of the pituitary TRH-degrading enzyme [296]. These two effects may act in concert to decrease TRH stimulation of TSH secretion. Thyroid hormones exert direct effects on hypothalamic function that modulate TSH secretion. TRH mRNA levels in the PVN are increased in hypothyroidism and are reduced by T3 and T4 [297–300]. Hypothalamic lesions in the PVN prevent the full increase in plasma TSH and pituitary TSH b mRNA levels seen in response to hypothyroidism [301]. Hypothalamic SRIH content is decreased in hypothyroid rats, and is restored by T3 treatment. Finally,T3 directly stimulates SRIH release from hypothalamic tissue [302]. These combined effects of thyroid hormones on TRH and SRIH decrease TRH release from the hypothalamus, and thereby indirectly decrease TSH secretion. Other Peripheral Factors that Affect TSH Secretion

Glucocorticoids Pharmacologic doses of glucocorticoids suppress basal TSH levels, blunt TSH responses to TRH, and attenuate or abolish the nocturnal TSH surge in humans and animals [303–311]. Some patients with Cushing’s syndrome have low TSH levels and loss of the nocturnal TSH surge, probably due to endogenous hypercortisolism. In healthy subjects, infusions of hydrocortisone (100–300 mg/day) that increase serum cortisol to levels seen in moderate stress suppress 24-hour TSH secretion by 60% to 70% [312]. Infusions of much lower doses of hydrocortisone in healthy subjects (34–46 mg/day) lead to similar decrements in 24hour TSH secretion. These hydrocortisone doses were designed to lead to mild increases in serum cortisol levels, similar to endogenous levels seen during short-term fasting or other minor stressors. The resulting serum cortisol levels, although higher than baseline endogenous levels, are still

within the “normal” range for healthy, nonstressed subjects. These data suggest that even low-dose, near-physiologic glucocorticoid administration affects TSH secretion, and that mild increases in endogenous cortisol levels may exert significant effects on TSH levels [313]. In all of these studies, the changes in TSH levels are due to decreased TSH pulse amplitude without alteration in TSH pulse frequency, with more profound suppression of nocturnal TSH secretion and abolition of the TSH surge. Physiologic glucocorticoid levels also affect TSH secretion [215,216,304,306,314,315]. Many reports have described elevated serum TSH levels in untreated patients with adrenocortical insufficiency that resolve with steroid replacement. These studies are compromised by the high incidence of autoimmune thyroid disease in these patients, since glucocorticoids could have independent immunomodulating effects on autoimmune thyroid disease. However, studies of metyrapone (an inhibitor of cortisol synthesis) administration to healthy subjects have confirmed a reciprocal relationship between endogenous cortisol and TSH levels [216], and studies of physiologic hydrocortisone replacement in patients with adrenal insufficiency show that increased daytime TSH levels seen in the absence of cortisol are decreased by physiologic cortisol levels [215]. Glucocorticoid suppression of TSH levels may occur directly at the pituitary gland, and/or via hypothalamic effects. The former possibility is supported by the maintenance of TSH pulse frequency and the suppression of TSH responses to exogenous TRH after glucocorticoid administration [312]. Some animal studies suggest that glucocorticoids exert direct effects on thyrotropes, although they appear to be highly dependent on dose and time-course of steroid administration [316–319]. However, in contrast to effects of thyroid hormones, it does not appear that glucocorticoids directly affect TSH gene transcription. For example, administration of dexamethasone to rats does not alter pituitary TSH content or TSH b-subunit mRNA levels, although it does attenuate TSH elevations and enhance T3-mediated TSH suppression in hypothyroid rats [139,320]. In addition to direct pituitary effects, other studies have shown that dexamethasone increases hypothalamic TRH levels, while circulating TRH levels are decreased. These results suggest that dexamethasone may inhibit TRH release from the hypothalamus [321]. Reports that the proposed consensus sequence for glucocorticoid receptor binding is present in the 5¢-flanking region of the TRH gene also support the possibility of hypothalamic effects of glucocorticoids on TRH [322]. Patients with Cushing’s syndrome or subjects receiving prolonged courses of glucocorticoids may have low serum T4 as well as TSH levels. Whether such patients have tissue hypothyroidism, and whether they should be treated with thyroid hormone, is unclear; however, patients with acute or chronic illnesses and similar abnormalities in thyroid hormone levels do not appear to benefit from thyroid hormone therapy.

Chapter 5

Sex Steroids Serum and pituitary TSH concentrations are higher in male than in female rats, are reduced by castration, and can be restored by androgen administration [54]. Exogenous testosterone administration to castrated male or female rats increases basal and TRH-stimulated serum TSH levels [323]. In contrast, androgen administration to intact female rats decreases pituitary TSH b-subunit mRNA concentrations without altering serum or pituitary levels of TSH [140]. Estrogen administration to euthyroid rats does not alter serum TSH levels. In contrast, in hypothyroid rats, pharmacologic doses of estrogen may enhance thyroid hormone feedback of TSH synthesis. In euthyroid humans, early studies reported that androgens suppress TSH responses to TRH. However, most studies suggest that changes in endogenous or exogenous sex steroid levels do not significantly affect basal or TRHstimulated TSH levels [324,325]. Other studies confirm that there is no significant gender difference in the basal mean and pulsatile secretion of TSH or in the TSH response to TRH [326]. Therefore, although the data are not conclusive, sex steroids do not appear to play a major regulatory role in TSH secretion under normal conditions in humans. Cytokines The cytokines, which are circulating mediators of the inflammatory response that are produced by many cells, have been shown to affect the hypothalamic– pituitary–thyroid axis. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) decrease serum TSH levels in healthy human subjects, and TNF and interleukin-1 (IL-1) decrease TSH levels in animals [168,327–331]. Administration of these cytokines leads to thyroid hormone levels similar to those seen in acute nonthyroidal illness [332]. In rats, TNF reduces hypothalamic TRH content and pituitary TSH gene transcription. IL-1 stimulated type II 5¢-deiodinase activity in rat brain, which may decrease TSH secretion by increasing intrapituitary T3 levels. In addition, IL-1 and IL-6 are produced by rat anterior pituitary cells, and may serve as autocrine or paracrine factors in TSH secretion during illness [333,334]. Nonsteroidal Anti-inflammatory Agents The nonsteroidal anti-inflammatory agents (NSAIDs), including aspirin, salsalate, ibuprofen, indomethacin, and naproxen, are used extensively to treat a wide variety of acute and chronic inflammatory conditions. Their major mechanism of action appears to be inhibition of prostaglandin synthesis. A number of studies suggest that many NSAIDs lead to decreased serum TSH levels, within hours of administration [335–340]. Usually TSH levels are lower than nontreated baseline, but remain within the broad normal range. However, serum TSH levels can occasionally decrease below the normal range in patients taking NSAIDs, especially at higher doses. In most cases, this decrease in TSH is thought to be an indirect effect due to NSAID displacement of thyroid hormones from protein binding sites, with transient increase in free thyroid hormone levels and feedback sup-

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pression of TSH. However, one study suggests that at least one of the NSAID classes (meclofenamate and fenclofenac) may directly inhibit TRH-induced TSH release by rat anterior pituitary cells in vitro [341]. ACTION OF TSH TSH acts on the thyroid gland by binding to the TSH receptor [342]. Excellent reviews of this subject have been published [100,343,344]. This receptor is located on the plasma membranes of thyroid cells and consists of a long extracellular domain, a transmembrane domain and a short intracellular domain. Knowledge of the molecular structure of the receptor has allowed a better understanding of the mechanism of action of TSH that results in the production of thyroid hormone. Studies with recombinant TSH receptor have provided insights into the role of TSH receptor antibodies in autoimmune thyroid disease. In addition, mutations of the TSH receptor have been described that result in clinical syndromes of hypothyroidism and hyperthyroidism.

TSH Receptor Gene The human TSH receptor gene is located on chromosome 14 locus q31 and spans a region greater than 60 kb in size containing ten exons [345]. Exons one through nine have 327, 72, 75, 75, 75, 78, 69, 78, and 189 bp, respectively, and encode part of the extracellular domain, whereas exon ten is greater than 1412 bp and encodes the rest of the extracellular domain as well as all of the transmembrane and the intracellular domains. The promoter region of the human TSH receptor gene has also been partially characterized [345]. The major transcriptional start site, designated as +1, is located 157 bp upstream of the translation initiation codon ATG. There are no consensus CAAT or TATA boxes but there are degenerate CAAGGAAAGT and TAGGGAA boxes located at positions -86 and -43, respectively. The regions of the promoter important for tissue-specific expression and those responsive to TSH and cAMP, the two main regulators that have been shown to inhibit the rat TSH receptor gene expression [346], are yet to be defined. Northern blot analysis has revealed two major transcripts of the human TSH receptor of 3.9 and 4.6 kb in size that differ only in the length of the 3¢ untranslated region [347,348].

TSH Receptor Structure The TSH receptor is synthesized as a single polypeptide chain of 764 amino acids that includes a 20-amino acid signal peptide [349]. However, the TSH receptor has been found to exist on the cell surface as a single chain and also as a two-subunit form, produced by internal cleavage apparently at two sites, releasing a potentially immunogenic 5– 7-kDa peptide [344,350]. The amino-terminal half of the protein contains 16 hydrophilic leucine-rich repeats (LRR)

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that form the extracellular domain and includes six potential glycosylation sites. The asparagine-linked oligosaccharides appear to be important for correct folding, membrane targeting and receptor function [351,352]. The LRR are the common feature of the superfamily of LRR proteins. One of these, the ribonuclease inhibitor, has been cocrystallized with its ligand [353], and this has allowed the construction of a model of the extracellular domain of the TSH receptor bound to TSH [354], as shown in Fig. 5.15. The carboxyl-terminal half of the protein, modeled after the structure of the G protein-coupled receptors, based on rhodopsin [355], is also shown in Fig. 5.15. This region contains seven hydrophobic transmembrane segments, three extracellular loops, three cytoplasmatic loops and a short cytoplasmatic tail of 82 amino acids (Fig. 5.15).

Determinants of TSH Interaction with its Receptor The entire extracellular domain as well as parts of the transmembrane domain of the TSH receptor contribute to TSH binding. However, two regions, from residue 201 to 211 and 222 to 230, are particularly important in TSH-specific binding [356]. In contrast, a different region of the extracellular domain, from residue 287 to 404, appears to be important for binding of TSH receptor antibodies in autoimmune thyroid disease [357]. Other authors have reported considerable overlap of TSH binding regions and antibody epitopes [343]. Interestingly, studies using rat FRTL-5 cells have shown that thyroid stimulating autoantibodies (TSAbs or TSI) stimulate whereas TSH binding inhibitory antibodies (TBIAbs) inhibit TSH-mediated gene expression, suggesting that these antibodies must act on different epitopes of the receptor that differ in their signal transduction mechanism [346]. The transmembrane domain of the TSH receptor also appears to be important in ligand binding. A point mutation in the fourth transmembrane domain of the TSH receptor gene has been described in the hyt/hyt congenitally hypothyroid mouse that abolishes TSH binding [358]. Inactivating TSH receptor mutations are a rare cause of congenital hypothyroidism in humans, although 12 such mutations have been identified, eight of which map to the aminoterminal domain [359–362]. Specificity of TSH binding is conferred by the TSH b-subunit. It appears that amino acid residues from 58 to 69, within the bL3 loop, and from 88 to 105, the “seat-belt” region of the TSH b-subunit [363] play an important role in binding to and activation of the TSH receptor. The carboxylterminal end of TSH b contains multiple lysine residues (positions 101, 107 and 110) and a cysteine at position 105 that are critical for the ability to bind to the receptor [364]. Congenital hypothyroidism due to biologically inactive TSH was found to result from a frameshift mutation with loss of b-cysteine105 [365,366] (see p. 197). Several regions of the a-subunit are also important for TSH activity, particularly the residues a11–20 and a88–92 (see Fig. 5.12)

FIGURE 5.15. Schematic model of the human thyroidstimulating hormone (TSH)–TSH receptor complex. The receptor is depicted in accordance with models based on the leucine rich repeats (LRR)-containing ribonuclease inhibitor (353) and G proteincoupled rhodopsin (355). In the center, the a-subunit (white ribbon) and TSHb-subunit (black ribbon) are shown folded and combined as depicted in Fig. 5.12, except that the TSH molecule is inverted, so that the a hairpin loops are oriented toward the extracellular loops of the trasmembrane domain of the receptor, and the b hairpin loops toward the concave surface of the LRR. From Grossmann et al. [100].

[176,367]. In addition, the oligosaccharide chain at position a-asparagine52 plays an important role in both binding affinity and receptor activation. A mutant TSH lacking the a-asparagine52 oligosaccharide showed increased in vitro activity, although this same mutation had the opposite effect on CG binding to its native receptor [368]. However, such a mutation also increased TSH clearance and this decreased in vivo activity [368]. In addition, the oligosaccharide chains on the TSH subunits are critically important for signal transduction [149,150,369]. In this regard, the a-subunit oligosaccharides are important for all the pathways activated by the receptor, whereas the TSH b-subunit oligosaccharide only

Chapter 5

influences the adenylate cyclase pathway [370]. The mechanism by which the oligosaccharides influence signal transduction is not known. A model for the action of the glycoprotein hormones has been proposed that suggests a role for the oligosaccharides in directly modulating the influx of calcium into the target cell [371]. The ability of chorionic gonadotropin to bind to the TSH receptor was demonstrated in rat thyroid cells [372] and recently confirmed in studies using recombinant human TSH receptor [373,374]. The activity of CG was estimated to be less than 0.1% compared to TSH. LH was found to have a 10-fold higher potency for activation of the TSH receptor when compared to CG, but a mutant of CG that lacks the carboxyl-terminal region of CG b from amino acid residues 115 to 145 showed a potency equivalent to that of LH [374]. This truncated form of CG is one of the forms in the heterogeneous population of CG molecules produced in normal pregnancy and in trophoblastic tumors, and may be present in amounts sufficient to cause significant thyroid gland stimulation [375]. The ocurrence of gestational hyperthyroidism due to a mutation in the TSH receptor that increases its sensitivity to CG has also been described [376].

Signal Transduction at the TSH Receptor The three intracytoplasmatic loops of the transmembrane domain appear to be important for signal transduction [377]. The TSH receptor is coupled to the Gs protein cascade, probably through the carboxyl-terminus of the third cytoplasmatic loop [378]. Thus, binding of TSH activates adenylate cyclase to produce cAMP [379,380]. The phosphatidylinositol pathway is also activated [381], but this pathway is slower and requires a higher concentration of TSH [382,383]. The unliganded TSH receptor has been found to have significant constitutive activity [384,385], suggesting that regulation may involve the release of an inhibitory restraint. This would explain the relatively high frequency of activating mutations of the TSH receptor compared to inactivating mutations. In cases of congenital hyperthyroidism [384,386], the mutations were located in the extracellular domain and the second, fourth, fifth and sixth transmembrane domains, while in the hyperfunctioning adenomas [384,387] the mutations were found to localize to the carboxyl-terminus of the third cytoplasmatic loop and adjacent sixth transmembrane domain. All these mutations resulted in constitutive activation of adenylate cyclase [388]. Germline mutations of the cytoplasmatic tail of the TSH receptor have been described in 33.3% of patients with toxic multinodular goiter and 16.3% with Graves’ disease, and this mutation was found to result in an exaggerated cAMP response to TSH [389]. In addition, specific amino acids in the third cytoplasmatic loop have been identified that are important for the phosphatidylinositol pathway but do not appear to play a role in the adenylate cyclase pathway [390].

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Effects of TSH TSH action on the receptor results in activation of the adenylate cyclase pathway and to some extent the phosphatidylinositol pathway, as described above, and leads to the activation of protein kinase A and C with resulting phosphorylation of multiple proteins, including nuclear histones [391]. Proteins phosphorylated by the protein kinase C pathway appear to be different from those phosphorylated by protein kinase A [392]. In addition, phosphoprotein phosphatases are activated and lead to the dephosphorylation of another set of proteins [392]. The effects of TSH on the thyroid gland include changes in cell morphology, iodine metabolism, synthesis of thyroid hormone and thyroid gland growth. Effects of TSH on Thyroid Cell Morphology

TSH causes dramatic changes in the morphology of the thyroid. The initial response to TSH is the incorporation of exocytotic vesicles into the cell membrane at the apical pole of the follicular cells that is quickly followed by formation of cytoplasmatic projections and microvilli [393]. The number of cytoplasmatic projections has been correlated with the level of TSH [394]. After 8 hours of stimulation, the follicular cells become columnar and filled with colloid droplets and luminal colloid is nearly depleted collapsing the follicles [395]. In contrast, when TSH decreases the follicular cells become cuboidal and colloid increases, distending the follicles [395]. Lysosomes migrate from the basal pole toward the apical pole where they fuse with the colloid droplets and then migrate toward the basal pole, becoming smaller and denser [393]. The cytoskeletal system, that includes myosin, actin, tropomyosin, calmodulin, profilin and tubulin, has been implicated in this process [396,397]. Effects of TSH on Iodine Metabolism

Iodide transport into the cell is stimulated by TSH via the adenylate cyclase pathway [398]. Although thyroid peroxidase transcription and mRNA stability are increased by TSH through the adenylate cyclase pathway [399], the generation of peroxide and iodide organification appear to be mediated by a phosphatidylinositol pathway independent of protein kinase C [400]. Conversely, iodine inhibits activation of the adenylate cyclase system by TSH [401]. Effects of TSH on the Synthesis of Thyroid Hormone

The endpoint of TSH action is the production of thyroid hormone by the thyroid gland. The process begins with thyroglobulin gene transcription. The transcriptional rate and possibly the mRNA stability are increased by TSH [402]. TSH stimulates iodide uptake and organification, as described above. TSH then acts on the iodinated thyroglobulin stored in the luminal colloid and stimulates its hydrolysis resulting in the release of the constituent amino acids, including the iodotyronines T3 and T4.

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Effects of TSH on Thyroid Gland Growth

After long-term stimulation by TSH, the thyroid gland enlarges as a result of hyperplasia and hyperthophy. Acutely, TSH has a rapid mitogenic effect on the thyroid gland that is evident within 5 minutes [403]. It increases DNA synthesis through the adenylate cyclase pathway [404], specifically through activation of protein kinase A type I [405]. TSH may also regulate growth by cAMP-independent pathways [406] and interactions with the action of the growth factors epidermal growth factor (EGF) and insulinlike growth factor-I (IGF-I) [407,408]. It has been found that TSH and other growth factors increase the mRNA levels of the proto-oncogenes c-fos and c-myc in rat thyroid cells [409]. TSH inhibits apoptosis [410], perhaps by regulating p53 and bcl-2, as shown for gonadotropins [411,412]. Mutations within the a33–44 region were found to reduce growth stimulation but not affect cAMP production [413], although a clear dissociation of the various actions by TSH analogs has not yet been achieved. TSH-induced Receptor Desensitization

The phenomenon of desensitization has been described both in vivo and in vitro, whereby prior TSH stimulation leads to a 30% to 70% decrease in the subsequent cAMP response to TSH stimulation [414,415]. Recent studies using recombinant TSH receptor have shown that desensitization does not occur when the receptor is expressed in nonthyroidal cells, suggesting that this phenomenon requires a cellspecific factor [416]. Extrathyroidal Actions of TSH

The ocurrence of precocious puberty in cases of severe juvenile primary hypothyroidism [417] has suggested that high levels of TSH are able to cross-activate the gonadotropin receptors. This interaction has now been demonstrated using recombinant human TSH, which has been found to be capable of activating the FSH [418] but not the CG/LH receptor [419]. Expression of both TSH and its receptor has been reported in lymphocytes [420,421], and has led to the speculation that TSH may have other nonclassic functions. The TSH receptor was also found to be expressed in adipocytes [422], and TSH was found to stimulate proliferation and inhibit differentiation of preadipocytes in vitro [423]. More studies are needed to determine the physiological significance of the extrathyroidal effects of TSH, as this may impact the safety of future treatment modalities for thyroid cancer that may attempt to target radioisotopes to the TSH receptor [424,425].

TSH MEASUREMENTS Accurate and specific measurements of serum TSH concentrations have become the cornerstone for diagnosing and treating the vast majority of thyroid disorders. The first mea-

surements of TSH in circulating blood used insensitive and nonspecific bioassays that measured an end point of TSH action, for example, a rise in cyclic AMP levels in cultured thyroid cells [426–428]. Such assays were labor-intensive and time-consuming. Subsequently, immunological approaches were used to measure TSH in human blood when antibodies to human TSH were first developed in 1963. The availability of these antibodies and crudely purified human TSH preparations allowed investigators to develop the first radioimmunoassays for human TSH.

Radioimmunoassay of TSH During the two decades between 1963 and 1983 radioimmunoassays were widely employed for the measurement of TSH in human serum [429–434]. Modifications and improvements in the techniques of radioimmunoassays allowed serum TSH assays to be moderately sensitive and specific [435–439]. The most sensitive radioimmunoassays of TSH had functional detection limits between 0.5 to 1 mU/l of TSH. These assays, known as “first generation assays,” were useful in distinguishing elevated serum levels of TSH in primary hypothyroidism from those normal values found in euthyroid subjects. One hundred percent of primary hypothyroid subjects had elevated TSH levels. In contrast, these “first generation assays” could not accurately quantitate values within the normal range, and there was considerable overlap with the values found in euthyroid and hyperthyroid subjects.

Immunometric Assay of TSH The first monoclonal antibody to human TSH was developed in 1982 and introduced a new era in the technology for measuring TSH [440]. Monoclonal antibodies had defined epitope specificity allowing them to be used in “sandwich-type” assays subsequently termed immunometric assays (Fig. 5.16) [441]. Immunometric assays were quickly shown to be superior to classic radioimmunoassays [442– 448]. The principles of these assays are quite different. Radioimmunoassays used low amounts of labeled antigen in combination with very dilute antibody mass. In contrast, immunometric assays label one of the monoclonal antibodies, the “signal antibody.” This signal may be radioisotopic or chemiluminescent. Another monoclonal antibody with a different epitope specificity is linked to a solid support and is called the “capture antibody.” Both antibodies are used in excess, sandwiching TSH between the two antibodies and thus capturing all TSH molecules in a given sample. These modifications in the measurement of TSH resulted in important changes. First, the assays were highly specific with no cross-reaction to the other human glycoprotein hormones. Second, 100% of euthyroid controls have detectable and quantifiable levels of TSH residing within a normal range of approximately 0.5–5 mU/l. Third, there is little or no overlap in TSH values in patients with hyperthyroidism

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FIGURE 5.16. Schematic representation of an immunometric assay for thyroid-stimulating hormone (TSH). The assay uses one labeled monoclonal antibody (the signal antibody) and another monoclonal antibody with a different epitope specificity linked to a phase face support (the capture antibody). All TSH molecules are sandwiched between the two monoclonal antibodies. From Ridgway [441].

FIGURE 5.17. Improved thyroidstimulating hormone (TSH) assays with greater discrimination between normal controls and hyperthyroid subjects. A schematic representation of TSH levels in euthyroid (white circles) vs thyrotoxic (black circles) samples. The sera were measured in first, second, third, and fourth generation TSH assays. The lower limit of sensitivity for each generation of assay is shown by the vertical bars. From Spencer [452].

compared to euthyroid controls. Thus, immunometric TSH assays allow physicians to immediately discriminate euthyroid subjects from both hyperthyroid and hypothyroid patients [449–451]. The degree to which a given assay can separate undetectable TSH levels found in hyperthyroid subjects from normal values in euthyroid controls had improved steadily (Fig. 5.17) [452]. These improvements have resulted in progressively lower functional detection limits, defined as the lowest TSH value detected with an interassay coefficient of variation £20% (Fig. 5.18) [452]. Thus, first generation assays (usually radioimmunoassays) have functional detection limits of 1–2 mU/l, second generation assays 0.1–0.2 mU/l, third generation assays 0.01–0.02 mU/l and fourth generation assays 0.001–0.002 mU/l. At the present time, the most sensitive commercially available TSH assays are third generation assays. The most widely used assays, however, are second generation. Only research laboratories which have extensively modified assay procedures are able to reach fourth generation technical performance [451].

Free TSH b- and a-subunit Measurements In 1974 the TSH b- and a-subunits were purified from human TSH and specific antibodies to them developed [453]. The availability of specific antibodies to free TSH band a-subunit allowed for the development of radioimmunoassays to these subunits. In general, measurements of free TSH b have not been clinically useful because they have been very concordant with measurements of intact TSH [454,455]. In addition, the free TSH b assay is not very sensitive and free TSH b-subunit levels are not detectable in either euthyroid subjects or patients with hyperthyroidism. In contrast, measurement of the free a-subunit has been useful in the evaluation of pituitary and placental disease because in these diseases, there can be discordances between free a-subunit levels and intact hormone levels. Free asubunit is detectable and measurable by radioimmunoassay in euthyroid and eugonadal human subjects [455–458]. More recently, immunometric assays for free a-subunit have

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FIGURE 5.18. Schematic representation of the generation system for thyroid-stimulating hormone (TSH) assay nomenclature. Each generation represents a 10-fold improvement in functional assay sensitivity. The black bars denote the 95% confidence limit of measurement. For example, at TSH levels of 0.01 to 0.02 mU/l with a 20% interassay coefficient of variation, third generation assays have a 95% confidence limit corresponding to the horizontal axis values indicated by the black bar. From Spencer [452].

FIGURE 5.19. Schematic representation of the use of sensitive thyroid-stimulating hormone (TSH) assays in patients with increasing free T4 levels. There is a log/linear relationship between serum TSH concentrations and free T4 concentrations.

been developed which reveal a normal range for free asubunit of 0.1–1.6 ng/mL [459]. Elevated values of free asubunit are found in the sera of patients with TSH-secreting or gonadotropin-secreting pituitary tumors [460–467], as well as choriocarcinoma [468]. Elevated free a-subunit levels have also been reported in a variety of non-pituitary and non-placental malignancies including cancers of the lung, pancreas, stomach, prostate, and ovary [469–476].

Provocative Testing of TSH Basal measurements of TSH and free a- or TSH b-subunits are best interpreted in the context of knowledge of free T4 and/or free T3 serum concentrations. The sensitive inverse and reciprocal negative feedback regulation between circulating free T4 levels and TSH secretion permits accurate diagnoses to be made (Fig. 5.19). However, under certain

circumstances provocative stimulation of TSH is necessary for a full understanding of the integrity of the hypothalamic–pituitary–thyroid axis. This subject has recently been reviewed [477]. The TRH stimulation test was developed to investigate the integrity of this axis. TRH is a hypothalamic tripeptide (pyroglutamyl-histidyl-prolineamide) that directly stimulates TSH biosynthesis and secretion. Given intravenously, intramuscularly or orally, TRH causes a reproducible rise in serum TSH levels in euthyroid subjects [134,218]. The test is performed by giving 200–500 mg of TRH intravenously and measuring TSH at 0, 20–30, 60, 120 and 180 minutes after injection. In euthyroid subjects, there is an immediate release of TSH rising to peak levels approximately 20–30 minutes after TRH injection, usually reaching values five- to 10-fold higher than basal [478,479]. Using third and fourth generation assays across a wide spectrum of normal and abnormal basal TSH levels,

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FIGURE 5.20. The relationship between basal and absolute (thyrotropinreleasing hormone [TRH]-stimulated minus basal thyroid-stimulating hormone [TSH]) TRH-stimulated TSH response in 1,061 ambulatory patients with an intact hypothalamic–pituitary (H–P) axis compared with that in untreated and T4-treated patients with central hypothyroidism. From Spencer et al. [451].

the increase of TSH after TRH stimulation has been between 2.8- and 22.9-fold [451] (Fig. 5.20). In hyperthyroid subjects with undetectable basal serum TSH levels, there is little or no response to TRH stimulation [449, 451]. Patients with low basal serum TSH levels secondary to pituitary insufficiency (secondary hypothyroidism) or hypothalamic disease (tertiary hypothyroidism) have absent or attenuated TSH responses to TRH [480,481]. In contrast, patients with elevated TSH levels due to primary hypothyroidism have exuberant responses to TRH stimulation. However, elevated TSH levels in patients with pituitary TSH-secreting tumors usually fail to respond to TRH stimulation [462] (Fig. 5.21).

DISORDERS OF TSH PRODUCTION Abnormalities in TSH secretion and the integrated circadian rhythms of pulsatile TSH secretion can be caused by diseases in the hypothalamus, pituitary and thyroid gland. In some instances, novel molecular mechanisms have precisely defined the causes of defective TSH secretion. In other instances, descriptive pathophysiology awaits more definitive mechanistic explanations for the disorders.

Hypothalamic Disorders Since the hypothalamus is the source of factors that have important effects on TSH production and secretion, diseases in this part of the brain can dramatically influence serum TSH levels. Theoretically, diseases which affect the production of the hypothalamic factors including TRH, SRIH, or dopamine could influence TSH production. Structural abnormalities in the hypothalamus have resulted in clinical hypothyroidism, which presumably is due to decreased or defective TRH production (Table 5.1). Unfortunately, this pathophysiological explanation for the hypothyroidism is theoretical, since accurate measurements of hypothalamically-derived TRH are not readily available. Measurements of TRH in peripheral plasma are difficult to interpret since the source of TRH in plasma is largely due to extrahypothalamic TRH production [482,483]. Nevertheless, indirect evidence has suggested that TRH deficiency plays an important role in the etiology of hypothyroidism in these cases. Indeed, exogenous administration of TRH to patients with hypothalamic hypothyroidism can restore serum thyroid hormone levels towards normal and result in clinical improvement [484,485]. Elevated SRIH or dopamine could also cause decreased TSH

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FIGURE 5.21. Schematic representation of thyrotropin-releasing hormone (TRH) stimulation tests in patients with a variety of thyroid disorders.

Table 5.1. Neoplasia

Infiltrative

Trauma

Infection

Vascular Congenital

Causes of hypothalamic hypothyroidism Pituitary adenoma Craniopharyngioma Dysgerminoma Meningioma Sarcoidosis Histiocytosis X Eosinophilic granuloma Radiation Head injury Post surgical Tuberculosis Fungus Virus Stalk interruption Midline defects Rathke’s pouch cysts

thus effecting hypothalamic hypothyroidism. Indeed, administration of GH has been associated with this syndrome [250,486], presumably by stimulating hypothalamic SRIH production. However, until measurements of hypothalamic SRIH secretion are available, this mechanism also remains theoretical. In fact, enhanced peripheral conversion of T4 to T3 induced by GH could have the same effect. Future studies involving the use of specific antagonists to the SRIH or dopamine receptors on pituitary thyrotropes may prove useful in unraveling specific causes of hypothalamic hypothyroidism. The serum levels of TSH in hypothalamic hypothyroidism may be either low, normal, or even minimally elevated [480,487–490]. The paradoxical finding of low serum thyroid hormone levels in association with normal or elevated basal TSH levels suggest that the circulating TSH in hypothalamic hypothyroidism is biologically defective [484,485,488]. In fact, TRH deficiency has been associated

FIGURE 5.22. Twenty-four hour thyroid-stimulating hormone (TSH) pulsations measured every 15 minutes in a patient with central hypothyroidism due to hypothalamic hypothyroidism (solid line) vs a normal control (dashed line). The nocturnal surge of TSH is not present in the patient with central hypothyroidism, although the pulse frequency is similar in both the patient and the normal control. From Samuels et al. [208].

with differences in glycosylation patterns of the TSH molecule which result in decreased TSH receptor binding and activation [163,485] (see pp. 182, 185 and 190). The 24hour secretory profile of TSH in patients with hypothalamic hypothyroidism is also abnormal [208,488,491,492]. The frequency of the TSH pulses is the same as euthyroid controls, but the amplitude of the pulses is decreased, particularly at night-time [208], resulting in a loss of the normal nocturnal surge (Fig. 5.22) (see p. 186).

Pituitary TSH Disorders Abnormal pituitary function can be the sole cause for altered TSH secretion. Increases or decreases in pituitary

Thyroid-stimulating Hormone

Chapter 5

opment of thyrotropes, somatotropes, and lactotropes, was found to have mutations in the coding region that alter the function of the Pit-1 protein or completely disrupt its structure. The absence of Pit-1 prevents normal pituitary development resulting in hypoplasia of the pituitary. In heterozygotes, where a normal allele is present, the abnormal Pit-1 protein can bind to DNA but not be able to effect transactivation, interfering with the function of the normal Pit-1 (dominant negative mechanism). This disorder often results in pituitary hypoplasia in addition to the hormone deficiencies. Interestingly, a similar combined hormone deficiency syndrome has been reported in two murine models in which the Pit-1 gene is defective: a point mutation found in the Snell dwarf (dw) and [12] and a major deletion in the Jackson dwarf (dwJ) [499]. A more frequent cause of CPHD has recently been delineated by the discovery of a new pituitary-specific transcription factor called “prophet of Pit-1” (PROP-1). This factor is a paired-like homeodomain protein in which a mutation in the murine species causes the Ames dwarf (df) mouse phenotype [22]. Subsequently, patients with CPHD were found to have mutations in the PROP-1 gene [500–502]. Most recently, 50% of families with CPHD have been shown to contain mutations in the PROP-1 gene [21], far exceeding the prevalence of mutations in the Pit-1 gene as a cause for CPHD. The mutations are all found in the homeodomain part of the molecule. Interestingly, the phenotype of patients with PROP-1 mutations includes deficiencies not only of GH, prolactin and TSH but also of LH and FSH. Furthermore, the development of hormone deficiencies may not be neonatal but rather progressively occur up to the age of adolescence (Fig. 5.23). To date no patient with these mutations has developed clinically relevant ACTH deficiency. Thus, congenital hypothyroidism due to pituitary TSH deficiency has been found at the molecular level to be due to germ cell point mutations of either the pituitary-specific

TSH production can be caused by either congenital or acquired abnormalities. Decreased Pituitary TSH Production–Congenital

Congenital hypothyroidism can be caused by a defective or absent production of TSH. It can present as isolated TSH deficiency or the TSH deficiency may be combined with other anterior pituitary defects. The patients are born with typical clinical features of congenital hypothyroidism, but are remarkable for the absence of a goiter. Circulating levels of free T4 and T3 are low and TSH levels are usually undetectable. In addition, serum TSH levels fail to increase with a standard TRH stimulation test. The disease is generally inherited as an autosomal recessive disorder, and affected individuals have severe mental and growth retardation. Molecular mechanisms which are responsible for the isolated TSH deficiency have been described in a limited number of cases (Table 5.2). In one family a single base substitution at nucleotide position 145 of the TSHb gene altered the CAGYC region [180,493], a critically important contact point for the noncovalent combination of the TSH b-and a-subunits (see p. 183). In another kindred, a single base substitution introduced a premature stop codon, resulting in a truncated TSH b-subunit which included only the first 11 amino acids [148]. In other cases, the disorder involves the production of biologically inactive TSH with loss of bcysteine105 [365,366,494], resulting in a similar phenotype, except that in some of these cases circulating TSH was detectable. Another cause of congenital pituitary TSH deficiency is combined pituitary hormone deficiency (CPHD). Subjects with this disorder have congenital hypothyroidism and growth retardation secondary to TSH, GH and prolactin deficiencies [495–498]. Within the last decade, molecular mechanisms for this unusual defect have been elucidated [16–19]. The pituitary-specific transcription factor Pit-1 (see p. 173), which is critically important for normal devel-

Table 5.2.

197

Congenital hypothyroidism: isolated TSH b defects I

II

III

Inheritance Syndrome Serum T4 Serum TSH Response to TRH Nucleotide change Protein defect

Autosomal recessive Cretinism Ø None detected None detected Missense, G145A G29R (CAGYC region) No combination with a

Autosomal recessive Cretinism Ø Ø Impaired Deletion, T410 C105V and frameshift. (seat-belt region) Inactive TSH

Reported cases

3 families in Japan [180]

Autosomal recessive Cretinism Ø None detected None detected Nonsense, G94T Premature stop (bL1 loop region) Truncated TSHb (11 amino acids) 2 families in Greece [148]

2 families in Brazil [365], 2 families in Germany [366,494]

100

35

GH TSH LH/FSH

80

Percentage

Hypothalamic–Pituitary Function

SECTION 1

28

60

21

40

14

20

7

0

0

2

4

6

8

10

12

14

16

18

Years

transcription factors PROP-1 or Pit-1 or the TSH b-subunit gene. Decreased Pituitary TSH Production–Acquired

The acquired causes of pituitary TSH deficiency generally relate to destructive processes in the anterior pituitary. These can include infiltrative or infectious disorders, compression secondary to neoplastic processes, or active ischemic and hemorrhagic processes involving the pituitary gland. The most common cause of acquired pituitary TSH deficiency is neoplastic destruction of normal anterior pituitary cells by either a primary pituitary neoplasm, a craniopharyngioma, or infiltrating metastatic disease to the pituitary. In acquired pituitary TSH deficiency multiple pituitary deficiencies are concomitantly associated; acquired isolated TSH deficiency is rarely, if ever, seen. When hypothyroidism is due to a pituitary disorder, the disease is called “secondary hypothyroidism,” and when due to a hypothalamic disorder (see p. 195) it is called “tertiary hypothyroidism.” Most patients with acquired pituitary TSH deficiency have symptoms of hypothyroidism as well as symptoms of LH, FSH, GH, and usually ACTH deficiency. Serum free T4 and T3 levels are low in association with a low or low/normal basal TSH level. The low basal TSH level fails to respond to TRH stimulation. It is often difficult to distinguish secondary and tertiary hypothyroidism. The basal levels of free T4, free T3 and TSH are similar in either etiology. However, in secondary hypothyroidism, the TSH response to TRH is usually completely absent [488,503–505] (Fig. 5.21). In contrast, tertiary hypothyroidism usually demonstrates a TSH response to TRH stimulation which is not absent, but rather delayed and attenuated, resulting in peak TSH values at 60 to 180 minutes after injection of TRH [488,506–510]. These patterns are different from that seen in normal controls and primary hypothyroidism, in which the peak TSH response to TRH stimulation is between 20 and 30 minutes follow-

20

22

0

Patients

198

FIGURE 5.23. The development of the hormonal deficiencies in 35 patients with gene mutations of the transcription factor Prophet of Pit-1 (PROP-1). The time of ocurrence of the specific hormone deficiency is indicated by the age of the patients in years. The data is expressed as a percentage of the patients on the left axis and as the number of patients on the right axis. All patients eventually showed evidence of all deficiencies, but these developed gradually over the years. GH, growth hormone; TSH, thyroid stimulating hormone; LH/FSH: luteinizing hormone/follicle stimulating hormone. From Deladoëy et al. [21].

ing the injection of TRH. Nevertheless, the TSH response to TRH is not a perfect discriminator between secondary and tertiary hypothyroidism, or between these disorders and a normal response [480,490,508]. The nocturnal surge of TSH found in normal subjects (see p. 183) does not occur in patients with either secondary or tertiary hypothyroidism, and its absence may prove to be a superior way of identifying patients with these disorders [208,491,492]. Finally, the basal serum prolactin concentration can sometimes be helpful in differentiating secondary from tertiary hypothyroidism. In secondary hypothyroidism the prolactin is usually low or normal if the destructive pituitary process is not a prolactinoma. In contrast, in tertiary hypothyroidism there is disruption of normal hypothalamic function, including the dopaminergic inhibitory tone on lactotrope cells, resulting in elevated serum prolactin levels. Increased Pituitary TSH Production–Primary

Most cases of elevated serum TSH levels are a result of primary thyroidal disease, not primary pituitary disease. However, two important causes of primary pituitary disease resulting in elevated levels of serum TSH have been described and extensively studied. TSH-secreting Pituitary Tumors

TSH-secreting pituitary tumors are rare neoplasms of the anterior pituitary. They comprise less than 1% of all pituitary tumors [511]. The clinical presentation, diagnostic work up, and therapeutic approach to TSH-secreting pituitary tumors will be discussed in Chapter 13. These tumors are characterized by a slow and indolent growth. Phenotypically, the cells are quite differentiated and synthesize the TSH b- and a-subunits characteristic of the normal thyrotropes. However, the a-subunit is synthesized in excess of the TSH b-subunit [460,462]. This phenomenon is useful in that a molar ratio of a-subunit : TSH of greater than 1 supports the diagnosis of a TSH-secreting pituitary tumor. The

Chapter 5

molecular basis for increased transcription of both the a- and TSH b-subunit genes and the excessive a-subunit gene transcription relative to the TSH b-subunit gene is

unknown. However, the defect does not appear to be the result of aberrantly initiated mRNAs for the TSH b- or asubunit. Both TSH b- and a-subunit mRNAs appear to be of sizes similar to those found in normal TSH cells [512]. Furthermore, the transcriptional initiation site of the TSH b-subunit has been mapped in a human TSH-secreting tumor and is consistent with the authentic start-site of normal TSH b-subunit gene transcription [512]. TSH-secreting tumors fail to respond to TRH stimulation [513–515] (Fig. 5.24). This reproducible finding might implicate a constitutive TRH receptor activation in the pathogenesis of these tumors. Detailed studies of the TRH receptor have not been performed in TSH-secreting tumors, but it is conceivable that there is constitutive activation of the TRH receptor due to a somatic cell mutation in the TRH receptor gene of the thyrotrope, similar to the mutation of the TSH receptor gene found in hyperfunctioning thyroid nodules [388]. Another characteristic of these tumors is their failure to respond to thyroid hormone by the normal negative feedback of thyroid hormone on TSH production, suggesting an abnormality in the TR. The altered TR expression may result from a posttranscriptional defect, since in two TSH-secreting tumors examined TRb and TRa mRNA levels were normal but the respective proteins were not detected [516]. Nevertheless, the combination of absent TRH and thyroid hormone responsiveness suggests that the defect in TSH-secreting tumors is very basic, capable of altering processes originating at the cell membrane (TRH response) and within the cell nucleus (T3 response). In contrast, inhibition of TSH release in response to SRIH is preserved in these tumors [511] (Fig. 5.24). This suggests that the pathogenetic mechanism resides proximal to the processes of hormone release. Thyroid Hormone Resistance Syndromes

Another group of pituitary gland disorders resulting in elevated levels of serum TSH are the thyroid hormone resis-

Thyroid-stimulating Hormone

199

tance syndromes [517–519]. In 1967, Refetoff et al. [520] were the first to describe three siblings who were clinically euthyroid or hypothyroid with goiters, stippled epiphyses, and deaf mutism. Each of the children had elevated levels of protein-bound iodide which were subsequently shown to be associated with high serum total and free thyroid hormone levels, elevated TSH levels, and peripheral tissue responses that were refractory to not only the endogenous high levels of thyroid hormone, but also exogenously administered supraphysiological levels of thyroid hormone [518]. Since 1967 over 700 cases of thyroid hormone resistance belonging to about 250 families have been identified [521,522]. It has become clear that there is a wide clinical spectrum in the phenotypic presentation of this disorder. At one end were cases exhibiting thyroid hormone resistance in virtually every tissue studied. In contrast, other cases were characterized more by pituitary resistance to thyroid hormone with peripheral responses similar to hyperthyroidism. Thus, the concept arose that there are two clinically distinct disorders: one, generalized resistance to thyroid hormone (GRTH) (Fig. 5.25), and the other, selective pituitary resistance to thyroid hormone (PRTH) (Fig. 5.26) [513,514]. This distinction is clinically important because cases with selective PRTH have clinical hyperthyroidism and warrant treatment of the hyperthyroidism, whereas those with GRTH are generally euthyroid and sometimes, in fact, hypothyroid. In these cases, treatment of hyperthyroxinemia with antithyroid drug therapy, radioactive iodine or surgery would be inappropriate [523]. Both disorders represent diagnostic dilemmas. Clinical presentations are often not characteristic of classic hyperthyroidism or hypothyroidism. Yet, the laboratory abnormalities are often quite spectacular, with dramatic elevations of thyroid hormone levels, inappropriately normal or elevated serum TSH levels, and elevated radioactive iodine uptake, with diffuse homogenous uptake in an enlarged thyroid gland [512–514]. The molecular basis in most cases of GRTH and PRTH is an abnormality in the thyroid hormone receptor (TR). There are two known TR genes: the TRa gene on

FIGURE 5.24. Thyroid-stimulating hormone (TSH) responses to various stimulation and suppression tests in a patient with a TSH pituitary tumor. Thyrotropinreleasing hormone (TRH) (500 mg intravenously) resulted in no TSH response, dopamine (4 mg/minute for 4 hours) resulted in no suppression of TSH secretion, SRIH (SRIF, 500 mg bolus followed by 250 mg/minute for 4 hrs) resulted in significant suppression of serum TSH levels.

200

SECTION 1

Hypothalamic–Pituitary Function

FIGURE 5.25. Generalized resistance to thyroid hormone is characterized by resistance to the action of thyroid hormone at both pituitary and peripheral tissues. The patient is euthyroid clinically with increased total and free thyroid hormone levels, and an increased or normal thyroid-stimulating hormone (TSH). From McDermott and Ridgway [517].

FIGURE 5.26. Selective pituitary resistance to thyroid hormone is characterized by resistance to the action of thyroid hormone at the level of the pituitary, but not peripheral tissues. Patients are hyperthyroid clinically, with elevated total and free thyroid hormone levels and increased or normal thyroid-stimulating hormone (TSH) levels. From McDermott and Ridgway [517].

FIGURE 5.27. Mutations of the T3 receptor b (TRb) gene in patients with generalized resistance to thyroid hormone (GRTH) are located in exons 9 and 10 which encode the T3 binding domain of the TRb receptor. From McDermott and Ridgway [517].

chromosome 17 and the TRb gene on chromosome 3 [524]. Both genes encode two different isoform products using alternative mRNA splicing. The TRa gene produces TRa1 and an a2 isoform which fails to bind thyroid hormone. The TRb gene produces two isoforms, TRb1 and TRb2 proteins, both of which bind thyroid hormone. The TRb2 isoform appears to be selectively expressed in the anterior pituitary gland and certain parts of the central nervous system. All thyroid hormone receptor isoforms are intranuclear proteins which interact with the DNA of genes influenced by thyroid hormone. Binding of thyroid hormone the receptor stimulates or suppresses transcription of the targeted gene. GRTH was found to be linked to the TRb gene locus

on chromosome 3 [525], and was then localized to point mutations in the ninth and tenth exons of the TRb gene [521,525,526] which encode for the T3-binding and adjacent hinge domains [517,527] (Fig. 5.27). These mutations usually disrupt normal T3 binding without altering DNA binding. Interaction with corepressors and coactivators has been shown to be altered in some cases [124,528,529]. In addition, GRTH has been described to occur in the absence of TRb or TRa mutations [522,530]. These cases may result from a mutation in one of those cofactors, analogous to mice deficient in steroid receptor coactivator 1, that exhibit a similar phenotype [123]. Most cases of GRTH are heterozygotes and inherited as autosomal dominant traits, with

Chapter 5

only half of their TRb receptors being abnormal. The mutated TRb1 receptor protein has been shown to be able to interfere with the function of other normal TRb1, TRb2 or TRa1 receptors, resulting in a dominant negative effect [526,531–533]. Rare individuals who are homozygous for the mutation have been reported and, in general, are more severely affected [534,535]. Cases of GRTH have also been described where a major complete TRb gene deletion results in the absence of TRb receptors. In these cases, the disorder was transmitted as an autosomal recessive and only homozygotes were affected [536]. TRa gene mutations have not been reported in GRTH [517]. The mutations in patients with PRTH have not been as widely studied. However, TRb gene mutations in the T3 binding domain have been found in PRTH [537–539]. Mutations found to be associated with PRTH appear to affect the activity of the pituitary-specific isoform TRb2 and not TRb1 [117]. However, it is interesting that patients classified as either GRTH or PRTH have been found to contain the same point mutation [537,538], and patients within a given kindred, thus having the same mutation, can also present phenotypically with either GRTH or PRTH. This phenotypic heterogeneity underlies the view that both syndromes represent different ends of the clinical spectrum of a common genetic disorder. Yet, it is helpful to separate these syndromes to direct the differential dignosis and clinical management.

GRTH In GRTH, the degree of resistance may vary from tissue to tissue, both within an individual and within a family. Affected individuals may be asymptomatic and discovered incidentally, whereas others may have nonspecific symptoms, mental retardation, short stature, hyperactivity, or even symptoms suggestive of hyperthyroidism [540–543].

Table 5.3. [517]

Thyroid-stimulating Hormone

The differential diagnosis of a clinically euthyroid subject with elevated total T4 and normal or elevated TSH can be difficult [544,545] (Table 5.3). It is also sometimes difficult to be sure whether the patient is in fact euthyroid, hypothyroid or hyperthyroid. When clinical findings are inconclusive, a variety of tissue markers may be useful. These include basal metabolic rate, cardiac systolic time intervals, serum levels of angiotensin converting enzyme, sex hormone binding globulin, ferritin, and gastrin. If all of these peripheral measures of thyroid hormone action are normal, then the patient can be categorized as having clinical euthyroidism. It is important then to exclude abnormalities of T4 binding by altered T4-binding proteins. If the patient also has no acute medical or psychiatric illness and is not taking amphetamines or amiodarone, then a presumptive diagnosis of GRTH may be made. This diagnosis can be confirmed by demonstrating that suppression of pituitary TSH secretion requires supraphysiological levels of T4 or T3. If the diagnosis of GRTH is made, treatment is generally contraindicated and may be harmful [523]. The increased thyroid hormone levels seen in this disorder are an appropriate and compensatory response to the elevated TSH levels that arise as a result of the pituitary resistance to circulating levels of thyroid hormone. Inadvertent administration of anti-thyroid drugs, radioactive iodine or surgical thyroidectomy needs to be avoided since these therapeutic modalities will lower thyroid hormone levels and result in hypothyroidism. Such iatrogenically induced hypothyroidism has clinical consequences, and requires treatment with supraphysiologic doses of thyroid hormone.

PRTH There are fewer reported cases of PRTH than GRTH and in many instances of PRTH detailed family studies have not been performed [513–515,517]. Both sporadic and familial

Causes of euthyroid hyperthyroxinemia. From McDermott and Ridgway

GRTH TBG excess FDH or TBPA excess Anti-T4 antibodies Acute medical illness Acute psychiatric Amphetamines Amiodarone, ipodate, iopanioc acid

201

Total T4

Total T3

T3 resin uptake

Free T4

Free T3

TSH

TRH Test

≠ ≠ ≠ ≠, Ø ≠ ≠ ≠ ≠

≠ ≠ N N Ø N ≠ Ø

N, ≠ Ø N N Ø, N, ≠ Ø, N N N

≠ N N N Ø – – ≠

≠ N N N ≠ – – Ø

N, ≠ N N N, ≠ N N N N, ≠

N, ≠ N N N, ≠ N Ø, N N ≠

T4, thyroxine; T3, triiodothyronine; TSH, thyroid-stimulating hormone; TRH, thyrotropin-releasing hormone; TBG, thyroxine-binding globulin; FDH, familial dysalbuminemic hyperthyroxinemia; TBPA, thyroxine-binding prealbumin; N, normal.

202

SECTION 1

Hypothalamic–Pituitary Function

cases have been reported, and the inheritance patterns of PRTH are incompletely clarified [517]. Patients with PRTH have clinical thyrotoxicosis and the evidence for clinical thyrotoxicosis is often overwhelming, including elevated levels of basal metabolic rate, fast cardiac systolic time intervals, and elevated serum concentrations of sex hormone binding globulin and angiotensin-converting enzyme. In other cases, the clinical presentation is much more subtle with only minor abnormalities found in the peripheral responses to thyroid hormone, for example, only a fast cardiac pulse rate. In the laboratory evaluation of PRTH, the TSH level is normal or elevated, a finding that clearly distinguishes it from all other primary thyroid disorders causing hyperthyroidism. Only one other disorder has clinical hyperthyroidism, high levels of thyroid hormone and inappropriately normal or elevated TSH values: the TSHsecreting tumor. Thus, a distinction between these two disorders is mandatory (Table 5.4). In TSH-secreting tumors, TSH fails to respond to TRH stimulation, whereas in PRTH there is an exuberant response [513–515]. Furthermore, patients with TSH-secreting tumors have elevated concentrations of free a-subunit with a-subunit : TSH molar ratios of greater than 1, whereas patients with PRTH have a-subunit : TSH molar ratios less than or equal to 1 [460–462,511]. Finally, patients with TSH-secreting pituitary tumors most commonly have very abnormal pituitary glands morphologically reflected in abnormal structural studies of the pituitary, whereas cases with PRTH have normal pituitary radiographic images [511]. Since patients with PRTH and TSH-secreting pituitary tumors both have clinical hyperthyroidism, treatment is warranted. Direct ablation of the thyroid gland by radioactive iodine or surgery has been used successfully in both. Ideally, TSH-secreting pituitary tumors should be treated first with transsphenoidal resection in an attempt to remove the tumorous source of excessive TSH production. In contrast, pituitary surgery for PRTH would not be successful unless a total hypophysectomy was performed. Since TSH overproduction is the primary defect in PRTH, many attempts

Table 5.4. Causes of thyroid-stimulating hormone (TSH)mediated hyperthyroidism. From McDermott and Ridgway [517]

Symptoms Total and free T4 Total and free T3 TSH TSH response to TRH a-Subunit a/TSH molar ratio

PRTH

TSH Tumor

Thyrotoxicosis ≠ ≠ N/≠ ≠ N £1

Thyrotoxicosis ≠ ≠ N/≠ Flat ≠/N >1

T4, thyroxine; T3, triiodothyronine; TRH, thyrotropin-releasing hormone; PRTH, pituitary resistance to thyroid hormone; a/TSH molar ratio, (a-subunit [ng/ml] ∏ TSH [mU/l] ¥ 10); N, normal.

have been made to develop alternative medical therapies to suppress the TSH hypersecretion. These include L-T3 [546], D-T4 [547,548], and triiodothyrocetic acid administration [549–551]. None of these have been universally successful. More recently, the use of octreotide, a SRIH analog, and bromocriptine have both been shown to acutely reduce TSH and thyroid hormone levels [552–558]. Unfortunately, neither have been effective over longer therapeutic intervals and rebound elevations of the serum thyroid hormone levels, with escape from pituitary TSH suppression, have occurred. Altered Pituitary TSH Production–Secondary

The most common way that pituitary TSH production is influenced is via its inverse relationship with circulating levels of thyroid hormone. Thus, elevated levels of free T4 and free T3 cause a decrease in pituitary TSH synthesis and secretion. In contrast, decreases in circulating free T4 or free T3 levels cause a dramatic augmentation in pituitary TSH production (see pp. 178 and 187). In human studies, measurements of serum TSH levels using immunometric assays have shown an inverse linear relationship between serum TSH levels and circulating levels of thyroid hormone (Fig. 5.19). Patients with clinical hypothyroidism have dramatic elevations of serum TSH, whereas those with clinical hyperthyroidism have low or absent levels of circulating TSH. As the measurements for TSH have improved from first to fourth generation TSH assays, patients with hyperthyroidism have been found to have lower and lower serum TSH levels [449–452] (Fig. 5.18). Using fourth generation TSH assays, patients with hyperthyoidism either have TSH levels below the detection level of 0.001 mU/l, or very low levels in the range of 0.001 to 0.005 mU/l [451]. These extraordinarily low serum TSH levels found in hyperthyroidism suggest that the thyrotrope is exquisitely sensitive to elevated levels of thyroid hormone. The mechanisms responsible for this are currently under active investigation. Thyroid hormone decreases transcription from the TRH gene in the hypothalamus [297,298], and at the level of the pituitary it decreases both the a and TSHb gene transcription [101,102] (see p. 178). In hypothyroidism, transcription of the a- and TSHb-subunit genes has been found to be dramatically elevated [101,102,112,559]. Thyroid hormone also inhibits TSH secretion from the thyrotrope (see p. 187). In fact, it transiently increases cellular content of TSH [111,560]. Thyroid hormone influences TSH secretory pulse amplitude but not frequency [305,561]. Finally, elevated levels of thyroid hormone cause a 20% to 30% increase in TSH metabolic clearance rate, whereas the opposite is seen with hormone deficiency [188]. Thus, the effects of thyroid hormone on TSH serum profiles are multifactorial, involving effects at the level of the hypothalamus, pituitary and peripheral TSH clearance. The differential diagnosis of a low serum TSH level includes any primary thyroid disorder causing elevated

Chapter 5

circulating levels of thyroid hormone (Table 5.5). The most common cause is excessive thyroid hormone administration. Low serum TSH levels may be found in euthyroid sick syndrome during the early acute phases, in various causes of hyperthyroidism, or following the administration of superphysiological dopamine or glucocorticoids, as well as hypopituitarism. In contrast, an elevated serum TSH level may be due to any primary thyroid disorder which lowers circulating levels of thyroid hormone (Table 5.6). In the USA, the most common causes are autoimmune thyroiditis, ablation of the thyroid gland by radioactive iodine, surgical removal of the thyroid gland, or antithyroid drugs. In third world countries, iodine deficiency is still a common cause of defective thyroid hormone production and elevated serum TSH levels. Rarely, it is due to a TSH-secreting pituitary tumor. Subclinical Hyperthyroidism and Hypothyroidism

Subclinical hyperthyroidism and subclinical hypothyroidism are terms that refer to clinical syndromes in which the only abnormality in the diagnostic evaluation is an alteration of the serum TSH concentration. Specifically, in subclinical hyperthyroidism the TSH level is low, usually ranging between 0.005 and 0.5 mU/l, whereas in subclinical hypothyroidism the basal serum TSH concentration is elevated, usually greater than 5 mU/l. The patients generally do not present with clinical symptoms that would be diagnostic of either hyperthyroidism or hypothyroidism. Further-

Table 5.5. Differential diagnosis of a low sensitive thyroidstimulating hormone level L-thyroxine therapy Euthyroid sick syndrome Hyperthyroidism Graves’ disease Hyperfunctioning thyroid nodule Hyperfunctioning multinodular goiter Subacute thyroiditis Painless thyroiditis Glucocorticoids Dopamine Hypopituitarism

Table 5.6. Differential diagnosis of a high sensitive thyroidstimulating hormone (TSH) level Autoimmune thyroiditis Ablation of the thyroid gland Radioactive iodine Thyroidectomy Anti-thyroid drugs Iodine deficiency TSH-secreting pituitary tumors

Thyroid-stimulating Hormone

203

more, the serum concentrations of free T4 and free T3 are within the normal range. Thus, the subclinical designation refers to the fact that physicians cannot make a clinical diagnosis because the disorder is either very mild or early in its evolution. These disorders have been widely identified because the immunometric TSH assays amplify the sensitivity and specificity of abnormal serum TSH levels. The sensitivity of the assays is so highly developed that abnormalities in TSH secretion are found before serum circulating thyroid hormone levels fall or rise outside of the normal range, and certainly before classical clinical symptoms occur. The differential diagnosis of subclinical hyperthyroidism and hypothyroidism is the same as that described above for the clinical disorders (Tables 5.5 and 5.6). However, the most common cause of subclinical hyperthyroidism is inadvertent administration of excessive amounts of thyroid hormone. Iatrogenic subclinical hyperthyroidism is very common and may occur in as many as a third of patients taking thyroid hormone for replacement therapy [450]. More importantly, subclinical hyperthyroidism has long-term consequences and is not merely a biochemical curiosity. Premature osteoporosis, increased cardiac chronotropy and ionotropy, increased cardiac atrial premature beats, increased left ventricular mass and deteriorating quality of life scores all provide compelling evidence that a low serum TSH level represents an important biologic signal [562–564]. Conversely, the most common cause of subclinical hypothyroidism is inadequate treatment of primary hypothyroidism with thyroid hormone, that occurs in as many as a fifth of patients on thyroid hormone replacement therapy [450]. The abnormal serum TSH level in subclinical hypothyroidism reflects important biological disturbances including reduced cardiac chronotropy and ionotropy, increased serum lipid levels, decreased neurophysiological performance, and decreased quality of life [565–569]. Recently, Haddow et al. reported that mild hypothyroidism in pregnant women (mean TSH 13 mU/l) was associated with slightly lower neurophysiological performance in the euthyroid offspring evaluated through age 7 to 9, and showed that treatment, even when inadequate, resulted in an improvement [570]. This suggests that correcting subclinical hypothyroidism may be critical for the early stages of development. In conclusion, controversy still exists on the question of whether isolated abnormalities in serum TSH levels without definitive clinical symptoms warrant therapy or are merely insignificant biochemical aberrations. However, the majority of evidence would favor the view that isolated increases or decreases in serum TSH levels deserve a thorough evaluation and, in most instances, the abnormal TSH level is an important signal and needs therapeutic intervention. USE OF RECOMBINANT THYROTROPIN Using recombinant DNA technology, human TSH has been produced in Chinese hamster ovary cells and purified for

204

SECTION 1

Hypothalamic–Pituitary Function

use in human subjects [156,571]. The most important current approved indication for the use of recombinant human TSH (rhTSH) is for the diagnostic follow-up evaluation of patients who have been previously treated for differentiated thyroid cancer [572]. Two Phase III studies [573,574] have shown that daily intramuscular injections (0.9 mg) of rh TSH for 2 days produces elevated serum TSH concentrations (50–150 mU/l) which remain above 25 mU/l for 4 days. Such substantial increases in serum TSH levels provide an effective stimulus for radioactive iodine incorporation and thyroglobulin release by residual normal or malignant thyroid tissue. Current practice recommends performing radioactive iodine whole body scans and thyroglobulin measurements in the hypothyroid state when endogenous high serum TSH levels stimulate potential residual or cancerous thyroid cells. Comparisons of whole body scans and serum thyroglobulin levels during stimulation with rhTSH while the patient is taking thyroid hormone suppressive therapy versus during hypothyroidism after thyroid hormone withdrawal shows equivalent, though not identical, results [574]. The overall detection of residual normal thyroid tissue or thyroid cancer using rhTSH was 90% of that detected during hypothyroidism following thyroid hormone withdrawal. In addition, the detection of metastatic disease using rhTSH was 100% of that detected by hypothyroid whole body scanning and serum thyroglobulin measurements. Such comparative studies convincingly demonstrated that patients strongly preferred having the whole body scans and serum thyroglobulin measurements performed after rhTSH while taking thyroid hormone therapy because of the absence of hypothyroid symptomatology, resulting in an improved quality of life. Based on this evidence, rhTSH has been approved for the diagnostic follow-up evaluations of patients with treated differentiated thyroid cancer. Future uses of this product await appropriate prospective studies but may include therapy of thyroid cancer, the diagnostic evaluation of central hypothyroidism, or the therapy of cases of hyperthyroidism where the uptake may be enhanced by stimulation with rhTSH. ACKNOWLEDGMENT The authors would like to thank Linda Trefry for excellent secretarial assistance. REFERENCES 1 Voss JW, Rosenfeld MG. Anterior pituitary development: short tales from dwarf mice. Cell 1992;70:527–530. 2 Treier M, Gleiberman AS, O’Connell SM et al. Multistep signaling requirements for pituitary organogenesis in vivo. Genes and Dev 1998;12: 1691–1704. 3 Hermesz E, Mackem S, Mahon KA. Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke’s pouch of the mouse embryo. Development 1996;122:41–52. 4 Lamonerie T, Tremblay JJ, Lanctot C et al. Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes and Dev 1996;10:1284–1295.

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autoimmune thyroid disease and nonhomologous with gonadotropin receptors. Relationship of functional and immunogenic domains. J Biol Chem 1991;266:19413–19418. Stein SA, Oates EL, Hall CR et al. Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse. Mol Endocrinol 1994;8:129–138. Refetoff S, Sunthorntepvarakul T, Gottschalk ME, Hayashi Y. Resistance to thyrotropin and other abnormalities of the thyrotropin receptor. Recent Prog Horm Res 1996;51:97–120. Abramowicz MJ, Duprez L, Parma J et al. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest 1997;99: 3018–3024. Costagliola S, Sunthorntepvarakul T, Migeotte I et al. Structure-function relationships of two loss-of-function mutations of the thyrotropin receptor gene. Thyroid 1999;9:995–1000. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid 1999;9:735–740. Grossmann M, Szkudlinski MW, Wong R et al. Substitution of the seat-belt region of the thyrotropin (TSH)-b subunit with the corresponding regions of the choriogonadotropin or follitropin confers luteotropic, but not follitropic, activity to chimeric TSH. J Biol Chem 1997;272:15532– 15540. Leinung MC, Bergert ER, McCormick DJ, Morris JC. Synthetic analogs of the carboxyl-terminus of b-thyrotropin: the importance of basic amino acids in receptor binding activity. Biochemistry 1992;31:10094–10098. Medeiros-Neto G, Herodotou DT, Rajan S et al. A circulating biologically inactive thyrotropin caused by a mutation in the b subunit gene. J Clin Invest 1996;97:1250–1256. Biebermann H, Liesenkotter KP, Emeis M et al. Severe congenital hypothyroidism due to a homozygous mutation of the bTSH gene. Pediatr Res 1999;46:170–173. Leinung MC, Reed DK, McCormick DJ et al. Further characterization of the receptor-binding region of the thyroid-stimulating hormone a-subunit. Proc Natl Acad Sci USA 1991;88:9707–9711. Grossmann M, Szkudlinski MW, Tropea JE et al. Expression of human thyrotropin in cell lines with different glycosylation patterns combined with mutagenesis of specific glycosylation sites: characterization of a novel role for the oligosaccharides in the in vitro and in vivo bioactivity. J Biol Chem 1995;270:29378–29385. Szkudlinski MW, Thotakura NR, Weintraub BD. Subunit-specific functions of N-linked oligosaccharides in human thyrotropin: role of terminal residues of a- and b-subunit in metabolic clearance and bioactivity. Proc Natl Acad Sci USA 1995;92:9062–9066. Thotakura NR, Desai RK, Szkudlinski MW, Weintraub BD. The role of the oligosaccharide chains of thyrotropin a- and b-subunits in hormone action. Endocrinology 1992;131:82–88. Renwick A, Wiggin P. An antipodean perception of the mode of action of glycoprotein hormones. FEBS Lett 1992;297:1–3. Davies TF, Platzer M. hCG-induced receptor activation and growth acceleration in FRTL-5 thryoid cells. Endocrinology 1986;118:2149–2151. Tomer Y, Huber GK, Davies TF. Human chorionic gonadotropin (hCG) interacts directly with recombinant human TSH receptors. J Clin Endo and Metab 1992;74:1477–1479. Yoshimura M, Hershman JM, Pang XP et al. Activation of the thyrotropin (TSH) receptor by human chorionic gonadotropin and luteinizing hormone in Chinese hamster ovary cells expressing functional human TSH receptors. J Clin Endo and Metab 1993;77:1009–1013. Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonadotropin. Thyroid 1995;5:425–434. Rodien P, Bremont C, Sanson ML et al. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 1998;339:1823–1826. Chazenbalk GD, Nagayama Y, Russo D et al. Functional analysis of the cytoplasmic domains of the human thyrotropin receptor by site-directed mutagenesis. J Biol Chem 1990;265;20970–20975. Parmentier M, Libert F, Maenhaut C et al. Molecular cloning of the thyrotropin receptor. Science 1989;246:1620–1622. Wolff J, Jones AB. The purification of bovine thyroid plasma membranes and the properties of membrane-bound adenyl cyclase. J Biol Chem 1971;246: 3939–3947. Yamashita K, Field JB. Preparation of thyroid plasma membranes containing TSH-responsive adenyl cyclase. Biochem Biophys Res Commun 1970;40: 171–178.

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381 Philip NJ, Grollman EF. Thyrotropin and norepinephrine stimulate the metabolism of phosphoinositides in FRTL-5 thyroid cells. FEBS Lett 1986;202:193–196. 382 Field JB, Ealey PA, Marshall NJ, Cockcroft S. Thyroid-stimulating hormone stimulates increases in inositol phosphates as well as cyclic AMP in the FRTL5 rat thyroid cell line. Biochem J 1987;247:519–524. 383 Laurent E, Mockel J, Van Sande J et al. Dual activation by thyrotropin of the phospholipase C and cyclic AMP cascades in human thyroid. Mol Cell Endocrinol 1987;52:273–278. 384 Van Sande J, Parma J, Tonacchera M et al. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endo and Metab 1995;80: 2577–2585. 385 Chazenbalk GD, Kakinuma A, Jaume JC et al. Evidence of negative cooperativity among human thyrotropin receptors overexpressed in mammalian cells. Endocrinology 1996;137:4586–4591. 386 Esapa CT, Duprez L, Ludgate M et al. A novel thyrotropin receptor mutation in an infant with severe thyrotoxicosis. Thyroid 1999;9:1005–1010. 387 Nogueira CR, Kopp P, Arseven OK et al. Thyrotropin receptor mutations in hyperfunctioning thyroid adenomas from Brazil. Thyroid 1999;9:1063– 1068. 388 Parma J, Duprez L, Van Sande J et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993; 365:649–651. 389 Gabriel EM, Bergert ER, Grant CS et al. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. J Clin Endo and Metab 1999;84:3328– 3335. 390 Kosugi S, Okajima F, Ban T et al. Mutation of alanine 623 in the third cytoplasmic loop of the rat thyrotropin (TSH) receptor results in a loss in the phosphoinositide but not cAMP signal induced by TSH and receptor autoantibodies. J Biol Chem 1992;267:24153–24156. 391 Cooper E, Spaulding SW. Hormonal control of the phosphorylation of histones, HMG protein and other nuclear proteins. Mol Cell Endocrinol 1985;39:1–20. 392 Contor L, Lamy F, Lecocq R et al. Differential protein phosphorylation in induction of thyroid cell proliferation by thyrotropin, epidermal growth factor or phorbol ester. Mol Cell Biol 1988;8:2494–2503. 393 Ericson LE. Exocytosis and endocytosis in the thyroid follicle cell. Mol Cell Endocrinol 1981;22:1–24. 394 Nilsson M, Engstrom G, Ericson LE. Graded response in the individual thyroid follicle cell to increasing doses of TSH. Mol Cell Endocrinol 1986;44:165–169. 395 Collins WT, Capen CC. Ultrastructural and functional alterations of the rat thyroid gland produced by polychlorinated biphenyls compared with iodide excess and deficiency, and thyrotropin and thyroxine administration. Virchows Arch 1980;33:213–231. 396 Nielsen TB, Ferdows MS, Brinkley BR, Field JB. Morphological and biochemical responses of cultured thyroid cells to thyrotropin. Endocrinology 1985;116:788–797. 397 Roger PP, Rukaert F, Lamy F et al. Actin stress fiber disruption and tropomyosin isoform switching in normal thyroid epithelial cells stimulated by thyrotropin and phorbol esters. Exp Cell Res 1989;182:1–13. 398 Knopp J, Stolc V, Tong W. Evidence for the induction of iodide transport in bovine thyroid cells treated with thyroid stimulating hormone or dibutyryl cyclic adenosine 3¢5¢ monophosphate. J Biol Chem 1970;245:4403–4408. 399 Damante G, Chazenbalk G, Russo D et al. Thyrotropin regulation of thyroid peroxidase mesenger ribonucleic acid levels in cultured rat thyroid cells: evidence for involvement of a non-transcriptional mechanism. Endocrinology 1989;124:2889–2894. 400 Corda D, Kohn LD. Phorbol myristate acetate inhibits adrenergically but not thyrotropin-regulated function in FRTL-5 rat thyroid cells. Endocrinology 1987;120:1152–1160. 401 Burke G. Effects of iodide on thyroid stimulation. J Clin Endo and Metab 1970;30:76–84. 402 Tosta Z, Chabaud O, Chebath J. Identification of thyroglobulin mRNA sequences in the nucleus and cytoplasm of cultured thyroid cells: a fast transcriptional effect of thyrotropin. Biochem Biophys Res Commun 1983; 116:54–61. 403 Bybee A, Tuffery AR. Rapid proliferative response of rat thyroid gland to a single injection of TSH in vivo. J Endocrinol 1989;121:27–30. 404 Ealey P, Ahene CA, Emmerson JM, Marshall NJ. Forskolin and thyrotropin stimulation of rat FRTL-5 thyroid cell growth: the role of cyclic AMP. J Endocrinol 1987;114;199–205. 405 Van Sande J, Lefort A, Beebe S. Pairs of cyclic AMP analogues that are

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specifically synergistic for type I and type II cAMP dependent protein kinase mimic thyrotropin effects on the function, differentiation expression and mitogenesis of dog thyroid cells. Eur J Biochem 1989;183:699–708. Karsenty G, Alquier C, Jelsema C, Weintraub BD. Thyrotropin induces growth and iodothyronine production in a human thyroid cell line without affecting adenosine 3¢5¢ monophosphate production. Endocrinology 1988;123: 1977–1983. Tramontano D, Moses AC, Veneziani BM, Ingbar SH. Adenosine 3¢5¢monophosphate mediates both the mitogenic effect of thyrotropin and its ability to amplify the response to insulin-like growth factor I in FRTL-5 cells. Endocrinology 1988;122:127–132. Westermark K, Westermark B, Karlsson FA, Ericson LE. Location of epidermal growth factor receptors in porcine thyroid follicle cells and receptor regulation by thyrotropin. Endocrinology 1986;118:1040–1046. Tramontano D, Chin WW, Moses AC, Ingbar SH. Thyrotropin and dibutyryl cyclic AMP increase levels of c-myc and c-fos mRNAs in cultured rat thyroid cells. J Biol Chem 1986;261:3919–3922. Kawakami A, Eguchi K, Matsouka N et al. Thyroid-stimulating hormone inhibits Fas antigen-mediated apoptosis of human thyrocytes in vitro. Endocrinology 1996;137:3163–3169. Tilly JL, Tilly KI, Kenton ML, Johnson AL. Expression of members of the Bcl-2 gene family in the immature rat ovary: equine gonadotropin-mediated inhibition of granulosa cell apoptosis is associated with decreased Bax and constitutive Bcl-2 and Bcl-xlong messenger ribonucleic acid levels. Endocrinology 1995;136:232–241. Tilly KI, Banerjee S, Banerjee PP, Tilly JL. Expression of the p53 and Wilms’ tumor suppressor genes in the rat ovary: gonadotropin repression in vivo and immunohistochemical localization of nuclear p53 protein to apoptotic granulosa cells of atretic follicles. Endocrinology 1995;136:1394–1402. Grossmann M, Szkudlinski MW, Dias JA et al. Site-directed mutagenesis of amino acids 33–44 of the common a-subunit reveals different structural requirements for heterodimer expression among the glycoprotein hormones and suggests that cAMP production and growth promotion are potentially dissociable functions of hTSH. Mol Endocrinol 1996;10:769–779. Field JB, Dekker A, Titus G et al. In vitro and in vivo refractoriness to thyrotropin stimulation of iodine organification and thyroid hormone secretion. J Clin Invest 1979;64:265–271. Shuman SJ, Zor U, Chayoth R, Field JB. Exposure of thyroid slices to thyroid-stimulating hormone induces refractoriness of the cyclic AMP system to subsequent hormone stimulation. J Clin Invest 1976;57:1132–1141. Chazenbalk GD, Nagayama Y, Kaufman KD, Rapoport B. The functional expression of recombinant human thyrotropin receptors in non-thyroidal eukaryotic cells provides evidence that homologous desensitization to thyrotropin stimulation requires a cell-specific factor. Endocrinology 1990;127:1240–1244. Barnes NDH AB, Ryan RJ. Sexual maturation in juvenile hypothyroidism. Mayo Clin Proc 1973;48:849–856. Anasti JN, Flack MR, Froelich J et al. A potential novel mechanism for precocious puberty in juvenile hypothyroidism. J Clin Endo and Metab 1995;80:276–279. Nagayama Y, Yamasaki H, Takeshita A et al. Thyrotropin binding specificity for the thyrotropin receptor. J Endocrinol Invest 1995;18:283–287. Paschke R, Vassart G, Ludgate M. Current evidence for and against TSH receptor being the common antigen in Graves’ disease and thyroid associated ophthalmopathy. Clin Endocrinol (Oxf.) 1995;42:565–569. Peele ME, Carr FE, Baker JR et al. TSHb subunit gene expression in human lymphocytes. Am J Med Sci 1993;305:1–7. Endo T, Ohta K, Haraguchi K, Onaya T. Cloning and functional expression of thyrotropin receptor cDNA from fat cells. J Biol Chem 1995;270: 10833–10837. Haraguchi K, Shimura H, Kawaguchi A et al. Effects of thyrotropin on the proliferation and differentiation of cultured rat preadipocytes. Thyroid 1999;9:613–619. Morris JC. Structure and function of the TSH receptor: its suitability as a target for radiotherapy. Thyroid 1997;7:253–258. Weintraub BD, Szkudlinski MW. Development and in vitro characterization of human recombinant thyrotropin. Thyroid 1999;9:447–450. McKenzie JM. The bioassay of thyrotropin in serum. Endocrinology 1958; 63:372–382. Bakke JL, Lawrence N, Arnett F, MacFadden W. The fractionation of exogenous and endogenous thyroid-stimulating hormone from human and rat plasma and tissues. J Clin Endo and Metab 1961;21:1280–1289. D’Angelo SA. Blood thyrotropin levels in thyrotoxic patients before and after hypophysectomy. J Clin Endo and Metab 1963;23:229–234.

Chapter 5 429 Utiger RD, Odell WD, Condliffe PG. Immunologic studies of purified human and bovine thyrotropin. Endocrinology 1963;73:359–365. 430 Odell WD, Wilber JF, Paul WE. Radioimmunoassay of thyrotropin in human serum. J Clin Endo and Metab 1965;25:1179–1188. 431 Utiger RD. Radioimmunoassay of human plasma thyrotropin. J Clin Invest 1965;44:1277–1286. 432 Odell WD, Wilber JF, Utiger RD. Studies of thyrotropin physiology by means of radioimmunoassay. Recent Prog Horm Res 1967;23;47–78. 433 Mayberry WE, Gharib H, Bilstad JM. Radioimmunoassay for human thyrotropin: clinical value in patients with normal and abnormal thyroid function. Ann Int Med 1971;74:471–480. 434 Hershman JM, Pittman Jr JA. Utility of the radioimmunoassay of serum thyrotropin in man. Ann Int Med 1971;74:481–490. 435 Patel YC, Burger HG, Hudson B. Radioimmunoassay of serum thyrotropin: sensitivity and specificity. J Clin Endo and Metab 1971;33:768–774. 436 Ridgway EC, Weintraub BD, Cevallos JL et al. Suppression of pituitary TSH secretion in the patient with a hyperfunctioning thyroid nodule. J Clin Invest 1973;52:2783–2792. 437 Nisula BC, Louvet J-P. Radioimmunoassay of thyrotropin concentrated from serum. J Clin Endo and Metab 1978;46:729–733. 438 Wehmann RE, Rubenstein HA, Nisula BC. A sensitive, convenient radioimmunoassay procedure which demonstrates that serum hTSH is suppressed below the normal range in thyrotoxic patients. Endocr Res Commun 1979;6:249–255. 439 Wehmann RE, Gregerman RI, Burns WH et al. Suppression of thyrotropin in the low-thyroxine state of severe nonthyroidal illness. N Engl J Med 1985; 312:546–552. 440 Ridgway EC, Ardisson LJ, Meskell MJ et al. Monoclonal antibody to human thyrotropin. J Clin Endo and Metab 1982;55:44–48. 441 Ridgway EC. Thyrotropin radioimmunoassays: Birth, life and demise. Mayo Clin Proc 1988;63(10):1028–1034. 442 Ishikawa E, Imagawa M, Yoshitake S et al. Major factors limiting sensitivity of sandwich enzyme immunoassay for ferritin, immunoglobulin E and thyroidstimulating hormone. Ann Clin Biochem 1982;19:379–384. 443 Seth J, Kellett HA, Caldwell G et al. A sensitive immunoradiometric assay for serum thyroid stimulating hormone: a replacement for the thyrotrophin releasing hormone text? Br Med J 1984;289:1334–1336. 444 Wood WG, Waller D, Hantke U. An evaluation of six solid-phase thyrotropin (TSH) kits. J Clin Chem Clin Biochem 1985;23:461–471. 445 Odell WD, Griffin J, Zahradnik R. Two-monoclonal-antibody sandwich-type assay for thyrotropin, with use of an avidin-biotin separation technique. Clin Chem 1986;32:1873–1878. 446 Van Heyningen V, Abbott SR, Daniel SG et al. Development and utility of a monoclonal-antibody-based, highly sensitive immunoradiometric assay of thyrotropin. Clin Chem 1987;33:1387–1390. 447 Klee GG, Hay ID. Assessment of sensitive thyrotropin assays for an expanded role in thyroid function testing proposed criteria for analytic performance and clinical utility. J Clin Endo and Metab 1987;64:461–471. 448 Ross DS. New sensitive immunoradiometric assays for thyrotropin. Ann Int Med 1986;104:718–720. 449 Spencer CA, LoPresti JS, Patel A et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endo and Metab 1990;70:453–460. 450 Ross DS, Daniels GH, Gouveia D. The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an outpatient endocrine clinic. J Clin Endo and Metab 1990;71:764–769. 451 Spencer CA, Schwarzbein D, Guttler RB et al. Thyrotropin (TSH)-releasing hormone stimulation test responses employing third and fourth generation TSH assays. J Clin Endo and Metab 1993;76:494–498. 452 Spencer C. New Roles for TSH Measurement in Thyroid Testing. Thyroideducational Series, Monograph 4, Rochester: Kodak Clinical Diagnostics Ltd., 1992. 453 Kourides IA, Weintraub BD, Levko MA et al. A and b subunits of human thyrotropin: purification and development of specific radioimmunoassays. Endocrinology 1974;94:1411–1421. 454 Kourides IA,Weintraub BD, Ridgway EC, Maloof F. Increase in the b subunit of human TSH in hypothyroid serum after thyrotropin releasing hormone. J Clin Endo and Metab 1973;37:836–840. 455 Kourides IA, Weintraub BD, Ridgway EC, Maloof F. Pituitary secretion of free a and b-subunit of human thyrotropin in patients with thyroid disorders. J Clin Endo and Metab 1975;40:872–885. 456 Bigos ST, Ridgway EC, Kourides IA, Maloof F. The spectrum of pituitary alterations with mild and severe thyroid impairment. J Clin Endo and Metab 1978;46:317–325.

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457 Kourides IA, Weintraub BD, Re RN et al. Thyroid hormones, estrogen, and glucocorticoid effect on two different pituitary glycoprotein hormone asubunit pools. Clin Endocrinol (Oxf.) 1978;9:535–542. 458 Kourides IA, Ridgway EC, Maloof F. Discordant responses of TSH and its free a and b-subunits after TRH with incremental thyroid hormone replacement in primary hypothyroidism. J Clin Endo and Metab 1979;49:700–705. 459 Grover AS, Griffin J, Odell W. An ultra-sensitive, specific, 2nd antibody immunoradiometric assay for the free a subunit. Clin Chem 1986;32(10):1873–1878. 460 Kourides IA, Weintraub BD, Rosen SW et al. Secretion of a-subunit of glycoprotein hormones by pituitary adenomas. J Clin Endo and Metab 1976;43:97–106. 461 Kourides IA, Re RN, Weintraub BD et al. Metabolic clearance and secretion rates of subunits of human thyrotropin. J Clin Invest 1977;59:508– 516. 462 Kourides IA, Ridgway EC, Weintraub BD et al. Thyrotropin-induced hyperthyroidism: use of a and b-subunit levels to identify patients with pituitary tumors. J Clin Endo and Metab 1977;45:534–543. 463 Ridgway EC, Klibanski A, Ladenson PW et al. Pure a-secreting pituitary adenomas. N Engl J Med 1981;304:1254–1259. 464 Klibanski A, Ridgway EC, Zervas NT. Pure a-subunit secreting pituitary tumors. J Neurosurg 1983;59:585–589. 465 Borges JLC, Ridgway EC, Kovacs K et al. Follicle-stimulating hormonesecreting pituitary tumor with concomitant elevation of serum a-subunit levels. J Clin Endo and Metab 1984;58:937–941. 466 Vance ML, Ridgway EC, Thorner MO. FSH and a-subunit secreting pituitary tumor treated with bromocriptine. J Clin Endo and Metab 1985;61:580–584. 467 Klibanski A, Deutsch PJ, Jameson JL et al. Luteinizing hormone-secreting pituitary tumor: biosynthetic characterization and clinical studies. J Clin Endo and Metab 1987;64:536–542. 468 Blackman MR, Weintraub BD, Rosen SW et al. Human placental and pituitary glycoprotein hormones and their subunits as tumor markers: a quantitative assessment. J Natl Cancer Inst 1980;65:81–93. 469 Muggia FM, Rosen SW, Weintraub BD et al. Ectopic placental proteins in nontrophoblastic tumors: serial measurements following chemotherapy. Cancer 1975;36:1327–1337. 470 Kahn CR, Rosen SW, Weintraub BD et al. Ectopic production of chorionic gonadotropin and its subunits by islet cell tumors: a specific marker for malignancy. N Engl J Med 1977;197:565–569. 471 Bender RA, Weintraub BD, Rosen SW. Prospective evaluation of two tumorassociated proteins in pancreatic adenocarcinoma. Cancer 1979;45:591–595. 472 Broder LE, Weintraub BD, Rosen SW et al. Placental proteins and their subunits as tumor markers in prostatic carcinoma. Cancer 1977;40:211–216. 473 Metz SA, Weintraub BD, Rosen SW et al. Ectopic secretion of chorionic gonadotropin by a lung carcinoma. Pituitary gonadotropin and subunit secretion and prolonged chemotherapeutic remission. Am J Med 1978; 65:325–333. 474 Tashjian Jr AH, Weintraub BD, Barowsky NJ et al. Subunits of human chorionic gonadotropin: unbalanced synthesis and secretion by clonal cell strains derived from a bronchogenic carcinoma. Proc Natl Acad Sci USA 1973;70:1419–1422. 475 Rosen SW, Weintraub BD, Aaronson SA. Nonrandom ectopic protein production by malignant cells: direct evidence in vitro. J Clin Endo and Metab 1980;50:834–841. 476 Blackman MR, Weintraub BD, Rosen SW et al. Comparison of the effects of lung cancer, benign lung disease, and normal aging on pituitary–gonadal function in men. J Clin Endo and Metab 1988;66:88–95. 477 Faglia G. The clinical impact of the thyrotropin-releasing hormone text. Thyroid 1998;8:903–908. 478 Bowers CY, Schally AV, Schalch AS et al. Activity and specificity of synthetic thyrotropin-releasing hormone in man. Biochem Biophys Res Commun 1970;39: 352–355. 479 Hershman JM, Pittman Jr JA. Response to synthetic thyrotropin-releasing hormone in man. J Clin Endo and Metab 1970;31:457–460. 480 Patel YC, Burger HG. Serum thyrotropin (TSH) in pituitary and/or hypothalamic hypothyroidism: normal or elevated basal levels and paradoxical responses to thyrotropin-releasing hormone. J Clin Endo and Metab 1973;37: 190–196. 481 Faglia G, Beck-Peccoz P, Ambrosi B et al. Prolonged and exaggerated elevations in plasma thyrotropin (TSH) after thyrotropin releasing factor (TRF) in patients with pituitary tumors. J Clin Endo and Metab 1971;33:999–1002. 482 Jackson IMD, Reichlins S. Thyrotropin-releasing hormone (TRH): distribution in hypothalamic and extrahypothalamic brain tissues of mammalian and submammalian chordates. Endocrinology 1974;95:854–862.

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483 Mallik TK, Wilber JF, Pegues J. Measurements of thyrotropin-releasing hormone like material in human peripheral blood by affinity chromatography and radioimmunoassay. J Clin Endo and Metab 1982;54:1194–1198. 484 Faglia G, Beck-Peccoz P, Ballabio M, Nava C. Excess of b-subunit of thyrotropin in patients with idiopathic central hypothyroidism due to the secretion of TSH with reduced biological activity. J Clin Endo and Metab 1983;56:908–914. 485 Beck-Peccoz P, Amr S, Menezes-Ferreira NM et al. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism: effect of treatment with thyrotropin-releasing hormone. N Engl J Med 1985;312: 1085–1090. 486 Porter BA, Refetoff S, Rosenfield RL et al. Abnormal thyroxine metabolism in hyposomatotrophic dwarfism and inhibition of responsiveness to TRH during GH therapy. Pediatrics 1973;51:668–674. 487 Faglia G, Beck-Peccoz P, Ferrari C et al. Plasma thyrotropin resoponse to thyrotropin-releasing hormone in patients with pituitary and hypothalamic disorders. J Clin Endo and Metab 1973;37:595–601. 488 Faglia G, Bitensky L, Pinchera A et al. Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin. J Clin Endo and Metab 1979;48:989–998. 489 Illig R, Krawczynska M, Torresani T, Prader A. Elevated plasma TSH and hypothyroidism in children with hypothalamic hypothyroidism. J Clin Endo and Metab 1975;41:722–728. 490 Snyder PJ, Jacobs LS, Rabello MM et al. Diagnostic value of thyrotropinreleasing hormone in pituitary and hypothalamic disorders. Ann Int Med 1974;81:751–757. 491 Bartalena L, Martino E, Falcone M et al. Evaluation of the nocturnal serum thyrotropin (TSH) surge, as assessed by TSH ultrasensitive assay, in patients receiving long term L-thyroxine suppression therapy and in patients with various thyroid disorders. J Clin Endo and Metab 1987;65:1265–1271. 492 Caron PJ, Nieman LK, Rose SR, Nisula GC. Deficient nocturnal surge of thyrotropin in central hypothyroidism. J Clin Endo and Metab 1986;62: 960–964. 493 Hayashizaki Y, Hiraoka Y, Tatsumi K et al. DNA analyses of five families with familial inherited thyroid stimulating hormone (TSH) deficiency. J Clin Endo and Metab 1990;71:792–796. 494 Docker BM, Pfaffle RW, Pohlenz J, Andler W. Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin b-subunit gene follows an autosomal recessive inheritance. J Clin Endo and Metab 1998;83:1762–1765. 495 Rogol AD, Kahn CR. Congenital hypothyroidism in a young man with growth hormone, thyrotropin, and prolactin deficiencies. J Clin Endo and Metab 1976;39:356–363. 496 Winter JSD, DeGroot GW, Fairman C. Idiopathic sexual precocity in a boy with growth hormone, prolactin, and thyrotropin deficiencies. J Clin Endo and Metab 1974;39:356–363. 497 Wit JM, Drayer NM, Jansen M et al. Total deficiency of GH and prolactin and partial deficiency of thyroid stimulating hormone in two Dutch families: a new variant of hereditary pituitary deficiency. Horm Res 1989;32:170–177. 498 Yoshimoto M, Kinoshita E, Baba T et al. A case of severe pituitary dwarfism associated with prolactin and thyroid stimulating hormone deficiencies. Acta Paediatr Scand 1990;79:1247–1251. 499 Behringer RR, Mathews LS, Palmiter RD. Dwarf mice produced by genetic ablation of growth hormone expressing cells. Genes and Dev 1988;2:453–461. 500 Wu W, Cogan JD, Pfaffle RW et al. Mutations in PROP-1 cause familial combined pituitary hormone deficiency. Nature Genet 1998;18:147–149. 501 Fofanova O, Takamura N, Kinoshita E et al. Compound heterozygous deletion of the PROP-1 gene in children with combined pituitary hormone deficiency. J Clin Endo and Metab 1998;83:2601–2604. 502 Fluck C, Deladoey J, Rutishauser K et al. Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP-1 gene mutation resulting in the substitution of Arg–>Cys at codon 120 (R120C). J Clin Endo and Metab 1998;83:3727–3734. 503 Foley Jr TP, Owings J, Hayford JT, Blizzard RM. Serum thyrotropin responses to synthetic thyrotropin-releasing hormone in normal children and hypopituitary patients. J Clin Invest 1972;51:431–437. 504 Karlberg B, Almqvist S. Clinical experience with thyrotropin-releasing hormone (TRH) stimulation test in patients with thyroid, pituitary and hypothalamic disorders. Acta Endocrinol (Copenh.) 1973;72:697–713. 505 Schalch DS, Gonzales-Barcena D, Kastin AJ et al. Abnormalities in the release of TSH in response to TRH in patients with disorders of the pituitary, hypothalamus and basal ganglia. J Clin Endo and Metab 1972;35:609–615. 506 Costom BH, Grubach MM, Kaplan SL. Effect of thyrotropin-releasing factor on serum thyroid stimulating hormone: an approach to distinguishing

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hypothalamic from pituitary forms of idiopathic hypopituitary dwarfism. J Clin Invest 1971;50:2219–2225. Hall R, Ormston BJ, Besser GM, Cryer RJ. The thyrotropin-releasing hormone test in disease of the pituitary and hypothalamus. Lancet 1972;1:759–763. Mclaren EH, Hendricks S, Pimstone BL. Thyrotropin response to intravenous thyrotropin-releasing hormone in patients with hypothalamic and pituitary diseases. Clin Endocrinol (Oxf.) 1974;3:113–122. Mitsuma T, Shenkman L, Suphavai A, Hollander CS. Hypothalamic hypothyroidism: diminished thyroidal response to thyrotropin-releasing hormone. Am J Med Sci 1973;265:315–319. Suter SN, Kaplan SL, Aubert ML, Grumbach MM. Plasma prolactin and thyrotropin and the response to thyrotropin-releasing factor in children with primary and hypothalamic hypothyroidism. J Clin Endo and Metab 1978;47:1015–1020. Smallridge RC. Thyrotropin-secreting pituitary tumors. In: Mazzaferri EL, Samaan NA, eds. Endocrine Tumors. Boston: Blackwell Scientific Publications, 1993. Samuels MH, Wood WM, Gordon DF et al. Clinical and molecular studies of a thyrotropin-secreting pituitary adenoma. J Clin Endo and Metab 1989;68:1211–1215. Gershengorn MC, Weintraub BD. Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone: a new syndrome of “inappropriate secretion of TSH”. J Clin Invest 1975;56:633–642. Weintraub BD, Gershengorn MC, Kourides IA, Fein H. Inappropriate secretion of thyroid-stimulating hormone. Ann Int Med 1981;95:339–351. Faglia G, Beck-Peccoz P, Piscitelli G, Medri G. Inappropriate secretion of thyrotropin by the pituitary. Horm Res 1987;26:79–99. Gittoes NJ, McCabe CJ, Verhaeg J et al. An abnormality of thyroid hormone receptor expression may explain abnormal thyrotropin production in thyrotropin-secreting pituitary tumors. Thyroid 1998;8:9–14. McDermott MT, Ridgway EC. Thyroid hormone resistance syndromes. Am J Med 1993;94:424–432. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocrine Rev 1993;14(3):348–399. McDermott MT, Ridgway EC. Central hypothyroidism. Endocrinol Metab Clin NA 1998;27:187–203. Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deafmutism, stippled epiphyses, goiter, and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endo and Metab 1967;27:279–294. Refetoff S. Syndromes of thyroid hormone resistance. American Journal of Physiology 1982;243:E88–E98. Pohlenz J, Weiss RE, Macchia PE et al. Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor b gene. J Clin Endo and Metab 1999;84:3919–3928. Refetoff S, Salazar A, Smith TJ, Scherberg NH. The consequences of inappropriate treatment because of failure to recognize the syndrome of pituitary and peripheral tissue resistance to thyroid hormone. Metabolism 1983;32:822–834. Lazar MA, Chin WW. Nuclear thyroid hormone receptors. J Clin Invest 1990;86:1777-1782. Usala SJ, Bale AE, Gesundheit N et al. Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbAb gene. Mol Endocrinol 1988;2:1217–1220. Chatterjee VKK, Nagaya T, Madison LD et al. Thyroid hormone resistance syndrome: inhibition of normal receptor function by mutant thyroid hormone receptors. J Clin Invest 1991;87:1977–1984. Parrilla R, Mixson AJ, McPherson JA et al. Characterization of seven novel mutations of the c-erbAb gene in unrelated kindreds with generalized thyroid hormone resistance: evidence for two “hot spot” regions in the ligand binding domain. J Clin Invest 1991;88:2123–2130. Yoh S, Chatterjee VKK, Privalski ML. Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptor and transcriptional corepressor. Mol Endocrinol 1997;11:470–480. Liu Y, Takeshita A, Misiti S et al. Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors. Endocrinology 1998;139:4197–4202. Weiss RE, Hayashi Y, Nagaya T et al. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptors a or b genes may be due to a defective cofactor. J Clin Endo and Metab 1996;81:4196–4203. Sakurai A, Miyamoto T, Refetoff S, DeGroot LJ. Dominant negative transcriptional regulation by a mutant thyroid hormone receptor b in a family

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with generalized resistance to thyroid hormone. Mol Endocrinol 1991;4:1988– 1994. Meier CA, Dickstein BM, Ashizawa K et al. Variable transcriptional activity and ligand binding of mutant b1 3,5,3¢-triiodothyronine receptors from four families with generalized resistance to thyroid hormone. Mol Endocrinol 1992;6:248–258. Chatterjee VKK, Adams M, Beck-Peccoz P. Clinical and genetic analysis of eleven families with generalised thyroid hormone resistance syndrome. Endocrinology 1992;130(Suppl):135. Ono S, Schwartz ID, Mueller OT et al. Homozygosity for a “dominant negative” thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone. J Clin Endo and Metab 1991;73:990–994. Usala SJ, Menke JB, Watson TL et al. A homozygous deletion in the c-erbAb thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Mol Endocrinol 1991;5:327–335. Takeda K, Sakurai A, DeGroot LJ, Refetoff S. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein coding region of the thyroid hormone receptor b gene. J Clin Endo and Metab 1992;74:49–55. Usala SJ, Menke JB, Hao EH. Mutations in the c-erbA-b gene in two different patients with selective pituitary resistance to thyroid hormones. Presented at the 74th Annual Meeting of the Endocrine Society, San Antonio, Texas, June 1992. Endocrinology 1992;130(Suppl.):135. Sasaki S, Nakamura H, Tagami T et al. Pituitary resistance to thyroid hormone associated with a base mutation in the hormone-binding domain of the human 3,5,3¢-triiodothyronine receptor-b. J Clin Endo and Metab 1993;76:1254–1258. Nakamura H, Sasaki S, Tagami T et al. Analysis of the T3 receptor genes in patients with generalized resistance to thyroid hormone and selective pituitary form. Thyroid 1992;2:5–36. Brooks MH, Barbato AL, Collins S et al. Familial thyroid hormone resistance. Am J Med 1981;71:414–421. Gharib H, Klee GG. Familial euthyroid hyperthyroxinemia secondary to pituitary and peripheral resistance to thyroid hormones. Mayo Clin Proc 1985;60:9–15. Magner JA, Petrick P, Menezes-Ferreira MM et al. Familial generalized resistance to thyroid hormones: report of three kindreds and correlation of patterns of affected tissues with the binding of [125]triiodothyronine to fibroblast nuclei. J Endocrinol Invest 1986;9:459–470. Smallridge RC, Parker RA, Wiggs EA et al. Thyroid hormone resistance in a large kindred: physiologic, biochemical, pharmacologic, and neuropsychologic studies. Am J Med 1989;86:289–296. Borst GC, Eil C, Burman KD. Euthyroid hyperthyroxinemia. Ann Int Med 1983;98:366–378. Stockigt JR. Euthyroid hyperthyroxinemia. Thyroid Today 1985;7:1–7. Rosler A, Litvin Y, Hage C et al. Familial hyperthyroidism due to inappropriate thyrotropin secretion successfully treated with triiodothyronine. J Clin Endo and Metab 1982;54:76–82. Hamon P, Bovier-Lapierre M, Robert M et al. Hyperthyroidism due to selective pituitary resistance to thyroid hormones in a 15-month-old boy: efficacy of D-thyroxine therapy. J Clin Endo and Metab 1988;67:1089–1093. Dorey F, Strauch G, Gayno JP. Thyrotoxicosis due to pituitary resistance to thyroid hormones, successful control with D-thyroxine: a study in three patients. Clin Endocrinol (Oxf.) 1990;32:221–228. Beck-Peccoz P, Piscitelli G, Cattaneo MG, Faglia G. Successful treatment of hyperthyroidism due to nonneoplastic pituitary TSH hypersecretion with 3,5,3¢-triiodothyroacetic acid (TRIAC). J Endocrinol Invest 1983;6:217– 223. Salmela PI, Wide L, Juustila H, Ruokonen A. Effects of thyroid hormones (T4, T3) bromocriptine and TRIAC on inappropriate TSH hypersecretion. Clin Endocrinol (Oxf.) 1988;28:497–507. Kunitake JM, Hartman N, Henson LC et al. 3,5,3¢-triiodothyroacetic acid therapy for thyroid hormone resistance. J Clin Endo and Metab 1989;69:461–466. Williams G, Kraenzlin M, Sandler L. Hyperthyroidism due to nontumoural inappropriate TSH secretion: effect of a long-acting somatostatin analogue (SMS 201–995). Endocrinology 1986;113:42–46.

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553 Williams G, Anderson JV, Williams SJ, Bloom SR. Clinical evaluation of SMS 201–995: long-term treatment of gut neuroendocrine tumours, efficacy of oral administration, and possible use of non-tumoural inappropriate TSH hypersecretion. Acta Endocrinol (Copenh.) 1987;116(Suppl 286):26–36. 554 Isales CM, Tamborlane W, Gertner JM et al. Effect of short-term somatostatin and long-term triiodothyronine administration in a child with nontumorous inappropriate thyrotropin secretion. J Pediatr 1988;112:51–55. 555 Beck-Peccoz P, Medri G, Piscitelli G et al. Treatment of inappropriate secretion of thyrotropin with somatostatin analog SMS 201–995. Horm Res 1988;29:121–123. 556 Beck-Peccoz P, Mariotti S, Guillausseau PJ et al. Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with the somatostatin analog SMS 201–995. J Clin Endo and Metab 1989;68:208–214. 557 Sriwatanakul K, McCormick K, Woolf P. Thyrotropin (TSH)-induced hyperthyroidism: response of TSH to dopamine and its agonists. J Clin Endo and Metab 1984;58:255–261. 558 Takamatsu J, Mozai T, Kuma K. Bromocriptine therapy for hyperthyroidism due to increased thyrotropin secretion. J Clin Endo and Metab 1984;58:934–936. 559 Gurr JA, Kourides IA. Thyroid hormone regulation of thyrotropin a- and bsubunit gene transcription. DNA 1985;4:301–307. 560 Ross DS, Downing MF, Chin WW et al. Changes in tissue concentrations of thyrotropin, free thyrotropin-b, and a-subunits after thyroxine administration: Comparison of mouse hypothyroid pituitary and thyrotropic tumors. Endocrinology 1983;112:2050–2053. 561 Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC. Pulsatile secretion of TSH in man. J Clin Endo and Metab 1986;63:661–668. 562 Ross DS, Neer RM, Ridgway EC, Daniels GH. Subclinical hyperthyroidism and reduced bone density as a possible result of prolonged suppression of the pituitary–thyroid axis with L-thyroxine. Am J Med 1987;82:1167– 1170. 563 Biondi B, Fazio S, Carella C et al. Cardiac effects of long term thyrotropinsuppressive therapy with levothyroxine. J Clin Endo and Metab 1993;77:334–338. 564 Biondi B, Fazio S, Carella C et al. Control of adrenergic overactivity by bblockade improves quality of life in patients on long-term suppressive therapy with levothyroxine. J Clin Endo and Metab 1994; 78:1028–1033. 565 Ridgway EC, Cooper DS, Walker H et al. Peripheral responses to thyroid hormone before and after L-thyroxine therapy in patients with subclinical hypothyroidism. J Clin Endo and Metab 1981;53:1238–1242. 566 Cooper DS, Halpern R, Wood LC et al. L-thyroxine therapy in subclinical hypothyroidism: A double-blind, placebo-controlled trial. Ann Int Med 1984;101:18–24. 567 Arem R, Phesch W. Lipoprotein and apolipoprotein levels in subclinical hypothyroidism. Arch Intern Med 1990;150:2097–2100. 568 Staub JJ, Althaus BU, Engler H et al. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med 1992;92(6):631– 642. 569 Monzani F, Del Guerra P, Caraccio N et al. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin Investig 1993;71:367–371. 570 Haddow JE, Palomaki GE, Allan WC et al. Maternal thyroid deficiency during pregnancy and subsequent neurophysiological development of the child. N Engl J Med 1999;341:549–555. 571 Watanabe S, Hayashizaki Y, Endo Y et al. Production of human thyroidstimulating hormone in Chinese hamster ovary cells. Biochem Biophys Res Commun 1989;149:1149–1155. 572 Meier CA, Braverman LE, Ebner SA et al. Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (Phase I/II Study). J Clin Endo and Metab 1994;78:188–196. 573 Ladenson PW, Braverman LE, Mazzaferri EL et al. Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma. N Engl J Med 1997;337:888–896. 574 Haugen BR, Pacini F, Reiners C et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endo and Metab 1999;84:3877–3885.

C h a p t e r

6 Follicle-stimulating Hormone and Luteinizing Hormone Shalender Bhasin Charles E. Fisher Ronald S. Swerdloff

INTRODUCTION Luteinizing hormone (LH), follicle-stimulating hormone (FSH), chorionic gonadotropin (CG), and thyroid stimulating hormone (TSH) are structurally and evolutionarily related and are grouped together in one family. All four members of this glycoprotein hormone family evolved from a common ancestral gene. Of these, only LH, FSH, and CG have gonadotropic properties. This chapter will focus on LH and FSH. Both of these gonadotropic hormones are secreted contemporaneously by a single cell type in the pituitary. There are many similarities in the mechanisms that regulate the synthesis and secretion of LH and FSH. There is considerable structural homology between the LH and FSH proteins and their gonadal receptors. Conversely, there are also several physiologic and clinical paradigms where the expression of LH and FSH proteins becomes divergent. Thus mechanisms for both coordinate and divergent regulation of these two gonadotropins are operative within the gonadotrope. Gonadotropins play an extremely important role in reproduction; their presence is essential but not sufficient to initiate and maintain germ cell development. Although the precise details of when gonadotropins first emerged, or how mechanisms for endocrine control of the gonads evolved, are not known, this must have been a relatively later event during evolution. In the beginning, when life forms were unicellular or simple multicellular organisms, the regulation of reproduction must have occurred by autocrine or paracrine mechanisms. Historically, the gonadotropin story is a recent one, being barely 50 years old. Much of our knowledge about gonadotropic hormones has accumulated over the last 30 216

years through the contributions of literally hundreds of outstanding investigators. A Pub Med search for “*Gonadotropins” in mid-2000 returned 49,522 hits: 1391 for 1999 and the first half of 2000 alone. The concept that the pituitary gland secretes factors necessary for testicular growth and spermatogenesis originated from the hypophysectomy studies of Smith [1]. Greep [2] later provided evidence for dual gonadotropin control of testicular function, i.e., an interstitial cell-stimulating hormone (ICSH or LH) stimulating Leydig cells and a follicle-stimulating hormone stimulating the seminiferous tubules. Androgens were first isolated in the 1930s, Walsh et al. [3] demonstrating that androgen alone could maintain spermatogenesis. These observations created some confusion about the relative roles of androgens and gonadotropins in initiating and maintaining spermatogenesis—a confusion which has persisted until today. Pioneering studies by McCullagh [4] suggested that nonsteroidal factors of testicular origin could prevent the development of castration cells in the pituitary. These studies formed the basis of the inhibin concept but it took another 50 years for isolation and characterization of inhibin [5,6]. The introduction of ion-exchange celluloses for chromatography in the 1950s greatly enhanced the ability to purify gonadotropin preparations of relatively high potency and opened the way for structural studies [6]. In the late 1960s and 1970s, the biochemical structures of LH and FSH became known [7]. Development of LH and FSH radioimmunoassay by Odell et al. [8,9] made it possible to measure these hormones in blood and biologic fluids and conduct in vivo studies. In a series of elegant experiments using a difficult but highly innovative monkey model, Knobil et al. [10–12] showed that pulsatile gonadotropin-releasing hormone (GnRH) secretion is critical for normal LH and FSH secretion. This concept proved pivotal in guiding scores of

Chapter 6

subsequent human studies and providing the scientific basis for the development and clinical applications of GnRH agonist analogs. In the early 1970s, the isolation and characterization of thyrotropin-releasing hormone (TRH) and GnRH were reported [13,14]. The development of solid-phase peptide synthesis technology led to the synthesis and testing of thousands of GnRH analogs. This new class of therapeutic agents would later find widespread pharmaceutical applications. In the mid and late 1980s, the group led by Veldhuis and Johnson [21] developed and validated several new algorithms for the analysis of episodic hormone secretion. These studies along with those from several other laboratories [21–23] in patients with idiopathic hypogonadotropic hypogonadism provided new insights into the pathophysiology of the GnRH pulse generator. These pulse detection and deconvolution techniques have enhanced our understanding of the mechanisms of pulsatile hormone secretion. Veldhuis and Johnson have recently described novel mathematical algorithms to elucidate the feedback and feedforward relationships between LH, FSH and testicular testosterone secretion. The advent of molecular approaches in endocrinology greatly accelerated the pace of discovery. For instance, the cloning of genes encoding the gonadotropin subunits in the early 1980s opened up a new avenue of study for the molecular mechanisms that regulate the gonadotropins [15–20]. The next decade witnessed significant advances in our understanding of mechanisms regulating the gonadotropin genes. The cloning of the LH and FSH receptor genes [24–27] was another watershed event, which helped clarify

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several issues related to LH and FSH action. Our knowledge of the structure and function of gonadotropin receptors has rapidly advanced. Both activating and inactivating mutations of LH and FSH beta subunit genes and their receptors have been described [28–29]; the studies of the associated phenotypes have provided unique insights into the function of these hormones and their receptors. The recognition that an orderly expression of a number of homeodomain proteins is crucial to pituitary development was another landmark event [30–32]; the study of phenotypes associated with mutations of a number of homeodomain transcription factors such as Pit-1, Pou1, Prop1, and Hesx-1 provided pivotal evidence of the important role of these proteins in the development of differentiated cell types within the pituitary [30–32]. All these developments have collectively resulted in an explosion of exciting new information and an exponential advance in our understanding of how reproduction is regulated in mammals. DEVELOPMENT, EMBRYOLOGY, AND HISTOLOGY

Origin and Migration of the GnRH Neurons During Development The neurons that secrete gonadotropin-releasing hormone (GnRH) originate in the region of the olfactory apparatus [33]. These neurons must then migrate, along with the olfactory and vomeronasal nerves, into the forebrain and then into their final location in the hypothalamus. Figure 6.1 shows the migratory route of these GnRH neurons

FIGURE 6.1. Migration of the GnRH neurons studied by immunohistochemical staining. The neurons that secrete GnRH originate in the region of the olfactory apparatus. This figure shows the migratory route of the GnRH neurons in the mouse embryo as determined by GnRH immunohistochemistry. Sagittal sections of the brain were stained for the presence of GnRH. On day 11, GnRH neurons are seen in the vicinity of the vomeronasal organ (VMO) and the olfactory placode. By day 13, the migration of these neurons into the nasal septum along with the nervus terminalis and the vomeronasal nerve is evident. By day 16, most of the GnRH neurons have entered the forebrain and some the preoptic area of the hypothalamus. vno = vomeronasal organ; ob = olfactory bulb; poa = pre-optic area; gt = ganlion terminalis. From Schwanzel-Fukuda and Pfaff [33].

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in the mouse embryo, as determined by using GnRH immunohistochemistry [33]. In this study, sagittal sections of the mouse brain were stained for the presence of GnRH. On day 11, GnRH neurons were seen in the vicinity of the vomeronasal organ (VNO) and the olfactory placode. By day 13, the migration of these neurons into the nasal septum along with the nervus terminalis and the vomeronasal nerve is evident. By day 16, most of the GnRH immunoreactive neurons had entered the forebrain and some into the preoptic area of the hypothalamus [33]. This orderly migration of GnRH neurons requires the coordinated action of direction-finding molecules, adhesion proteins such as the KALIG-1 gene product, and enzymes that help the neuronal cells burrow their way through intercellular matrix. Mutations of any of these proteins could arrest the migratory process and result in GnRH deficiency. In at least a subset of patients, idiopathic hypogonadotropic hypogonadism can be viewed as a developmental migratory disorder resulting from failure of the GnRH neurons to migrate into the hypothalamus [33].

Gonadotropin-Secreting Cells in the Pituitary For details of the morphology of the gonadotroph the reader is referred to reviews by Kovacs and Horvath [34], Childs et al. [35], and Moriarty [36]. The bulk of immunocytologic evidence suggests that a single cell type within the pituitary secretes both LH and FSH [34–37]. Some gonadotrophs may, however, stain only for FSH or LH and it is not clear if these monohormonal cells represent separate cell types or a similar cell type in different secretory phases [38,39]. Gonadotrophs constitute about 10% to 15% of anterior pituitary cells [34,36,37]. They are dispersed throughout the anterior pituitary close to the capillaries. Their location, in close approximation to the lactotrophs, has led some investigators to suggest a paracrine interaction between the two cell types. Gonadotrophs are medium-sized cells, usually oval or irregular in shape with a prominent nucleus [34–37]. Electron microscopy reveals a spherical and eccentric nucleus, prominent rough endoplasmic reticulum (RER) and Golgi complexes and several vesicles containing secretory granules. The secretory granules are electron-dense and are of two sizes: the larger ones measuring 350 to 450 nm and the smaller ones 150 to 250 nm [34–37]. Gonadotrophs are easily demonstrable in the fetal and prepubertal pituitary gland [40]. However, their number is low before sexual maturation. Gonadotrophs from the male and female pituitary glands cannot be distinguished on morphologic grounds. Castration leads to an increase in size as well as number of gonadotrophs. In addition, these castration cells are characterized by large vacuoles in the cytoplasm due to dilatation of the endoplasmic reticulum, which may displace the nucleus to one side [40]. Gonadotroph hyperplasia and hypertrophy that follow removal of the

gonad may lead to an increase in the size of the sella. On the other hand, studies in patients with idiopathic hypogonadotropic hypogonadism reveal only a few poorly developed gonadotropes [34]. It remains uncertain whether there are different functional or clonal types of gonadotrophs in the human pituitary. In studies of rat pituitary cells fractionated by elutriation, most of the gonadotropin-staining cells are among the largest cells [35]. However, a significant number of cells among the poorly granulated small cell fractions also secrete gonadotropins [35,38,39]. Small gonadotrophs may represent the immature population that later gives rise to the highly responsive large secretory cells [35]. Childs et al. [35] propose that adenohypophyseal cells are derived from a common multipotential stem or progenitor cell. These progenitor cells divide and produce a second subset of cells capable of dividing and therefore, essential for self-renewal. The third type or the “maturing cells” seen after the first week of neonatal development in the rat [34] undergo further differentiation to form the fully mature subtype. This proposal speculates that the different morphologic forms of gonadotrophs seen in the adult animal may represent different developmental or maturational stages. Studies in neonatal and adult rats suggest that GnRH may stimulate proliferation, maturation, and differentiation of gonadotroph precursor cells. There is also some evidence suggesting that different morphologic forms may represent distinct functional subtypes that can respond differentially to diverse hormonal stimuli. The methodologic difficulties of separating different pituitary cell types have been a major hindrance to progress in this field.

Molecular Basis of Pituitary Development Genetic analyses of mutations associated with developmental disorders of the pituitary have revealed the molecular mechanisms of pituitary development and cell lineage determination [30–32]. Coordinated, temporal expression of a number of homeodomain transcription factors directs the embryological development of the pituitary and its differentiated cell types. Three homeobox genes Lbx3, Lbx4, and Titf1 are essential for early organogenesis [30–32]. Cell specialization and proliferation of differentiated cell types requires the expression of transcription factors, Pit1 and Prop1. Pit-1 has a POU-specific and a POU-homeo DNA-binding domain [41]. The Prop1 gene encodes a transcription factor with a single DNA-binding domain [30–32]. While Pit-1 mutations are associated with deficiencies of GH, TSH, and prolactin, mutations in Prop1 are associated with deficiencies of LH and FSH in addition to deficiencies of GH, prolactin, and TSH. Expression of HESX1 gene precedes expression of PROP1 and PIT1 and mutations in this gene are associated with a syndrome that includes septo-optic dysplasia and panhypopituitarism (Fig. 6.2) [41–46].

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FIGURE 6.2. Development disorders due to mutations of the homeodomain proteins. From Parks [30].

BIOCHEMICAL STRUCTURE AND MOLECULAR BIOLOGY OF LH AND FSH

Biochemical Structure The family of pituitary glycoprotein hormones includes LH, FSH, TSH, and CGs [7,46]. Each of these hormones is heterodimeric, consisting of an a- and a b-subunit (Fig. 6.3) [7,46]. The primary structures of the a-subunits of LH, FSH,TSH, and CG are nearly identical within a species; the biologic specificity is conferred by the dissimilar b-subunit. Significant homology between the two subunits has prompted the suggestion that these subunits arose from a common ancestral gene [7,45,47]. Individual subunits are not biologically active; formation of the heterodimer is essential for biologic activity. The subunits are highly linked internally by disulfide bonds. Consequently, location of the

cysteines, to some degree, confers the three-dimensional structure of the glycoprotein by determining the folding [7,47]. The two subunits are noncovalently associated. When amino acid sequences of the different b-subunits are compared, it becomes readily apparent that the cysteine residues can be aligned [48]. The regions of similarity between different b-subunits are felt to be involved in binding to the a-subunits and the variable regions in receptor binding [48]. The a-subunit of LH contains two asparagine-linked carbohydrate chains, while the b-subunit chain contains one or two [49,50]. In addition, the CG b-subunit also contains Olinked oligosaccharides not found on the LH dimer [51,52] (see Fig. 6.3). The reader is referred to two excellent reviews on the structure-activity relationships [53,54]. A number of approaches can, and have, been used to elucidate the structure-activity relationships and define the regions

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FIGURE 6.2.

Continued

FIGURE 6.3. Schematic depiction of the subunit structure and glycosylation sites of the four glycoprotein hormones and their subunits. Asn-linked oligosaccharides are depicted as and Ser/Thr-linked oligosaccharides as . From Baenziger [50].

involved in hormone-receptor interaction [53,54]. One strategy is to construct synthetic fragments corresponding to sequences on the subunits and assess their binding activity [55]. Another is to use a battery of monoclonal antibodies [56–58] directed against discrete epitopes on the glycopeptide. Still others have used site-directed mutagenesis experiments to elucidate the structure-activity relationships. All of these approaches have been used to construct a conformational map of the LH molecule. Two regions of the LH bsubunit appear particularly interesting: the loop sequence 93–100, and a second 38–57 region [53,54]. The 93–100 region appears important for specificity of LH/human CG

(hCG) binding [51]. The region 38–57 appears important for some aspects of receptor activation and secondary structure [53,54]. Charlesworth et al. [59] have used a panel of monoclonal antibodies and a number of synthetic peptides to characterize the glycoprotein a-subunit. These studies suggest that two dominant regions of the a-subunit are involved in antibody binding: region 9–33, and region 72–92 [59].

Comparative Endocrinology of Gonadotropins The high degree of homology in the biochemical structure

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and nucleotide sequence of the four glycoprotein hormones (LH, FSH,TSH, and CG) suggests evolution from a common ancestral gene [7,46,47,51,60]. It has been speculated that the ancestral molecule was probably a pituitary glycoprotein with functional characteristics of a gonadotropin [51]. It is believed that TSH diverged from the ancestral glycoprotein first [51,52]. The time point in evolution when two functionally and biochemically distinct gonadotropin hormones (LH and FSH) emerged from a single gonadotropin is not known. Both have been identified in mammals, birds, reptiles, and amphibians [51,52,53]. In fish, there are two distinct gonadotropins but their functional identity to LH and FSH has not been demonstrated. Comparative studies that have examined the interrelationship of gonadotropins of various vertebrates by comparing their amino acid composition have found some salient structural differences in the evolution of LH and FSH [61,62]. The asparagine content of LH and FSH varies greatly between the higher and the lower vertebrates. On the other hand, increase in proline content has occurred only in LH during evolution. The relative positions of proline residues have, however, been conserved during the evolutionary process. It has been proposed that the progressive increase in the number of these residues in LH during the course of evolution is responsible for the narrow species specificity of the LH molecule [61]. On the other hand, FSH-b evolved rather randomly so that FSH molecules are less species-specific, or even nonspecific throughout the tetrapod vertebrates. Emergence of chorionic gonadotropin (CG) as a separate gonadotropin occurred relatively recently during evolution [63–65]. Unlike LH, which is found in the pituitaries of a large number of species, CG is found only in the placenta of certain mammalian species such as horses, baboons, and humans [59,63–65]. Marked structural and functional similarity between LH and CG had suggested that the CG gene arose directly from a FSH-LH or an LH like ancestral gene. Talmadge et al. [63] compared nucleotide sequence of the single gene for human LH (hLH)-b with two of the seven genes for hCG-b. These investigators proposed, based on these sequence comparisons, that hCG arose by duplication of an ancestral LH-b-like gene. Duplication was followed by a series of selected changes but very few neutral changes. A single base deletion in the termination codon resulted in incorporation of what was the 3¢ untranslated region of the ancestral LH-b gene into the coding region of the newly evolved CG. A two-nucleotide insertion downstream from the original termination codon created a new termination codon, resulting in a 24-amino acid carboxy terminal extension in the CG molecule, which was not present in the ancestral gene [47,63].

Synthesis and Posttranslational Processing of LH Subunits The a- and b-subunits of LH and FSH are encoded by separate genes [15–20]. The a-subunit is initially synthesized as

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a precursor with a molecular mass of 14 kDa, whereas the LH b subunit has a precursor of molecular mass 15–17 kDa [66–71]. Precursors are processed by enzymatic removal of amino terminal leader peptides and also by addition of carbohydrates. The glycosylation occurs cotranslationally in several steps [72–75]. First, oligosaccharide complexes are transferred en bloc to nascent proteins via lipid-linked intermediates or isoprenoid-dolichol-pyrophosphate carriers [74,75]. The complexes are added to specific asparaginyl residues with sequences of the form Asn-X-Thr (Ser) [74]. The core carbohydrates are of the general structure: Glc–13 (a-Man4–6 Man b1–4 GIc), Ac b1–4 Glc Nac-Asn. Second, glucose residues are removed by glucose-specific glucosidases in the region of the RER, leaving a high-mannose oligosaccharide [76,77]. The carbohydrates undergo further remodeling by removal of some mannose residues and the addition of sugars such as fucose, galactose, and sialic acid resulting in the formation of complex carbohydrate structures [50,76–80]. The oligosaccharides of bovine and human LH and FSH, but not human FSH, contain sulfate and GalNAc [50,81]. It is not known whether rat LH subunits are sulfated and sialylated, but sulfation of mouse TSH subunit has been demonstrated. Thus tissue and protein specific differences occur in the processing of glycoprotein hormones. Smith and Baenziger [82] and Baenziger [50] have shown the presence of a recognition marker for Gal-N-acetyl transferase, one of the enzymes involved in the glycosylation process, on the a-subunit. These investigators suggest that the b-subunits regulate the access of this recognition marker and thereby can differentially modulate posttranslational remodeling, glycosylation, and sulfation of different glycoprotein hormones. For example, hFSH-b prevents access of this recognition marker for Gal-N-acetyl transferase [50]. Therefore, the hFSH is not sulfated. The functional role of the carbohydrate side-chains remains somewhat uncertain [83–86]. The diversity and almost ubiquitous presence of secretory and structural proteins in the plant and animal kingdoms have prevented the development of a unifying hypothesis to explain the role of the carbohydrate side-chain. Two types of approaches have been used to examine the functional role of the carbohydrate: first, observing the effects of inhibition of subunit glycosylation by chemical inhibitors of glycosylation in vitro; and second, using enzymatic or chemical means to remove the carbohydrate chain [83]. These studies suggest multiple roles for the carbohydrate side-chain in the hormone assembly, secretion, and action [83]. High mannose precursor oligosaccharide may be important in protecting the glycoprotein from intracellular proteolysis and aggregation and may help the molecule attain the conformation necessary for subunit combination [84]. The removal of the complex oligosaccharides alters the metabolic clearance rate of the glycoprotein [85]. The deglycosylated hCG generated by chemical or enzymatic deglycosylation retains significant receptor-binding activity. However, studies in Sairam’s laboratory demonstrated that chemically deglycosylated

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Table 6.1. Structures of the glycoprotein alpha, luteinizing hormone beta, human chorionic gonadotropin beta, and follicle-stimulating hormone beta genes

Locus

Gene length (Kb)

Number of exons (introns)

mRNA length (Kb)

Number of amino acids

Number of glycosylation sites (location)a

6p21.1–23 1p22 19q13.3 19q13.3 11p13

9.4 4.9 1.5 1.9d 3.9

4 (3) 4 (3) 4 (3) 4 (3) 4 (3)

0.8 0.7 0.7 1.0 1.8

92 118c 121 145 111

2 (N: 52,78)b 1 (N: 23) 1 (N: 30) 6 (N: 13,30; S: 121,127,132,138) 2 (N: 7,24)

Subunit Common a TSHb LHb CGb FSHb

a Oligosaccharide chains are attached either to asparagine (N) (N-linked) or to serine (S) (O-linked). N or S residues are numbered according to their position in the respective sequence. b Free-subunit may also contain an additional site of O-glycosylation at threonine (T) 39. c 118-Amino acid coding region; six amino acids can be cleaved at the C-terminal end. d In contrast to all other glycoprotein hormone subunit genes which exist as a single copy, hCG is encoded by a cluster of six genes which vary in length.

hCG binds to the receptor but fails to induce cyclic adenosine monophosphate (cAMP) or testosterone production. Thus, the carbohydrate side-chain may be essential for transduction of biologic signals [86].

Molecular Biology of LH and FSH Subunit Genes Structure and Organization of the a-Subunit Gene

In the rat, mouse, cow, and the human, a single gene codes for the a-subunit of the four glycoprotein hormones [17–19,47,86–89]. The general organization of the asubunit gene is quite similar in these four species in that each gene consists of four exons and three introns [47] (Table 6.1). Although the positions of the three introns are conserved, the size of the first varies considerably between species, largely accounting for the differences in the overall size of the a gene in these four species [90]. The coding regions of the genes bear a great deal of homology in these species [47]. The 5¢ flanking regions of the human and bovine a-genes also have a high degree of homology. An a-subunit messenger RNA (mRNA) species of 0.73–0.8 kilobase (kb) length corresponds to a 24-amino acid leader sequence followed by a 96-amino acid mature polypeptide in the rat, mouse and the cow, and a 92-amino acid protein in humans. A mutation of the intron/exon splice junction between the second intron and the third exon results in the smaller size of the human a-protein [90]. cAMP is an important regulator of a-subunit gene expression and increases a-subunit mRNA in JEG-3 choriocarcinoma cells [91–92]. Nuclear run-on assays have shown that cAMP increases a mRNA levels predominantly by stimulation of a gene transcription [91]. Treatment with cycloheximide, an inhibitor of protein synthesis, does not affect the degree of cAMP stimulation of a mRNA, although the basal a mRNA levels are decreased. These data have led to

an emerging consensus that cAMP actions are mediated via posttranslational modification (e.g., phosphorylation) of preexisting transcription factors [92]. The regulatory elements within the 5¢ flanking region of the a gene have been examined by a number of groups using a variety of molecular approaches including deletion analysis, DNAse I footprint analysis, and gel shift assays [93–107]. These studies suggest that the 5¢ flanking sequences between -846 and +44 base pair (bp) direct maximal expression of CAT activity in JEG-3 cells [93–96]. This region also contains multiple transcriptional regulatory elements that regulate the tissue-specific, basal and cAMPinduced expression of a gene [92–98]. Removal of the sequence between -169 and -100 bp causes marked loss of both basal and cAMP stimulated expression. This region contains an 18-bp cAMP response element (CRE) that includes the palindrome, TGACGTCA [90–91]. Several protein-binding regions have been characterized between -18 and -84 bp [92]. These include binding sites for cAMP response element-binding protein (CREB), consensus CAAT box-binding motifs downstream of CRE, and two distinct upstream regulatory elements (URE-1 and URE-2) that bind tissue-specific proteins, relatively restricted to placental cells [93,96,100]. The 18-bp CRE can confer cAMP responsiveness to heterologous promoters. However, intact URE is essential for placental expression. Multiple adjacent protein binding domains in the a gene promoter interact to regulate the transcription of a gene under basal conditions and in response to cAMP stimulation [91–100]. The structure and functional characteristics of the cAMP responsive transactivating protein CREB that binds to the CRE have been the subject of intense investigation by several groups [101–104]. The CREB protein belongs to a family of DNA-binding proteins which includes c-fos, cjun, c/EBP, GCN4, c-myc [101–104], all of which are characterized by the presence of leucine zippers [101–104]. The

Chapter 6

leucine zipper sequence consists of four leucines, spaced seven residues apart, and is involved in protein–protein interaction. The members of this family of proteins can form homo- or heterodimers through the leucine zippers [103]. The zipper region of the protein is entirely in an ahelical conformation [102,103]. The complementary DNA (cDNA) encoding the full-length CREB protein in JEG-3 cells has been cloned and predicts a 326-amino acid protein with a molecular mass of 35-kDa [102]. The carboxy terminal end of the CREB protein (58 residues) contains a positively charged basic region and the leucine zipper region [102]. The basic region is believed to be involved in the recognition of the cAMP-responsive DNA sequences. The first 268 residues contain a cluster of positively charged residues and a number of serine and threonine residues which may be the putative sites for phosphorylation [102]. This part of the molecule, unlike the DNA binding domain, is relatively unstructured and constitutes the transcription activation domain. GnRH-induced transcription of the human gonadotropin-alpha gene promoter is increased by estradiol [105,106]. Duan et al. [108] have reported that estradiol decreases CREB phosphorylation and this in turn lowers basal alpha-promoter activity but increases its responsiveness to GnRH. The LH-b Gene

The organization of the LH-CG-b gene cluster is quite complex [60,63] and in the human incorporates seven CGlike genes, including one which codes for hLH-b gene [47]. LH-b gene is relatively small in size (approximately 1.5 kb in length) [63,105,107]. The general organization of the LH-b gene (three exons and two introns) is similar to other glycoprotein hormone b genes (see Table 6.1). Studies by Talmadge et al. [63] suggest that LH-b and CG-b genes diverged only recently in evolution. Several differences are notable between the LH-b and CG-b genes. First, CG-b gene is present only in primate and equine species, whereas LH-b genes are present in all vertebrates that have been examined. Second, LH-b gene codes for a 24-amino acid leader peptide and a 121-amino acid mature protein. In contrast, the mature hCG-b protein contains a 24-amino acid carboxy terminal extension because of a single base mutation in the termination codon of its ancestral LH-b gene and a two-nucleotide insertion downstream of this site [47,63]. Third, LH-b and CG-b genes have different transcriptional start sites and probably utilize different promoters [108,109]. The LH beta subunit gene expression is regulated by at least two types of transcriptional mechanisms and factors: those that regulate the tissue and cell-type specific expression of LH beta gene within the gonadotrope and those that mediate its responsiveness to GnRH [110–118]. Regulation of LH beta subunit transcription is modulated by interaction with transcription factors that are controlled by testosterone, estrogens, and inhibins and activins. We do not

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know how these two regulatory mechanisms interact to transduce regulated expression of LH beta gene within the pituitary. The rat LH-b promoter contains a putative estrogen responsive element [104,117] located between -1388 and -1105 bp upstream of the start site. This region contains a 15-bp palindrome (GGACACCATCTGTCC) that displays high degree of sequence similarity to the estrogen responsive element described in some other estrogen responsive genes. The data from filter binding and gel shift assays indicate that the receptor binds to a palindromic region (-1173 to -1159) bp upstream from the transcriptional start site. Mutations of this region lead to loss of this estrogenstimulatory effect [104,117]. Using nuclear run-off assays to measure the rates of transcription in perifused pitiuitary fragments, Shupnik demonstrated that the transcription of LH beta gene is induced by pulsatile GnRH administration in vitro [118]. Continuous infusion of GnRH upregulates only the alpha-gene transcription, but not LH or FSH beta subunit gene transcription [118]. Pulsatile GnRH administration also modifies polyadenylation of LH sunit mRNAs [116]. The difficulties of obtaining expression of LH-b subunit genes in cultured cells have limited progress in understanding the mechanisms of transcriptional regulation of LH-b gene. No stable cell lines have been developed to date which express LH-b subunit gene. Successful transfection of placental cell lines JAR, JEG3, and a nonplacental cell line with hCG-b subunit gene has been reported [92,120]. However, no studies have been successful in obtaining reasonably abundant expression of LH-b gene in any cell line. These data suggest that the LH-b subunit gene transcription may require highly tissue-specific transcription factors [119]. Kim et al. [119] recently reported expression of LH-b promoter in primary cultures of rat pituitary cells. These investigators were able to transfect rat pituitary cells with an LH-b promoter: luciferase fusion construct. Treatment of transfected cells with GnRH modestly increased the LH-b luciferase activity. Progressive deletions of the 5¢ flanking region of the LH-b gene revealed that significant transcriptional activity was retained even after extensive deletion of the promoter region. A construct with only 75 bp of the 5¢ flanking sequence had 38% of the activity expressed by a 1.7 kb construct. In the ovine species [114], 1.9 kb of ovine LH b promoter sequence is sufficient for tissue specific expression within the pituitary and for regulation by GnRH and sexsteroids. Keri et al. [111] have described bipartite NF-Y (CBF/CP1) binding sites within the proximal bovine LH beta promoter which is responsible for regulation of basal transcriptional activity but does not mediate responsiveness to GnRH [111]. The FSH-b Gene

The general organization of the rat and bovine FSH-b gene is similar to that of other glycoprotein hormone b genes

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in that it has three exons and two introns [47,119–125]. The first exon contains only the 5¢ untranslated sequences while the second and third exons contain the entire coding sequence (see Table 6.1). The third exon also contains a relatively long 3¢ untranslated sequence. The transcription initiation site is located 63 nucleotides upstream of the first exon-intron boundary. A TATA box is present 31 nucleotides upstream of the transcription initiation site. The data on the upstream regulatory elements in the FSH b gene are still emerging. However, two features are particularly noteworthy. First, there is a striking lack of similarity between the 5¢ flanking regions of FSH-b and LH-b subunit genes [47]. This is somewhat surprising since there are significant similarities in the regulation of the two genes. Second, the 5¢ flanking region of the FSH-b gene contains a sequence at -1318 homologous to a conserved palindromic sequence, which can function as an estrogen-responsive element in some other genes. However, it needs to be demonstrated whether this element in this gene functions in a manner similar to the other classical estrogen-responsive elements. Fusion genes containing the FSH-b promoter have been transfected into a number of cell lines but, to date, very low or no detectable expression has been seen [124]. Analysis of the ovine FSH-beta promoter has revealed that two functional activating protein-1 (AP-1) enhancers in the proximal promoter are important for its expression and regulation by GnRH [126]. GnRH-regulated expression of FSHbeta gene involves activation of protein kinase C signaling pathway [126–128].

BIOLOGIC ROLES OF LH AND FSH

Roles of LH and FSH in the Male (Fig. 6.4) LH binds to specific receptors on the Leydig cells and stimulates testosterone production in vitro and in vivo. LH/hCG [24,25] as well as FSH receptors [26] have been cloned. The cloning of cDNAs has shown that the LH/hCG receptor is a single polypeptide [24,25] which can both bind the hormone and stimulate cAMP production. The cloned cDNA encodes for a protein of 700 amino acids, including a 26-amino acid signal peptide and a mature protein with a molecular mass of 75 kDa. It is notable that the purified

LH/hCG receptor has an apparent molecular mass of 93 kDa on SDS gel electrophoresis. The difference between the predicted (75 kDa) and observed (93 kDa) molecular mass may be due to the glycoprotein nature of the receptor [24,25]. LH/HCG receptor (Fig. 6.5a) is coupled to a Gs protein and shares considerable homology with other G protein-coupled receptors such as rhodopsin, adrenergic, muscarinic acetylcholine, and serotonin [24,25], and to TSH [27] and FSH [26] receptors. All these receptors are transmembrane proteins and share a common structural motif of seven membrane-spanning domains. The large amino terminus of the receptor protein constitutes the extracellular domain. The carboxy terminus consists of the seven membrane-spanning segments and a small cytoplasmic tail. The carboxy terminal cytoplasmic segment has several serines and threonines which may serve as putative sites for phosphorylation. There are six potential sites for N-linked glycosylation on the amino terminal extracellular domain. The extracellular domain can be aligned into several imperfectly repeated leucine-rich segments, each of 25 amino acids [24,25]. LH is required for maintaining the very high intratesticular levels of testosterone, essential for spermatogenesis [129–134]. Circulating testosterone is also essential for maintaining sexual function, secondary sex characters, and a number of other androgen-dependent physiologic processes such as the bone, mineral, and protein metabolism and muscle mass and function. LH stimulates production of cAMP within the Leydig cells, although some studies have reported marked stimulation of steroidogenesis by low doses of LH that do not significantly increase cAMP production. These studies raise the possibility that other signalling pathways may also be involved in mediating LH action. The role of FSH in the male remains uncertain. FSH is known to bind to specific receptors on Sertoli cells and stimulate the production of a number of proteins including inhibinrelated peptides, transferrin, androgen-binding protein, androgen receptor, and a 7glutamyl transpeptidase. However, the role of FSH in the spermatogenic process remains unclear. The classical theory proposes that LH acts on Leydig cells to stimulate generation of high intratesticular levels of testosterone [129–134]. Testosterone then acts on the spermatogonia and primary spermatocytes leading the

FIGURE 6.4. Functions of the gonadotrophs in the male and female. Functions of follicle stimulating hormone (FSH) in the male and female. The plus signs and horizontal arrows indicate potentially unrecognized new functions of FSH since the discovery of FSHb gene mutations. LH, luteinizing hormone. Modified from Layman [683].

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FIGURE 6.5a. Structure of the LH receptor protein. Schematic representation of the human LH/hCG receptor protein with each of the known mutations. The single letter code for amino acids is used. The normal amino acids are shown, but the activating mutations are indicated by black circles with light letters, whereas the inactivating mutations are indicated by gray circles with white letters. The corresponding codon numbers are also shown. Note that most activating mutations occur in the sixth transmembrane domain and third intracellular loop, whereas inactivating mutations occur in the extracellular domain, transmembrane domains V–VII, and the third intracellular loop. Activating mutations include Asp578Gly, Ile542Leu, Asp564Gly, Asp578Tyr, Cys581Arg, Met571Ile, Thr577Ile, Ala568Val, Ala572Val, and Met398Thr. Two reported mutations, Met575Ile and Asp582Gly, did not fit with the numbering system published and are not included. Inactivating mutations are Cys545X, Ala593Pro, Arg554X, Ser616Tyr, and Arg133Cys. An X indicates a stop codon, which is TAA, TAG, or TGA. From Layman [683].

FIGURE 6.5b. Structure of the FSH receptor protein. Schematic model of the FSH receptor. The extracellular domain consists of several LRRs that are made up of alternating sheets (indicated by rectangles numbered consecutively in Arabic numerals according to the alignment shown in Fig. 6.3) and helices (indicated by the coils). The transmembrane domain consists of seven hydrophobic segments (Roman numerals) spanning the cell membrane and connected by intra- and extracellular loops. Within the intracellular domain a putative fourth intracellular loop is depicted. From Simoni et al. [444].

germ cells through the meiotic division. FSH is felt to be essential for spermiogenesis, i.e., the maturation process by which spermatids develop into mature spermatozoa. A large body of data about the role of testosterone in spermatogenesis is available from studies in the rat [129–133] or the nonhuman primate [134–135]. In both these species, testosterone alone can maintain spermatogenesis when administered shortly after hypophysectomy or stalk resection

[129–135]. However, if testosterone is given after a lapse of several weeks to months, it is much less effective in reinitiating spermatogenesis. It is worth noting that spermatogenesis maintained by treatment of hypophysectomized male rodents or nonhuman primate by testosterone is qualitatively, but not quantitatively, normal [134]. Combination of testosterone and FSH appears to be more effective than testosterone alone in reinitiating spermatogenesis [134].

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Thus, both FSH and testosterone are required for qualitative, as well as quantitatively, normal spermatogenesis. Matsumoto et al. [136–137] have used another experimental paradigm to examine the roles of LH and FSH in the spermatogenic process. These investigators suppressed endogenous LH and FSH output and sperm counts by administration of pharmacologic doses of testosterone enanthate. In these men, made hypogonadotropic by testosterone, LH or hCG alone significantly increased sperm concentrations. Separate administration of FSH alone also increased sperm counts to the same degree achieved by LH alone. More interestingly, simultaneous administration of LH and FSH led to higher sperm concentrations than achieved by either hormone alone. These data suggest that although LH alone can maintain or reinitiate spermatogenesis, FSH might be required for quantitatively normal sperm counts. However, this experimental model is flawed by the presence of very high testosterone levels [136–137]. Published data and empiric clinical experience indicate that in men with prepubertal onset of both LH and FSH deficiency, LH or hCG alone is unable to initiate spermatogenesis [138–144]. On the other hand, if gonadotropin deficiency is acquired after the patient has completed pubertal development, LH or hCG alone can reinitiate qualitatively normal spermatogenesis. Thus, FSH is required for initiating the spermatogenic process but once this has occurred, testosterone in high doses can maintain spermatogenesis. These observations suggest that FSH may be involved in some sort of “programming” in the peripubertal period, after which LH alone can maintain germ cell development and maturation. Androgen concentrations in the testis are much higher than those in serum. This observation had led to speculation that high intratesticular levels of testosterone are required for spermatogenesis. However, considerable confusion exists with regard to the significance of intratesticular testosterone levels [129,130,133,134]. For example, stimulatory effects of exogenous testosterone on spermatogenesis in the rat are not associated with proportionately marked elevations of testicular testosterone levels. In the adult hypophysectorized or GnRH antagonist-treated monkey treated with testosterone, no direct relationship is found between serum and testicular testosterone levels and spermatogenesis [134]. Sharpe et al. [133] reported that the method of postmortem collection of testicular tissue can profoundly affect estimation of intratesticular testosterone concentrations. Thus, the relationship between intratesticular testosterone concentrations and spermatogenesis is complex and remains a matter of uncertainty. The mechanisms by which testosterone and FSH regulate germ cell development are unknown. The final transduction of the FSH and testosterone signals to the germ cells must require mediation of Sertoli cells, given that the receptors for these hormones are present only on the Sertoli cells and are lacking on the germ cells. The nature of this cell-to-cell communication between Sertoli, Leydig, and germ cells remains unknown.

The Roles of LH and FSH in the Female (see Fig. 6.4) The role of LH and FSH in the ovary is much better delineated. LH is a major regulator of ovarian steroid synthesis. LH/hCG receptors are present on the luteal cells. LH effects are mediated predominantly through the cAMP pathway. LH causes rapid increases in the amount of cholesterol available for steroidogenesis [145–147]. The transfer of cholesterol from the outer to the inner membrane where it becomes available for steroidogenesis is mediated by a Steroidogenic Acute Regulatory Protein (StAR) [148]. The StAR protein regulates this rate-limiting step in the steroidogenic process, and is in turn regulated by LH. In addition, LH causes an increase in the activity of the sidechain cleavage enzyme [145–147], a cytochrome P450linked enzyme that converts cholesterol to pregnenolone. LH increases the delivery of cholesterol to the side-chain cleavage enzyme thus increasing its capacity to convert more cholesterol to pregnenolone. The long-term effects of LH include stimulation of the gene expression and synthesis of a number of key enzymes in the steroid biosynthetic pathway, including the side-chain cleavage enzyme, 3-b-hydroxysteroid dehydrogenase, 17-ahydroxylase, and 17,20-lyase [149–150]. FSH stimulates the activities of 17-b-hydroxysteroid dehydrogenase and aromatase enzymes [151–152]. FSH is, therefore, critical in regulating estrogen production in the ovary. FSH receptors are acquired by granulosa cells in early stages of their cytodifferentiation [153] and FSH is believed by many to be important in the cytodifferentiation of granulosa cells [154–156]. FSH plays a critical role in follicle growth, although a number of growth factors also play an important role in stimulating granulosa cell mitosis [157]. FSH action in stimulating estradiol production by the granulosa cells is mediated via the cAMP pathway. Estradiol increases the sensitivity of granulosa cells to FSH [158] and plays a permissive role in FSH action by augmenting FSHstimulated cAMP formation [158]. FSH receptor cDNAs have been cloned from the rat Sertoli cell [26]. FSH receptor is also a G-protein linked, single polypeptide consisting of a large glycosylated extramembranous domain which is connected to a C-terminal structure containing seven transmembrane segments (see Fig. 6.5b), [26]. The extracellular domain appears responsible for the recognition and binding of the hormone ligand. The FSH and LH/CG receptors display 50% sequence homology in their extracellular domains and 80% homology in the transmembrane segments [24–26].

ASSAY SYSTEMS FOR THE MEASUREMENT OF GONADOTROPINS Two types of measurement systems are currently available for quantitation of LH and FSH in blood (Table 6.2). First are immunoassays which quantitate the mass of immuno-

Chapter 6 Table 6.2. Available methods for measurement of luteinizing hormone and follicle-stimulating hormone in serum or plasma Method Measurement of mass: immunoassays Traditional radioimmunoassay Immunofluorometric assay

Immunochemiluminescent assay

Measurement of bioactivity Receptor binding assays Classical bioassays LH (i) Rat interstitial cell testosterone assay (ii) Mouse interstitial cell testosterone assay FSH (i) Granulosa cell aromatase assay (ii) Sertoli cell aromatase assay

Comments

Sensitivity limited a-subunit crossreactivity Sensitivity much better No a-crossreactivity No radioactivity involved Sensitivity much better No a-crossreactivity No radioactivity involved Using rat interstitial cells Rat MA-1 cells Cumbersome Susceptible to serum effects

Sensitivity limited

reactive species; second are assays which measure bioactivity, including: (i) ligand binding assays that quantitate receptor binding; and (ii) bioassays that quantitate the net bioactivity of circulating LH and FSH species. Ideally, complete characterization of circulating LH and/or FSH status should include assessment of mass (by immunoassays) and biologic activity (by ligand binding and bioassays). However, because of their cumbersome nature, assays based on ligand binding and bioactivity have not been widely used in clinical practice. As outlined elsewhere in this chapter, in several clinical situations, such as acute illness, some pituitary tumors, monitoring of GnRH agonist treatment, chronic renal failure, and aging, the assessment of LH and/or FSH mass by radioimmunoassays (RIAs) may diverge significantly from that based on bioassays due, in part, to the problems inherent in one or both types of assay systems.

Radioimmunoassays for LH and FSH The original RIAs for measurements of serum LH and FSH were first described over 20 years ago [8,9]. These proved extremely useful in studying LH and FSH secretion and its regulation in health and disease. However, the original RIAs for hLH and hFSH had a number of limitations (Table 6.3). While crossreactivity of other pituitary glycoprotein hormones has not been a significant problem in LH and FSH radioimmunoassays, the crossreactivity of the free a-subunit in the LH RIA is considerable. The displacement curves obtained with graded doses of purified free a-subunit preparation in the LH RIA are not parallel to those obtained

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Table 6.3. Limitations of the traditional luteinizing hormone radioimmunoassays Limited specificity due to crossreactivity of: (i) free a-subunit (ii) other pituitary glycoprotein hormones Limited sensitivity Lack of homogeneous reference preparations Microheterogeneity of circulating LH species Divergence of measured immuno- and bioactivity in certain clinical, physiologic, and experimental situations

with the LH urinary reference preparations. This makes it difficult to quantitate the contribution of a-subunit crossreactivity to the measured LH immunoreactivity. Another problem pertains to the microheterogeneity of circulating LH and FSH species [159–162]. The biologic significance of the heterogeneity of circulating LH and FSH isoforms is not known; it has been speculated that posttranslational modifications may contribute to heterogeneity of circulating isoforms and may also result in altered biologic activity. A third problem was that most of the existing reference preparations of LH and FSH are not homogeneous and have varying degrees of impurities. Both pituitary and urinary reference preparations (Second International Reference Preparation of Human Menopausal Gonadotropin; 2nd IRP-hMG) continue to be widely used in RIAs. Although potency estimates are available, direct comparisons of the data obtained by using the two types of reference preparation may not always be valid because of the problems of microheterogeneity of circulating isoforms and different degrees of contamination of the reference material being used. Fourth, the sensitivities of the conventional LH and FSH RIAs are limited so that the serum concentrations of follicle-stimulating hormone in some normal men are close to or below the limit of assay sensitivity. The precision of the conventional RIAs was not optimum in the low range. This greatly limited their application in clinical and physiologic paradigms requiring measurements of low or suppressed levels, e.g., during the peripubertal period, in hypogonadotropic disorders, or during GnRH analog-induced gonadotropin suppression.

Recent Improvements in LH and FSH Immunoassays A number of commercially available, two-site-directed immunoradiometric or nonisotopic methods (e.g., immunofluorometric assay, IFMA, or immunochemiluminescent assay, ICMA) have now overcome many of the limitations of the original RIAs. The sensitivity is much better, e.g., a time-resolved LH IFMA can measure serum LH levels down to 0.1 mIU/ml of 2nd IRP-hMG [163–164].

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Furthermore, crossreactivity is no longer a problem in these two-site-directed assays, and correlation with bioassays is also much better than the original radioimmunoassays [165]. These more sensitive LH and FSH measurement systems have been extremely useful in studying physiologic events characterized by low LH and FSH levels. For example, changes in the low serum LH and FSH levels in early puberty had been difficult to study due to the sensitivity problems of traditional RIAs. However, reexamination of gonadotropin levels using IFMA has now greatly clarified the issue. Another instance when specificity of two-site directed assays proved critical was in GnRH agonist studies [165– 166]. For several years, it was known that serum LH levels in GnRH agonist-treated men, measured by conventional RIA, did not decrease in proportion to the far greater decline in serum testosterone levels. However, serum bioassayable LH concentrations markedly decreased during GnRH agonist treatment so that the bioassayable to immunoassayable (B/I) LH ratios decreased during treatment [166]. Subsequent studies revealed that the LH levels measured by IFMA decreased correspondingly with those measured by bioassay [166]. These observations led to the recognition that the change in LH B/I ratios during GnRH agonist treatment were due, at least in part, to the crossreactivity of the free a-subunit in the LH RIA [165,166].

Receptor-Binding Assays Two types of receptor-binding assay have been in use in research, but neither has yet attracted wide clinical applicability. The traditional assay uses 125I-hCG/125I-LH or 125IFSH as the ligand, and crude rat gonadal homogenates as the source of membrane receptors [167,168]. The use of a MA-10 tumor cell line for characterization of the LH receptor-binding in human serum has been validated by Whitcomb and Schneyer [169].

Bioassays For LH and FSH Bioassays for LH are based on this hormone’s stimulation of testosterone secretion from dispersed Leydig cells. Two types of bioassay, widely used for measurement of serum LH bioactivity, include the mouse interstitial cell testosterone assay (MICT) [170] or the rat interstitial cell testosterone assay (RICT) [171,172]. The free or unassociated subunits have no intrinsic biologic activity and, therefore, do not crossreact in the LH or FSH bioassay. Operationally, the MICT is somewhat easier to use than the RICT because mouse Leydig cells can be mechanically dispersed. However, both assays have been used by many laboratories worldwide. LH bioactivity can also be assessed in MA-10 cells, a Leydig cell-derived tumor cell line, which responds to LH by an increase in progesterone secretion. However, this procedure has not been validated for measurement of serum LH levels. Several in vitro bioassays have been developed for FSH [173]. These include the plasminogen activator produc-

tion by rat granulosa cells, stimulation of aromatase activity in rat Sertoli cells, cAMP production by rat seminiferous tubules, and 3H-thymidine incorporation into mouse ovaries [173,174]. These assays, because of low sensitivity and serum interference, were not practical for measurement of circulating FSH bioactivity. However, two types of bioassay available now are sufficiently sensitive for serum bioassayable FSH measurement. These include the granulosa cell aromatase bioassay (GAB), recently validated by Jia and Hsueh [174], and the Sertoli cell aromatase bioassay first described by Van Damme et al. [175]. For a long time, measurement of serum FSH by bioassay had been difficult because of unpredictable serum effects. Jia and Hsueh [174] showed that these could be minimized by prior treatment of serum with polyethylene glycol. Although these assays now allow measurement of bioassayable serum FSH down to about 2.5 mlU/ml, they are cumbersome, time-consuming, and require difficult cell culture procedures.

Free a-Subunit Secretion Although a large body of evidence indicates that free uncombined a-subunit is secreted by the pituitary into the circulation, it is generally believed that the free b-subunit is not secreted to any significant degree via this route. In the human, the secretion of free a-subunit appears to be regulated under several physiologic circumstances. Exogenous GnRH and TRH both increase free a-subunit levels [176–179]. Conversely, hypothyroidism and castration are attended by increased free a-subunit levels [180]. Frequent sampling has clearly demonstrated the pulsatile nature of free a-subunit secretion [181,182] with LH and free a-subunit pulses being concordant in both normal and GnRHdeficient individuals [181]. Serum levels of free a subunit increase after menopause and decrease after estrogen therapy [180]. Collectively, these data suggest that such secretion is regulated, at least in part, by GnRH; however, persistent secretion is clearly demonstrable after suppression of gonadotropes by GnRH antagonist administration [182]. This residual secretion may be the contribution of thyrotropes. However, Winters et al. [183] reported residual secretion of free a-subunit even after administration of Lthyroxine to men with GnRH deficiency; these data suggest that free a-subunit secretion may be partly tonic. Secretion may also become dissociated from that of LH dimer under some circumstances; for example, during GnRH agonist treatment, free a-subunit levels are persistently elevated, even when serum LH levels are markedly suppressed [166]. Similarly, as discussed elsewhere in this book, patients with thyrotrope or gonadotroph adenomas have markedly elevated levels of free a-subunit [184]; consequently, measurement of serum free a-subunit levels can provide a useful marker for the detection of these adenomas. Free a-subunit levels in serum can be measured by commercially available RIAs. Many such assays use polyclonal antisera which have significant LH and FSH crossreactivity. More specific assays, using monoclonal antibodies, are now being widely used [185].

Microheterogeneity of Circulating and Pituitary Isoforms of Gonadotropin Hormones It has long been known that when proteins contained in pituitary extracts are separated on the basis of their isoelectric point, several peaks of LH immunoreactivity can be seen [186–188]. The plasma immunoreactive LH species also exhibit considerable microheterogeneity [189]. In rats and sheep, castration, steroid hormone replacement, and cryptorchidism alter the chromatofocusing profile of pituitary LH species [186–190]. Thus under these experimental paradigms, LH microheterogeneity appears to be hormonally regulated. Purified human pituitary LH has also been demonstrated to be heterogeneous, but there is some disagreement between laboratories regarding the number of isoforms or the isoelectric points [161]. Although the exact biochemical structure of different LH isoforms is not known, it is generally believed that a large percentage of LH charge heterogeneity is due to differences in the oligosaccharide moieties [190]. The components of the carbohydrate chain that are capable of altering the charge include the N-acetyl neuraminic acid (sialic acid) or N-acetylgalactosamine sulfate; the other sugars are neutral with regard to charge. Thus, the number and position of these negatively charged moieties determine the overall charge. A large proportion of the hLH microheterogeneity is associated with terminal sialic acid residues [191]. In some physiologic and pathologic states, the ratios of immunoreactive and bioactive LH concentrations may not change proportionately, or may diverge [191]. For example, during acute illness, GnRH agonist treatment [166] and in older men, the B/I ratios may decrease. The hypothesis that these differences in B/I ratios are due to changes in biologic activity of LH isoforms associated with posttranslational modifications of the oligosaccharide side-chain, however, remains to be tested. Changes in B/I ratios have also been reported in men and women treated with agonist analogs of GnRH [166]. However, the change in B/I ratios in some earlier studies was due, in part, to the crossreactivity of the a-subunit in the conventional LH radioimmunoassays [166–168]. When LH concentrations are measured by highly specific twosite-directed IMFAs, the immunoreactive and bioactive LH levels change concordantly [166–168]. The LH bioassays are highly susceptible to a variety of serum effects; for these reasons, the changes in B/I ratios need to be interpreted with great caution. With recent refinements in FSH bioassays, there has been great interest in studying FSH microheterogeneity and its biologic concomitants. In a recent study, Dahl et al. [192] reported that FSH B/I ratios decreased in men treated with a GnRH antagonist. When sera from such men were fractionated by chromatofocusing, the profile of FSH isoforms

229

was different from that of control sera. In addition, these investigators noted that some isoforms inhibited the biologic activity of native FSH. The concept that isohormones with antagonistic properties (antihormones) may circulate in vivo, although very provocative, needs further confirmation. The physiologic significance and the biochemical characterization of FSH antihormones awaits further studies. REGULATION OF LH AND FSH SECRETION (Figs. 6.6 and 6.7)

Regulation by GnRH Pulsatile secretion of GnRH is essential for maintaining normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion from the pituitary. (see Fig. 6.3). GnRH is a major regulator of gonadotropin secretion, and increases LH and FSH secretion from pituitary cells both in vitro and in vivo. The pattern of GnRH signal (amplitude and frequency) is important in determining the quantity and quality of gonadotropins secreted [10,11,22,23,193]. In a series of pioneering studies in a primate model, Knobil and coworkers [10,11] demonstrated that pulsatile secretion of Positive energy balance

Fat cells CRH Leptin

NP-Y

Hypothalamus GnRH

–

• Light • Olfaction • Emotion • Stress • Other environmental factors

+ CNS –

Pituitary +

+

+ FSH

–

LH β-end

Corticotrope Inhibin B/ activins/follistatin

Estradiol

The free a-subunit reference preparations have significant amounts of contamination by other pituitary glycoprotein hormones.

Follicle-stimulating Hormone and Luteinizing Hormone

T

Chapter 6

+

+ Leydig cells

Sertoli cells

+ T

+

Germ cells

Testis

FIGURE 6.6. Schematic view of the hypothalamic– pituitary–gonadal axis in man.

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SECTION 1

1039

LH (ng/ml)

5 pulses/hour

1 pulse/hour

400

35

350

30

300

25

250

20

200

15

150

10

100

5

50

0

15

10

5

0

5

10

15

20

25

30

35

40

FSH (ng/ml)

1 pulse/hour

40

0

Days

(a)

999 Pulsatile 200

15

150

10

100

5

50

0 (b)

Continuous

10

5

0

5

10

15

20

25

30

Days

GnRH was essential for normal LH and FSH secretion. In this model, rhesus monkeys underwent ovariectomy to remove the gonadal steroid feedback to the pituitary [10]. The GnRH secreting neurons in the hypothalamus were destroyed by radiofrequency lesions. Therefore, this model provided a unique opportunity to examine the in vivo response of the isolated gonadotrope to GnRH and other regulatory factors. Basal LH and FSH secretion in these animals, in the absence of GnRH, is very low. Pulsatile administration of GnRH, at a frequency of 1 mg pulse each hour, restored LH and FSH secretion. When the same daily dose of GnRH (24 mg given over 24 hours) was administered as a continuous infusion LH and FSH secretion decreased indicating downregulation of the gonadotropes (panel A). A marked increase in the GnRH pulse frequency (6 pulses/hour) also desensitized the gonadotrope, resulting in decreased LH and FSH secretion (panel B). These studies [10,11] established that the pulsatile release of GnRH at an optimum pulse frequency and amplitude is integral to optimum gonadotrope function. In subsequent experiments, Wildt et al. [193] demonstrated that the frequency and amplitude of GnRH pulses played a critical role in determining the output of LH and FSH from the pituitary. Further evidence of the important

35

0

FSH (ng/ml)

LH (ng/ml)

Pulsatile 20

FIGURE 6.7. Knobil’s experiments: pulsatile GnRH administration is essential for physiologic LH and FSH secretion.

role of GnRH in regulation of LH and FSH secretion has come from observations that administration of a GnRH antagonist inhibits LH and FSH output and suppresses a, LH-b, and FSH-b mRNA levels [194–196]. Another model used to study the role of GnRH is the castrated male rat in which serum testosterone concentrations are maintained in supraphysiologic range by subcutaneous insertion of silastic testosterone implants [197–199]. Steiner et al. [200] have shown that GnRH pulses are infrequent or totally absent in this animal model. In this GnRH deficient rat model, pulsatile administration of GnRH increases GnRH receptors, LH-b and a mRNA levels [197–200]. The dose of GnRH pulses appears critical to the regulation of LH-b-subunit mRNA levels in that doses lower or higher than 25 ng are ineffective [197,198]. In contrast, the a-subunit mRNA is less dose dependent; all the GnRH doses studied, ranging from 10–250 ng, increased a mRNA. Maximum increases in a and LH-b mRNAs were seen with 25 ng pulses given every 30 minutes. In static cultures of pituicytes, GnRH fails to increase LH subunit mRNA levels even though the release of LH into the media is markedly increased by GnRH [201–203]. On the other hand, Haisenleder et al. [204] and Shupnik [205] have demonstrated that GnRH pulses increase the rates of

Chapter 6

transcription of all three gonadotropin subunits, namely a, LH-b, and FSH-b. Maximum increases in transcription rates are observed 1 hour after initiation of pulsatile GnRH administration. The duration of this increase is limited and by 24 hours, LH-b and FSH-b transcription rates fall to baseline. The frequency of GnRH stimulus is felt to be important in differential regulation of LH-b and FSH-b genes [198]. Faster frequencies increase a and LH-b, and slower frequencies FSH-b leading to speculation that alterations in GnRH pulse frequency may be one mechanism by which two functionally distinct gonaclotropins can be regulated by a single hypothalamic-releasing hormone. Further evidence for the importance of a pulsatile pattern of GnRH release in regulation of the LH subunit is provided by data showing that continuous infusion of GnRH or administration of a GnRH agonist leads to a decrease in LH-b mRNA levels but that the a mRNA levels remain elevated [202,203,206,207]. These data provide further evidence for the importance of the pattern of GnRH signal in differential regulation of LH and FSH output. A great deal of information about the physiology of GnRH secretion has emerged from examination of the LH and FSH pulse patterns in normal men and women, and from GnRH replacement studies in patients with idiopathic hypogonadotropic hypogonadism (IHH). Studies in such patients with hypothalamic GnRH deficiency have indicated that GnRH pulses at a dose of 25 ng/kg, given intravenously to men, previously induced by pulsatile GnRH administration, can replicate a normal LH pulse in all its characteristics [22,23]. The peak GnRH levels achieved after intravenous administration of this dose (500–1000 pg/ml) are similar to those obtained in the primates by direct sampling of the hypophyseal–portal blood [22,23]. At least in IHH men, an interpulse interval of 2 hours appears optimum [22,23]. Increasing the frequency of GnRH pulses leads to progressive decrease in LH responsiveness to GnRH [23]. Decreasing the pulse frequency (or increasing the interpulse interval) increases the amplitude of the subsequent LH pulse. There is a linear relationship between the log of the dose of GnRH pulse and the amount of LH, FSH, and free a-subunit secreted. The magnitude of the LH response is considerably greater than that of FSH [23]. It is interesting that increasing the GnRH pulse frequency to four per hour from one every 2 hours, while keeping the GnRH dose constant, results in progressive increase in LH pulse amplitude, while the FSH response remains unchanged. This situation is reminiscent of the LH and FSH profile seen in patients with polycystic ovary disease (PCO) [208]. Studies by Waldstreicher et al. [209] demonstrate high frequency of GnRH secretion in PCO patients. Intensive sampling in normal adult men and women reveals a wide spectrum of LH pulse characteristics [21–23]. The median values for LH pulse parameters in men, reported in one such recent study [21] were as follows: interpulse interval 55 minutes; LH peak duration 40

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minutes; LH pulse amplitude 37% of basal (1.8 mlU/ml incremental). Wide variations in LH pulse parameters in apparently normal men and women dictate a need for caution in interpretation of mild deviations in LH pulse frequency and amplitude parameters. The sampling frequency and the paradigm used to quantitate pulse characteristics can have significant impact on the false-negative and falsepositive rates and consequently on the observed pulse parameters [21]. GnRH action on the gonadotroph is mediated via its binding to specific membrane receptors. GnRH binding to its receptor leads to aggregation of receptors; microaggregation of the receptor leads to calcium-dependent LH release [210]. A large body of evidence indicates that Ca2+ serves as the second messenger system in GnRH action [211]. Calciumchelating agents inhibit GnRH-stimulated LH release; calcium ionophores increase LH release in the absence of GnRH, and GnRH leads to mobilization of intracellular and extracellular calcium [212]. Calmodulin activation appears to occur after calcium influx into the gonadotroph [213]. GnRH also activates the turnover of the inositol phosphate cycle [214]. Breakdown of phosphoinositicles to diacylglycerol and inositol trisphosphate continues throughout the duration of the GnRH-stimulated LH release [215]. In the pituitary gonadotroph, GnRH stimulates calciumindependent, G-protein-mediated phospholipase C-type hydrolysis of phosphatidyl-4,5-inositol bisphosphate, resulting in generation of inositol-1,4,5-trisphosphate and diacylglycerol; GnRH has been shown to stimulate protein kinase C in the gonadotroph. However, GnRH-mediated effects on LH release can be dissociated from protein kinase C activation [216].

Testosterone Several lines of evidence unequivocally indicate that testosterone plays an important role in feedback regulation of gonadotropins in the male. Serum LH levels rise promptly and serum FSH more gradually after castration in a number of experimental animals [216–218]. The mRNAs for a, LH-b [219,220], and FSH-b [221] all rise after castration, although the changes in FSH-0 mRNA are more modest. The changes in FSH-b mRNA levels are triphasic: after an initial fourfold rise by day 7, FSH-b mRNA levels decrease to a 1.5-fold increase at 4 weeks and then rise again to 400% to 500% of baseline by 90 days. The postcastration rise in serum LH and LH-b mRNA levels is brought about both by an increase in the gonadotrope number and hypertrophy of individual gonadotrophs [222–224]. Testosterone replacement, started at the time of, or soon after, castration can attenuate the postcastration rise in a and LH-b mRNAs and serum LH levels, but has little effect on FSH-b mRNA levels [220]. The effects of testosterone on FSH secretion and synthesis are complex. The net in vivo effect of testosterone

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administration to normal men is inhibition of serum FSH levels [225–227]. It is, however, clear that the direct effects of testosterone on FSH output at the pituitary level are stimulatory [228–232]. In isolated pituitary cell cultures, testosterone increases FSH release into the media [228,229]. This is attended by a three-to-fourfold increase in FSH-b mRNA levels [232]. In intact male rats, in whom GnRH actions are blocked by administration of a GnRH antagonist, testosterone also increases serum FSH levels in a dose-dependent manner [230,231]. Bhasin et al. [230] demonstrated that in castrated animals treated with GnRH antagonist, graded doses of testosterone increase serum FSH levels. These data indicate that the stimulatory effects of testosterone on serum FSH levels are not mediated through effects on a gonadal inhibitor of FSH, but rather directly at the pituitary level. Wierman and Wang [232], using a similar GnRH antagonist-treated rat model, have shown that testosterone increases FSH-b but not LH-b mRNA levels. However in the intact male animal, testosterone inhibits GnRHstimulated FSH secretion, thus accounting for the net inhibition of serum FSH levels. Testosterone inhibits LH secretion when given to normal men and rats [225–227]. These inhibitory effects are felt largely to be at the hypothalamic level, a conclusion based on observations that testosterone decreases the frequency of LH pulses in normal eugonadal men [227,233–236]. Androgens have no direct effects on LH-b mRNA levels in rat pituitary monolayer cultures. Similarly, in GnRH antagonist-treated male rats, graded doses of testosterone lead only to an increase in FSH-b but not LH-b mRNA levels [232]. Scheckter et al. [237] have also demonstrated that in men with idiopathic hypogonadotropic hypogonadism, the amplitude of LH pulses, initiated and maintained by pulsatile GnRH therapy, is reduced by testosterone administration, indicating that testosterone may also have additional actions at the pituitary level in attenuating pituitary response to GnRH. Finkelstein et al. [238] have recently reexamined the issue of whether testosterone suppresses LH by action directly at the pituitary or the hypothalamic level. These investigators made use of IHH men with complete GnRH deficiency, in whom LH and FSH secretion had been normalized by pulsatile GnRH administration. The responses of these patients to testosterone infusion were compared to those of normal eugonadal men with an intact hypothalamic–pituitary axis. In GnRH-deficient men, testosterone infusion significantly decreased mean LH levels and LH pulse amplitude. On the other hand, in normal men, LH pulse frequency significantly decreased during testosterone infusion. Collectively, these studies demonstrate that testosterone or one of its metabolites inhibits gonadotropin secretion at both the pituitary and hypothalamic levels in men. Testolactone, an aromatase inhibitor, attenuates the testosterone-induced inhibition of LH secretion in both normal and GnRH-deficient men [236,239]. Testolactone

alone increased mean LH levels, the increase being greater in men who received testolactone alone than in those receiving testosterone plus testolactone. These data [239] suggest that inhibitory effects of testosterone are mediated both directly by testosterone itself and indirectly through its aromatization to estradiol. However, administration of a nonaromatizable androgen dihydrotestosterone also inhibits LH secretion consistent with the proposal that aromatization of testosterone is not essential for mediating its inhibitory effects on LH secretion [236]. The available evidence suggests that 5-a reduction of testosterone is not essential for the LH-inhibitory effects of testosterone. Administration of a potent 5-a reductase inhibitor, finasteride, to normal men does not result in elevated LH and FSH levels [240], consistent with the proposal that testosterone can directly inhibit LH output without obligatory 5-a reduction. Veldhuis et al. [235] demonstrated that an opiate receptor antagonist, naltrexone, effectively blocks the LH-inhibitory effects of dihydrotestosterone. These authors speculate that the hypothalamic effects of testosterone are mediated via opiatergic pathways.

Estradiol The complexity of estradiol effects on gonadotropin secretion has been well reviewed [236,239]. The effects of estradiol on gonadotropin secretion can be both stimulatory and inhibitory in vivo, depending on the study paradigm, the presence or absence of GnRH, and the prevailing physiologic conditions. The steady-state mRNA levels and transcription rates for LH-b and FSH-b subunits change throughout the rat estrus cycle [241,242], consistent with observations that estrogens can regulate gonadotropins both positively and negatively. The discrepancies that exist in the literature with regard to the estrogen effects on gonadotropin secretion can be explained in part by the differences in the experimental models used. It is generally believed that the stimulatory effects of estrogens on gonadotropin synthesis and secretion in vivo are exerted directly at the pituitary level, while the inhibitory effects are mediated at the hypothalamic level [22,29,252]. First, estrogen administration leads to a decrease in LH pulse frequency suggesting a hypothalamic site of action [243,244]. Second, estradiol treatment of hypothalamic slices decreases GnRH mRNA as assessed by in situ hybridization [245]. Third, transcription of all three subunits is negatively regulated by estradiol in vivo, even though the direct in vitro effects on pituitary are stimulatory [246,252]. Several lines of evidence provide support for the concept that positive feedback effects are mediated at the pituitary level under several physiologic paradigms. First, estrogen increases LH-b mRNA synthesis in vitro in pituitary fragments, while no changes are seen in FSH-b mRNA [22,29]. Second, in hypogonadotropic (hpg) mouse with GnRH deficiency, daily injections of estradiol increase a-subunit mRNA [247]. Third, Knobil [10] unequivocally demon-

Chapter 6

strated that in hypothalamus-lesioned monkeys, cyclic changes in gonadotropin secretion resembling those seen during the normal menstrual cycle can be reproduced by estradiol treatment alone. Fourth, in a hypothalamic– pituitary disconnected sheep model, an LH surge can be mimicked by estradiol treatment [248]. However, detractors argue that the GnRH concentrations in the median eminence [249] or portal vein [250] are increased at the time of LH surge in monkeys and sheep. Estradiol can also exert inhibitory effects at the pituitary level under some physiologic circumstances. For example, in sheep, estradiol decreases the amount of a-subunit and FSH-b mRNAs in ovine [250] pituitary cultures [251,252] by transcriptional mechanisms; the sheep appears to be different in this respect. Estrogen can reduce pituitary LH responsiveness to GnRH in vitro and in vivo, e.g., in monkeys with radiofrequency lesions to their hypothalami, and maintained on GnRH pulses, estrogens reduce LH secretion suggesting that inhibitory effects of estradiol may also be mediated at the pituitary level [10,11]. Again, the ovine species is different in that in hypothalamic–pituitarydisconnected animals, treated with GnRH, estradiol has no effect on LH-b subunit mRNAs [253]. Estradiol inhibits LH pulse amplitude in normal men and in GnRH-deficient men maintained on GnRH [236,239]. These studies thus provide evidence that in the human male, estradiol inhibits LH by an action predominantly at the pituitary site. In sum, estrogens can exert both stimulatory and inhibitory effects on gonadotropin synthesis and secretion depending on the dose, duration, the presence or absence of GnRH, and other physiologic factors. However, the complexities of model systems and disagreements among investigators over the interpretation of these observations preclude enunciation of a unifying hypothesis to explain all physiologic paradigms.

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the luteal phase [256,258]. Furthermore, there is some evidence that b-endorphin concentrations in the portal blood are increased during the luteal phase [256,258]. Progesterone can also augment the stimulatory effects of estrogen on LH secretion. In late follicular phase, serum progesterone levels are rising and along with estrogens, enhance LH responses to GnRH [259]. These changes are important in causing an ovulatory LH surge. In a different part of the cycle, progesterone may also augment the estrogen-inhibitory effects on LH secretion [260].

Inhibins, Activins, and Follistatins The hypothesis that a peptide of gonadal origin selectively regulates FSH secretion was postulated over 50 years ago [5,6,261]. However, in spite of a large body of physiologic data in support of this hypothesis, isolation of inhibin proved to be a difficult task. Finally, in 1985, four groups were successful in isolating and characterizing the structure of inhibin-related peptides [262–267]. These studies revealed that inhibins are dimeric proteins consisting of a common a-subunit and one of two b-subunits, bA or bB (Fig. 6.8). The heterodimers of a : bA are called inhibin A and a: a : bB heterodimers, inhibin B [5,6,261]. Inhibins A and B are equipotent in their FSH inhibiting potency. In addition, bA-subunits can form homodimers called activin A or heterodimers with the b-subunits called activin AB. Both activins A and B stimulate FSH secretion in vitro [5,6]. Inhibin-related peptides are peptides are widely distributed in organ systems and have significant homology with members of a family of proteins that includes mullerian inhibiting substance, transforming growth factor-b, a bone matrix protein, and the decapentaplegic gene complex of Drosophila [268]. It has been speculated that much like other members of this family, inhibin-related peptides play an important role as regulators of growth and differentiation in

Progesterone Effects of progesterone on gonadotropins have not been studied as well as those of estrogens, and some uncertainty persists with regard to the nature and mechanisms of progesterone effects. During the luteal phase of the human menstrual cycle, when progesterone concentrations are the highest, LH pulse frequency markedly slows [254]. Similar decreases in LH pulse frequency during the luteal phase have been recorded in sheep [255] and monkeys [256]. However, in rats, progesterone may also affect LH pulse amplitude [257]. These observations have suggested that progesterone actions are mediated at the level of hypothalamic GnRH pulse generator. Administration of progesterone during the follicular phase results in LH secretory patterns that resemble those of the normal luteal phase [250]. Progesterone effects on hypothalamic GnRH secretion appear to involve opiatergic pathways, since naloxone, an opioid antagonist, increases the LH pulse frequency during

FIGURE 6.8. Inhibins and activins. Inhibin and activins are dimeric proteins made up of two subunits. Inhibins are made up of an alpha subunit that is linked to one of two beta subunits, whereas activins are made up by dimerization of two beta subunits.

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diverse tissues. Thus, activin has been shown to interact with erythropoietin to stimulate erythropoiesis [6]. Activin is also an important regulator of homeobox genes. In the testis, activin has been shown to regulate spermatogonial multiplication [269]. The role of inhibins in the adult male animal remains unclear. Immunoneutralization studies in rats reveal that infusion of anti-inhibin sera leads to an increase in serum FSH levels only in the female and prepubertal male animal, but not in the adult male [270,271]. These studies questioned the in vivo role of inhibin as an FSH regulator in the adult male. Serum inhibin levels have been measured in men with a variety of testicular disorders but have failed to show any inverse correlation between FSH and serum inhibin levels. Subsequently, Culler and coworkers [272,273] demonstrated that when Leydig cells in adult male rats are destroyed by a Leyclig cell-specific toxin, EDS, administration of anti-inhibin sera leads to an increase in serum FSH. These data suggest that under basal conditions in the adult male, testosterone plays a more important role in FSH regulation and that inhibin effects are unmasked only when testosterone levels are lowered. Although the original inhibin hypothesis postulated inhibin as a selective regulator of FSH, it is now clear that under some conditions, inhibins can also regulate LH output [5,6]. Conversely, both FSH and LH regulate inhibin production by Sertoli cells in the rat and the human male [274–277]. FSH and LH both predominantly increase inhibin-a mRNA [274,275,278,279]. This is somewhat perplexing since the a-subunit is the more abundant of the inhibin subunits. In the case of the pituitary glycoprotein hormones, regulation takes place generally at the level of the less abundant, rate limiting b-subunits. FSH effects on inhibin subunits are mediated via cAMP [276]. However, unlike FSH, which predominantly affects the a-subunit mRNA levels, cAMP increases both a and bB mRNAs in vitro [279]. These data suggest that FSH effects are more complex and may involve other mechanisms in addition to the cAMP pathway. Another class of FSH inhibitors called follistatins were described by Ueno et al. [280] and Robertson et al. [281]. Follistatins are glycosylated single chain polypeptides with structural homology to pancreatic secretory inhibitory (PSTI) protein and human epidermal growth factor (hEGF) [5]. The mature human follistatin contains four repeating domains; three are highly similar among themselves and to hEGF and PSTI. Follistatin gene has been cloned, is more than 5 kb in length and has six exons and five introns. Follistatin is highly cysteine-rich and has a very acidic carboxy terminal region. The precise physiologic role of follistatins is not known; however, emerging data suggest that they may act primarily to suppress FSH release. In addition, follistatins are potent inhibitors of estrogen production in granulosa cells and can bind activin. Activins regulate intragonadal function both in the male and the female [6]. In the testis, activins suppress LH-

stimulate testosterone production while inhibins suppress it. In granulosa cells, activins increase aromatase activity but inhibit progesterone synthesis [5,6]. Emerging evidence suggests that activin B may act as an autocrine/paracrine mediator in the pituitary and modulate FSH-b gene expression and secretion by gonadotrophs [282].

The Biochemical Pathways that Link Energy Balance and Reproductive Axis (Fig. 6.9) Humans have known since antiquity that energy balance and nutritional status are intimately linked to the reproductive axis in both men and women [283–289]. The onset of puberty, the length of the reproductive period, the number of offspring, and the age of menopause have all been linked to body weight and composition, particularly the amount of body fat [285–289]. Normal reproductive function requires an optimal nutritional intake; both caloric deprivation and consequent weight loss, and excessive food intake and obesity are associated with impairment of reproductive function [283–315]. The temporal aspects of sexual maturation are more closely associated with body growth than with chronological age [290]. In the animal kingdom, during periods of food scarcity, small animals with a short life span may not even achieve puberty before death. In animals with longer life spans, sexual maturation may be delayed during food deprivation. Undernutrition, caused by famine, eating disorders and exercise, results in weight loss and changes in body composition and endocrine milieu that can impair reproductive function [283–297,307–314]. As a general rule, weight loss and body composition changes resulting from undernutrition are associated with reduced gonadotropin (GnRH) secretion; the decrease in FSH and LH levels correlates with the degree of weight loss [291,292]. However, both hypogonadotropic and hypergonadotropic hypogonadism have been described in cachexia associated with certain chronic illnesses such as HIV-infection [294]. Collectively, these observations provide compelling evidence that energy balance is an important determinant of reproductive function in all mammals. We do not know the precise nature of the biochemical pathways that connect these two body systems essential for the survival of all species. The prevalent hypothesis is that the metabolic signals, that regulate hypothalamic GnRH secretion, are mediated through leptin and neuropeptide Y [290,295–300]. Leptin, the product of the obesity (ob) gene, is a circulating hormone secreted by the fat cells that acts centrally to regulate the activity of CNS effector systems that maintain energy balance [301]. Leptin stimulates LH secretion by activation of the nitric oxide synthase in the gonadotropes [300], (Fig. 6.9). Leptin also inhibits neuropeptide Y secretion. Neuropeptide Y has a tonic inhibitory effect on both leptin and GnRH secretion. Leptin also stimulates nitric oxide (NO) production in the mediobasal hypothalamus; NO stimulates GnRH secretion by the hypothalamic GnRH secreting neurons [300]. Therefore, the net

FIGURE 6.9. Relationship between energy balance and reproductive function. (a) The biochemical pathways that link energy balance and reproductive axis. We do not know the precise nature of the biochemical pathways that connect these two body systems, which are essential for the survival of all species. The prevalent hypothesis is that the metabolic signals, that regulate hypothalamic secretion of gonadotropin releasing hormone (GnRH), are mediated through leptin and neuropeptide Y. Leptin, the product of the obesity (ob) gene, is a circulating hormone secreted by the fat cells that acts centrally to regulate the activity of central nervous system effector systems that maintain energy balance. Leptin stimulates luteinizing (LH) secretion by activation of the nitric oxide (NO) synthase in the gonadotropes. Leptin also inhibits neuropeptide Y secretion. Neuropeptide Y has a tonic inhibitory effect on both leptin and GnRH secretion. Leptin also stimulates NO production in the mediobasal hypothalamus; NO stimulates GnRH secretion by the hypothalamic GnRH-secreting neurons. Therefore, the net effect of leptin action is stimulation of hypothalamic GnRH secretion. Caloric deprivation in experimental animals is associated with reduced leptin levels and a concomitant reduction in circulating LH levels. Leptin administration to calorically deprived mice reverses the inhibition of gonadotropin secretion that attends food restriction. Similarly, genetically ob/ob mice with leptin deficiency have hypogonadotropic hypogonadism and are infertile; treatment of these mice with leptin restores gonadotropin secretion and fertility. Collectively, these observations suggest energy deficit and weight loss are associated with impaired GnRH secretion (b), in part because of decreased leptin secretion and a reciprocal increase in neuropeptide activity. Although there is agreement that leptin is an important metabolic signal that links energy balance and reproductive axis, it remains unclear whether it is the primary trigger for the activation of the GnRH pulse generator at the onset of puberty. Emerging evidence suggests that leptin is essential but not sufficient for initiation of puberty. Adapted with permission from Bross et al. [684].

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effect of leptin action is stimulation of hypothalamic GnRH secretion [295–300]. Caloric deprivation in experimental animals is associated with reduced leptin levels and a concomitant reduction in circulating LH levels [296]. Leptin administration to calorically-deprived mice reverses the inhibition of gonadotropin secretion that attends food restriction [296]. Similarly, genetically ob/ob mice with leptin deficiency have hypogonadotropic hypogonadism and are infertile; treatment of these mice with leptin restores gonadotropin secretion and fertility [296]. Collectively, these observations suggest energy deficit and weight loss are associated with impaired GnRH secretion (Fig. 6.9), in part, because of decreased leptin secretion and a reciprocal increase in neuropetide Y activity. While there is agreement that leptin is an important metabolic signal that links energy balance and reproductive axis, it remains unclear whether it is the primary trigger for the activation of the GnRH pulse generator at the onset of puberty. Emerging evidence suggests that leptin is essential but not sufficient for initiation of puberty.

The Minnesota Experiment: the Effects of Experimental Caloric Deprivation on Reproductive Function in Young Men In the late 1940s, Ancel Keys and coworkers studied human starvation in an experiment in which 32 young men volunteered to live on the campus of the University of Minnesota and consume a diet providing approximately 1600 kcal per day, about two thirds of their normal energy requirement [315]. The volunteers lost an average of 23% of their initial body weight; more than 70% of body fat and 24% of lean tissue was lost in the process. Keys et al. [315] found that a decrease in caloric intake and subsequent weight loss first caused a loss of libido. Continued weight loss resulted in a reduction of prostate fluid and there was lessened motility and longevity of sperm; the production of sperm was reduced when men weighed approximately 25% less than the normal weight for their height. Weight gain restored reproductive function in these volunteers.

ONTOGENESIS OF LH AND FSH SECRETION

Fetal Life Historical and Anthropological Examples of the Link between Nutritional Status and Fertility

The Dutch Hunger Winter Between October 1944 and May 1945, during the course of the Second World War, the German army restricted food supplies in certain Dutch cities resulting in substantial reduction in average daily energy intake to less than 1000 kcal (Fig. 6.10) [303,304]. Some adjacent cities, where food supplies were not curtailed by the Germans, were not affected by the famine (control cities). Susser and Stein have reported the effects of acute food scarcity on this previously healthy and nutritionally replete population [302–304]. Fifty percent of women affected by the famine developed amenorrhea. The conception rate dropped to about 53% of that normally expected and correlated with the decreased caloric ration [303,304]. In addition to the decrease in fertility, undernutrition resulted in an increase in perinatal mortality, congenital malformations, and schizophrenia [304]. These observations indicate that optimal caloric intake is essential for normal fertility and prenatal growth. The Association of Weight Change and Fertility in !Kung San of Botswana The !Kung San of Botswana were a tribe of hunter-gatherers until about 20 years ago [305]. The body weight of the men and women in the tribe varied substantially throughout the year depending upon the availability of food. In the summer months, the food supply was more abundant and the body weight increased, while the nadir of body weight was achieved in winter months. The number of births in the tribe peaked about 9 months after the peak of body weight [306]. This is another example of how the availability of food can affect fertility patterns in nature (Fig. 6.11).

GnRH is demonstrable in the fetal hypothalamus as early as 6 weeks of gestation [316–318]. The fetal pituitary contains measurable amounts of LH and FSH by 10 weeks, and by 11 to 12 weeks LH response to GnRH can be shown. Serum levels of LH and FSH rise gradually to a peak at about 20 weeks [317]. In the second half of pregnancy, serum LH and FSH levels in the fetus decline gradually. The precise mechanism of this decline is not known, but several factors operative in the second half of pregnancy may be responsible. The rise in sex steroid secretion by the fetal gonad, the rising maternal estrogen levels, and the development of negative feedback mechanisms may all contribute to tonic inhibition of the hypothalamus and the pituitary gland by the ambient sex steroid concentrations [316,317]. The relative roles of placentally derived hCG and fetal LH and FSH in the development and differentiation of fetal gonad and accessory sex organs is not fully defined. Placental hCG probably plays a significant role in stimulating androgen production by the fetal testis in early pregnancy. High androgen levels are required for differentiation of Wolffian structures in the male. In addition, FSH stimulates differentiation and development of seminiferous tubules. These data are consistent with observations that patients with IHH have normal differentiation of Wolffian structures and external genitalia because the placental hCG drives the fetal testis to produce sufficient androgen, even in the absence of pituitary LH and FSH. However, because of FSH deficiency, these patients have arrested or retarded development of seminiferous tubules. On the other hand, testicular descent is partly dependent, during the later part of pregnancy, on androgen levels which, during this period of fetal life, are maintained by pituitary LH. Administration of an anti-androgen, flutamide, during the transabdominal portion

Chapter 6

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of testicular descent results in failure of testis to descend within the scrotum [319]. Therefore, it is not surprising that undescended testis is a common association of IHH. Patients with the rare but curious syndrome of “anorchia” or “vanishing testis” usually have normally differentiated external genitalia and Wolffian structures. These findings provide evidence of the prior presence of normal testes and normal placental hCG secretion during critical periods of sexual differentiation in these patients. Thus a thorough

FIGURE 6.10. The Dutch Hunger winter during the German siege. Adapted with permission from Stein et al. [304] and Susser and Stein [302].

understanding of the ontogenetic changes in gonadotropin secretion can be helpful in defining the pathophysiology of the disorders of sexual differentiation.

Postnatal Life and Childhood Years After birth, serum LH and FSH levels rise again, albeit transiently [320]. In the first 6 months of postnatal life, LH and FSH levels are measurable in blood [320–322]. In fact, the

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FIGURE 6.11. Correlations of feeding pattern and fertility in the !Kung San of Botswana. The relationship of body weight and number of births in a tribe of !Kung San of Botswana. The body weight of men and women in the tribe varies throughout the year depending on the availability of food. In summer months, the food supply is more abundant and the body weight increased while the nadir of body weight was achieved during the winter months. The number of births peaked about 9 months after the peak of body weight. From Van Der Walt LA et al. [305].

pulsatile pattern of LH and FSH secretion is easily discernible during this brief period of reactivation of the hypothalamic–pituitary axis [323]. Serum LH and FSH levels peak around 2 to 3 months of age and then decline to undetectable levels by 9 to 12 months, serum testosterone levels undergo similar changes. This brief period of postnatal life thus provides a unique, albeit narrow, window in which the normality of the hypothalamic–pituitary gonadal axis can be assessed before gonadotropin and sex steroid levels fall back to the low range. During childhood years, the hypothalamic–pituitary gonadal unit is kept in abeyance until the onset of puberty [324–328]. However, the pituitary and the testis retain the ability to respond to GnRH and to hCG, respectively. The response of prepubertal pituitary to GnRH stimulus is relatively damped. In addition, the GnRH-induced rise in serum FSH in prepubertal humans is greater than that in LH. This is in contrast to an adult individual in which a single dose of GnRH causes a greater rise in LH. During pubertal maturation, serum LH and FSH levels rise [324–328]. It is generally believed that activation of FSH secretion precedes that of LH. However, relative insensitivity of LH and FSH RIAs and low circulating levels had made it difficult to discern early changes in LH and FSH

secretion. In fact, random blood levels of LH and FSH in individual subjects are difficult to interpret. Sleep-entrained pulsatile secretion of LH is highly characteristic of early stages of puberty [323]. Nocturnal LH pulses are associated with concordant testosterone secretion [323]. Earlier data, utilizing traditional RIAs, reported a two-to sixfold increase in serum LH and FSH levels during puberty [326]. Studies utilizing LH bioassays which are more sensitive than traditional RIAs report a greater fold increase in bioassayable LH levels across puberty [326,327]. More recently, highly sensitive two site-directed immunoradiometric, immunofluorometric, and chemiluminescent assays have become available. Apter et al. [328] reexamined the serial changes in LH and FSH concentrations during different stages of pubertal development, using highly sensitive IMFAs. These authors reported that the mean LH concentrations increased 116-fold between 7 years of age and adulthood, while mean FSH concentrations increased sevenfold, and estradiol levels 12-fold. The increase in FSH was gradual, but the rise in LH was abrupt and steep. The onset of changes in FSH did, however, precede the rise in LH concentrations. Unlike the traditional RIAs, time-resolved immunofluorometric and chemiluminescent assays can discriminate prepubertal from pubertal children and, therefore, may be very useful in the diagnostic work-up of pubertal disorders.

Aging and Gonadotropins There is agreement that serum testosterone levels decline progressively in men with advancing age (Fig. 6.12); almost 25% of men over the age of 70 have serum testosterone levels in the hypogonadal range [329–334]. The sex hormone-binding globulin levels increase with age, resulting in a greater decrease in free and bioavailable testosterone than total testosterone [331,333]. The diurnal rhythm of testosterone secretion, observed in younger men, may be attenuated or lost in older men. While there is consensus that mean serum levels of total, free, and bioavailable testosterone fall in the later decades of life, many elderly men retain serum testosterone in the “normal” male range [335]. There is also an increase in circulating estradiol and estrone levels with age due, in part, to the increased peripheral aromatization of androgen to estrogen [235,236,331–333]. Aging-associated decline in testosterone levels occurs due to defects at all levels of the hypothalamic–pituitary–gonadal axis. Androgen secretion by the testis of elderly men is decreased due to primary abnormalities at the gonadal level. This is supported by their higher basal LH and FSH levels [330–337], decreased testosterone response to hCG [330–338], and diminished Leydig cell mass in aging men [339]. In addition, secondary defects may exist at the hypothalamic–pituitary level, as indicated by the somewhat blunted LH and FSH responses of older men to GnRH [337]. The circulating levels of free alpha-subunit are also higher in older men as compared to younger men [337].

Chapter 6

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FIGURE 6.12. Age related changes in LH, FSH and testosterone secretion. (a) Relation between serum total testosterone level and age by health status as determined by a metaanalysis of 44 studies. Continuous line = all illness excluded (R2 = 0.44); dashed line = endocrine illness excluded (R2 = 0.25); dotted line = no illness excluded (R2 = 0.0); long dashed line = no information (R2 = 0.63). Reprinted from Gray et al. [340]. (b) Fifteen-year longitudinal changes in serum total testosterone in normal men, ages 66 to 87 years at study entry. Adapted from Morley et al. [341]. (c) Serum luteinizing hormone (LH) levels (open symbols) and follicle-stimulating hormone (FSH) levels (solid symbols) in men as a function of age from three studies. From Tenover [685].

The age-related changes in reproductive hormones are often compounded by the effects of concomitant illness, changes in body composition, and medications. Although the data available on the relationship of age to serum androgen levels are mostly cross-sectional in nature, two longitudinal studies [340,341] have now confirmed the aging-associated decline in serum testosterone levels. Some cross-sectional studies have been criticized for selecting elderly subjects that are generally more healthy than the general population [342]. However, even after taking in to account the confounding influence of the time of sampling, assay variability, concomitant illness, and medications, it is apparent that testosterone levels decline with advancing age. The Effect of Aging on the Coordinate Secretion of the Pituitary Hormones

Veldhuis et al. [343–345] have used a novel, modelindependent statistic approximate entropy to measure the irregularity and asynchronicity of pituitary hormone secretion. These studies [344,345] have revealed that older men secrete LH more irregularly than younger men. The older men also have less synchronicity between LH and testosterone secretion than younger men. Therefore, aging is associated with abnormalities of the normal feedback control mechanisms that control the flow of information between different components of the hypothalamic–pituitary-testicular network, and a disruption of the orderly pattern of pulsatile hormonal secretion [346].

Gonadotropin Secretion During the Menstrual Cycle The cyclical pattern of intricate changes in gonadotropin secretion, ovarian sex steroid secretion, and the responses of the endometrium and reproductive tract to these hormonal

changes constitute the menstrual cycle. Menstrual bleeding serves as a useful clinical marker and, by tradition, the first day of the bleeding is designated day 1 of the cycle. The cycle length is usually between 25 and 30 days. Extensive reviews of the hormonal and histologic changes during the menstrual cycle have been published [347–351]. This section will focus primarily on the changes in the gonadotropins. During the early follicular phase, serum FSH levels are relatively higher but LH, estradiol and progesterone levels are low [347–350]. This relative preponderance of FSH in the early part of the cycle is felt to be important in the recruitment and maturation of a cohort of ovarian follicles, one of which will eventually ovulate [349,350]. Suppression of plasma FSH during the early follicular phase delays the development of the dominant follicle in the nonhuman primate and prolongs the follicular phase [350]. Conversely, superphysiologic doses of FSH can lead to simultaneous development of several follicles [350]. The mechanisms that lead to selection of the dominant follicle and atresia of all others are not fully understood. FSH promotes follicular growth and estradiol production, and induces LH receptors on granulosa cells [248–250]. Serum estradiol levels gradually rise as the follicular phase progresses and follicular growth occurs. Increasing estradiol levels suppress serum FSH levels. In the late follicular phase, serum estradiol levels begin to rise rapidly. The positive feedback effects of the high, late follicular phase estradiol levels increase LH and FSH secretion and pituitary responsiveness to GnRH. The estrogen effects are augmented by the rising progesterone concentrations which also enhance LH response to GnRH [259], resulting in the mid-cycle LH surge. In some species, increased GnRH output in the periovulatory period has been demonstrated, although it remains unclear if in the human GnRH plays a permissive, essential or nonessential role in the ovulatory LH surge [351].

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Furthermore, in women with GnRH deficiency, pulsatile administration of GnRH at a fixed dose and frequency can recreate the gonadotropin profile of a normal menstrual cycle [351–354]. In some experimental models, cyclic changes in gonadotropin secretion can be replicated without hypothalamic involvement [355]. The FSH peak at the midcycle is of a smaller magnitude than the LH peak. After ovulation, the FSH levels decrease and remain low during the luteal phase. On the other hand, LH appears essential for maintaining corpus luteum function; LH stimulates the production of progesterone and estradiol by the luteinized follicle. In the absence of fertilization, corpus luteum function gradually declines as indicated by decreasing progesterone and estradiol levels during the latter part of the luteal phase. Serum FSH levels rise, partly in response to a decrease in serum levels of estradiol and progesterone levels, initiating events for the next cycle. The pattern of LH pulses has been well characterized during different phases of the menstrual cycle [254,256,352] and these data have been used to derive inferences about the hypothalamic GnRH secretion. Several generalizations can be made. First, the LH pulse characteristics change markedly during different phases of the cycle. LH pulses are of higher frequency (interpulse interval 1 to 2 hours) during the early follicular phase; the LH pulse amplitude tends to be more uniform. The LH pulse frequency increases during the late follicular phase. The pulse generator slows markedly during the luteal phase [254–256]; the interpulse interval may range from 2 to 6 hours. The pulse amplitude also varies considerably between pulses. With the availability of inhibin radioimmunoassays, serum inhibin levels have been studied across the menstrual cycle [355,356]. These are low in early follicular phase and begin to rise in the late follicular phase reaching a peak 6 hours prior to the midcycle LH surge, after which levels decrease for about 48 hours before beginning to rise again. The maximal inhibin levels are seen 7 to 8 days after the LH surge. These data [256] suggest that inhibin is produced both by the maturing follicle and the corpus luteum. The serum inhibin levels, therefore, reflect progressive increase in inhibin production by the growing follicle during the late follicular phase followed by decreased production from the declining follicle. The luteal phase rise reflects inhibin production by the corpus luteum [256]. The changes in the expression of gonadotropin subunit genes have been examined during the rat estrous cycle [357–359]. In the female rat, the estrous cycle has a length of 4 days. Serum LH and FSH concentrations are low throughout the cycle except for the surge on the late afternoon and everting of proestrus. LH-b and a-subunit mRNAs change little on the day of metestrus, but increase twofold during diestrus [358]. LH-b mRNA levels increase threefold before the preovulatory rise in serum LH, but a mRNA levels remain unchanged during the proestrus gonadotropin surges. FSH-b mRNA levels increase during the metestrus morning, falling to basal levels by metestrus

evening [359]. On proestrus afternoon, FSH-b mRNA concentrations increase but the maximal expression of FSH-b mRNA is seen 2 hours after the proestrus FSH surge [358]. Thus, the changes in the expression of the three gonadotropin subunit genes do not tightly correlate with the circulating LH and FSH levels and the exact mechanisms regulating these cyclic changes in gene expression remain to be uncovered [260,357–359].

DIAGNOSTIC TESTS

GnRH Stimulation Test The effects of graded single doses of GnRH (25–100 ug), given intravenously, on serum LH and FSH secretion in normal men and women have been extensively studied [353–357]. Rapid and dose-dependent increases in serum LH and FSH levels are seen with peak levels of both hormones within 20 to 30 minutes [360]. Increases in serum LH are greater than those in serum FSH levels. Serum testosterone levels do not change significantly, unlike the situation in the monkey. Mortimer et al. [361] evaluated the utility of a 100 ug GnRH bolus as a diagnostic test in classifying 155 patients with disorders of the hypothalamic–pituitary–gonadal axis. It is notable that a wide range of LH responses was seen with peak values ranging from 8 to 34 mIU/ml of LER 907. Patients with primary testicular failure exhibited an exaggerated response. However, significant heterogeneity of LH and FSH responses was observed in patients with disorders of the hypothalamus and pituitary such that the patients with hypothalamic disorders could not be distinguished with certainty from those with pituitary disease. Patients with IHH as a group have diminished LH responses [362] and often exhibit a greater FSH than LH response. A similar prepubertal pattern [363] of diminished LH and FSH response and reversal of the usual LH/FSH ratios after GnRH administration can be seen in patients with anorexia nervosa; restoration to adult pattern occurs after refeeding and weight gain. After repetitive administration of GnRH pulses, LH and FSH responses are normalized in both groups of patients indicating the intactness of the pituitary. Many patients with obvious nongonadotrope adenomas may have normal LH and FSH responses to GnRH [361,362]. On the other hand, patients with hypothalamic disorders may have diminished response to single dose of GnRH [362]. The LH and FSH responses to GnRH also vary with the sex, age, degree of sexual maturation, and in adult women on the phase of menstrual cycle [364]. Thus, GnRH stimulation test has had only a limited usefulness in the diagnosis of hypothalamic–pituitary disorders. In most instances, careful evaluation of baseline hormone levels (LH, FSH, and testosterone) in the appropriate context of historical and radiologic data is sufficient to arrive at the correct diagnosis. The availability of more sensitive, specific, and

Chapter 6

precise immunometric assays for LH and FSH is likely to further erode the utility of GnRH stimulation test in adults. GnRH Stimulation Test in Pediatrics

Serum LH and FSH responses have been characterized after intravenous bolus and infusion of GnRH in normal children and in children with a variety of pubertal disorders [363]. In general, an approximate two-fold increase in serum LH levels and a three- to fourfold increase in serum FSH levels can be seen. However, basal levels of LH and FSH in prepubertal children are low and close to the limits of sensitivity of traditional LH and FSH assays. The responses are also highly variable depending on the sex, degree of sexual maturation, and bone age of the individual. In spite of initial hopes, the GnRH stimulation test has not been useful in differentiating delayed puberty from IHH [362,363]. Similarly, in patients with hGH deficiency, LH and FSH responses to GnRH prior to initiation of hGH therapy are usually diminished, but are not predictive of subsequent gonadotropin deficiency [363].

Clomiphene Test Clomiphene is an antiestrogen, but acts as a partial agonist in that it also has weak estrogenic activity at high doses [365,366]. In adult men and women, its antiestrogenic action predominates in vivo, resulting in increased secretion of GnRH and thereby LH and FSH. In prepubertal children with very low or negligible amounts of estrogen, it acts as an estrogen and inhibits LH and FSH [365]. The adult pattern of stimulatory LH and FSH responses is acquired during mid-to late puberty. The usual protocol is to administer 100 mg clomiphene orally each day for 1 to 4 weeks [365]. Serum LH levels generally increase by 100% or more, while FSH levels show about a 50% increase over baseline. In women, a triphasic response may be seen: there is an initial increase in LH peaking on about the fourth or fifth day. After discontinuation of clomiphene on day 7, LH levels decrease and then rise again between days 9 to 14 [365]. A normal response to clomiphene indicates normality of the hypothalamic–pituitary axis. However, an abnormal/ absent response does not distinguish hypothalamic from pituitary disease. Responses are usually absent in patients with IHH, anorexia nervosa, and hyperprolactinemic disorders. Clinical indications for the clomiphene test are extremely limited; it has had some use as a research tool in establishing the normality and maturity of the hypothalamic– pituitary unit.

Naloxone Test Opiatergic agents inhibit gonadotropin secretion primarily through inhibition of hypothalamic GnRH-secreting nuclei [367–369]. Conversely, opiate antagonists, such as naloxone,

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increase LH secretion. Opioid effects on LH secretion are modulated in part by sex steroid hormones [369]. Accordingly, effects of naloxone vary in different stages of sexual maturation [370] and during the menstrual cycle [371]. In prepubertal children or in early stages of puberty, naloxone does not elicit any increase in serum LH levels [370]. During the late follicular and luteal phases of the menstrual cycle, naloxone elicits an unambiguous increase in LH secretion [371]; the effects are variable in early follicular phase. Similar increase in LH secretion is induced by naloxone in normal adult males [372]. Response to naloxone is lost in postmenopausal women [373] but can be restored by estrogen replacement. Naloxone has been useful in research for eliciting the site of action of drugs/agents that affect gonadal function; however, the test has little or no clinical use.

Detection and Characterization of Gonadotropin Pulse Patterns Soon after the introduction of LH and FSH RIAs by Odell et al. [8,9], it became apparent that these hormones are secreted into the circulation in a pulsatile pattern. The ability to measure small amounts of hormones in serum samples led to recognition that secretion of many, if not all, hormones is episodic [21]. Although the mechanistic basis and physiologic significance of episodic hormone secretion remain somewhat unclear, recent years have seen growing interest in the development of discrete pulse-detection algorithms. In physical sciences, a number of signal detection methods have existed for a considerable time, including spectral analysis, crossspectral analyses, and other procedures for smoothing and filtering data to enhance detection of a signal of interest. However, several difficulties inherent in the biologic data have confounded efforts to develop a single, ideal pulse-detection algorithm. As opposed to the highly episodic physical or mathematical events, LH pulse pattern in humans is characterized by a lack of absolute regularity in the frequency and amplitude of LH pulses, nonuniformity of within-assay precision in different regions of the RIA dose-response curves, crossreactivity of other hormones, less than perfect correlation of RIA values with bioassay data, and dependence of false-positive and falsenegative rates on sampling intensity [21,374,375]. Several peak-detection methods are currently available. For detailed analyses of the pulse-detection methods the interested reader is referred to two excellent reviews by Urban et al. [21] and Veldhuis and Johnson [375]. An ideal pulse-detection program should be objective, simple to use, adaptable to a variety of physiologic situations, defined in relation to its strengths and limitations, particularly with regard to the false-negative and false-positive errors, and “accommodating of the nonuniformity of assay precision and signal/noise ratios” [21,374,375]. Santen and Bardin [376] developed the first algorithm which defined a peak as a 20% increase in the hormone

242

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concentration in a single sample over the preceding sample. Subsequent modifications of the method include selection of a chosen multiple (e.g., threefold) of the assay coefficient of variation (CV) to define the pulse. The simplicity of use and apparent freedom from assumptions have made this a widely used and published program. The Ultra Program, described by Van Cauter and colleagues [377,378], defines a peak as consisting of an upstroke and downstroke, each of which must exceed the interassay CV by two or three times. All hormone values that do not satisfy the threshold criteria for defining the upstroke and downstroke are removed, leaving only the significant pulses. Merriam and Wachter [379] described the Pulsar Program, which first removes long-term trends in the data by a detrending or smoothing technique. The residual series, obtained by subtracting the smoothed baseline series from the original data, is then analyzed for peaks using a set of thresholds based on height and width and referred to as G coefficients. The Cycle Detector Program of Clifton and Steiner [380] estimates noise by one-way analysis of variance (ANOVA) of assay replicates. Data are scanned with serially adjusted thresholds until the probability of rejecting true peaks and artifacts is equal. A cycle comprises an increase, a decrease, and a subsequent increase so that the number of cycles is one less than the number of peaks. Regional Dual Threshold Method, and the Cluster Analysis Program, were both developed by Veldhuis and colleagues [21,381]. Unlike the Regional Dual Threshold method, which evaluates single points as possible peaks and nadirs, the Cluster Program examines the behavior of clusters of points to test for peaks or nadirs [381]. It involves two major steps: first the data are scanned for all significant increases based on a pooled t-statistic; and second, the data are scanned for all significant decreases. The t-statistic can be derived by using the actual experimental replicates present in the nadir and peak clusters or from dose-adjusted standard deviations calculated from one of many variance models. This program has undergone extensive validation by its developers using simulated and real biologic data [375,382,383]. Oerter et al. [384] developed the Detect Program; this algorithm uses line-fitting techniques to establish a baseline. Positively and negatively sloped line-fitting segments are defined as rises and falls. Points are considered part of the baseline if the slope of line joining two points is not significantly different from zero. Individual upstrokes and downstrokes are combined into complete peaks. Such refinements have enhanced the validity and applicability of pulse-detection algorithms, but some problems remain. The nonconcordance of pulses detected by an algorithm-based computer-assisted analysis to those identified by visual inspection is always puzzling. Similarly, sensitivity of the currently available gonadotropin assays is limiting in that it confounds interpretation of low-amplitude

peaks; the physiologic significance of which remains unclear. Also, the inabilty to sample the GnRH concentrations in the hypothalamic effluent in the human has denied access to a truly independent “gold standard” for pulsatile secretion, against which other methods could be validated. Several recent important developments in this field are worthy of note. First, the development of highly sensitive and specific immunoassays for quantitation of LH and FSH should clarify the nature and significance of low-amplitude pulses. The adaptation and validation of crosscorrelation methods for demonstrating coincidence of two or more hormone pulses has now revealed that LH, FSH, and free a-subunit are secreted concordantly [375]. Type I (falsepositive) and type 11 (false-negative) statistical errors have been better defined. Application of deconvolution to pulse analysis has now made it possible to determine the instantaneous secretory rates of hormones [385]. Deconvolution techniques resolve the hormone series into appearance and disappearance curves. Rodbard’s laboratory [384] has published a deconvolution algorithm which allows estimation of instantaneous secretion rate, using an assumed disappearance rate constant. A more complex multiple-parameter convolution model has been published by Veldhuis et al. [385] which overcomes many of the limitations of the earlier deconvolution models and permits determination of: (i) identity and characterization of all secretory episodes; (ii) production rates of the hormone; and (iii) estimation of half-life of hormone disappearance. The reader is referred to the original papers describing this method [384,385] and a recent review of these issues [375]. Although LH and FSH are secreted by the same pituitary cell, it was unclear until recently whether two hormones are secreted simultaneously or independently by the gonadotroph. Visual inspection of the time series for LH and FSH often failed to show apparent coincidence, primarily due to the differences in clearance rates of the two hormones. Developments of conditional probability modeling methods have now shown a high degree of concordance between LH, FSH, free a-subunit, and testosterone pulses and between b endorphin and cortical pulses in normal men [375]. The application of these new and more rigorous methods should certainly provide new insights into the pathophysiology of neuroendocrine secretory events. CLINICAL DISORDERS AFFECTING THE GONADOTROPH The disorders affecting gonadotropin secretion and action can be broadly classified in to two categories: first, hypogonadotropic disorders, or those associated with decreased LH and/or FSH secretion or action; and second, hypergonadotropic disorders, or those characterized by excessive or physiologically inappropriate secretion of LH and/or FSH.

Chapter 6

Hypogonadotropic Disorders Because LH and FSH are trophic hormones for the testes and ovaries, impaired secretion of these gonadotropins (hypogonadotropism) results in hypogonadism. Clinically, patients with hypogonadotropic hypgonadism may present with one or both of the following: 1. Symptoms and signs of sex steroid (androgen in male and estrogen in the female) deficiency; 2. Infertility due to impaired germ cell development. The symptoms and signs of androgen deficiency depend on its time of onset and the degree of gonadotropin deficiency. Androgen deficiency during fetal life may result in failure of the Wolffian structures to develop, ambiguity of external genitalia due to failure of fusion, hypospadias, microphallus, or a combination of these [386]. In patients with isolated hypogonadotropism, placental hCG stimulates the fetal testis to produce sufficient androgen in early fetal life [387,388]. Therefore, most of the patients with congenital GnRH deficiency have normal Wolffian structures and external genitalia. However, during the second half of pregnancy, the fetal gonad is under the control of fetal pituitary LH and FSH. Therefore, severe LH and FSH deficiency during this period may result in undescended testes and microphallus, since testicular descent is partly androgen dependent [386]. If androgen deficiency occurs after birth but before puberty, sexual development is delayed or arrested; these children present with delayed adolescence. Other androgendependent events that occur in the peripubertal period, such as the epiphyseal fusion of long bones and calcification of laryngeal cartilages, are also delayed. Delay in the fusion of the epiphyses results in continued growth of long bones causing reversal of the upper segment to lower segment ratios, and eunuchoidal proportions (span greater than height by more than 2 cm). Men with prepubertal androgen deficiency retain their high-pitched voice and do not develop the male pattern temporal recession of the hairline. Androgen deficiency acquired after completion of puberty is characterized by regression of the secondary sex characters, impairment of libido and sexual function, loss of muscle mass, increased fat mass, and infertility. However, these changes occur insidiously so that many years might elapse before these patients seek medical attention. This may partly explain why men with prolactin secreting pituitary adenomas usually have much larger tumors (macroadenomas) at the time of initial presentation. Early interruption of the menstrual cycle in women, on the other hand, alerts them to seek medical advice earlier, leading to an earlier diagnosis (microadenomas). Disorders associated with hypogonadotropic hypogonadism can be classified into congenital and acquired disorders (Table 6.4). Acquired disorders are much more common than congenital disorders and may result from functional abnormalities in GnRH secretion or from

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Table 6.4. Congenital and acquired causes of hypogonadotropic hypogonadism Congenital disorders Idiopathic hypogonadotropic hypogonadism Mutations of the KALIG-1 gene Mutations of GnRH receptor gene Mutations of DAX-1 gene Other unknown mutations Fertile eunuch syndrome Prader–Willi syndrome Laurence–Moon–Biedl syndrome Basal encephalocele Multiple lentigenes syndrome Cerebellar ataxia and hypogonadotropic hypogonadism Rud syndrome Mutations of LH-beta Mutations of FSh-beta Mutations of LH receptor Mutations of FSH receptor Miscellaneous disorders Acquired disorders Functional disorders Anorexia nervosa and amenorrhea associated with weight loss Amenorrhea of athletes, joggers and ballet dancers Correlations of feeding pattern and fertility in !Kung bushmen Drug-related hypothalamic dysfunction Systemic illness Hyperprolactinemia Hemochromatosis Organic disorders Neoplastic Inflammatory and infiltrative

organic diseases such as neoplastic, inflammatory, or infiltrative diseases. Congenital Hypogonadotropic Disorders

Idiopathic Hypogonadotropic Hypogonadism Kallman et al. [389] first described a syndrome characterized by delayed or arrested sexual development and anosmia. These patients have selective gonadotropin deficiency resulting from an isolated defect in GnRH secretion [390–392]. The primary pathogenic defect in these patients is hypothalamic and the impaired gonadotropin secretion is secondary to the hypothalamic abnormality in GnRH secretion [391]. Associations Although anosmia and hyposmia are the most well-known and the first associations described in this syndrome, a number of other somatic abnormalities have been recorded [390,421–424]. The more common associations include color blindness, cleft lip and palate, and cranial nerve defects (including eighth nerve deafness), horseshoeshaped kidneys, cryptorchidism, and optic atrophy.

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FIGURE 6.13. Heterogeneity of pulsatile gonadotropin secretion in patients with idiopathic hypogonadotropic hypogonadism. Adapted from Crowley et al. [23].

Heterogeneity of Pulsatile Gonadotropin Secretion in Patients with Idiopathic Hypogonadotropic Hypogonadism (Fig. 6.13) There is considerable heterogeneity in the clinical presentation of IHH [393]. The phenotype, to a large degree, is determined by the severity of GnRH deficiency. Those with the most severe deficiency may present with complete absence of pubertal development, sexual infantilism, and in some cases with varying degrees of hypospadias and undescended testes. Male patients may have complete absence of secondary sex characteristics, infantile testes, and azoospermia while female patients may present with primary amenorrhea. Patients with partial GnRH deficiency may have varying degrees of delay in sexual development in proportion to the severity of gonadotropin deficiency. Spratt et al. [393] studied the secretory profiles of LH and FSH in men and women with IHH; these studies revealed that the patients with IHH are quite heterogeneous in their LH-secretory profiles [393]. The largest subset comprises patients who display no pulsatile LH secretion at all. This apulsatile group represents one extreme characterized by the most severe GnRH deficiency. A smaller subset displays low-amplitude pulses. Another subset of patients has LH pulses at a markedly reduced frequency. A fourth subset is characterized by sleep-entrained pulses reminiscent of the pattern seen in early stages of puberty; these patients can be considered to suffer from a “developmental arrest.” Two variants of IHH are particularly interesting. The term “fertile eunuch syndrome” has been used to describe patients with eunuchoidal proportions and delayed sexual development but who have normal-sized testes. Such individuals appear to have sufficient gonadotropins to stimulate high intratesticular testosterone levels and to initiate spermatogenesis, but not enough testosterone secretion into the

blood to adequately virilize the peripheral tissues; they are, in fact, partially gonadotropin-deficient. Another variant with predominantly FSH deficiency has also been described [394], although these patients are rare. Genetics of IHH From a genetic perspective, idiopathic hypogonadotropic hypogonadism is a heterogeneous disorder [27,394,395]. Only a third of IHH patients have a positive family history [394]. Of those with a positive family history, approximately 20% has an X-linked pattern of inheritance, one-third has autosomal recessive, and one-half autosomal dominant mode of inheritance [27,395]. Physical and genetic mapping studies [396,397] have assigned the locus for the X-linked form of Kallmann’s syndrome to chromosomal region, Xp22.3. Two groups [398,399] independently cloned an adhesion molecule-like protein from this region encoded by the KALIG-1 (Kallmann’s syndrome interval-1) gene. The protein product of the KALIG-1 gene presumably regulates migration of the GnRH and olfactory neurons and their morphogenesis [401–403]. Bick et al. (Fig. 6.14) [400] analyzed genomic DNA from 77 men with idiopathic hypogonadotropic hypogonadism and found deletions of the KALIG-1 gene in two men. Other groups have described point mutations in KALIG-1 gene; most of these mutations have been located in fibronectin-III domain of the KALIG1 gene [401]. The point mutations in KALIG-1 gene account for only a small fraction of patients with X-linked form of idiopathic hypogonadotropic hypogonadism [401,404–416], it is certain that additional as yet unidentified X-linked genes are implicated in other subsets of Kallmann’s syndrome [27]. Some patients with idiopathic hypogonadotropic hypogonadism have been found to have contiguous, interstitial deletions of the X chromosome [423].

Chapter 6 500 bp

Follicle-stimulating Hormone and Luteinizing Hormone

245

Stop codon

T312A

5771BP

5' Breakpoint

5' Breakpoint

CCCGCAACTTCAAATTTGGCTCGAGGCTGT

TTATGCTACAAATTAGTGCCTTGTAGCATG

Junction

CCCGCAACTTCAAATGTGCCTTGTAGCATG

Schwanzel-Fukuda and Pfaff [402] studied the migration of the GnRH neurons in the mouse embryo. These neurons first appear in the epithelium of the olfactory placode in the mouse embryo (Table 6.1) and then migrate to the forebrain and finally to their ultimate hypothalamic location. Such observations suggest that IHH may be a developmental defect resulting from an abnormal migration of the luteinizing hormone-releasing hormone (LHRH) neurons, much like DiGeorge syndrome, which results from abnormal migration of the branchial arches. Further support for this hypothesis comes from magnetic resonance imaging (MRI) studies, which show that the olfactory bulbs and sulci are poorly developed in patients with IHH who have anosmia or hyposmia [403]. The genetic basis of the renal abnormalities seen in many patients with Kallmann’s syndrome is not known [420–422]. Mutations of the DAX-1 Gene are Associated with Hypogonadotropic Hypogonadism (Fig. 6.15) The product of the DAX-1 gene is an orphan nuclear receptor [417–419]. The mutations in the C-terminal end of the DAX-1 gene have been associated with X-liked hypogonadotropic hypogonadism, and adrenal insufficiency (adrenal hypoplasia congenita). Patients with DAX-1 mutations usually have erratic LH pulses. However, mutations in the DAX-1 gene are an unusual cause of idiopathic hypogonadotropic hypogonadism, accounting for less than 1% of the cases. These patients typically have normal testosterone response to hCG, indicating normal Leydig cell function. A contiguous gene syndrome characterized by an interstitial deletion of Xp has been reported in a man with Duchenne’s muscular dystrophy, hypogonadotropic hypogonadism, and adrenal insufficiency.

FIGURE 6.14. Mutations of the KALIG-1 Gene are associated with IHH and anosmia. Panel A shows the 3¢ end of the KALIG-1 gene and the region that is deleted in these two men. The positions and the sequences of the PCR primers used to amplify the patient’s genomic DNA are shown. The nucleotide sequence of the region that flanks the deletion is shown in panel B. Adapted from Bick et al. [400].

Mutations of the GnRH Receptor Gene are Associated with Hypogonadotropic Hypogonadism (Fig. 6.16), [17,25,425, 426] Several families with hypogonadotropic hypogonadism due to mutations of the GnRH receptor have been reported [425]. The GnRH receptor is a G-protein coupled receptor with an extracellular amino-terminus, seven transmembrane regions, and an intracellular carboxy-terminus [425]. Hormone binding to the extracellular elements of the receptor results in intracellular activation of phospholipase C and increased mobilization of the intracellular calcium. De Roux et al. [425] described a family with compound heterozygous mutation of the GnRH receptor. One mutation was in the first extracellular loop of the GnRH receptor and was associated with decreased GnRH binding to its receptor [425]. The second mutation that was located in the third intracellular loop did not alter GnRH binding to the receptor but decreased the activation of phospholipase C [425]. The patients with GnRH receptor mutations have normal sense of smell. In these families, the pattern of inheritance of idiopathic hypogonadotropic hypogonadism is autosomal recessive; GnRH receptor mutations account for almost 40% of cases in families with autosomal recessive pattern of inheritance and 10% of sporadic cases. Consanguinity is often present in these families. The male : female distribution among affected individuals is equal. A Large Deletion of the GnRH Gene Explains Hypogonadotropic Hypogonadism in the Hypgonadotropic (hpg) Mouse The GnRH gene has been characterized in many species including the rat, mouse, and human [427–430]. In the rat and the mouse, the GnRH gene has been mapped to chromosome 8 [428] and consists of four exons and three

935delC 942-943ins(AC) 986-987del(GG)insA

315-316insT

273-274del(CG)insT

119delG 145delG 153-154del(AG) 154-155del(GA)

Frameshift

1250-1251ins(GGAT) 1267-1268ins(CC) 1292delG 1326delT 1376-1377del(AT)insG

Hypothalamic–Pituitary Function

SECTION 1

375-376ins(GCCC) 416-417insA 477delT 501delA 518del23bp 543delA 545-546ins(ACCC) 548delG 551-552del(AA) 562-563ins(CAGG) 585delTins(CG) 629-630insG 749-759del(11bp) 754delC 785complex-del/ins 815-857complex-del43ins18 839delT

246

1

470

Q420X

Q395X

Q375X W369X

Q283X

W235X W235X W235X Q252X L263X Y271X

501delA W171X W171X W171X W172X

S153X

Y130X

Y91X Y91X

Nonsense

702delC

3' 405delT

5'

1

470 3'

N4401

R425G

E377K K382N V385G

R267P delV269 delV269 W291C A300V

Missense/dV269

Y399X

W171X W171X

5'

1

470 5'

245-272

451-470

3'

FIGURE 6.15. Mutations of the DAX-1 gene are associated with IHH and adrenal insufficiency. Naturally occurring DAX-1 mutations. The locations of DAX-1 mutations are depicted relative to their domain structure. The nuclear receptor-like domain is shaded, and the aminoterminal repeats are depicted by arrows. The junction of exons 1 and 2 is denoted by an arrowhead. The black bar represents the reported transcriptional silencing domain [17]. Because the number system and designation of mutations differ in various original reports, all mutations are indicated as described below [31]. The A of the ATG translational initiation codon is designated nucleotide +1. The locations of frameshift mutations are shown at the position of the actual mutation rather than at the location of the resultant premature stop codon. For mutations that occur within nucleotide repeats, the mutation (either insertion or deletion) is depicted as the 3¢-most nucleotide within the repeat. Frameshift and nonsense mutations that lead to premature truncation of the protein are shown in the top two panels. Nucleotide insertions or deletions are illustrated in the top figure, and the locations of mutations that create stop codons are shown in the middle figure. Missense mutations and the single codon deletion (delV269) are shown in the bottom panel. Mutations described in this report are shown in bold below the schematic diagrams. Note the broad distribution of mutations and the relatively high frequency of frameshift and nonsense mutations. From Reutens et al. [686].

introns. The first exon codes for the 5¢ untranslated sequences, the second for the signal peptide, the GnRH decapeptide and the first 12 amino acids of the GnRHassociated peptide (GAP), the third for amino acids 13–41 of GAP, and the fourth for amino acids 42–54 of GAP and the 3¢ untranslated sequences. The hypogonadotropic (hpg) mouse is an interesting model of GnRH deficiency [429]. These mice have small testes and accessory sex organs, are infertile [429], and fail to respond to a single bolus of GnRH by an increase in LH and FSH secretion. However, repeated administration of GnRH normalizes LH and FSH secretion. Similarly, grafts of the hypothalamic preoptic area restore gonadotropin

secretion, consistent with the premise that the primary abnormality in hpg mice is in hypothalamic GnRH neurons [430]. Molecular studies of the GnRH gene in hpg mice have revealed a large deletion encompassing the third and the fourth exon [427,430]; the nucleotide sequences encoding the GnRH decapeptide are not deleted. Interestingly, in situ hybridization studies have demonstrated that the mRNA coding for the GnRH decapeptide is transcribed in the hypothalamus. However, the GnRH peptide is not translated, suggesting that sequences in the 3¢ untranslated region or in the introns may be required for translation of the GnRH mRNA. The critical role of this deletion in the

Chapter 6

causation of the reproductive disorder was established by demonstrating that transgenic hpg mice bearing a wild type GnRH transgene had restoration of the reproductive processes [427,430]. These studies in hpg mice had raised hopes that patients with IHH might also have a somewhat analogous molecular defect. Several investigators have [431,432] examined the structure of the GnRH gene in patients with IHH, using Southern blot and polymerase chain reaction-based analyses. These studies have failed to uncover major deletions or rearrangements of the GnRH gene in patients with IHH by Southern blot analysis or sequencing of polymerase chain reaction (PCR) products [431,432]. However, more subtle defects within the GnRH gene have not been completely excluded. Mutations of Known Genes Cannot Account for the Majority of Cases of Idiopathic Hypogonadotropic Hypogonadism Known mutations of the KALIG-1, GnRH receptor, and DAX-1 gene can account for only 25% to 30% of cases of hypogonadotropic hypogonadism (10% to 15% KALIG-1, GnRH-receptor 15%, and DAX-1 <1%). Therefore, additional autosomal and X-linked genes will likely be implicated in other cases of idiopathic hypogonadotropic hypogonadism. Fertile Eunuch Syndrome This term has been used to describe patients with eunuchoidism and delayed sexual development, but with normal-sized testes [420]. Such individuals appear to have sufficient gonadotropin to stimulate high intratesticular testosterone levels and to initiate spermatogenesis, but not enough testosterone secretion into the blood to adequately virilize the peripheral tissues; they are partially gonadotropin-deficient.

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Mutations in the Genes Encoding LH beta and FSH beta Subunits Hypogonadism Caused by Mutations in the FollicleStimulating Hormone b-Subunit Gene (Fig. 6.17) Inherited mutations of the FSH beta genes are uncommon [433–437], but have been reported to produce male hypogonadism and delayed puberty in boys [433–437]. FSH-deficient male mice are fertile although they have small testes and subnormal spermatogenesis [438]. Female mice deficient in the FSH beta subunit, produced by the embryonic stem cell technology, are infertile with a block in folliculogenesis prior to antral follicle formation [438]. A 46, XX patient, homozygous for an FSH beta point mutation, presented with primary amenorrhea and infertility, and low serum FSH levels [434]. Analysis of the FSH beta gene revealed a two-nucleotide deletion that resulted in a frame shift of subsequent codons and premature termination [434]. A relative of the index case was postmenopausal and had subnormal FSH levels. The two point mutations in the FSH-beta gene observed in this family were both located in exon 3 at codons 51 and 61 [434]. The mutant cDNAs (Val61X and Cys51Gly) were stably transfected into Chinese hamster ovary cells and the FSH concentrations in the medium were measured by immunoradiometric assay. The CHO cells transfected with the mutant FSH beta genes secreted very little FSH into the medium, compared with cells transfected with the wild type gene [434]. Hypogonadism Associated with Inactivating Mutations of the LHb Gene (Fig. 6.18) A single patient with mutation of the LH beta subunit gene has been reported [433]; this individual presented with delayed pubertal development [433]. He had increased serum immunoreactive LH levels

FIGURE 6.16. Mutations of the GnRH receptor gene are associated with autosomal recessive form of IHH. The structure of the human GnRH receptor protein, with an extracellular domain, seven transmembrane domains, three extracellular loops, and three intracellular loops. The three reported mutations are indicated by the arrows. The single letter code is used for amino acids. From Layman [688].

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are associated with increased bioactivity and a reduced serum half-life [435,436]. The clinical significance of this polymorphism is not known. Inactivating Mutations of LH and FSH Receptor Genes Inactivating Mutations of the LH Receptor Gene are Associated with Hypogonadism and Leydig Cell Hypoplasia A number of families with resistance to LH action due to inactivating mutations of LH receptor have been reported [439–447]. Men with LH receptor mutations present with a spectrum of phenotypic abnormalities ranging from feminization of external genitalia in 46, XY males to Leydig cell hypoplasia, primary hypogonadism, and delayed sexual development [440,442]. In a patient with Leydig cell hypoplasia and hypogonadism, a T to A mutation in position 1874 of the LH receptor gene was found [442]. Testicular histology in this man revealed the absence of mature Leydig cells in the interstitium; the seminiferous tubules had thickened basal lamina and spermatogenic arrest at the elongated spermatid stage. Female member of the kindred with LH receptor mutation revealed normal development of secondary sex characteristics, increased LH levels and amenorrhea. Inactivating Mutations of FSH-Receptor Gene Only one report [448] of FSH receptor mutation is on record. In this instance, an inactivating mutation of the FSH receptor gene was associated with familial ovarian dysgenesis and primary amenorrhea. Related men in the family had variable alterations of spermatogenesis and fertility.

FIGURE 6.17. The organization of the FSH beta gene and the location and consequence of mutations in it. (a) The organization of the human FSH beta gene and the relative location of the three exons and two introns. The exons are shown as boxes. The numbers beneath the boxes indicate the location of the amino acids in the FSH beta protein. The shaded regions refer to the translated regions of the gene. The location of two known mutations in exon 3 are shown by arrows. (b) FSH concentrations in the media from Chinese hamster ovary cells transfected with the wild type FSH beta gene or the mutant FSH beta genes. Results are mean ± SD. Val61X and Cys51Gly are the FSH beta mutants with mutations at those locations in the FSH beta protein. Adapted with permission from Layman et al. [434].

but decreased bioactive LH concentrations. The mutant LH in this patient had a homozygous substitution of glycine in position 54 with arginine (G54R). The mutant LH, expressed in Chinese hamster ovary cells, had decreased receptor binding activity. The male individuals in the family who were heterozygous for this mutation had lower testosterone levels [433]. Heterozygous females had regular menstruation and were fertile. A polymorphic variant of LH has been reported in Finland and Japan [435,436]. The variant LH has two amino acid substitutions, W8R and I15T, that

Activating Mutations of LH and FSH Receptor Genes Activating Mutations of the LH Receptor Gene Are Associated with Gonadotropin-Independent Sexual Precocity (Fig. 6.19) Activating or gain-of-function mutations of the LH receptor are associated with gonadotropin independent, sexual precocity in boys, but do not produce a discernible phenotype in females [447]. Analysis of LH receptor in this patient showed a C to T substitution in exon 11 that resulted in an Ala to Val change. When the COS-7 cells were transiently transfected with the wild type or Ala373Val mutant LH receptor cDNA, the mutant cDNA construct had higher basal and hCG-stimulated cAMP accumulation [447]. Activating Mutations of FSH Receptor Only a single case of activating mutation of the FSH receptor is on record; this patient was fertile even after surgical hypophysectomy that had lowered his FSH immunoreactivity to undetectable levels [34,39,40,449,450]. Activating Mutations of the LH and FSH Receptors and Gonadal Tumors It has been hypothesized that activating mutations of the LH and FSH receptors might cause development of ovarian and testicular neoplasms [450]. Activating mutations of FSH receptor have not been reported in

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FIGURE 6.18. Mutations of the LH beta subunit gene are associated with hypogonadism. (a) The structure of the LH beta gene and the location of the PCR primers used for amplifying the gene. The mutant LH had a homozygous substitution of glycine in position 54 by Arg, shown by a vertical arrow. (b) The immunoreactivity and the receptor-binding activity of the mutant LH expressed in Chinese hamster-ovary cells. The mutant LH had decreased receptor binding activity. Adapted with permission from Weiss et al. [116].

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ovarian tumors. A single patient with LH receptor mutation and seminoma has been reported, although a cause and effect relationship between LH receptor mutation and the testicular tumor has not been established [450].

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F I G U R E 6 .1 9 . Activating mutations of LH receptor are associated with gonadotropin independent sexual precocity. (a) Partial sequence of exon 11 and the location of the C to T substitution that results in an Ala to Val changes. (b) Basal and hCG stimulated camp production by COS-7 cells transiently transfected with either the wild-type or with Ala373Val mutant LH receptor cDNA constructs. LH receptor cDNA cloned in reverse orientation served as control. The mutant cDNA had higher basal and hCG-stimulated camp accumulation in COS-7 cells. Adapted from Gromoll et al. [447].

Prader–Willi Syndrome A syndrome consisting of obesity, hypotonic musculature, mental retardation, hypogonadism, short stature, and small hands and feet has been well described [451–456]. Hypogonadism, cryptorchidism, and

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micropenis are common [451]. Histologically, the testis is immature without germinal cells, but with Sertoli cells and diminutive tubules [452]. The LH response to a single bolus of GnRH is subnormal in comparison to obese controls [451]. The degree of gonadotropin deficiency in these patients is variable. A few patients with hypergonadotropic hypogonadism have also been described. Clomiphene has been shown to turn on the pituitary–gonadal axis of individuals of either sex with Prader–Willi syndrome to secrete gonadotropins and gonadal steroids. Prader–Willi syndrome is a disorder of genomic imprinting that commonly results from deletions of proximal portion of paternally derived chromosome 15q [455,456], and is associated with constitutional obesity, mental retardation, and hypogonadotropic hypogonadism. The maternally derived copies of genes responsible for the Prader–Willi syndrome in proximal 15q are normally silent [456]. Therefore, the deletion of the paternally derived copy of the normally active genes produces the disease. Prader–Willi syndrome can also result if both copies of the gene are derived from the mother because the maternal copies are inactivated presumably by DNA methylation [456]; this condition is known as uniparental disomy. Structural abnormalities of the imprinting center can also produce the Prader–Willi syndrome. The genes responsible for the Prader–Willi syndrome have not been identified. Allele-specific methylation at locus D15S63 can be detected by a PCR method and has been used as a diagnostic test for this syndrome [462,463]. Laurence–Moon–Biedl Syndrome This condition is characterized by obesity, hypogonadism, mental retardation, polydactyly, and retinitis pigmentosa [457–461]. Renal abnormalities are common and include glomerular sclerosis, mesangial proliferation, and cyst formation. The syndrome is inherited as an autosomal recessive disorder. Delayed adolescence is a common feature. However, in adult patients, prevalence of hypogonadism is seen in about half the patients [458]. Retinal degeneration is seen early in life, between 4 and 10 years of age. Basal Encephalocele A rare cause of hypothalamic failure is basal encephalocele with midfacial anomalies including a broad nasal root and cleft lip. In these patients, the pituitary can herniate through the floor of the sella turcica resulting in altered secretion of growth hormone, FSH, LH, and prolactin. Multiple Lentigenes Syndrome A complex comprising multiple lentigenes, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness, and an autosomal hereditary pattern has been described [459]. Delayed or absent pubertal development due to hypogonadotropic hypogonadism occurs in association with this syndrome.

Cerebellar Ataxia and Hypogonadatropic Hypogonadism Volpe et al. [460] have described familial hypogonadotropism in association with pes cavus and cerebellar ataxia. Rud Syndrome The constellation of mental retardation, epilepsy, and congenital ichthyosis has been identified and named Rud syndrome [461]. Miscellaneous Congenital Hypogonadotropic Disorders A large number of congenital defects and syndromes have been decribed in association with hypogonadotropic hypogonadism. An extensive list of these disorders can be found in textbooks of genetic disorders [461]. Developmental Disorders of the Pituitary due to Mutations of the Homeodomain Transcription Factors (Fig. 6.2)

[464–470] Mutations in the Pit-1 homeodomain transcription factor have been associated with failure of several differentiated cell types to develop within the pituitary gland and deficiencies of GH, prolactin and TSH [466,467]. These patients have either small or normal-sized pituitary glands. Pit-1 induces the transcription of the growth hormone and prolactin genes and is also necessary for the control of the TSH-beta gene transcription. Both autosomal dominant and recessive forms of inheritance have been described depending on the DNA binding properties of the mutant protein. Patients with mutations of Propl have deficiencies of LH and FSH in addition to the deficiencies of GH, prolactin and TSH [468]. ACTH secretion is normal at birth but corticotropes may degenerate secondarily. These patients have normal, small, or sometimes large pituitary glands. Gsx-1, an orphan homeobox gene, is required for normal pituitary development. Homozygous mutations of the Gsx1 gene are associated with extreme dwarfism, sexual infantilism, and increased perinatal mortality. The pituitary gland from affected individuals is small and hypocellular, and has a reduced number of growth-hormone and prolactinproducing cells. Another homeobox gene, Hesx1, also encodes a pituitary transcription factor that is first expressed at gastrulation in mouse embryo [469]. Mutations of the Hesx1 gene have been described in humans and mice with septo-optic dysplasia. A novel, homeodomain gene that is transcribed as two alternately spliced mRNAs that encode for two separate proteins, Ptx2a and Ptx2b, is a candidate gene for Rieger syndrome, an autosomal dominant disorder with variable craniofacial, dental, eye and pituitary anomalies [470]. Combined pituitary hormone deficiency has been linked to missense mutations in Lhx3 gene, that encodes a member of the LIM class of homeodomain proteins. Homozygous mutations in Lhx3 in members of two unrelated consanguineous families were associated with deficiencies of mul-

Chapter 6

tiple pituitary hormones except ACTH and a rigid cervical spine [470A]. Two patients had small, hypoplastic pituitaries and one had an enlarged anterior pituitary. Acquired Hypogonadotropic Disorders

Functional disorders Clinical Paradigms of Chronic Undernutrition Associated with Reproductive Dysfunction Delayed Onset of Menses in Ballet Dancers The onset and progression of puberty in girls are markedly affected by intense exercise training and energy drain. The studies of ballet dancers in the peripubertal age range demonstrate that menarche is substantially delayed in these girls compared to normal controls (onset of menarche is 15.4 years in ballet dancers vs. 12.6 years in normal controls [471– 475]). Periods of rest or reduction in exercise intensity due to injury are associated with rapid sexual development and the occurrence of menses [471]. While breast development and menarche are delayed in ballet dancers, the development of pubic hair is not affected, consistent with the proposal that separate control mechanisms exist for the regulation of adrenarche and menarche [475]. Although ballet dancers have lower body weight and body fat than age-matched controls, we do not know whether the resetting of the hypothalamic GnRH pulse generator in ballet dancers is due to energy drain, low body weight, or low body fat [471–475]. Frisch [473–475] has proposed that achievement of a minimum fat to body mass ratio (approximately 17% fat to body mass) is necessary for triggering the onset of menarche. This hypothesis is supported by studies showing a correlation between increased GnRH secretion and the percentage of body fat in pubertal girls [475]. However, some investigators have questioned whether low body fat is the sole, critical determinant of the onset of puberty. Menstrual Dysfunction and Hypogonadotropic Hypogonadism in Female Athletes There is a high prevalence of amenorrhea, anovulatory cycles, and other menstrual irregularities in adult female athletes, particularly, long-distance runners, dancers, and swimmers [476–485]. The athletes tend to weigh less, have a lower percentage of body fat, and a later onset of menarche than age-matched healthy controls [476–485]. In long-distance runners, the number of miles run each week tends to correlate with the degree of menstrual dysfunction [476]. The female athletes typically exhibit hypogonadotropic hypogonadism, presumably due to an acquired hypothalamic GnRH deficiency. Serum estradiol levels and the frequency of LH pulses are lower in athletes who are amenorrheic than in nonexercising controls [478]. Some, but not all, female athletes with hypothalamic amenorrhea will respond to pulsatile GnRH administration, suggesting that additional pathophysiologic mechanisms may be operative. The bone mineral content of amenorrheic

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athletes is lower than age-matched controls, presumably due to the cumulative effects of estrogen deficiency [485]. Female athletes have a lower prevalence of breast cancer and other estrogen-dependent reproductive neoplasms than nonathletic controls due to decreased estrogen exposure [477]. Frisch [474,475] has hypothesized that maintenance of normal reproductive function in women requires a minimum fat to body mass ratio of 22%. Body fat plays an important role in estrogen production and metabolism. Testosterone and androstenedione are converted to estrogens by aromatase enzyme in adipocytes. Excessively lean women such as marathon runners or those suffering from anorexia nervosa produce a greater amount of catechol estrogens than women with a greater percent of body fat. Catechol estrogens tend to have less estrogenic activity than noncatechol estrogens such as estradiol. Also, there is an inverse relationship between the percentage of body fat and sex hormone binding globulin concentrations. Therefore, alterations is SHBG concentrations may affect estrogen metabolism and clearance in lean women. Women with exercise-induced amenorrhea also have abnormalities of their hypothalamic–pituitary–adrenal axis including higher cortisol levels in early morning, and blunted cortisol and ACTH response to CRH in comparison to healthy controls, leading to speculation that alterations in the cortisol axis may play a role in the pathophysiology of gonadal dysfunction [480,482–484]. Hypogonadotropic Hypogonadism in Patients with Anorexia Nervosa Anorexia nervosa is a psychiatric disorder characterized by distortion of body image and selfinduced weight loss [486–494]. Loss of body weight is associated with prepubertal patterns of LH and FSH secretion in which both LH and FSH are low and respond poorly to GnRH stimulation [491]. Refeeding and restoration of body weight are associated with normalization of pulsatile LH and FSH secretion, illustrating the correlation between energy balance, body weight and reproductive function. Variants of eating disorders such as bulimia and mild forms of self-induced dieting are common in young women and may be missed unless the physician maintains a high index of suspicion. Maternal Undernutrition and Lactational Amenorrhea: Results from Demographic and Health Surveys in SubSaharan Africa A survey of postpartum women in seven sub-Saharan countries found maternal nutritional status to be inversely associated with the duration of lactational amenorrhea. Undernourished women (BMI < 18.5 kg/m2) had a higher probability of remaining amenorrheic (odds ratio; 95% confidence interval: 1.6; 1.2–2.3) than better nourished women [495]. Overall, the duration of lactational amenorrhea was 1.4 months longer in undernourished

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women than better nourished women, suggesting that maternal nutritional status may independently affect the return of ovulation after childbirth. Because breast-feeding and the associated lactation amenorrhea are important determinants of fertility in countries where effective contraceptive modalities are not widely available, these data suggest that undernutrition may play a role in limiting family size by extending the duration of amenorrhea after child birth.

depending on the criteria used to define the condition. For example, menstrual abnormalities preexist in a third of these patients [502,503], and underweight women are more likely to experience postpill amenorrhea than obese women. Roughly 20% of patients may have hyperprolactinemia. Nevertheless, in a subset of patients with postpill amenorrhea, the pulsatile pattern of gonadotropin secretion is lost and the response to GnRH is blunted, suggesting hypothalamic–pituitary dysfunction.

Long-Term Effects of Running on the Hypothalamic– Pituitary–Gonadal Axis in Men Whereas abnormalities of GnRH secretion and menstrual function are well documented in female athletes, similar reproductive abnormalities have not been widely reported in male athletes [31,32,496,497]. Although it is possible that the signs and symptoms of androgen deficiency in men may be subtle and, therefore, remain undetected, clinically important hypogonadism does not appear to be common in male endurance athletes. Serum testosterone and LH concentrations are usually normal or low normal in male endurance athletes [31,32,497]. In one such study, MacConnie et al. [313] examined the hypothalamic–pituitary–gonadal axis in six highly trained marathon runners who were running 125 to 250 km every week. The frequency and amplitude of LH pulses were significantly lower in runners than age-matched controls, even though mean plasma LH, FSH and testosterone concentrations were not significantly different between the two groups. The acute response of LH to increasing doses of GnRH was lower in the runners than in the controls [313]. The finding of pituitary hyposensitivity to GnRH serves as indirect evidence of impaired hypothalamic-GnRH secretion in male marathon runners. These data indicate that male marathon runners, in a manner similar to the female runners, also exhibit perturbations of hypothalamic GnRH pulse generator, although clinically overt androgen-deficiency is less common in male runners than in their female counterparts [313].

Hypothalamic Dysfunction with Stress or Systemic Illness The role of stress has been difficult to define, partly reflecting the difficulties of defining and quantitating stress in humans. Nevertheless, stress-related menstrual irregularities have been well described, the most common being amenorrhea with low to normal gonadotropins and low to normal estrogen secretion, thereby suggesting hypothalamic suppression [504–516]. Suppression of LH or both gonadotropins has been described in stressed postmenopausal women. A varying degree of reproductive dysfunction is associated with all types of stress, be it due to caloric deprivation [498,499,504], physical stress, emotional or psychical stress and stress related to illness [503,515]. As was stated above, weight loss of 20% or more associated with anorectic disorders is attended by almost complete cessation of menstrual periods. Examples of reproductive dysfunction due to physical stress include amenorrhea seen in marathon runners [483] and joggers [476–481], and delayed menarche in ballet dancers [471–475]. Women under psychologic stress experience menstrual disturbances. An extremely high incidence of amenorrhea has been documented in concentration camp internees (20% to 60%), prisoners under sentence of death (100%), in new recruits into the armed forces (6%), and in women entering the religious life (15%) [503,506,515]. In men, occurrence of reproductive dysfunction in association with stress is not well documented. During acute medical illnesses, hypogonadotropic hypogonadism is common.

Drug-Related Hypothalamic Dysfunction Marijuana decreases gonadotropin secretion when administered to ovariectomized monkeys [500,501]. It blocks reflex ovulation in the rabbit and prevents ovulation in the rhesus monkey. Delayed puberty, primary amenorrhea, and secondary amenorrhea may be seen in preadolescent, adolescent, and young adult marijuana users. Normal menstrual cycles resume within 3 to 6 months after discontinuation of marijuana use. Men who are heavy users of marijuana have decreased testosterone secretion and sperm production. The mechanism of marijuana-induced hypogonadism appears to be decreased GnRH secretion [501]. Gynecomastia observed in some marijuana users may be due to plant estrogens in the crude preparations Patients presenting with postpill amenorrhea constitute a heterogeneous group [502]. The incidence of postpill amenorrhea varies in different reports from 0.2% to 3.1%

Suppression of Hypothalamic–Pituitary–Gonadal Axis During Illness Hypogonadism in critical illness is well documented. The degree of suppression of the hypothalamic–pituitary–gonadal axis correlates with the severity of illness [517]. Serum testosterone levels fall at the onset of illness and recover during recuperation from illness, suggestive of a relationship to progression of illness, within a patient. Although a majority of acutely ill patients have hypogonadotropic hypogonadism, a subset of patients may have increased LH and FSH levels consistent with primary testicular dysfunction [517]. Although the magnitude of gonadotropin suppression is generally correlated to the severity of illness, there is considerable heterogeneity in serum gonadotropin profiles in acutely ill patients. Although a majority of patients with acute illness suffer from hypogonadotropic hypogonadism,

Chapter 6

others may have elevated levels of LH and FSH, suggestive of primary gonadal dysfunction. The pathophysiology of reproductive dysfunction that attends the course of acute illness is unknown. Malnutrition, cytokines and other mediators and products of systemic inflammatory response, and drugs may all contribute to the suppression at multiple levels of the reproductive axis [517]. One concomitant of the stress response is the increase in adrenal glucocorticoid secretion. This probably results from an increase in corticotropin-releasing hormone (CRH) and perhaps vasopressin secretion. CRH has been shown to markedly inhibit the GnRH pulse generator [515], such effects probably being mediated via opiatergic pathways, since they are blocked by naloxone [508]. Cortisol itself can attenuate gonadal response to gonadotropins, but it is more likely that cortisol directly inhibits hypothalamic GnRH gene expression [512,509]. This proposal is consistent with the demonstration of a glucocorticoid response element in the GnRH gene. A large body of emerging data has begun to shed light on the interactions between the immune and the endocrine systems [509–512,515]. These data may, in part, explain the reproductive dysfunction observed in patients with acute illness and cancer. It has been shown that lipopolysaccharide found in the bacterial cell wall inhibits LH secretion [511]. The inhibitory effects of lipopolysaccharide on LH are probably mediated through CRH. Cytokines such as interleukin-la and mediators of the systemic inflammatory response may attenuate serum LH levels [511] and the gonadal effects of gonadotropins in both the male and the female. It is likely that many other products of the immune system may modulate the hypothalamic–pituitary gonadal axis, either indirectly through their effects on the adrenal axis, or directly at any of the three levels of the hypothalamic–pituitary–gonadal axis. CRH and lymphokines may play an important role in this interconnection [515]. Similarly, in many chronic illnesses such as that associated with the human immunodeficiency virus, end stage renal disease, chronic obstructive lung disease, and some types of cancer, there is a high frequency of low testosterone levels in chronic illnesses associated with wasting [518–535]. In these chronic disorders, muscle wasting occurs frequently, and is associated with debility, poor quality of life, and adverse disease outcome [518–532]. Therefore, strategies that can reverse androgen deficiency may attenuate muscle wasting and improve physical function, improve quality of life and reduce utilization of health care resources in men with sarcopenia associated with chronic illness. Androgen deficiency, defined solely in terms of low testosterone levels, is a common complication of HIVinfection in men [518,519]. In a survey of 150 HIV-infected men who attended our HIV Clinic, approximately, a third had serum total and free testosterone levels in the hypogonadal range [518]. Other investigators have reported similar prevalence of hypogonadism in HIV-infected men [519,532]. Twenty percent of HIV-infected men with low

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testosterone levels have elevated LH and FSH levels and thus have hypergonadotropic hypogonadism [518]. These patients presumably have primary testicular dysfunction. The remaining 80% have either normal or low LH and FSH levels; these men with hypogonadotropic hypogonadism either have a central defect at the hypothalamic or pituitary site or a dual defect involving both the testis and the hypothalamic–pituitary centers. The pathophysiology of hypogonadism in HIV-infection is complex and involves defects at multiple levels of the hypothalamic–pituitary testicular axis. Malnutrition, mediators and products of the systemic inflammatory response, drugs such as ketoconazole, and metabolic abnormalities produced by the systemic illness all contribute to a decline in testosterone production. In a recent study, a majority of men with chronic obstructive lung disease had low total and free testosterone levels [531]. Similarly, there is a high frequency of hypogonadism in patients with cancer, end stage renal disease on hemodialysis, and liver disease, and patients receiving glucocorticoids for systemic diseases [532,533]. Low testosterone levels correlate with adverse disease outcome in HIV-infected men. Serum testosterone levels are lower in HIV-infected men who have lost weight than in those who have not [519,530]. Longitudinal follow up of HIV infected homosexual men reveals a progressive decrease in serum testoterone levels [528]; this decrease is much greater in HIV-infected men who progress to AIDS than in those who do not [533]. We do not know whether the decrease in testosterone levels is a consequence of weight loss or is a contributory factor that precedes muscle wasting. In a longitudinal study, Dobs et al. [528] measured serum testosterone levels in a cohort of HIV-infected men and reported that serum testosterone levels decline early in the course of events that culminate in wasting. Testosterone levels correlate with muscle mass and exercise capacity in HIV infected men [530] leading to speculation that hypogonadism may contribute to muscle wasting and debility. Although patients with HIV-infection may lose both fat and lean tissue, the loss of lean body mass is an important aspect of the weight loss associated with wasting. The magnitude of depletion of nonfat tissues is an important determinant of the time of death in AIDS [520–522]. There is a high prevalence of sexual dysfunction in HIVinfected men [525]; decreased testosterone levels are only one component of the multifactorial pathophysiology of sexual dysfunction in these patients. With the increasing life expectancy of HIV-infected men, frailty and sexual dysfunction have emerged as important quality of life issues. Hypothalamic Dysfunction in Polycystic Ovary (PCO) Disease Although PCO disease is not truly a hypogonadal state, it is mentioned here solely to point out the abnormalities of LH and FSH secretion associated with this disorder. Patients with PCO disease have elevated serum concentrations of LH with normal or low FSH. The high LH/FSH ratio may contribute to defective ovulation by

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causing a cycle initiation defect, since a relative deficiency of FSH during the follicular phase is associated with inadequate luteinization. The high mean LH concentrations are due to an increase in LH pulse frequency and/or pulse amplitude and are thought to reflect a similar abnormality in hypothalamic GnRH. This view is further supported by recent data showing that abnormally high release of LH relative to FSH can be obtained by administering native GnRH in more frequent pulses than are required to maintain normal gonadotropin concentrations [22]. Hyperandrogenemia, Metabolic Abnormalities, and Body Composition Changes in Polycystic Ovarian Syndrome (PCOS) PCOS, a common disorder in premenopausal women, is characterized by increased androgen secretion, chronic anovulation, obesity and insulin resistance [536–543]. The syndrome is often associated with significant defects of insulin secretion and action [541–542]. Obesity in these patients is often associated with increased waist-to-hip ratio consistent with the intra-abdominal accumulation of fat. Increases in lean and fat mass contribute to the overall increase in body weight. The pathophysiologic basis of PCOS is unknown. Several studies have demonstrated that insulin stimulates ovarian synthesis of androgens, as well as estrogens and progesterone [537]. Insulin acts synergistically with LH in stimulating ovarian androgen production, and also upregulates LH receptors, thus increasing ovarian responsiveness to circulating LH [537]. Increased estrogen levels enhance pituitary sensitivity to GnRH resulting in increased LH secretion. LH and insulin act synergistically to produce thecal luteinization. This results initially in mild overproduction of androgens, which is sufficient to induce follicular atresia [537]; continued stimulation of stromal and thecal cells by LH and insulin leads to further increase in circulating androgens. Serum Androgen Levels in PCOS Probands, Sisters of Patients with PCOS and Control Women Both PCOS and the insulin resistance that accompanies it appear to have major genetic components [540–542]. Familial clustering has been described and the mode of inheritance is dominant type. A recent study [542] of the sisters of women with polycystic ovary syndrome has established that there is familial aggregation of hyperandrogenemia in kindreds. In this study, 24% of sisters of PCO probands were affected with the syndrome. Total testosterone, non-SHBG bound testosterone and DHEAS were all significantly increased not only in probands but also amongst their sisters. Many of the sisters of patients with this clinical disorder had high androgen levels but normal menstrual cycles; these patients presumably had either a milder form or an early stage of the disease. Women with polycystic ovary syndrome are often insulin resistant, have insulin secretory defects, and are at significantly increased risk for type 2 diabetes and impaired

glucose tolerance [542]. A significant proportion of women with this clinical disorder have been found to have a defect in insulin-mediated receptor autophosphorylation. Fifty percent of first-degree relatives of patients with this disorder have type 2 diabetes mellitus or impaired glucose tolerance by the oral glucose tolerance test, indicating that glucose intolerance in this disorder may also have a genetic basis. Reproductive Dysfunction and Endocrine Abnormalities of Obesity Obesity is associated with a spectrum of endocrine alterations, including changes in the plasma levels, secretion patterns and clearance rates of circulating hormones. Obesity and Androgens in Men In a majority of obese men with mild to moderate obesity, the alterations in total testosterone levels are due to changes in circulating levels of sex hormone binding globulin (SHBG). Because SHBG levels decrease in inverse proportion to the degree of obesity, serum total testosterone levels decrease as body weight increases [544–548]. Serum free testosterone levels, measured by equilibrium dialysis or as non-SHBG bound testosterone, however, remain within the normal range in a large majority of men with mild to moderate obesity, or may be slightly reduced [546,547]. The ratio of free to total testosterone levels is, therefore, higher in obese men than in nonobese men [547]. Serum total, non-SHBG bound, and free testosterone levels are inversely correlated with body mass index. Serum estradiol levels may be higher in obese men as compared to healthy, non-obese controls, because of aromatization of testosterone to estradiol in the fat cells. Weight loss is associated with a reversal of many of these abnormalities including an increase in serum total and free testosterone levels and a decrease in estradiol levels. The decrease in SHBG levels in obese men is believed to be due, in part, to the increase in circulating insulin concentrations that attends weight gain. Insulin is an inhibitor of SBHG production and plasma insulin levels correlate inversely with SHBG levels. A subpopulation of massively obese men may have a defect in the hypothalamic–pituitary axis as suggested by low free testosterone in the absence of elevated gonadotrophins or hyper-response to LRH [547]. These individuals have low total and free testosterone levels and low or inappropriately “normal” LH and FSH levels. It has been speculated that very high estrogen levels in massively obese men may suppress GnRH and gonadotropin secretion. Testosterone response to human chorionic gonadotropin stimulation, an LH-like hormone, is normal in most obese men, indicating normal testicular reserve and function [546,547]. Reproductive Function in Obese Women Obesity impacts on reproductive function early in life. Obese adolescent girls

Chapter 6

have an earlier onset of puberty [471–475]. It has been speculated that attainment of a critical amount of body fat and weight is essential for triggering the onset of puberty. Because obese girls cross this critical threshold earlier than lean girls, the onset of menses occurs at an earlier age in obese girls than in their lean counterparts. Excess body fat has been associated with an increased risk of oligo- or anovulation [536–539]. Obesity is associated with an increased risk of hyperandrogenism and anovulatory cycles in women [536,537]. The unbound fraction of testosterone is increased in overweight women with predominantly upper body fat deposition (i.e. a high waist to hip ratio). Androgen metabolism is also accelerated in obesity [537]. This increased clearance of androgens may result from an obesity-associated reduction in sex hormone binding globulin (SHBG). Serum SHBG and a percentage of free testosterone levels are negatively correlated with waist-tohip ratio (WHR) and weight expressed as a percentage of ideal body weight [537]. Weight Loss Improves Insulin Sensitivity in Obese, Hyperandrogenic Women Weight loss results in a significant decrease in the mean fasting and postglucose plasma insulin and C-peptide values in obese, amenorrheic hyperandrogenic women [538]. After weight reduction, the sum of insulin, C-peptide and glucose values after a standardized oral glucose load was lower than that before treatment and was similar to that in normal weight women. Weight Reduction Decreases Serum Androgen Levels in Infertile, Obese Women With weight loss, plasma androgens are reduced and ovulation is restored in 85% of women who lose at least 15% of their body weight [537,538]. This is due to a reduction in extraglandular aromitization found in association with obesity. These data demonstrate that with weight loss, there is improvement in both hyperinsulinemia and androgen levels, and restoration of menstrual cycles in many patients. Hyperprolactinemia and Hypogonadotropism Elevated levels of prolactin are often associated with low serum LH and FSH levels [548]. In fact, the clinical presentations of a small prolactinoma may be solely related to the attendant hypogonadotropic hypogonadism. Gonadotropin deficiency in hyperprolactinemic disorders may result from one or more of the following mechanisms. 1. Prolactin inhibits hypothalamic GnRH secretion either directly or through modulation of tuberoinfundibular dopaminergic pathways [548–555]. This hypothesis is supported by several lines of evidence. Serum testosterone levels are uniformly suppressed in men with hyperprolactinemia but the testicular response to hCG [556] and the pituitary response to GnRH are usually preserved. Similarly, ovaries of

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hyperprolactinemic women respond well to gonadotropins. Gonadotropin responses to GnRH in hyperprolactinemic women are normal or increased. Finally, increments of LH and FSH during the clomiphene test in hyperprolactinemic patients also indicate integrity of the hypothalamic–pituitary circuit. 2. The prolactin-secreting tumor may destroy the surrounding gonadotrophs by direct invasion or compression. 3. The pituitary tumor may cause compression of the pituitary stalk resulting both in hyperprolactinemia (the net hypothalamic input on lactotrophs is inhibitory) and hypogonadotropism. Sperm densities are often decreased in hyperprolactinemic men [550]. Sexual function and sperm concentrations are restored to normal after normalization of serum prolactin levels. While sexual dysfunction in most of these patients is related to hypogonadism, testosterone therapy has been reported to be ineffective in some men with impotence, suggesting that factors other than androgen deficiency may also be operative. Acquired Disorders Hemochromatosis This is an iron-storage disorder in which parenchymal iron deposition results in damage to a number of tissues especially liver, pancreas, heart, and pituitary [557–559]. Hypogonadism and testicular atrophy are common in men with hemochromatosis [557–559]. Both the pituitary and the testis can be involved by excessive iron deposition. However, the pituitary defect is the predominant lesion in a majority of patients with hemochromatosis and hypogonadism [558]. Thus, hypogonadotropic hypogonadism is by far the more common defect. Diagnosis of hemochromatosis is suggested by the association of diabetes mellitus, hepatic enlargement, heart disease, characteristic skin pigmentation, arthritis, and hypogonadism. Excessive parenchymal iron stores can be demonstrated by determination of high transferrin saturation, very high serum ferritin concentrations, high chelatable iron stores using the agent desferrioxamine, and liver biopsy [559]. Chronic renal failure and gonadal dysfunction Hypogonadism is very common in patients with end-stage renal disease [560–567]. Abnormalities at multiple levels of the hypothalamic–pituitary–gonadal axis contribute to hypogonadism. Sperm concentrations and semen quality are usually depressed; steroidogenesis is also suppressed to varying degrees [560]. Depression of libido and potency is common in uremic men [563]. Sexual dysfunction in uremic men is usually multifactorial in nature; atherosclerotic disease, neuropathy, androgen-deficiency, malnutrition, chronic illness, hypertension, diabetes mellitus, and drugs all contribute to sexual dysfunction [563]. Hypogonadism and

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sexual dysfunction usually do not improve after initiation of dialysis [404]. However, restoration of normal kidney function after transplantation will often, but not always, lead to improvement of sexual function [563]. Circulating testosterone levels are low [561,562], due mainly to a decrease in production rates. Sex hormone binding globulin levels and mean clearance rate (MCR) of testosterone are not significantly altered. Serum LH and FSH levels in uremic men are normal or elevated. However, it is unclear whether the LH and FSH levels are increased in proportion to the decrease in serum testosterone levels. Some uremic men with suppressed testosterone levels have “normal” LH and FSH levels. This could either reflect a primary abnormality in the hypothalamic–pituitary unit or an alteration in the set point of gonadostat. Circulating levels of glycoprotein free a-subunit are increased in uremia [565]. An additional complicating factor is the common occurrence of hyperprolactinemia in uremia, primarily due to reduction in renal clearance and prolactin-elevating drugs [560]. Thus, impairment at multiple levels of the hypothalamic– pituitary–testicular axis exists in uremic patients and complexities of these interations result in varying patterns of hormonal abnormalities. In uremic women, the predominant disturbance appears to be central, as indicated by relatively normal gonadotropins and loss of positive feedback of estrogen on gonadotropin secretion [560–562]. Menstrual irregularities and infertility are very common [566,567]. Space-Occupying Lesions Neoplastic and nonneoplastic lesions in the region of the hypothalamus and pituitary can directly or indirectly affect gonadotrope function. Lesions involving the hypothalamus or the hypothalamic–pituitary connection may arise primarily in the hypothalamus, in the suprasellar structures, or within the sella itself and extend upwards. Pituitary tumors have been discussed elsewhere in this book. In the adult human, pituitary adenomas constitute the largest single category of space-occupying lesions affecting gonadotrope function. Hypothalamic Syndromes The tumors in the suprasellar region that affect hypothalamic function can often be distinguished from those localized within the sella by the presence or absence of several unique clinical features [568,569]. 1. Diabetes insipidus is distinctly unusual with lesions contained within the sella turcica. Its presence usually indicates a suprasellar lesion affecting the hypothalamic arginine vasopressin- (AVP) secreting nuclei in the preoptic and paraventricular region, or compressing the hypothalamic–pituitary stalk connection. The association of diabetes insipidus in patients with pituitary adenomas usually is indicative of suprasellar extension.

2. Visual field cuts always indicate a suprasellar location. In a large majority of men and women, the optic chiasm is prefixed, i.e., it is anterior and superior to the sella turcica. In a small subset, however, the chiasm may be postfixed. Therefore, pituitary adenomas in patients with prefixed location of the optic chiasm, can grow up from the sella and compress the stalk in its middle portion from below, resulting initially in superior temporal field defects. However, depending upon the origin and location of the suprasellar mass, a variety of visual field defects can result. 3. The presence of neurologic and/or neuropsychiatric syndromes should also alert the physician to the possibility of hypothalamic lesions. 4. Thermoregulatory and sleep defects also favor hypothalamic lesions. 5. Autonomic dysregulation characterized by extreme perspiration, sinus tachycardia, and low blood pressure are seen only in hypothalamic lesions. Bauer [568] reviewed 60 cases of hypothalamic lesions in which autopsy data were available. The most frequent manifestations were sexual abnormalities (precocious puberty, hypogonadism), diabetes insipidus, psychiatric disturbances, and eating disorders (emaciation or obesity). Lesions in different regions of the hypothalamus may also present some unique clinical features that can assist in anatomic and functional localization. For examples, lesions in or around the median eminence and ventromedial area, or those resulting in stalk compression, often lead to panhypopituitarism, hyperprolactinemia, and diabetes insipidus. Lesions of the lateral hypothalamus may present with anorexia and weight loss, perhaps related to destruction of the feeding center. Lesions of the ventromedial area lead to hyperphagia and obesity. Lesions of the caudal hypothalamus may cause sexual precocity. For a detailed map of the hypothalamic lesions, the reader is referred to a review by Martin et al. [569]. The neoplastic lesions may also compress or erode a number of contiguous structures so that the clinical picture is often more complicated.

Hypergonadotropic Disorders: Excessive or Nonphysiologic Secretion of Gonadotropins Physiologically inappropriate secretion of gonadotropins may occur in several clinical disorders (Table 6.5). Autonomous secretion of LH, FSH and/or free asubunit may characterize pituitary gonadotroph adenomas (see Chapter 15. Ectopic LH and FSH secretion is distinctly uncommon [570–572]. However, premature reactivation of the hypothalamic–pituitary-gonadal axis because of premature but regulated GnRH secretion from the eutopic (hypothalamic) site or unregulated GnRH secretion from an ectopic site (e.g., a hamartoma) can present with the clinical syndrome of precocious puberty.

Chapter 6 Table 6.5. Disorders characterized by excessive or physiologically inappropriate gonadotropin secretion Excessive gonadotropin production Gonadotropin-secreting adenomas Ectopic human chorionic gonadotropin-secreting adenomas Premature gonadotropin secretion Idiopathic precocious puberty Constitutional sexual precosity Central nervous system tumors Other central nervous system lesions such as hydrocephalus, granulomas, cysts, head trauma True sexual precocity in children with congenital adrenal hyperplasia or androgen-secreting tumors Miscellaneous Hypothyroidism Chronic renal failure McCune–Albright syndrome

Ectopic production of hCG has been described from a number of neoplasms of trophoblastic and nontrophoblastic origin [573–579]. These neoplasms include malignant melanoma, adrenocortical carcinoma, an undifferentiated retroperitoneal carcinoma, breast cancer, renal carcinoma, lung cancer, pancreas, stomach and colon cancer, and a variety of teratocarcinomas [573–575]. An hCG-like material extractable from most nonendocrine tissues of normal humans [577–579] has been shown to have little or no carbohydrate and possesses little biologic activity in vivo [420]. Selected carcinomas appear to glycosylate this material resulting in detectable blood levels and biologic activity (due to retarded clearance). More recently, using a two-site-directed radioimmunometric sensitive and highly specific assay for hCG, Odell et al. have reported that hCG immunoreactive material is secreted into the blood from the pituitary in a pulsatile manner [578]. Extraction of hCG immunoreactive material from the human pituitary has also been reported [579]. The rarity of ectopic LH- and FSH-secreting tumors along with the difficulties experienced by investigators in expressing the chimeric constructs containing the LH- and FSH-b subunit promoter regions in heterologous cell types collectively suggest that transcription of these two subunit genes requires highly tissue specific factors. Precocious Gonadotropin-Dependent Puberty

The onset and progression of puberty varies widely in males and females. For a detailed description of the variations in the pattern of pubertal changes, the interested reader is referred to excellent papers by Marshall and Tanner [580,581] and Zacharias et al. [582]. Pubertal development is considered precocious if a boy develops secondary sex characteristics before the age of 9 years, or a girl before the age of 8 years [582,583]. True or central sexual precocity is gonadotropin-dependent and results from premature GnRH

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secretion. For unclear reasons, central sexual precocity occurs more frequently in girls. In many such patients, no definable cause can be found and the condition is referred to as idiopathic precocious puberty. The timing of events that characterize the onset of puberty is normally distributed; consequently, some children who are quite normal will start pubertal development at an earlier age simply due to the nature of the Gaussian curve. There may be a familial predisposition towards earlier onset of puberty in some patients. Several tumors, mostly intracranial, can cause precocious sexual development [583–585]. Central nervous system tumors, both benign and malignant, are found more often in boys than in girls. Although hypothalamic hamartomas have been shown to ectopically produce GnRH, the majority of these tumors probably cause sexual precocity by removing the inhibitory influences on the GnRH-secreting nuclei, resulting in their premature activation. Astrocytomas, ependymomas, gliomas of the optic nerve or hypothalamus, and hamartomas of the tuber cinereum have all been reported in association with central sexual precocity. The availability of computed tomography (CT) and magnetic resonance imaging (MRI) scanning has made it easier to diagnose CNS tumors. Some germinomas secrete hCG and may result in premature androgen production; others are associated with premature gonadotropin secretion and true sexual precocity [583–585]. Besides intracranial tumors, a variety of other intracranial lesions can cause sexual precocity. These include granulomas, suprasellar cysts, hydrocephalus, and head trauma [583–585]. In some patients with congenital adrenal hyperplasia who have premature virilization due to excessive androgen production by the adrenal gland, institution of glucocorticoid therapy may trigger the onset of true gonadotropindependent sexual precocity. Similar events may occur in children with virilizing tumors after removal of the tumor [585]. True central precocity has also been noted in association with hypothyroidism. It is more common for children with hypothyroidism to have delayed sexual development than sexual precocity. Patients with McCune–Albright syndrome (cafe-au-lait spots, fibrous dysplasia of bones, and sexual precocity) often have autonomously functioning follicular cysts in the ovary, which may produce estrogens. However, some children with this syndrome have true gonadotropin-dependent sexual precocity [583–585]. EXPERIMENTAL MODELS OF THE GnRH/GONADOTROPIN RELATIONSHIP It has been difficult to study the regulation of GnRH secretion in the humans because the changes in GnRH concentrations in the portal circulation are dampened in the peripheral blood. The assays for GnRH have not been sen-

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Table 6.6.

Hypothalamic–Pituitary Function

Experimental models of hypogonadotropism

Human models Patients with idiopathic hypogonadotropic hypogonadism Examination of normal luteinizing hormone and follicle-stimulating hormone pulse patterns Patients with anorexia nervosa Animal models with hypogonadotropism Gonadectomized rhesus monkeys with radiofrequency ablation of hypothalamic gonadotropin-releasing hormone-secreting nuclei The hypogonadotropic mutant mouse The hypogonadotropic mink The stalk-sectioned sheep Models that permit sampling of the hypothalamic–pituitary effluent Inferior petrosal sinus catheterization in the human Superficial facial vein in the horse Portal vein cannulation in the sheep Push–pull cannula in the mediobasal hypothalamus in the rat

Table 6.7.

In vitro models of pituitary hormone regulation

Pituitary quarters Pituitary monolayer cultures Perifused pituitary cultures on cytodex beads Hypothalamic neuronal cultures Reverse-hemolytic plaque assay to examine hormone secretion from individual pituitary cells Transformed and immortalized gonadotroph cell lines derived from transgenic animals

sitive enough to measure the low circulating GnRH concentrations. Therefore, several experimental models have been used to examine the regulation of pituitary LH and FSH secretion by GnRH (Tables 6.6 and 6.7). The hpg mouse has GnRH deficiency because of a large deletion involving exons 3 and 4 of the GnRH gene [427–430]. Knobil and coworkers [10,11] have used an ovariectomized primate model in which the hypothalmic GnRH neurons have been ablated by radiofrequency lesions and the gonadal feedback is removed by removal of the ovaries. In these monkeys, the effects of pulsatile GnRH secretion can be studied without alterations in the gonadal feedback during the course of GnRH administration. The reproductive physiology of the mink is interesting because this species has a very high prevalence of infertility, one cause of which is hypogonadotropic hypogonadism [586]. Pulsatile GnRH secretion has been studied in sheep by cannulation of the portal circulation. In the horse, the venous outflow from the pituitary drains into a superficial facial vein that can be easily accessed. In the rat, a push–pull cannula placed into the mediobasal hypothalamus has been used to sample hypothalamic hormones and neuropeptides.

A number of investigators [22] have used patients with idiopathic hypogonadotropic hypogonadism and anorexia nervosa to examine the physiologic regulation of gonadotropin secretion and mechanisms of pubertal development in humans. A problem with these models is that the changes in LH and FSH levels perturb sex steroid concentrations and gonadal function thus altering the feedback upon the hypothalamus and the pituitary. The frequency and amplitude of LH and FSH pulses have been used as surrogates for the changes in hypothalamic GnRH pulse generator [22,23]. A great deal of information has emerged from the use of deconvolution techniques and mathematical models of hormonal feedback and feedforward applied to data derived from frequently sampled LH and FSH series [21,343–345]. By cannulating the inferior petrosal sinus in the human, the pituitary hormones can be sampled before they are diluted by the systemic circulation. Pituitary cells isolated from experimental animals and maintained either in monolayer culture or in perifusion chambers have been used as an in vitro model to examine the effects of GnRH on the expression of LH and FSH subunit genes. Neill et al. [587,588] have described a reverse hemolytic plaque assay that permits the detection and measurement of hormone secretion from individual pituitary cells in culture. A number of pituitary and neuronal cell lines have been generated and used to examine the regulation of GnRH and gonadotropin genes [589]. The regulation of GnRH secretion has been difficult to study in the human for several reasons. First, the assays for GnRH in serum have not been sensitive enough to allow measurements of the low circulating levels of GnRH [590,591]. Second, the changes in GnRH concentrations occurring in the portal circulation are significantly dampened in the peripheral circulation so that even if GnRH levels could be easily measured, the physiologic interpretation of the peripheral GnRH levels would remain somewhat suspect. Therefore, investigators in this field have relied on a number of animal and human models which have proven extremely useful in studying the physiologic regulation of GnRH and gonadotropin secretion. These models are listed in Table 6.6. The frequency and amplitude of LH and FSH pulses have been used as surrogates for the changes in the output of the hypothalamic GnRH pulse generator. There are conceptual problems with methods used to quantitate LH pulses, as outlined elsewhere in this chapter. However, recent refinements in the mathematical models to characterize LH pulses have greatly enhanced our understanding of the GnRH gonadotroph interrelationship [21, 343–345]. Patients with IHH have been extremely useful in studying the impact of GnRH pulse frequency and amplitude on LH and FSH output from the pituitary [22,23]. These patients, along with those with anorexia nervosa, have pro-

Chapter 6

vided useful models to study the changes that characterize the onset of puberty. A number of animal models have been very useful in studying GnRH physiology. Knobil’s group [10,11] was the first to clearly demonstrate that pulsatile release of GnRH from the hypothalamus is essential for maintaining normal LH and FSH output. These investigators used an ovariectomized rhesus monkey model in which the hypothalamic GnRH-secreting nuclei were ablated by radio-frequency lesions. The gonadal feedback was ablated by removal of the ovaries. In this in vivo monkey model, it was clearly demonstrated that pulsatile administration of GnRH is essential to maintain normal LH and FSH secretion and that continuous infusion of GnRH downregulates LH and FSH secretion. There are a large number of genetic models of hypogonadotropic hypogonadism in rodents, though these will not be reviewed extensively in this chapter. The hpg mouse characterized by hypogonadotropism and germ cell arrest has been well studied [592]. Seeburg et al. [427] demonstrated that GnRH deficiency in the hpg mouse is due to a large deletion in the GnRH gene (see elsewhere in this chapter for details). The expression of a wild-type GnRH transgene in hpg mice resulted in restoration of gonadotropin secretion and rescue of the accessory sex organ weights and spermatogenesis, thus confirming the critical role of GnRH deficiency in this disorder. Another example is that of the ob/ob mouse, an inbred mouse with obesity, GnRH deficiency [593] and associated abnormalities of growth. The reproductive physiology of the mink is rather interesting in that there is a high incidence of infertility in the male [586], one of the causes of which is hypogonadotropic hypogonadism. In a number of experimental species, it is possible to sample the portal circulation and directly assess hypothalamic GnRH secretion. For example, Clarke and coworkers [594,595] have studied pulsatile GnRH secretion in sheep by directly sampling the hypothalamic–pituitary portal circulation. In the rat, a push–pull cannula has been used to sample hormones/neuropeptides in the mediobasal hypothalamus (MBH) [596]. In some mammalian species, direct sampling of the pituitary effluent is possible, albeit technically difficult. For example, in the human, the venous drainage from the pituitary is lateralized. The left half drains onto the left side and the right half drains onto the right side. The anterior half of the pituitary gland drains into the cavernous sinus and the posterior half into the inferior petrosal sinus; the cavernous sinus then drains into the inferior petrosal sinus. Thus, by cannulating the inferior petrosal sinus, the pituitary hormones can be sampled before they are diluted by the systemic circulation. Inferior petrosal sinus catheterization has been successfully used for the diagnosis and lateralization of pituitary adenomas [597].

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In the horse, the venous effluent from the pituitary drains into the superficial facial vein, which is easily accessible in the subcutaneous tissue. This allows easy sampling of the hypothalamic–pituitary effluent.

In Vitro Experimental Models Examples of such in vitro experimental models are listed in Table 6.7. Initially, incubation of pituitary quarters or slices was the only available method to study in vitro regulation of pituitary hormones. Development of monolayer cultures of rat pituitary proved very valuable in studying the regulation of LH and FSH secretion [598,599]. However, the major limitation of monolayer cultures is that they do not accommodate pulsatile GnRH administration. In these in vitro cultures, unlike in vivo models, GnRH does not significantly increase LH-alpha-subunit mRNA levels. Lack of a pulsatile pattern of GnRH administration may be one of the factors responsible for the failure to demonstrate the increase in subunit mRNAs. An ultrashort loop feedback inhibition of gonadotrope by LH itself or one of its subunits that might accumulate in the medium could be another factor [600]. Perifused pituitary cells grown on cytodex beads have been useful in studying the effects of pulsatile GnRH administration and of various modulators on GnRH-stimulated LH secretion [601,602]. This experimental model allows a direct examination of the hormone secretion by the pituitary cells, since the clearance is dependent on the flow rate of the perifused medium and can be controlled. The perifused chambers can, however, be used for only a limited time. Another difficulty with mixed pituitary cell cultures has been the heterogeneity of cell types. This becomes particularly significant when the target of study happens to be the gonadotroph. LH, FSH, and TSH share a common asubunit and consequently thyrotropes in the mixed culture can contribute to the free a-subunit secretion. In this context, attempts have been made to enrich gonadotropes by sedimentation or centrifugal elutriation. However, these methods are technically difficult, have not been uniformly successful, and have not gained wide popularity. Neill et al. [587,588] have described a reverse hemolytic plaque assay which permits the detection and measurement of hormone secretion from individual pituitary cells in culture. The assay is technically demanding, but can be potentially a very powerful tool to examine regulation at the single-cell level. Mellon et al. [589] were recently successful in generating an immortalized pituitary cell line by targeting expression of an oncogene in transgenic mice using regulatory regions of LH b gene essential for tissue specific expression within the gonadotropes. For pituitary cells, SV40 T antigen expression was driven by the promoter region of the LH-b gene. This resulted in immortalization of a differentiated pituitary cell line which expresses both the a and LH-b genes and responds to GnRH.

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TREATMENT OF HYPOGONADOTROPIC DISORDERS When a neoplasm or other mass lesion is responsible for hypogonadotropic hypogonadism, therapy should be directed at the underlying cause when possible, to evoke a cure. In many instances of macroadenomas, cure by resection is not possible and adjunct treatment directed at shrinking the tumor and lowering hormone secretion is desirable. If gonadotropins are normalized, androgens and spermatogenesis are usually corrected. The goals of therapy are to induce and maintain virilization and normal sexual function, and stimulation of spermatogenesis in those desiring fertility. If fertility is not an immediate objective, virilization can usually be induced by androgen administration. For induction of spermatogenesis, therapy with gonadotropins or GnRH is usually required.

Gonadotropin Treatment of Hypogonadotropic Hypogonadism (Fig. 6.20) Preparations

Heller and Nelson [603] were the first to demonstrate the therapeutic efficacy of biologic preparations of gonadotropins in inducing spermatogenesis in men with hypogonadotropism. hCG and human menopausal gonadotropin (hMG) preparations have been commercially available for over three decades [603–608]. hCG is purified from the urine of pregnant women, being secreted primarily by the human placenta during pregnancy. hMG is derived from the urine of postmenopausal women. While hCG primarily stimulates Leydig cell testosterone produc-

tion by interacting with LH/hCG receptors, hMG contains LH and FSH activities in almost equal proportions. Highly purified preparations of hLH and hFSH, derived from human cadaver pituitaries, had become available for research studies from the National Pituitary Agency of the NIDDK. However, occurrence of a slow virus degenerative disease ( Jakob-Creutzfeldt disease) in a few patients treated with earlier preparations of human growth hormone [609] led to the withdrawal and cessation of the use of all human pituitary hormones for therapeutic purposes. Pituitary hormones prepared by recombinant DNA technology are likely to become available commercially in the near future. A highly purified hFSH preparation is commercially available and is being used extensively in gynecologic applications [610]. Recombinant hFSH, expressed in Chinese hamster ovary cell line and purified to homogeneity, is now available and has received recent FDA approval for induction of spermatogenesis in men with idiopathic hypogonadotropic hypogonadism [611–613]. The mature beta subunit of rhFSH has seven fewer amino acids than reported in the literature, but has similar oligosaccharide structures to purified urinary hFSH preparation [611]. Recombinant hFSH is also indistinguishable from purified urinary hFSH in its biologic activity in vitro and in vivo. rhFSH is available in ampoules containing 75 IU (approximately 7.5 ug FSH) which accounts for >99% of protein content. The pharmacokinetics of urinary hFSH and recombinant hFSH are similar. Biologic Effects of Gonadotropin Therapy

Pharmacologic doses of hCG when administered to normal men lead to biphasic testosterone and estradiol response

FIGURE 6.20. The response to treatment with human chorionic gonadotropin and human menopausal gonadotropin. The pretreatment values are means of two baseline determinations. The treatment values are means of the three highest sperm densities observed during treatment. The lower limit of the normal sperm count is depicted by the dashed lines. In men with postpubertal onset of gonadotropin deficiency, sperm counts increased into the normal range in all six patients. In contrast, only one out of eight men with prepubertal onset of gonadotropin deficiency achieved normal sperm count with hCG treatment alone. Combined administration of hCG and hMG resulted in normal sperm count in five out of seven patients with prepubertal onset of gonadotropin deficiency. Only one out of seven men with prepubertal onset of gonadotropin deficiency and cryptorchidism achieved normal sperm count in response to treatment with hCG and hMG. HCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin. Adapted with permission from Finkel et al. [621].

Chapter 6

[614–617]. When 1500 to 6000 units of hCG are given intramuscularly to normal adult men, an initial peak in serum testosterone levels can be observed 2 hours after the injection followed by a second larger and more sustained peak at 72 to 96 hours. Serum testosterone levels may remain elevated for as long as 6 days after a single hCG injection. Serum estradiol levels also exhibit a similar biphasic response. It is to be noted that the biphasic testosterone and estradiol responses are characteristic only of the postpubertal, normally virilized men [614–617]. In prepubertal boys or hypogonadotropic men, not previously primed with gonadotropins, only a monophasic increase in serum testosterone peaking 72 to 96 hours after hCG injection can be seen and there is significant latency before testosterone levels begin to rise. Smals et al. [614] have suggested that early testosterone response in normally virilized postpubertal men results from testosterone release from a readily releasable pool of preformed hormone and/or rapid induction of mature enzymatic machinery. Wang et al. [617] demonstrated that hypogonadotropic men, previously primed with hCG treatment, also exhibit a biphasic testosterone response to LH infusion, consistent with the proposal that maturation of the biphasic adult pattern is a function of prior gonadotropin priming of the testis. Multiple injections of pharmacologic doses of hCG lead to diminished testosterone response to subsequent hCG injections, a phenomenon referred to as desensitization [614–616]. Desensitization to hCG can be seen under several different clinical and experimental circumstances: first, multiple daily hCG injections do not result in higher serum testosterone levels than single daily injections; second, men with hCG-secreting neoplasia do not usually have elevated serum testosterone levels [614]. It has long been known that in prepubertal males, hCG, given alone, widens the seminiferous tubules and increases the number of primary spermatocytes [618,619]. However, spermatogenesis does not progress to completion and germ cell development remains arrested. Addition of hMG to patients on hCG results in an increase in testis size, progression of germ cell development, completion of spermiogenesis, and appearance of sperm in the ejaculate. Therapeutic Aspects

The best predictors of success of gonadotropin therapy in hypogonadotropic men include first, the testis size at presentation and, second, the time of onset of hypogonadotropism (prepubertally or postpubertally). In general, the larger the testis size, the greater the likelihood of success; best responses are seen in men with initial testis size of greater than 8 mL [620,621]. Similarly, patients who became hypogonadotropic after puberty (e.g., because of a pituitary tumor, surgery, irradiation, etc.) show higher overall success rates than those who have never undergone pubertal changes [620,621]. The presence of a coincidental or associated primary testicular abnormality may, of course, attenuate the testicular response to gonadotropin therapy.

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Some patients with IHH may also have cryptorchidism; earlier studies [622,623] indicated that these patients did not respond well to hCG therapy, leading to erroneous speculation that there may be dual defect in IHH, the first hypothalamic and the second testicular. Although a variety of treatment regimens are being used there is no consensus on what constitutes the optimum dose and schedule of gonadotropin administration. Published data and empiric clinical experience indicate that a dose of 1500–2000 IU [620–623] given intramuscularly three times weekly is a reasonable starting dose. Serum testosterone levels should be measured 6 to 8 weeks later, 48 to 72 hours after the hCG injection in order to adjust and optimize the regimen. The goal should be to adjust the dose to achieve serum testosterone levels in the midnormal range. Sperm counts should be monitored on a monthly basis. It may take several [620–623] months for spermatogenesis to be restored and patients often get very impatient and prematurely disappointed. Therefore, it is very important to forewarn patients about the potential length and expense of the treatment, and to provide conservative estimates of success rates. If after 6 months of therapy with hCG alone, serum testosterone levels are in mid-normal range, but the sperm concentrations are low, it is time to add hMG. Selection of the hMG dose is empiric. The common practice is to start with addition of a 1/2 –1 ampoule of hMG (1 ampoule = 75 IU LH plus 57 IU FSH). If after 3 months of combined treatment, sperm densities are still low, the dose of hMG can be increased to one or two ampoules. It may occasionally take 18 to 24 months or longer for spermatogenesis to be restored. The therapy is expensive but is otherwise well tolerated. Development of antibodies to hCG is not a common event [624–627]. Braunstein et al. [624] found no evidence of antibodies in 41 people treated with hCG for weight reduction. Another study found antibodies in less than 1% of men treated with short courses of hCG [625]. There are only a handful of case reports of treatment failure due to development of anti-hCG antibodies [624–627]. In men with postpubertal onset of hypogonadotropism, spermatogenesis can usually be reinitiated by hCG alone and the success rates are high [621] (Fig. 6.4). On the other hand, men in whom hypogonadotropic hypogonadism developed prior to completion of the pubertal maturation usually do not respond to hCG alone, but require combined treatment with hCG and hMG for longer duration, and the overall success rates are lower (see Fig. 6.4). Prior androgen therapy appears not to affect subsequent responsiveness to gonadotropin therapy [628]. The degree of gonadotropin deficiency, as reflected by the pretreatment testicular volume, is an important determinant of the response to gonadotropin therapy. In general men with testicular volumes of greater than 8 mL have higher response rates than those with testicular volumes of less than 4 mL [620].

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An open-label clinical trial by the Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism [610] evaluated the efficacy of self-administered highly purified hFSH (150 U three times a week) and hCG (2500 IU twice a week) in men with idiopathic hypogonadotropic hypogonadism. Serum testosterone concentrations normalized in all but one patient. Testicular volume increased three-fold during treatment, 80% of men who were initially azoospermic achieved a positive sperm count. The maximum sperm density during treatment was 25+/-8 million/ml. Three men developed gynecomastia.

Pulsatile GnRH Therapy Pioneering studies by Knobil’s group [10,11] had predicted that pulsatile administration of GnRH would be required to maintain normal LH and FSH output from the pituitary. As discussed earlier in this chapter, continuous infusion of GnRH in monkeys, made hypogonadotropic by radiofrequency lesions of the hypothalamic GnRH-secreting nuclei, downregulates LH and FSH secretion. Synthetic GnRH is commercially available for therapy of patients with hypogonadotropism due to GnRH deficiency [629]. However, success of GnRH therapy assumes normal pituitary and gonadal function. The agonist analogs of GnRH are not useful for restoring gonadotropin secretion, because after an initial short-lived stimulatory phase, GnRH agonists downregulate pituitary LH and FSH output [630–632]. A large number of clinical studies utilizing GnRH in a variety of treatment regimens have demonstrated successful induction of puberty by pulsatile administration of low doses of GnRH. Therapy is usually started with an initial dose of 25 ng/kg per pulse administered subcutaneously every 2 hours by a portable infusion pump [620,622,623,633–635]. Serum testosterone, LH, and FSH levels need to be monitored. The dose of GnRH may need to be increased until serum testosterone levels in the midnormal range are reached. There is considerable variability in GnRH dose requirement among different subjects and doses ranging from 25 to 200 ng/kg may be required to induce virilization [633]. Once pubertal changes have been initiated, the dose of GnRH can often be reduced without any adverse effects on serum testosterone, LH, and FSH levels. The gonadotropin secretion and gonadal function can be maintained for extended periods of time (months to years) in a majority of carefully selected patients with IHH by pulsatile GnRH therapy [633–635]. Development of antiGnRH antibodies is an uncommon occurrence, but can be a cause of treatment failure. Increase in sperm counts and testicular volume have been reported in over 70% of treated men. Improvement in sexual function and virilization can, however, be induced in over 90% of subjects. It is worth noting that some of the patients with IHH have associated cryptorchidism, and some of the nonresponders usually include patients who have prior history of surgically cor-

rected cryptorchidism and presumably an additional testicular defect. Local cutaneous infections do occur but are infrequent and minor. While induction of virilization by pulsatile GnRH administration in patients with IHH has provided important insights into the mechanisms of puberty and regulation of gonadotropin secretion by GnRH, this approach has no particular advantage over the traditional gonadotropin therapy [620,622,623]. In fact, wearing a portable infusion device can be quite cumbersome and follow-up of these patients often requires considerable physician supervision and laboratory monitoring. Liu et al. [620] compared an hCG/hMG regimen with pulsatile GnRH therapy in its efficacy in inducing spermatogenesis. After 2 years of therapy, 40% of GnRH-treated men and 80% of the hCG/hMG treated men produced sperm. The sperm concentrations in all men were below 5 ¥ 106/ml and were comparable in the two groups. Other surveys [622,623] have also found hCG/hMG and pulsatile GnRH therapy to be equally effective in inducing spermatogenesis. In one study [622], spermatogensis was induced in 54 of 57 courses of therapy, and pregnancies occurred in 26 of 36 courses. The two therapies did not significantly differ in terms of the time to first appearance of sperm or pregnancy rates. These and other data [620,622,623] demonstrate that pulsatile GnRH therapy is no more effective than the traditional gonadotropin replacement therapy in inducing spermatogenesis; both modalities are highly effective in achieving induction of spermatogenesis in men with gonadotropin deficiency.

Gonadotropin Inhibitors There has been great interest in the development of gonadotropin inhibitors because of their tremendous potential as therapeutic agents for the treatment of sex hormonedependent disorders and as contraceptive agents. Some of the agents currently in use, or under development include: (i) GnRH analogs (agonists and antagonists); (ii) structurally modified gonadotropins; and (iii) FSH receptor-binding inhibitors. A large number of GnRH analogs are currently available for therapeutic use [632,636]. Structurally modified gonadotropins and FSH receptor-binding inhibitors are still under investigation. The primary structure of GnRH was determined in 1971. Since then, over 2000 synthetic analogs have been synthesized and tested, which can be broadly divided into two classes: GnRH agonist analogs and GnRH antagonist analogs. Agonist analogs bind to the GnRH receptors and initiate the same series of postreceptor events that underlie LH release by native GnRH. However, chronic administration of GnRH agonists leads to paradoxical decrease in LH and FSH secretion and inhibition of gonadal function, a phenomenon referred to as downregulation. The antagonist analogs of GnRH, on the other hand, bind to GnRH receptors and block the action of GnRH. The antagonist analogs

Chapter 6

thus have no intrinsic ability to trigger the postreceptor events usually attributable to GnRH.

GnRH Agonists Structure-Activity Relationships Several key aspects of the structure-activity relationships are important in the design of GnRH agonists [see 637 for review]. 1. Nonapeptide alkylamide [Pro 9-ethylamide (NEt)] GnRH is more potent than native GnRH and has a longer duration of action. This key modification has formed the basis of many subsequent structural modifications. 2. Replacement of the Gly residue with D-alanine increases the potency three-to-fourfold. Substitution of 1-alanine is not useful. 3. When the Pro9-Net and D-Ala6 modifications are combined, the biologic potency of the resulting compound is additively amplified. 4. Substitutions resulting in more hydrophobic compounds have an extended biologic half-life and may have greater potency in vivo. Thus D-Nal6(2) GnRH is 200-fold more potent than native GnRH in suppressing estrus in rats [637]. Mechanism of GnRH Agonist-Induced Downregulation The mechanisms of GnRH agonist-induced downregulation in the human male are not fully understood [166,638]. After a transient initial stimulatory phase in which serum LH and FSH levels rise [643], there is a progressive decrease in immuno- and bioassayable LH concentrations and serum testosterone levels. The bioassayable LH concentrations decrease markedly and parallel the fall in serum testosterone levels (see Fig. 6.5). Earlier studies, using traditional LH RIAs, had noted that the decrease in serum immunoassayable LH was only modest and could not fully explain the far greater decline in serum testosterone levels (see Fig. 6.5). It was later observed that the serum levels of free a-subunit increase during GnRH agonist treatment and remain persistently elevated throughout treatment. The free a subunit crossreacts in many traditional LH RIAs and contributes to the disparity between LH immuno- and bioassayable concentrations. Subsequent studies, using the two-site-directed IFMA, which have negligible a-subunit crossreactivity, demonstrate a proportionate change in immunofluorometric and bioassayable LH concentrations [166]. Whether microheterogeneity of circulating LH resulting from GnRH agonist treatment also contributes to diminished biologic activity of circulating LH species remains to be tested. The chromatofocusing profile of gonadotropin isoforms during GnRH analog treatment differs from that seen before initiation of treatment, suggesting differences in isoelectric points, perhaps due to differences in the net charge [166]. However, the hypothesis that co- or posttranslational modifications of gonadotropins by GnRH agonist may attenuate biologic activity of LH has not yet been fully tested.

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In the rat, GnRH agonist analogs bind directly to GnRH receptors in the testis and directly inhibit testicular steroidogenesis [638–642]. High-affinity, stereospecific binding sites for GnRH have been demonstrated in dispersed rat Leydig cells [639–642]. Although desensitization of pituitary LH and FSP secretion also occurs during GnRH agonist treatment, it is generally felt that the antifertility effects of GnRH agonist in the rat are mediated predominantly by direct inhibition of testicular steroidogenesis [638]. In the nonhuman primate and in man, GnRH receptors have not been convincingly demonstrated in the testis [642]. The consensus is that inhibition of gonadal function in these higher species is brought about by action primarily at the pituitary site [166,643]. Serum testosterone responses to exogenously administered hCG are unaltered during GnRH agonist treatment [166,643]. The changes in GnRH receptor number and affinity are usually not significant enough to adequately explain the downregulatory effects of GnRH agonist. Studies of the changes in LH-subunit gene expression during GnRH agonist treatment have revealed that the decrease in LH output is brought about mostly by inhibition of the expression of the rate-limiting LH-b subunit [202,203,644]. On the other hand, expression of the asubunit is unchanged or increased, consistent with increased serum levels of free a-subunit observed during GnRH agonist treatment [202,203]. The changes in pituitary GnRH receptor number and affinity in GnRH-desensitized pituitaries have been studied by several different laboratories [166]. However, no consistent or dramatic change in GnRH receptor number or affinity has been found. Neither does downregulation appear to be caused by depletion of LH stores, since over half the LH content is retained in the GnRH agonist-treated pituitaries [166]. Furthermore, pituitaries desensitized by prior GnRH agonist treatment can respond to other secretagogues [636]. Thus, it can only be concluded from these data that desensitization involves some poorly understood postreceptor events. Therapeutic Applications of GnRH Agonists The wide clinical applicability of GnRH agonists has spurred development and testing of a large number of agonist analogs by the pharmaceutical industry and the Contraceptive Development Branch of the NICHD. GnRH agonists have been found to be effective therapeutic agents in many sex steroid (androgen or estrogen)-dependent clinical disorders [632,636]. Their lack of systemic toxicity has been striking. Most side effects have been related to a predictable decrease in androgen or estrogen secretion due to the desired downregulation of gonadotropin secretion. It also follows that gonadotropin-independent secretion of sex steroid secretion (for example, from an adrenal or an ovarian neoplasm) would not be affected by GnRH agonist treatment. A partial list of potential clinical indications for GnRH agonist use is provided below.

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Metastatic Prostate Cancer Androgen-dependence of prostate cancer has been recognized for a long time. Not surprisingly, the standard treatment of disseminated prostate cancer has centered around lowering androgen levels by surgical orchidectomy or estrogen therapy. It is now well established that chronic treatment with GnRH agonists offers an attractive alternative to orchidectomy or estrogen therapy [645–648]. Serum testosterone levels can be effectively lowered and maintained in the castrate range. The efficacy and safety of GnRH agonist analogs has been compared to diethylstilbestrol (DES, 3 mg/day) in patients with metastatic prostate cancer, with objective response rates and survival rates essentially similar in the two groups [645]. The side effects, including gynecomastia, nausea, vomiting, and thromboembolic complications occur with a greater frequency in the DES group; hot flashes are reported more often in the GnRH agonist group. This multicenter study [645] demonstrated conclusively that GnRH agonist therapy provides an equally effective and safe alternative to estrogen treatment. It should, however, be recognized that GnRH agonists, much like estrogen or orchidectomy, are only a palliative therapy and should not be considered curative. Eventually, androgen unresponsive clones emerge, resulting in treatment failures. However, in elderly patients with reduced life expectancy, who may be severely disabled by pain, GnRH agonist therapy can alleviate pain and provide extremely effective palliation of the disease. One problem with the use of GnRH agonist is the potential for disease flare during the early stimulatory phase; this may be prevented by concomitant administration of an anti-androgen [646]. Precocious Puberty A number of studies have shown the benefit of GnRH agonist therapy in children with gonadotropin-dependent central precocious puberty [649– 652]. GnRH agonist therapy lowers gonadotropin and sex steroid levels into the prepubertal range, and halts or regresses secondary sexual development [649]. In girls, menstrual bleeding completely ceases. Linear growth velocity slows during therapy [649–652]; however, skeletal maturation is retarded to a greater degree than linear growth such that predicted adult height is increased [652]. Sexual development resumes after discontinuation of treatment [652]; however, it is important to note that GnRH agonist analog therapy of sexual precocity will be effective only in children in whom the precocious sex steroid hormone production is gonadotropin-dependent. Conversely, children with gonadotropin-independent sexual precocity such as those with McCune–Albright syndrome or testotoxicosis are unlikely to respond to GnRH agonist therapy. Endometriosis This condition, the ectopic growth of endometrial tissue, is a relatively common disorder that affects women of reproductive age group. Traditional treatment includes conservative surgery, high-dose oral contraceptives, and danazol. The use of danazol, an androgenic derivative of 17-a-ethinyl-testosterone, is limited by side

effects including weight gain, reduced breast size, acne, and hirsutism. GnRH agonists have provided an attractive alternative to other therapeutic agents [653–655]. Clinical trials have demonstrated that in women with endometriosis, GnRH agonists improve symptoms, decrease staging score, and cause regression or arrest the spread of the condition [653–655]. The side effects of GnRH agonist analogs are predictable and are the result of decreased estrogen levels; overall incidence of side effects compares favorably with danazol. GnRH Analogs as Male Contraceptives Observations that surgical hypophysectomy leads to predictable azoospermia had led to speculation that pharmacologic suppression of gonadotropins will lead to suppression of spermatogenesis. Studies with testosterone esters demonstrated azoospermia in only about 40% to 60% of treated men [656–658]. Paradoxical inhibitory effects of GnRH agonists had raised hopes of their potential application as male contraceptives and clinical trials were begun in several laboratories. Initial studies [659] revealed that the GnRH agonist induced marked suppression of spermatogenesis, but concomitant suppression of testosterone levels was attended by a decrease in libido and potency, and hot flushes. In this regard, studies from our laboratory suggested that combined androgen and GnRH agonist treatment might lead to the development of an effective male contraceptive agent [660,661]. The combined use of GnRH agonist and an androgen was attractive for two reasons: first, testosterone would prevent the undesirable side effects of androgen deficiency; and second, since androgens alone are potent inhibitors of spermatogenesis in man, the addition of a second gonadotropin inhibitor might have additive or synergistic effects on the testis [660–664]. Clinical studies using a combined regimen of GnRH agonist and androgen revealed reversible azoospermia in 50% to 60% of treated men [661–664]. Thus, although maximal doses of GnRH agonists were not used in these studies, the goal of 100% azoospermia was not achieved at the doses tested. More recently, several antagonist analogs of GnRH have become available for clinical studies; these have several advantages over the agonist analogs. First, the efficacy of agonists in predictably and completely suppressing spermatogenesis has not been demonstrated, to date, in men. Antagonist analogs are far more potent in inhibiting gonadotropin secretion in men and experimental animals than are agonist analogs [665–670]. Finally, the antagonist analogs have the potential advantage of rapid onset of inhibitory action and do not have the initial stimulatory effects that characterize GnRH agonists [665–671]. Data from animal studies indicate that GnRH antagonists markedly inhibit LH, FSH, and testosterone levels and decrease testis and accessory sex organ weights [665–671]. Long-term studies in rats [665,666] and nonhuman primates [671] clearly show induction of reversible azoospermia by combined GnRH antagonist and androgen treatment.

Chapter 6

Studies in men reveal marked and rapid suppression of LH and FSH by GnRH antagonist analogs [667–669]. Combined treatment with a GnRH antagonist along with replacement doses of testosterone enanthate lead to azoospermia in about 90% of treated men. These data are most encouraging and suggest feasible application of a GnRH antagonist plus androgen regimen for male contraception. One concern about the currently available antagonist analogs has been erythema and induration at the site of injection. Availability of more potent GnRH antagonists, free of local irritant skin reaction, along with the development of long-acting delivery systems, might make the development of male contraceptives based on GnRH antagonists feasible. Uterine Fibroids Administration of GnRH agonists results in reduction in the size of uterine fibroids [672]. This is not surprising since uterine fibroids are estrogen responsive as evidenced by their growth during estrogen therapy and regression after menopause. Estrogen receptors have been demonstrated on uterine fibroids. The main problem is that the fibroids increase in size after discontinuation of GnRH agonist treatment [672]. In addition, regression of fibroids is attended by menopausal symptoms due to GnRH agonistinduced estrogen deficiency. However, this regimen can be useful for women in whom surgery is contraindicated or those in the perimenopausal period [672]. GnRH agonist treatment prior to surgery can also be useful in reducing tumor size so that a more conservative surgical procedure may be possible; this can be quite important in women desiring fertility [672]. Other Clinical Applications In women with PCO disease, GnRH agonist treatment inhibits excessive ovarian androgen secretion, thereby resulting in amelioration of hirsutism. Prior GnRH agonist treatment may also render such patients more responsive to ovulation induction by GnRH [673,674]. Since estrogen deficiency is a predictable outcome of GnRH agonist therapy, concomitant estrogen and progesterone replacement is a necessity. GnRH agonists have also been quite useful in ovulation induction protocols [675]. Spontaneous endogenous surges of LH that result in premature rupture of follicles have posed a significant problem in protocols for in vitro fertilization (IVF) or gamete intrauterine fertilization technique (GIFT). By inhibiting LH secretion, GnRH agonist pretreatment obviates these problems resulting from the undesirable LH surge. In premenopausal women with metastatic breast cancer, GnRH agonist treatment can induce objective tumor regression and response rates similar to those seen after surgical ovariectomy [676].

Gonadotropin Antagonists Because of wide potential clinical and contraceptive applications, there is considerable interest in developing agents

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that inhibit gonadotropin secretion or action. Unlike GnRH agonists which are already in wide clinical use, and GnRH antagonists which are now being tested in humans, most of the gonadotropin inhibitors described below are still in early developmental phase.

Deglycosylated Glycoprotein Hormones The sugar residues in the glycoprotein hormones can be removed by prolonged sequential treatment with exoglycosidases [677] or hydrogen fluoride [678]. Deglycosylated hCG retains its receptor-binding properties but its ability to induce target cell response in vitro is reduced [679]. The biologic effects of chemically deglycosylated choriogonadotropin (DG-hCG) have been examined in rat interstitial cells in vitro [679,680]. Despite effective receptorbinding activity in membrane preparations, DG-hCG fails to induce cAMP accumulation in cells. The ability to induce sterodogenesis is also markedly diminished [678– 680]. The DG-hCG antagonizes the action of the native CG. The authors conclude that DC-hCG interacts with the receptor but is unable to activate the postreceptor events essential for inducing biologic response. In vivo, DC-hCG administration in doses of 10–50 pg to pregnant rats inhibits implantation and terminates gestation [681]. DG-hCG administration later during pregnancy (days 8 to 11) results in fetal resorption. These data provide preliminary evidence that DG-hCG can function as gonadotropin antagonists in vivo [681].

Gonadotropin Receptor Binding Inhibitors Initial observations that mouse EGF and the b-subunit of hFSH can inhibit binding of intact hFSH to its receptors, and share a common tetrapeptide sequence Thr-Arg-AspLeu (TRDL) had raised the possibility that TRDL was located on the exposed, receptor-binding region of FSH. Sluss et al. [682] explored this possibility, using a polyclonal antiserum to hFSH, which recognizes determinants on intact hFSH and its b-subunit, but not the a-subunit. Synthetic TRDL inhibits binding of 125I-FSH to its receptor and also the biologic response of Sertoli cells to hFSH. These and other studies have suggested that the TRDL sequence may be located in a receptor contact region of FSH. Several linear peptides based on TRDL and other sequences on the FSH-b-subunit have been shown to induce FSH agonist and antagonist activities. However, several lines of evidence, much of virologic origin, suggest that complete functional antigenic sites are often three dimensional structures that consist of more than one linear peptide brought together by the conformation. Development of FSH antagonists based on three-dimensional, conformational models is an area of considerable interest because of its potential therapeutic and contraceptive applications.

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571 Fusco FE, Rosen SW. Gonadotropin producing anaplastic large cell carcinomas of the lung. N Engl J Med 1966;275:507–515. 572 Chambers WL. Adrenal cortical carcinoma in a male with excess gonadotropin in the urine. J Clin Endocrinol Metab 1949;9:451–456. 573 Braunstein GD, Vaitukaitis JL, Carbone PP et al. Ectopic production of human chorionic gonadotropin by neoplasms. Ann Intern Med 1973;78:39–45. 574 Braunstein GD, Raso J, Wade ME. Presence in normal human testes of a chorionic gonadotropin-like substance distinct trom LH. N Engl J Med 1975;293:1339-1334. 575 Yoshimoto Y, Wolfsen AR, Hirose F et al. Human chorionic gonadotropinlike material: Presence in normal human tissues. A J Obstet Gynecol 1976;134:729–733. 576 Yoshimoto Y, Wolfsen AR, Odell WD. Variable glycosylation in hCG production by cancers. Am J Med 1979;67:414–420. 577 Braunstein AD, Kamclar V, Rasoe J et al. Widespread distribution of a chorionic gonadotropin-like substance in normal human tissue. J Clin Endocrinol Metab 1979;49:917–925. 578 Odell WD, Griffin J. Pulsatile secretion of human chorionic gonadotropin in normal adults. N Engl J Med 1987;317:1688–1691. 579 Hoermann R, Spoent G, Moncavo R, Mann K. Evidence for the presence of hCG and free beta subunit of hCG in the human pituitary. J Clin Endocrinol Metab 1990;71:179–186. 580 Marshall WE, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1973;45:13–23. 581 Marshall WE, Tanner JM. Variations in the pattern of pubertal changes in girls. Arch Dis Child 1969;44:291–303. 582 Zacharias L, Rand WM, Wurtman RJ. A prospective study of sexual development and growth in American girls. The statistics of menarche. Obst Gynecol Sury 1976;31:325–337. 583 Sizonenko PC. Preadolescent and adolescent endocrinology: physiology and pathophysiology. II. Hormonal changes during abnormal pubertal development. Am J Dis Child 1978;132:797–805. 584 Bierich JR, ed. Disorders of Puberty. Clinics in Endocrinology and Metabolism. London: W B Saunders, 1975. 585 Wilkins L. The Diagnosis and Treatment of Endocrine Disorders of Childhood and Adolescent, 3rd edn. Springfield: Charles C Thomas, 1965. 586 Sundquist C, Ellis L, Bartke A. Reproductive endocrinology of the mink. Endocr Rev 1988;9:247–266. 587 Neill JD, Frawley LS. Detection of hormone release from individual cells in mixed populations using a reverse hemolytic plaque assay. Endocrinology 1983;112:1135–1137. 588 Neill JD, Smith OF, Luque EH et al. Detection and measurement of hormone secretion from individual pituitary cells. Recent Prog Horm Res 1987;43:175–230. 589 Mellon PM, Windle JJ, Hom F. Targeted immortalizabon of neuroendocrine cells to generate novel cultured model systems of pituitary and hypothalamus. Endocrinology 1991;73:9B (Abstract). 590 Nett TM, Akbar AM, Niswender GD et al. Radioimmunoassay for GnRH in serum. J Clin Endocrinol Metab 1973;36:88–96. 591 Heber D, Odell WD. Development of a GnRH RIA utilizing a superactive synthetic analog D(Nal)2 GnRH. Proc Soc Exp Biol Med 1978;158: 643–646. 592 Mason AJ, Hayflick JS, Zoeller RT et al. A deletion of truncating the GnRH gene is responsible for hypogonadism in the hpg mouse. Science 1986;234: 1372–1378. 593 Swerdloff RS, Batt RA, Bray GA. Reproductive hormonal function in the genetically obese (oblob) mouse. Endocrinology 1976;98:1359–1364. 594 Clarke IJ. New concepts in GnRH action on the pituitary gland. Seminars in Reproductive Endocrinology 1987;3:45–52. 595 Clarke IJ, Cummins JT, Crowder ME, Nett TM. Pituitary receptors for GnRH in relation to changes in pituitary and plasma gonadotropins in ovariectomized hypophyses-disconnected ewes II. A marked rise in receptor number during acute feedback effects of estradiol. Biol Reprod 1988;39:349–354. 596 Levine JE, Ramirez VD. In vivo release of LHRH estimated with push-pull cannulae from the mediobasal hypothalamus of ovariectomized, steroid primed rats. Endocrinology 1980;107:1782–1791. 597 Oldfield EH, Chrousos GP, Schulte HM et al. Preoperative localization of ACTH secreting pituitary microadencimas by bilateral and simultaneous inferior petrosal venous sinus sampling. N Engl J Med 1985;312:100–103. 598 Hymer WC, Hathfield JM. In: Conn PM, ed. Isolation and culture of pituitary cells. Methods in Enzymology, vol. 103. New York: Academic Press, 1983:257–287.

Chapter 6 599 Smith MA, Perrin NM, Vale WW. Desensitization of cultured pituitary cells to GnRH: evidence for a post-receptor mechanism. Mol Cell Endocrinol 1983;130:85–96. 600 LaBorde NP, Wolfsen AR, Heber D, Odell VM. Pituitary gland: the site of short-loop feedback for LH in the rabbit. J Clin Invest 1979;64: 1066–1069. 601 Loughlin JS, Badger TM, Crowley WF Jr. Perifused pituitary cultures: a model for LHRH regulation of LH secretion. Am J Physiol 1981,240:E591–596. 602 Badger TM, Loughlin JS, Naddaff PG. The LHRH desensitized rat pituitary: LH responsiveness to LHRH in vitro. Endocrinology 1983;111:793–799. 603 Heller CG, Nelson WO. Classification of male hypogonadism and discussion of the pathologic physiology, diagnosis and treatment. J Clin Endocrinol Metab 1948;8:345–366. 604 MacLeod J. Restoration of human spermatogenesis by menopausal gonadotropins. Lancet 1964;i:1196–1197. 605 Paulsen CA, Espeland GH, Michals EL. Effects of hCG, hMG, hLH and hGH administration on testicular function. Adv Exp Med Biol 1970;10:547–562. 606 Santen RJ, Paulsen CA. Hypogonadotropic eunuchoidism II. Gonadal responsiveness to exogenous gonadotrophins. J Clin Endocrinol Metab 1973;36:55–63. 607 Gemzell C, Kiessler G. Treatment of infertility after partial hypophysectomy with human pituitary gonadotropins. Lancet 1964;i:44–47. 608 Johnson SG. A study of human testicular function by the use of human menopausal gonadotropin and human chorionic gonadotropin in male hypogonadotropic eunuchoidism and infantilism. Acta Endocrinol 1966;53:315–341. 609 Fradkin JE, Schonberger LB, Mills JL et al. Creutzfeldt–Jakob disease in pituitary GH recipients in the US. JAMA 1991;265:880–884. 610 Burgues S, Calderon MD, Subcutaneous self-administration of highly purified follicle-stimulating hormone and human chorionic gonadotropin for the treatment of male hypogonadotropic hypogonadism. Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism. Hum Reprod 1997;12:980–986. 611 Recombinant Human FSH Product Development Group. Recombinant follicle-stimulating hormone: development of the first biotechnology product for the treatment of infertility. Hum Reprod Update 1988;4:862–881. 612 Liu PY, Turner L, Rushford D et al. Efficacy and safety of recombinant human FSH with urinary human chorionic gonadotropin for induction of spermatogenesis and fertility in gonadotropin-deficienct men. Hum Reprod 1999;14:1540–1545. 613 Zitmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol 2000;161:73–88. 614 Smals AGH, Pieters GFFM, Draver JIM et al. Leydig cell responsiveness to single and repeated human chorionic gonadotropin administration. J Clin Endocrinol Metab 1979;49:12–14. 615 Padron RS, Wischusen J, Judson B et al. Prolonged biphasic response of plasma testosterone to single intramuscular injections of human chorionic gonadotropin. J Clin Endocrinol Metab 1980;50:1100–1104. 616 Saez JM, Forest MG. Kinetics of human chorionic gonadotropin induced steroidogenic response of the human testis 1. Plasma testosterone: implications for human chorionic gonadotropin stimulation test. J Clin Endocrinol Metab 1979;49:278–283. 617 Wang C, Paulsen CA, Hopper BR et al. Acute steroidogenic responsiveness to human luteinizing hormone in hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1980;51:1269–1273. 618 Bergada C, Mancini RE. Effect of gonadotropins in the induction of spermatogenesis in human prepubertal testis. J Clin Endocrinol Metab 1969; 37:935–943. 619 Mancini RE, Seiguer AC, Lloret AD. Effect of gonadotropins on the recovery of spermatogenesis in hypophysectomized patients. J Clin Endocrinol Metab 1969;29:476–478. 620 Liu L, Banks SM, Barnes KM, Sherins RJ. Two year comparison of testicular responses to pulsatile GnRH and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1988;67:1140–1145. 621 Finkel DM, Phillips JL, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med 1985;313:651–655. 622 Buchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropin hypogonadism: a review of 42 cases. Eur J Endocrinol 1998;139:298–303.

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623 Kliesch S, Behre HM, Nieschlag E. High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypgonadotropic hypogonadism. Eur J Endocrinol 1994;131:347–354. 624 Braunstein AD, Bloch SK, Rasor JL, Winikoff J. Characterization of antihuman chorionic gonadotropin serum antibody after ovulation induction. J Clin Endocrinol Metab 1983;57:1164–1172. 625 Nieschlag E, Bemitz S, Topert M. Antigenicity of human chorionic gonadotropin preparations in men. Clin Endocrinol 1982;16:483–488. 626 Sokol RZ, McClure RD, Peterson M, Swerdloff RS. Gonadotropin therapy failure secondary to hCG induced antibodies. J Cin Endocrinol Metab 1981;52:929–932. 627 Claustrat B, David L, Faure A, Francois R. Development of antihuman CG antibodies in patients with hypogonadotropic hypogonadism: a study of 4 patients. J Clin Endocrinol Metab 1987;57:1041–1047. 628 Burger FIG, de Kretser DM, Hudson B, Wilson JD. Effects of preceding androgen therapy on testicular response to human pituitary gonadotropin in hypogonadotropic hypogonadism: a study of 3 patients. Fertil Steril 1981;35:64–68. 629 Spratt DI, Hoffman AR, Crowley WF Jr. Hypogonadotropic hypogonadism. In: Santen R, Swerdloff RS, eds. Male Reproductive Dysfunction. New York: Marcel Dekker, 1986:227–249. 630 Moore MP, Smith R, Donald RA et al. The effects of different dose regimens of D-Ser (TBu)6-LHRH-EA (HOE 766) in subjects with hypogonadotropic hypogonadism. Clin Endocrinol 1981;14:93–97. 631 Laron Z, Dickerman Z, Ben-Zeev Z et al. Long-term effects of D-Trp6 LHRH on testicular size and LH, FSH and testosterone levels in hypothalamic hypogonadotropic males. Fertil Steril 1981;35:328–331. 632 Vickery BH. Comparison of the potential for therapeutic utilities with GnRH agonists and antagonists. Endocr Rev 1986;7:115–124. 633 Hoffman AR, Crowley WF. Induction of puberty in men by longterm pulsatile administration of low-dose GnRH. N Engl J Med 1982;307: 1237–1241. 634 Spratt DI, Finkelstein JS, O’Dea LS et al. Long-term administration of gonadotropin-releasing hormone in men with idiopathic hypogonadotropic hypogonadism. A model for studies of hormone’s physiologic effect. Ann Intern Med 1986;105:848–855. 635 Whitcomb RW, Crowley WF Jr. Male hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am 1993;22:125–143. 636 Conn PM, Crowley WF. Gonadotropin releasing hormone and its analogues. N Engl J Med 1991;324:93–97. 637 Karten M, Rivier JE. GnRH analog design. Structure function studies toward the development of agonist and antagonists; rationale and perspective. Endocr Rev 1986;7:44–54. 638 Hsueh AJW, Jones PCB. Extrapituitary actions of GnRH. Endocr Rev 1981;2:437–461. 639 Bourne GA, Regiam S, Payne AH, Marshall JC. Testicular GnRH receptors: characterization and localization on interstitial tissue. Clin Endocrinol Metab 1980;51:407–409. 640 Clayton RN, Katrikinem M, Chan V et al. Direct inhibition of testicular function by GnRH mediation by specific gonadotropin-releasing hormone receptors in interstitial cells. Proc Natl Acad Sci USA 1980;777:4459–4463. 641 Perrin MH, Vaughn JM, Rivier JE, Vale WW. High affinity binding of a potent LHRH agonist in rat testis. Life Sci 1980;26:2251–2256. 642 Clayton RN, Huhtaniemi IT. Absence of GnRH receptors in human gonadal tissue. Nature 1982;299:56–58. 643 Heber D, Bhasin S, Steiner BS, Swerdloff RS. Characterization of early stimulatory and down-regulatory effects of a potent GnRH agonist in the human male. J Clin Endocrinol Metab 1984;58:1084–1089. 644 Yuan QX, Swerdloff RS, Bhasin S. Differential regulation of rat LH alpha and beta subunits during stimulatory and downregulatory phases of GnRH action. Endocrinology 1984;112:504–510. 645 The Leuprolide Study Group: Leuprolide versus diethyl stilbestrol for metastatic prostate cancer. N Engl J Med 1984;311:1281–1286. 646 Labrie F, Dupont A, Belanger A et al. Treatment of prostate cancer with GnRH agonists. Endocr Rev 1986;7:67–76. 647 Labrie F, Dupont A, Belanger A et al. Simultaneous administration of pure antiandrogens: a combination necessary for the use of LHRH agonists in the treatment of prostate cancer. Proc Natl Acad Sci USA 1984;81:3861–3863. 648 Labrie F, Dupont A, Belanger A, Lachance R. Flutamide eliminates the risk of disease flare in prostate cancer patients treated with LHRH agonist. J Urol 1987;138:804–806. 649 Boepple PA, Mansfield J, Wierman ME et al. Use of potent long acting agonist of GnRH in the treatment of precocious puberty. Endocr Rev 1986;7:24–33.

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650 Pescovitz OH, Comite F, Hench K et al. The NIH experience with precocious puberty. Diagnostic subgroups and response to short-term LHRH analog therapy. J Pediatr 1986;108:47–59. 651 Comite F, Cutler GB Jr, Rivier J et al. Short term treatment of idiopathic precocious puberty with a long-acting analog of LHRH. N Engl J Med 1981;305:1546–1550. 652 Manasco PK, Pescovitz OH, Feuillan PP et al. Resumption of puberty after long term LHRH agonist treatment of central precocious puberty. J Clin Endocrinol Metab 1988;67:368–772. 653 Barbieri RL. New therapies for endometriosis. N Engl J Med 1988;318:512–514. 654 Henzl MR. Gonadotropin-releasing hormone agonist management of endometriosis. A review. Clin Obstet Gynecol 1988;31:51–56. 655 Meldrurn DR, Change RJ, Lu J et al. Medical oopherectomy using long term GnRH agonist—a possible new approach to the treatment of endometriosis. J Clin Endocrinol Metab 1982;54:1081–1083. 656 Swerdloff RS, Campfield LA, Palacios A, McClure RD. Suppression of human spermatogenesis by depot androgen: potential for male contraception. J Steroid Biochem 1979;11:663–669. 657 Matsumoto A. Effects of chronic testosterone administration in normal men: safety and efficacy of high dose testosterone and parallel dose-dependent suppression of LH, FSH and sperm production. J Clin Endocrinol Metab 1990;70:282–287. 658 WHO Task Force on methods for the regulation of male fertility: contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet 1990;336:955–959. 659 Linde R, Doelle GC, Alexander AN et al. Reversible inhibition of testicular steroidogenesis and spermatogenesis by a potent GnRH agonist in normal men. N Engl J Med 1981;305:663–667. 660 Heber D, Swerdloff RS. Gonadotropin-releasing hormone analog and testosterone synergistically inhibit spermatogenesis. Endocrinology 1981;108:2019–2021. 661 Bhasin S, Heber D, Steiner BS, Swerdloff RS. Hormonal effects of GnRH agonist in the human male III. Effects of long-term combined treatment with GnRH agonist and androgen. J Clin Endocrinol Metab 1985;60:998–1003. 662 Doelle GC, Alexander AN, Evans RM et al. Combined treatment with a LHRH agonist and testosterone in man: reversible oligospermia without impotence. J Androl 1983;4:298–302. 663 Schurmeyer TH, Knuth UA, Freischmen CW et al. Suppression of pituitary and testicular function in normal men by constant GnRH agonist infusion. J Clin Endocrinol Metab 1984;59:14–24. 664 Bhasin S, Yuan QX, Steiner BS, Swerdloff RS. Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in men: effects of long term treatment with GnRH agonist infusion and androgen. J Clin Endocrinol Metab 1987;65:568–574. 665 Bhasin S, Fielder TL, Peacock NR et al. Dissociating antifertility effects of GnRH antagonist from its adverse effects on mating behavior in male rats. Am J Physiol 1988;254:E84–91. 666 Rivier C, Rivier J, Vale W. Effects of a potent GnRH antagonist and testosterone propionate on mating behavior and fertility in the male rat. Endocrinology 1981;108:1998–2001. 667 Salameh W, Bhasm S, Steiner B et al. Marked suppression of gonadotropins and testosterone by an antagonist analog of gonadotropin releasing hormone in men. Fertil Steril 1991;55:16–22. 668 Bagatell CJ, McLaschlan RL, de Kretser DM et al. A comparison of the suppressive effects of testosterone and a potent new gonadotropinreleasing

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C h a p t e r

7 The Posterior Pituitary Daniel G. Bichet

STRUCTURE OF THE NEUROHYPOPHYSIS; ANATOMY AND ELECTROPHYSIOLOGY OF VASOPRESSIN-PRODUCING CELLS The hypothalamus, which is located at the anterior end of the diencephalon (Fig. 7.1), embodies a group of nuclei that form the floor and ventrolateral walls of the triangularshaped third ventricle. A thin membrane called the lamina terminalis forms the anterior wall of this compartment and is believed to contain osmoreceptor cells in a structure known as the organum vasculosum. The subfornical organ (SFO) is also believed to contain these cells. The organum vasculosum of the lamina terminalis (OVLT), the SFO and the pituitary gland lack a blood–brain barrier. The supraoptic nucleus (SON) lies just dorsal to the optic chiasm and approximately 2 mm from the third ventricle. The paraventricular nucleus (PVN) lies closer to the thalamus in the suprachiasmatic portion of the hypothalamus, but it borders on the third ventricular space. These well-defined nuclei contain the majority of the large neuroendocrine cell bodies, known as the magnocellular or neurosecretory cells, that manufacture arginine-vasopressin and oxytocin. The neurohypophysis consists of: (i) a set of hypothalamic nuclei, namely the SON and PVN which house the perikarya of the magnocellular neurons; (ii) the axonal processes of the magnocellular neurons form the supraoptical hypophyseal tract; and (iii) the neurosecretory material of these neurons which is carried on to the posterior pituitary gland (see Fig. 7.1). Immunocytochemical and radioimmunological studies have demonstrated that oxytocin and vasopressin are synthesized in separate populations of the supraoptic nuclei and the PVN neurons [1,2]; whose central and vascular projections have been described in great detail [3]. Some cells express the prepro-AVP-NPII gene and other cells express the prepro-OX-NPI gene (vide infra).

Immunohistochemical studies have revealed a second vasopressin neurosecretory pathway that transports high concentrations of the hormone to the anterior pituitary gland from parvocellular neurons to the hypophysial portal system. In the portal system, the high concentration of AVP acts synergistically with corticotropin releasing hormone (CRH) to stimulate adrenocorticotropin (ACTH) release from the anterior pituitary. More than half of parvocellular neurons coexpress both CRH and prepro-AVP-NPII. In addition, while passing through the median eminence and the hypophysial stalk, magnocellular axons can also release arginine-vasopressin into the long portal system. Furthermore, a number of neuroanatomical studies have shown the existence of short portal vessels that allow communication between the posterior and anterior pituitary. Thus, in addition to parvocellular vasopressin, magnocellular vasopressin is able to influence ACTH secretion [4,5]. Other parvocellular neurons have been described, but their function is unknown or insufficiently characterized [6]. Oxytocin- and vasopressin-secreting cells can also be differentiated by their specific electrophysiological properties [7]. For example, in anesthetized lactating rats with suckling pups, oxytocin-secreting neurons are recognized by a slow irregular or continuous background firing which is interrupted every few minutes by a synchronous brief (1 to 2 seconds) high frequency (50–80 Hz) burst of activity that causes oxytocin release and milk ejection. Vasopressinsecreting neurons are characterized by a unique phasic discharge pattern during activation by both osmotic stimuli and hemorrhage. In terms of their osmosensitivity, an elevation in the osmotic plasma pressure causes an increase in firing in both oxytocin- and vasopressin-secreting cells, but the firing is characteristically phasic in the vasopressinsecreting cells [7]. 279

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FIGURE 7.1. Schematic representation of hypothalamus, posterior pituitary and surrounding structures. Four major neuronal tracts originate from the supraoptic and paraventricular nuclei: (i) to the posterior lobe of the pituitary (- -); (ii) to the hypophysial portal system (—); (iii) to the brain stem and the spinal cord; (iv) to the forebrain. Afferent fibers to these nuclei originate from the osmoreceptors and baroreceptors (not represented).

FIGURE 7.2. Structural organization of the vasopressin gene and the hormone precursor. From Richter and Schmale [347].

THE VASOPRESSIN AND OXYTOCIN GENES

Gene Structure Vasopressin and its corresponding carrier protein are synthesized as a composite precursor (Fig. 7.2) by the magnocellular neurons described above. The precursor is packaged into neurosecretory granules and transported axonally in the stalk of the posterior pituitary. On route to the neurohypophysis, the precursor is processed into the active hormone (Fig. 7.3). Preprovasopressin is encoded by the 2.5 kb AVPneurophysin II gene on chromosome 20 (20p13) [8–10]. Exon 1 of the AVP-NPII gene encodes the putative signal peptide, vasopressin, and the NH2-terminal region of NPII. Exon 2 gives rise to the central region of NPII and exon 3 accounts for the COOH-terminal region of neurophysin and glycoprotein. Provasopressin is generated by the removal of the signal peptide from preprovasopressin and the addition of carbohydrate to its glycoprotein domain in magno-

cellular neurons in the hypothalamus. Additional posttranslational processing occurs within neurosecretory vesicles during transport of the precursor protein to axon terminals in the posterior pituitary, yielding vasopressin, neurophysin and glycoprotein [11]. Mammalian vasopressin and oxytocin hormones are encoded by distinct but structurally related genes [8]. These genes are transcribed on opposite DNA strands (tail to tail) in humans [9,10] and rats [12] on chromosome 20, where they are separated by approximately 8 to 10 kb of intergenic sequences. A similarity in the nucleotide sequence encoding the neuropeptides, vasopressin and oxytocin, suggests that they may have arisen from a common ancestor by gene duplication; however, gene inversion would also be required. There is a head to tail arrangement in other evolutionarily duplicated gene systems such as the b-subunits of human chorionic gonadotrophin [13] or the C4/steroid 21-hydroxylase/gene X locus [14].

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281

FIGURE 7.4. Neurophysin II genomic and amino acid sequence showing the 1 bp (G) deleted in the Brattleboro rat. The human sequence (GenBank entry M11166) is also shown. It is almost identical to the rat prepro sequence. In the Brattleboro rat, G1880 is deleted with a resultant frameshift after 63 amino acids (amino acid 1 is the first amino acid of neurophysin II).

Expression of the Vasopressin Gene in Diabetes Insipidus Rats (Brattleboro Rats) FIGURE 7.3. Cascade of vasopressin biosynthesis. SP, signal peptide; AVP, arginine-vasopressin; NP, neurophysin; GP, glycoprotein. From Richter and Schmale [347]. See also [379].

Gene Regulation The regulation of mammalian vasopressin gene expression is closely correlated with the expression of its structural counterpart oxytocin. Both genes are similar in their protein encoding sequences, yet their translational products control different functions and, hence, their expression should depend on quite distinct physiologic stimuli. This is consistent with the finding that these two genes show little homology in their promoter regions, suggesting independent transcriptional control mechanisms. However, osmotic stimulation has been shown to upregulate both vasopressin and oxytocin gene transcription [15]. Late gestation and lactation also trigger the transcription of both vasopressin and oxytocin genes [16]. Cyclic 3¢,5¢-adenosine monophosphate (cAMP) has been shown to regulate bovine vasopressin expression in vitro via cis-acting element within the vasopressin promoter [17]. In rats, the vasopressin and oxytocin encoding genes are expressed in distinct sets of hypothalamic magnocellular neurons, which are specific for either vasopressin (vasopressinergic neurons) or oxytocin (oxytocinergic neurons) [18]. In situ hybridization experiments have demonstrated that, during osmotic stimulation, vasopressin and oxytocin genes are expressed exclusively in vasopressinergic and oxytocinergic neurons, respectively. No coexpression of the neuropeptides in the same neurons has been observed. Other factors of possible importance in either tissue- or cell-specific (or both) expression of the vasopressin and oxytocin genes have recently been examined [19–22].

The animal model of diabetes insipidus that has been most extensively studied is the Brattleboro rat. Discovered in 1961, the rat lacks vasopressin and its neurophysin, whereas the synthesis of the structurally related hormone oxytocin is not affected by the mutation [23]. Its inability to synthesize vasopressin is inherited as an autosomal semirecessive trait. Schmale and Richter [24] isolated and sequenced the vasopressin gene from homozygous Brattleboro rats, and found that the defect is due to a single nucleotide deletion of a G residue within the second exon encoding the carrier protein neurophysin. The shift in the reading frame caused by this deletion predicts a precursor with an entirely different C terminus (Fig. 7.4). The messenger RNA (mRNA) produced by the mutated gene encodes a normal AVP but an abnormal NPII moiety [24] which impairs transport and processing of the AVP-NPII precursor and its retention in the endoplasmic reticulum of the magnocellular neurons where it is produced [25,26]. Homozygous Brattleboro rats may still demonstrate some V2 (vide infra) antidiuretic effect since the administration of a selective non-peptide V2 antagonist (SR121463A, 10 mg/kg i.p.) induced a further increase in urine flow rate (200 to 354 ± 42 mL/24 h) and a decline in urinary osmolality (170 to 92 ± 8 mmol/kg) [27]. Oxytocin which is present at enhanced plasma concentrations in Brattleboro rats, may be responsible for the antidiuretic activity observed [28,29]. Oxytocin is not stimulated by increased plasma osmolality in humans.

Expression of the Vasopressin Gene in Autosomal Dominant and Autosomal Recessive Diabetes Insipidus in Humans Repaske et al. [30] reported in 1990 that the genetic locus for autosomal dominant central diabetes insipidus [31–35] was within or near the gene encoding for AVP.

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Table 7.1.

Name* 3delG (previously called 277delG)

Hypothalamic–Pituitary Function

Prepro-AVP-NPII mutations causing autosomal dominant and autosomal recessive human neurogenic diabetes insipidus

Type of mutation

Nucleotide change

Predicted amino acid change

Restriction-enzyme analysis

Deletion

Deletion of G of ATG, the first a.a. of the signal peptide

Frameshift starting with the first a.a. of the signal peptide

BamHI site created

Comments and putative functional consequence

References

Retention in the ER, alternative ATG with production of truncated signal sequence

[38,53]

CG Æ CA; alteration of the cleavage of the leader peptide

[40–43,54,56] (total of 7 families)

S17F

Missense

C Æ T at 274

Ser Æ Phe at codon 17

MboII site created

A19T

Missense

G Æ A at 279

Ala Æ Thr at codon 19

BstUI site abolished, PmlI site created

A19V

Missense

C Æ T at 280

Ala Æ Val at codon 19

BstUI site abolished

Y21H

Missense

T Æ C at 285

Tyr Æ His at codon 21

–

Substitution of the second a.a. in the antidiuretic hormone

[39]

P26L

Missense

C Æ T at 301

Pro Æ Leu at codon 26

–

Autosomal recessive, substitution of the seventh a.a. in the antidiuretic hormone

[57]

G45R

Missense

G Æ C at 1730

Gly Æ Arg at codon 45 (NP14)

BslI site created

G48V

Missense

G Æ T at 1740

Gly Æ Val at codon 48 (NP17)

BglI site abolished

R51C

Missense

C Æ T at 1748

Arg Æ Cys at codon 51 (NP20)

G54R

Missense

G Æ A at 1757

Gly Æ Arg at codon 54 (NP23)

–

–

[55]

G54R

Missense

G Æ C at 1757

Gly Æ Arg at codon 54

Bsp120I site abolished

–

[45]

[37]

[37,44,45] (3 independent families)

[37,45] Disruption of a b turn in AVP-NPII precursor

[46] [37]

G54V

Missense

G Æ T at 1758

Gly Æ Val at codon 54

ApaI site abolished

–

[47]

P55L

Missense

C Æ T at 1761

Pro Æ Leu at codon 55 (NP24)

DdeI site created

De novo mutation, amino acid substitution in NPII

[43,48]

E78del (previously called DE77)

Inframe deletion

Deletion of 3 nucleotides in region 1824– 1829

Deletion of Glu (glutamic acid) at codon 77 (NP46)

MnlI site abolished

2 sets of staggered 3 bp tandem repeats; unable to form a salt bridge between AVP and NPII

[37,49]

E78G

Missense

A Æ G at 1830

Glu Æ Gly at codon 78 (NP47)

[37]

L81P

Missense

T Æ C at 1839

Leu Æ Pro at codon 81 (NP50)

[37]

G88R

Missense

G Æ C at 1859

Gly Æ Arg at codon 88 (NP57)

MspI and BglI sites abolished

G88S

Missense

G Æ A at 1859

Gly Æ Ser at codon 88 (NP57)

MspI and BglI sites abolished

C92S

Missense

G Æ C at 1872

Cys Æ Ser at codon 92 (NP61)

HgaI site created

[37]

C92X

Nonsense

C Æ A at 1873

Cys Æ stop at codon 92 (NP61)

MnlI site created

[37]

[37] Failure of dimerization of NPII, alteration of axonal transport of postranslational processing

[37,43,50] (3 families)

The Posterior Pituitary

Chapter 7 Table 7.1.

Continued

Name*

Type of mutation

Nucleotide change

Predicted amino acid change

Restriction-enzyme analysis

Comments and putative functional consequence

References

G93W

Missense

G Æ T at 1874

Gly Æ Trp at codon 93 (NP62)

BpmI site created

–

[51]

G96C

Missense

G Æ T at 1883

Gly Æ Cys at codon 96 (NP65)

[37]

G96V

Missense

G Æ T at 1884

Gly Æ Val at codon 96

–

–

[52]

R97C

Missense

G Æ T at 1886

Arg Æ Cys at 97

–

–

[59]

C98X

Nonsense

C Æ A at nucleotide 1891

Cys Æ Stop at codon 99 (NP68)

DdeI site created

–

[51]

C105Y

Missense

G Æ A at 1911

Cys Æ Tyr at codon 105 (NP74)

–

–

[58]

C110X

Nonsense

C Æ A at 2094

Cys Æ Stop at codon 110 (NP79)

BbvI site abolished

E113X

Nonsense

G Æ T at 2101

Glu Æ Stop at codon 113 (NP82)

–

C Æ G at 2106

Pro Æ Pro at 114 (NP83) Glu Æ Stop at 115 (NP84)

2106 CG Æ GT

E118X

283

Nonsense

G Æ T at 2107

Nonsense

G Æ T at 2116

Glu Æ Stop at 118 (NP87)

[37]

–

[54] [37]

MaeI site created

[37]

* The names were assigned following the suggested nomenclature for [343].

The nucleotides and amino acids are numbered according to the prepro-AVP-NPII gene sequence [10], and GenBank accession number M11166; The codons corresponding to the moieties are 1 to 19—signal peptide, 20 to 28—AVP, 29 to 31—cleavage site, 32 to 124—NPII, and 126 to 164—glycopeptide. NP14 means the 14th amino acid of the protein neurophysin. For an update of recent mutations see [380].

Furthermore, they suggested that a defective AVP-NPII gene might be the basis for this disease. Neurogenic diabetes insipidus (OMIM 125700) [36] is a now well-characterized entity, secondary to mutations in the prepro-AVP-NPII (OMIM 192340) [36]. This disorder is also referred to as central, cranial, pituitary or neurohypophyseal diabetes insipidus. Patients with autosomal dominant neurogenic diabetes insipidus retain some limited capacity to secrete AVP during severe dehydration, and the polyuro–polydipsic symptoms usually appear after the first year of life [37], when the infant’s demand for water is more likely to be understood by adults. Thirty prepro-AVP-NPII mutations segregating with autosomal dominant or autosomal recessive neurogenic diabetes insipidus have been described [37–59] (Table 7.1). The mechanism(s) by which a mutant allele causes neurogenic diabetes insipidus could involve the induction of magnocellular cell death as a result of the accumulation of arginine-vasopressin precursors within the endoplasmic reticulum [60]. This hypothesis could account for the delayed onset and autosomal mode of inheritance of the disease. In addition to the cytotoxicity

caused by mutant AVP precursors, the interaction between the wild-type and the mutant precursors suggests that a dominant-negative mechanism may also contribute to the pathogenesis of autosomal dominant diabetes insipidus [61]. The absence of symptoms in infancy in autosomal dominant central diabetes insipidus is in sharp contrast with nephrogenic diabetes insipidus secondary to mutations in AVPR2 or in AQP2 (vide infra) in which the polyuro– polydipsic symptoms are present during the first week of life. Of interest, errors in protein folding represent the underlying basis for a large number of inherited diseases [62,63] and are also pathogenic mechanisms for AVPR2 and AQP2 mutants responsible for hereditary nephrogenic diabetes insipidus (vide infra). Why prepro-AVP-NPII misfolded mutants are cytotoxic to AVP-producing neurons is an unresolved issue. The nephrogenic diabetes insipidus AVPR2 missense mutations are likely to impair folding and to lead to the rapid degradation of the affected polypeptide and not to the accumulation of toxic aggregates, since the other important functions of the principal cells of the collecting ducts (where AVPR2 is expressed) are entirely normal.

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Three families with autosomal recessive neurogenic diabetes insipidus have been identified in which the patients were homozygous or compound heterozygotes for prepro-AVPNPII mutations [57,64]. Two of these families are characterized phenotypically by severe and early onset in the first three months of life, polyuria, polydipsia, and dehydration. As a consequence, early hereditary diabetes insipidus can be neurogenic or nephrogenic. CHEMISTRY, PROCESSING AND METABOLISM OF AVP AVP is a nonapeptide with a molecular weight of 1084 Da. The chemical structure of AVP and related peptides is given in Table 7.2 and Fig. 7.5. It is a strongly basic molecule (isoelectric point pH 10.9) due to the amidation of three carboxyl groups. Lysine-vasopressin, the antidiuretic hormone of the pig family, has the less basic amino acid lysine at position 8, resulting in a lower isoelectric

point (pH 10.0). Biological activity of these hormones is destroyed by oxidation or reduction of the disulfide bond [65,66]. Members of the vasopressin hormone family have been detected throughout the animal kingdom [67], comprising more than half a dozen variants including peptides such as vasotocin of nonmammalian vertebrates, the diuretic hormone of insects and the conopressins of molluscs. In vertebrates, their endocrine hormonal activity—controlling mainly water retention—is well documented, whereas in invertebrates, they may function primarily as neurotransmitters, although a hormonal diuretic activity has been demonstrated in the locust [68]. Acher and Chauvet [67] postulated the existence of a single ancestral peptide that developed along two evolutionary lines, one vasotocin-vasopressin and the other isotocin-mesotocin-oxytocin. However, recent evidence suggests that multiple genes, which code for numerous vasopressin-like hormones, are present in Australian macropods.

Table 7.2. Amino acid sequence of arginine vasopressin and related neurohypophysial nonapeptides*

Arginine vasopressin

Lysine vasopressin Arginine vasotocin Oxytocin Mesotocin Isotocin Glumitocin Valitocin Aspartocin

1 2 3 4 5 6 7 8 9 Cys-Tyr-Phe-Glu(NH2)-Asp(NH2)-Cys-Pro-Arg-Gly(NH2)

Phe Ile Ile Ile Ile Ile Ile Ile

Glu(NH2) Glu(NH2) Glu(NH2) Glu(NH2) Ser Ser Glu(NH2) Asp(NH2)

Lys Arg Leu Ile Ile Glu(NH2) Val Leu

Distribution Most mammals

Pig family Nonmammalian vertebrates Mammals, birds Reptiles Fish Fish Fish Fish

* From Baylis [344].

FIGURE 7.5. Contrasting structure of arginine-vasopressin (AVP) and oxytocin (OY). The peptides differ only by two amino acids F3 Æ I3 and R8 Æ L8 in AVP and OT, respectively. The conformation of AVP was obtained from [172] and the conformation of OT was obtained from the Protein Data Bank (PDB ld 1XY1). Note, for both hormones the formation of a disulfide bond between Cys residues at the 1 and 6 positions result in a peptide constituted of a 6 amino acid cyclic part and a 3 amino acid C-terminal part.

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cholinergic input to neurosecretory neurons may arise from cells located in the lateral hypothalamus [90]. In addition, the liaison between the subfornical organ (an osmoreceptor sensing mechanism) and the SON and PVN may involve endogenous angiotensin II-immunoreactive pathways [91]. Finally, the presence of endogenous opioid peptides [92–96] and opioid receptors [97] in the neural lobe has led to the suggestion that opioid peptides play a role in the release of neurohypophyseal hormones (vide infra, inhibition of vasopressin release by kappa agonists).

Neurophysins were first thought to be carrier-proteins for vasopressin and oxytocin. It is now recognized that NPI (for oxytocin) and NPII (for vasopressin) belong to the precursor of the respective hormone (see above section on the vasopressin and the oxytocin gene). After synthesis in the hypothalamic neurons, the vasopressin precursor migrates along the neuronal axons, many of which terminate in the posterior pituitary. The time from synthesis to release of the hormone into the systemic circulation is about 1.5 hours [69]. Pulse chase experiments indicate that cleavage occurs continuously during axonal transport [70], but both cleaved and uncleaved precursors [71] are present in the neurosecretory granules of the posterior pituitary. Only a small percentage of the synthetic peptide is released; some of the vasopressin-containing neurosecretory granules move away from the nerve endings and are unavailable for release. Once secreted into the circulation, vasopressin is accompanied, but not bound, by its specific neurophysin. Neurophysins themselves do not appear to have any biological activity, but since they are synthesized and released with vasopressin and oxytocin, their concentrations in the plasma reflect any changes in the release of the active hormones (see below). The plasma half-life of vasopressin is short, being about 5 to 15 minutes [72]. Clearance is independent of plasma vasopressin concentration as it involves a liver- and kidneydependent process [72,73]. Vasopressin is not protein-bound, but large quantities of vasopressin are associated with the platelets in man [74–80] and dogs [81]. Platelet-rich plasma AVP concentrations are approximately five- to sixfold higher than those of platelet-depleted plasma. Furthermore, irreversible platelet aggregation could bring about intraplatelet AVP release [82]. However, osmotic stimulation of AVP release does not influence platelet-associated AVP concentrations [77,79,80].

Vasopressin release can be regulated by changes in either osmolality [98] or cerebrospinal fluid (CSF) Na+ concentration [99] see also [100–102]. More recently, Voisin et al. demonstrated coincident detection of CSF Na+ and osmotic pressure in magnocellular osmoregulatory neurons of the SON [103]. The concept of cerebral osmoreceptors and their role in the control of vasopressin secretion derives from the classical studies of Verney [104]. These osmoreceptors have been shown to respond to changes in blood osmolality of 1% or less, and all of the available evidence leads to the conclusion that they are located in the anterior part of the brain, presumably in the anterior hypothalamus. The existence of hepatic or portal osmoreceptors in rats and dogs has been debated for a number of years (for review, see Liard et al. [105]). To determine whether extracerebral osmoreceptors contribute to vasopressin release when exposed to blood osmolality changes of about 1%, Liard et al. [105] administered a hypertonic saline solution to conscious dogs through

CENTRAL NERVOUS SYSTEM MEDIATORS OF VASOPRESSIN AND OXYTOCIN RELEASE

Table 7.3. secretion*

Neurohypophyseal neurons receive an abundance of afferent connections and it is not surprising that a number of putative chemical mediators within the central nervous system have been shown to influence vasopressin and oxytocin release (for review, see [83–86] (Table 7.3). The magnocellular neurons of the SON and PVN receive a dense noradrenergic innervation from the A1 neurons in the ventrolateral medulla [87]. It has been shown that micromolar concentrations of norepinephrine and a agonists induce a dose-dependent release of vasopressin from perfused rat hypothalamic explants in vivo [88]. In particular, micromolar concentrations of norepinephrine and a agonists have been shown to evoke excitations, whereas norepinephrine and b agonists applied in millimolar concentrations evoke a reduction in the excitability of SON neurons [89]. Dopaminergic fibers innervate SON and PVN from the diencephalic A11–A14 cell groups and may increase the activity of oxytocinergic neurons. Furthermore, endogenous

CONTROL OF AVP SECRETION

Osmotic Stimulation

Putative mediators of arginine vasopressin (AVP)

Biogenic monoamines

Norepinephrine Dopamine Acetylcholine Serotonine g-Aminobutyric acid (GABA) Glycine Histamine

Peptides

Angiotensin II Endogenous opioids Cholecystokinin (CCK) Substance P AVP

Others

NO Prostaglandins Electrolytes (potassium, calcium)

* Adapted from Sklar and Schrier [83].

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catheters chronically implanted into the inferior vena cava, the portal vein, the artery to a sole remaining kidney, and the common carotid arteries. The changes in the plasma sodium concentration and plasma osmolality were similar for all the routes of administration. Plasma vasopressin concentration increased more rapidly after intracarotid infusion than after infusions by any other route. Under the conditions tested, renal or portal hepatic osmoreceptors do not contribute to vasopressin release. Essential Criteria for Osmoreceptors

Three criteria must be met for cells to be identified as osmoreceptive. First, increasing the osmolality of the perfusing fluid should result in an increase in firing frequency, but no response should be obtained if the osmolality is increased with solutes such as urea or glycerol, since these solutes are able to diffuse across the cell membrane. Furthermore, the osmoreceptor cells should display a sensitivity to changes in osmolality which approaches that observed in vivo. Second, the putative osmoreceptors must, if they are not the magnocellular neurons themselves, have neuroanatomical connections with the magnocellular neurons. Third, if the osmoreceptors are separated from the magnocellular neurons, alterations in vasopressin secretion secondary to changes in plasma osmolality should occur [106]. The following candidates fulfill these criteria for osmoreceptors: magnocellular cells which synthesize vasopressin in the SON and PVN; the perinuclear zone around the SON; cells in the SFO and OVLT (organum vasculosum lamina terminalis); cells in the lateral preoptic area. The Blood–brain Barrier and Osmoreceptors

The anatomical basis of the blood–brain barrier is the capillary endothelium, a membrane in which adjacent cells are joined by tight functions [107]. The blood–brain barrier is impermeable to all solutes except for lipid-soluble compounds. Verney’s original studies on intracarotid injection suggested that solutes which could not penetrate the cell membranes and thus obligated the loss of cell water, e.g., NaCl, were the cause of antidiuresis, whereas solutes which could penetrate the cell membrane, but did not change the cell volume, e.g., urea, did not effect on water diuresis. This simple model assumes then that the osmoreceptors are directly exposed to peripheral extracellular fluid, i.e., that these osmoreceptors are outside the blood–brain barrier. Since the SON and PVN are located within the blood–brain barrier and blood–cerebrospinal fluid barrier, they cannot be the osmoreceptors responsible for vasopressin secretion in response to increased osmolality. Nor is the suggested presence of sodium receptors within or outside the blood–brain barrier compatible with the extensive experimental results available (for review, see Thrasher and Ramsey [106]). The hypothesis that the circumventricular organ (CVO), with its fenestrated perfusing capillaries, contains osmoreceptors is supported by the fact that all the aforementioned criteria for osmoreceptors are fulfilled. The

CVO then seems to provide essential osmoreceptive input to the vasopressin secreting cells in the SON and PVN. Functional deficits observed after lesions of the SFO and OVLT and extensive electrophysiological evidence also suggest that cells in both the OVLT and SFO are osmosensitive [106]. Stretch Inactivated Cationic Channels Transduce Osmoreception

Changes in excitatory synaptic drive, derived from osmosensitive neurons in the OVLT, combine with endogenously generated osmoreceptor potentials to modulate the firing rate of magnocellular cells (and hence the release of AVP). The cellular basis for osmoreceptor potentials has been characterized using patch-clamp recodings and morphometric analysis in magnocellular cells isolated from the supraoptic nucleus of the adult rat [102]. In these cells, stretch-inactivating cationic channels transduce osmotically evoked changes in cell volume into functionally relevant changes in membrane potential (Fig. 7.6). In addition, magnocellular neurons also operate as intrinsic Na+ detectors [103]. Osmotic Threshold: Sensitivity or Gain of the Osmoreceptor/Arginine-vasopressin Releasing Unit

The level of plasma osmolality at which hydrated subjects first responded to an intravenous infusion of 5% saline with a statistically significant fall in free water clearance (without a fall in osmolal clearance or creatinine excretion) was termed the osmotic threshold for vasopressin release [108]. This osmotic threshold, which was determined to be 288.5 mosm/kg [109], was raised by the administration of hydrocortisone [108], and plasma volume expansion [110], and lowered by plasma volume contraction [111]. With the development of sensitive radioimmunoassays, it was later demonstrated that, in healthy adults, the infusion of concentrated saline (850 mmol/L) caused a progressive rise in plasma osmolality and in plasma AVP concentrations [76,77,112,113]. A direct correlation between the two variables was established, defined by the function: pAVP = 0.30 (Posm - 280) (Fig. 7.7). The abscissal intercept, 280 mmol/kg, is the osmotic threshold. Because this intercept falls below the limit of detection of the assay methods, this “set” of the osmoreceptor mechanism should be referred to as the theoretical threshold for vasopressin release. Whether AVP secretion can be completely suppressed or whether a linear versus an exponential model should be used remain unclear [113,114]. A close relationship has also been demonstrated between urine osmolality and AVP concentrations except in patients with nephrogenic diabetes insipidus (Fig. 7.7). The exquisite sensitivity and gain of the osmoreceptor—AVP—renal reflex is given by the following example (Fig. 7.8). A normally hydrated man may have a plasma osmolality of 287 mmol/kg, a plasma vasopressin concentration of 2 pg/mL and a urinary osmolality of 500 mmol/kg. With an increase of 1% in total body water,

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287

FIGURE 7.6. Stretch inactivated (SI) cationic channels transduce osmoreception. Under resting osmotic conditions (middle panel) a portion of the SI cationic channels is active and allows the influx of positive charge (diagram). Hypotonic stimulation (left) provokes cell swelling and inhibits channel activity, thereby hyperpolarizing the cell. In contrast, hypertonic stimulation (right) causes cell shrinking. Activation of an increased number of channels under this condition augments charge influx and results in membrane depolarization. Traces representing changes in the activity of a single SI channel are shown below. From Bourque and Oliet [102].

FIGURE 7.7. The relationship between plasma AVP and plasma osmolality during the infusion of hypertonic saline solution (left side). Patients with primary polydipsia and nephrogenic diabetes insipidus have values within the normal range (open area) in contrast to patients with neurogenic diabetes insipidus, who show subnormal plasma ADH responses (stippled area). Relationship between urine osmolality and plasma ADH during dehydration and water loading (right side). Patients with neurogenic diabetes insipidus and primary polydipsia have values within the normal range (open area) in contrast to patients with nephrogenic diabetes insipidus, who have hypotonic urine despite high plasma ADH (hatched area). From Zerbe and Robertson [348].

plasma osmolality will fall by 1% (2.8 mmol/kg), plasma AVP will decrease to 1 pg/mL and urinary osmolality will diminish to 250 mmol/kg. Similarly, it is only necessary to increase total body water by 2% to suppress the plasma AVP maxi-

mally (<0.25 pg/mL) and to maximally dilute the urine (<100 mmol/kg). In the opposite direction, a 2% decrease in total body water will increase plasma osmolality by 2% (5.6 mmol/kg), plasma AVP will rise from 2 to 4 pg/mL and urine will be maximally concentrated (>1000 mmol/kg). Thus, in the context of these sensitivity changes, a 1 mmol rise in plasma osmolality would be expected to increase plasma AVP by 0.38 pg/mL and urinary osmolality by 100 mmol/kg. Such a small change in plasma osmolality (measured by freezing point depression) or plasma AVP (by radioimmunoassay) may be undetectable yet of extreme physiological importance. For example, a patient with a 24hour urinary solute load of 600 mmol must excrete 6 liters of urine with an osmolality of 100 mmol/kg to eliminate the solute; however, if the urine osmolality increases from 100 to 200 mmol/kg (due to an undetectable rise of 1 mmol in plasma osmolality and 0.38 pg/mL in plasma AVP), the obligatory 24-hour urine volume to excrete the 600 mmol solute load decreases substantially from 6 to 3 liters. Examination of Fig. 7.8 demonstrates that a maximal antidiuresis is obtained when the plasma AVP concentration reaches 5 pg/mL. Greater hyperosmolality, although releasing more AVP, fails to conserve any more renal water, thus exposing the body to the potential of severe dehydration. This can be avoided by the stimulation of the thirst osmoreceptor at a plasma osmolality of 298 mmol/kg. However, recent studies, using a visual analogue scale, have demonstrated that the onset of thirst occurs at a considerably lower plasma osmolality than was previously recognized; the values were similar to those of the threshold for vasopressin release [115,116]. It has been shown in both animals [117] and humans [118–120] that the act of drinking ameliorates thirst and inhibits the secretion of vasopressin before changes occur in

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FIGURE 7.8. Schematic representation of the effect of small alterations in the basal plasma osmolality on (a) plasma vasopressin and (b) urinary osmolality in healthy adults. From Robertson et al. [112].

the extracellular fluid volume or osmolality. In humans, it has been shown that AVP secretion is inhibited independently of osmotic or gastric factors by the activation of the cold-sensitive oropharyngeal receptors [120]. The presence of such cold-sensitive oropharyngeal receptors may explain the desire of severely dehydrated patients, i.e., patients with diabetes insipidus (neurogenic or nephrogenic), for cold liquids. There are considerable variations between individuals in osmoreceptor sensitivity and in the threshold for vasopressin release, however, these individual values remain constant for a relatively short period of time [121]. To determine if these interindividual differences are genetically influenced, Zerbe [121] compared the vasopressin osmolality relationships within monozygotic and dizygotic twin pairs. The threshold and sensitivity values correlated significantly within monozygotes but not within dizygotes, suggesting a genetic determinant for the set of the osmoregulatory system. Pregnancy causes a lowering of the threshold for vasopressin secretion without altering the gain of the osmoreceptors in both rats [122] and humans [123], thus accounting for the hypoosmolality of pregnancy. A role for human chorionic gonadotrophin in lowering this osmotic threshold has been postulated [124]. Vokes and coworkers [125] have demonstrated that osmoreceptor cells are insulin-sensitive, so that during insulin depletion they become impermeable to glucose and thus acquire an osmosensitivity to glucose. Durr et al. [126] pointed out that although glucose impermeability may account for the leftward shift in the AVP/plasma sodium relationship in insulin depletion, it cannot explain the simultaneous rightward shift observed in the AVP/plasma osmolality relationship [125]. Durr et al. [126] examined the respective roles of plasma osmolality and plasma tonicity (corrected or not for their relative cell permeability) in seven patients with diabetic ketoacidosis. They reasoned that decreasing permeability to glucose (s Æ 1) results in cell fasting and ketosis (HCO3- Æ 0). Conversely, improved permeability (s Æ 0) corrects the metabolic acidosis (HCO3Æ 26). An empirical formula for the relative osmoreceptor cell permeability (s) to glucose was derived from the plasma

HCO3- as s = [26 - HCO3-]/26. By using this concept of tonicity instead of osmolality, a three-dimension plot was constructed (Z = AX + BY + C) in which the plasma AVP/sodium and AVP/plasma tonicity curves did not appear displaced. Thus, the increased osmotic and decreased sodium thresholds observed in diabetic ketoacidosis represent analytic artifacts, since they are unaltered when properly analyzed using the tonicity concept [126].

Baroregulation It is now well established that afferent neural impulses arising from stretch receptors in the left atrium, carotid sinus and aortic arch inhibit the secretion of vasopressin. Conversely, when the discharge rate of these receptors is reduced, vasopressin secretion is enhanced (for review, see Goetz et al. [127] and Norsk [128]). Moreover, the relative potency of the cardiac and sino-aortic reflexes in the release of vasopressin appears to vary among species. For example, the increase in plasma vasopressin that occurs during moderate hemorrhage in the dog is attributable primarily to reflex effects from cardiac receptors; sino-aortic receptors appear to exert only minor influences on vasopressin release in this situation. In contrast, sino-aortic receptors appear to play the dominant role in eliciting vasopressin secretion during blood loss in nonhuman primates and humans [128]. In humans, blood pressure reductions of as little as 5%, induced by the ganglion blocking agent trimetaphan, significantly altered plasma AVP concentration [129]. Furthermore, an exponential relationship between plasma vasopressin and the percentage decline in mean arterial blood pressure has been observed with large decreases in blood pressure (Fig. 7.9). Since an interdependence exists between osmoregulated and baroregulated AVP secretion [130] (Fig. 7.10), under conditions of moderate hypovolemia, renal water excretion can be maintained around a lower set-point of plasma osmolality, thus preserving osmoregulation. As hypovolemia becomes more severe, plasma AVP concentrations attain extremely high values and baroregulation overrides the osmoregulatory system. An enhanced osmoreceptor sensitivity, but blunted baroregulation, has been described in elderly subjects [131].

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289

FIGURE 7.10. Schematic representation of the relationship between plasma vasopressin and plasma osmolality in the presence of differing states of blood volume and/or pressure. The line labeled N represents normovolemic normotensive conditions. Minus numbers to the left indicate percent fall, and positive numbers to the right, percent rise in blood volume or pressure. From Robertson [350]. FIGURE 7.9. Increase in plasma arginine vasopressin AVP during hypotension (vertical lines). Note that a large diminution in blood pressure in normal humans induces large increments in AVP. From Vokes and Robertson [349].

Hormonal Influences on the Secretion of Vasopressin

Studies on the direct effects of various peptides and other biological substances on the release of vasopressin may be confounded by the hemodynamic effects of these substances, which indirectly modulate vasopressin release via the cardiovascular reflexes. For example, the infusion of pressor doses of norepinephrine increases both arterial blood pressure and left atrial pressure. Each of these changes is capable of eliciting a reflex inhibition of vasopressin release which should reduce plasma vasopressin. However, the inhibitory effects of the sino-aortic and cardiac reflexes on vasopressin release seem to be offset by the direct stimulatory effect of circulating norepinephrine [127]. A similar situation may exist with the possible stimulation of vasopressin release by angiotensin. The direct stimulatory effect of angiotensin may be offset by inhibitory influences elicited from the cardiovascular reflexes. Angiotensin is a well-known dipsogen and has been shown to cause drinking in all the species tested [132]. Angiotensin II receptors have been described in the SFO and OVLT (for review see [86]). Brooks et al. [133] found that the infusion of exogenous angiotensin II increased vasopressin secretion and altered the baroreflex function in conscious dogs. Philips et al. [134] found that thirst and vasopressin secretion were stimulated in four out of 10 healthy subjects infused with angiotensin II. Furthermore, the AVP concentrations were higher in the responders than in the nonresponders. These effects occurred at plasma angiotensin concentrations that were well above those measured under physiological conditions

associated with thirst and vasopressin secretion such as water deprivation. To further assess the potential importance of angiotensin II in the regulation of vasopressin secretion in man, Morton et al. [135] submitted six normal subjects to a 3-day diet containing 10 mmol of sodium and 60 mmol of potassium per day. The mean cumulative sodium loss (±SD) for the six subjects was 208 ± 94 mmol. Sodium restriction had no effect on serum sodium concentrations. Sodium depletion increased the circulating concentrations of angiotensin II more than fivefold (p < 0.001), but had no effect on plasma AVP concentrations. In short, physiologic concentrations of angiotensin II do not cause an increase in plasma vasopressin concentration in normal subjects. However, the complex interaction between the direct stimulatory and cardiovascular inhibitory influences has not been studied. Of interest, knockout models for angiotensinogen [136] or for AT1A receptor [137,138] did not alter thirst or water balance. Disruption of the AT2 receptor only induced mild abnormalities of thirst post dehydration [139]. Earlier reports suggested that the intravenous administration of atrial peptides inhibits the release of vasopressin [140], but this was not confirmed by Goetz et al. [141]. Furthermore, Ogawa et al. [142] found no evidence that atrial natriuretic peptide, administered centrally or peripherally, was important in the physiologic regulation of plasma AVP release in conscious rats. The presence of endogenous opioid peptides [92–96] and opioid receptors [93] in the neural lobe has led to the suggestion that opioid peptides play a role in the release of neurohypophyseal hormones. It is now recognized that opioid drugs exert their pharmacologic effects through an interaction with specific receptors. These receptors are classified

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into several types: m, d, s and k. m Agonists such as morphine and methadone are responsible for the classical opiate effects of analgesia, respiratory depression, and physical dependence. They typically cause an antidiuresis in hydrated animals and humans [143]. In contrast, k agonists have analgesic properties, but do not cause respiratory depression nor physical dependence at the dose required for analgesia. They have been shown to cause a water diuresis in experimental animals and in humans, probably by the inhibition of vasopressin secretion [144–148]. K opioid agonists could have potential therapeutic benefits in the treatment of hyponatremia secondary to increased AVP secretion. A very rapid and robust release of AVP is seen in humans after cholecystokinin (CCK) injection [149]. Nitric oxide is an inhibitory modulator of the hypothalamo–neurohypophysial system in response to osmotic stimuli [150–153]. Vasopressin secretion is under the influence of a glucocorticoid-negative feedback system [154] and the vasopressin responses to a variety of stimuli (haemorrhage, hypoxia, hypertonic saline) in normal humans and animals appear to be attenuated or eliminated by pretreatment with glucocorticoids. Finally, nausea and emesis are potent stimuli of AVP release in humans and seem to involve dopaminergic neurotransmission [155]. VASOPRESSIN RECEPTORS AND ANTAGONISTS The molecular cloning and characterization of receptors for [Arg8] vasopressin and oxytocin were recently accomplished. The four different receptor subtypes, respectively V1a,V1b,V2 and oxytocin, have been cloned in mammals, lower vertebrates and invertebrates [156–164]. These receptors belong to the G-protein coupled receptor superfamily characterized by seven putative transmembrane helices (see review by Barberis et al. [165]). An extraordinarily large number of neurotransmitters, peptide hormones, neuromodulators, and autocrine and paracrine factors exert their physiological actions via binding to specific plasma membrane receptors that are coupled to distinct classes of heterotrimeric Gproteins [166]. The V1a, V1b, V2, and OT receptors are strikingly similar in both size and amino acid sequence. However, the V1a,V1b, and OT receptors are selectively coupled to Gproteins of the Gq/11 family which mediate the activation of distinct isoforms of phospholipase Cb resulting in the breakdown of phosphoinositide lipids. The V2 receptor, on the other hand, preferentially activates the G-protein, Gs, resulting in the activation of adenylyl cyclase. The classical vascular smooth muscle contraction, platelet aggregation and hepatic glycogenolysis actions of AVP are mediated by the V1a receptor that increases cytosolic calcium. In situ hybridization histochemistry using 35Slabeled cRNA probes specific for the V1a receptor mRNA showed high levels of V1a receptor transcripts in the liver among hepatocytes surrounding central veins and in the

renal medulla among the vascular bundles, the arcuate and interlobular arteries [167]. V1a receptor mRNA was found to be extensively distributed throughout the brain where AVP may act as a neurotransmitter or a neuromodulator in addition to its classical role on vascular tone [168]. Brain AVP receptors have been proposed to mediate the effect of AVP on memory and learning, antipyresis, brain development, selective aggression and partner preference in rodents, cardiovascular responsivity, blood flow to the choroid plexus and cerebrospinal fluid production, regulation of smooth muscle tone in superficial brain vasculature, and analgesia. It is, however, not known whether V1a brain receptors respond to AVP released within the brain proper or whether the receptors also respond to AVP from the peripheral circulation [168]. V1b receptors are not only expressed in the anterior pituitary [161] and kidney [160] as originally reported, but also in brain, uterus, thymus, heart, breast, and lung [163]. The physiologic role of these extrapituitary V1b receptors remains unknown, but some functions of AVP attributed in the past to V1a receptors or OT receptors may be due to the activation of V1b receptors [163]. In the rat adrenal medulla, AVP may regulate the adrenal functions by paracrine/ autocrine mechanisms involving distinct AVP receptor subtypes: V1a in the adrenal cortex and V1b in the adrenal medulla [169]. V2 transcripts are heavily expressed in cells of the renal collecting ducts (in humans and rodents) and in cells of the thick ascending limbs of the loops of Henle (in rodents only) [167]. Consistent with findings obtained with the adrenoreceptors [170] and muscarinic receptors [171], ligand binding to vasopressin receptor is predicted to occur in a pocket formed by the ring-like arrangement of the seven transmembrane domains [172]. This binding pocket may be common to all the different subtypes of this receptor family. It is speculated that the hormone-receptor complex is characterized by an intricate network of hydrogen bond interactions, rather than by a few well-defined points of contact and the agonist-binding site is located in a narrow cleft delimited by the transmembrane domains II to VII, about 15 A° away from the extracellular surface (Fig. 7.11). In addition to residues situated in the transmembrane regions, residues located in the extracellular domains also interact with the hormones (Fig. 7.12). As reviewed [173,174], species specificity and partial agonist activity have frustrated the search to discover antidiuretic hormone receptor antagonists that are effective aquaretic agents in vivo. The compound SKF101926 (desGlyd(CH2)5D-Tyr(Et)VAVP) was shown to be a potent V2 receptor antagonist having aquaretic activity in several animal species, including a primate species. However, SKF101926 lacked aquaretic activity and was a vasopressin agonist in humans [175]. Over the past decade, several orally-active nonpeptide AVP receptor antagonists have been reported [27,176–179]. The orally effective nonpeptide V2

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AVP

7

2

6 3

5

3 1

2

4

4

5 1 7 6 (b)

(a)

FIGURE 7.11. Ribbon representation of the V2 receptor [251]. (a) Side view from a direction parallel to the cell membrane surface. The positioning of the transmembrane domains 1–7 is counterclockwise when viewed from the extracellular surface of the receptor. The model is oriented such that the extracellular side is at the top of the image. (b) An upper view from a direction perpendicular to the outside of the cell membrane surface. His hypothetical model of interaction between AVP and the V2 receptor is constructed according to the model published by Mouillac et al. [172] pertaining to the V1a receptor. These images were produced using the MidasPlus program from the Computer Graphics Laboratory, University of California, San Francisco (supported by NIH RR01081).

antagonists are aquaretic drugs potentially useful to treat various clinical syndromes with abnormal water retention [180–182]. R181

Disulfide bond

R202

MEASUREMENTS OF ARGININEVASOPRESSIN, OXYTOCIN AND THEIR RELATED NEUROHYPOPHYSINS

D103

3

2 V206 4

6

7

AVP-R8

Y205 1 5

F I G U R E 7 . 1 2 . Ribbon representation of the V2 receptor similar to Figure 11(a) showing important exofacial residues. Amino acid residue D103 in the V2 receptor is important for high affinity binding and receptor selectivity; it is shown to be in close contact with residue 8 of AVP (AVP-R8). Replacement of Asp 103 with Tyr or Phe, the amino acids naturally occurring in the human V1a and oxytocin receptors, results in a potent increase in V1a or oxytocin agonist-binding affinities [351]. Missense mutations have occurred at V2 residues 181, 202 and 205 in families with X-linked NDI: arginine to cysteine substitutions (R181C and R202C), and tyrosine to cysteine substitution (Y205C). If these mutants are expressed on the cell surface, these new residues could possibly form additional cysteine bridges and alter the conformation of the V2 receptor.

Three developments were basic to the elaboration of a clinically useful radioimmunoassay for plasma AVP [183,184]: (i) the extraction of AVP from plasma with petrol-ether and acetone and the subsequent elimination of non-specific immunoreactivity; (ii) the use of highly specific and sensitive rabbit antiserum; and (iii) the use of a tracer (125I-AVP) with high specific activity. More than 30 years later, the same extraction procedures are being widely used [77,124,125], and commercial tracers (125I-AVP) and antibodies are available. AVP can also be extracted from plasma by using Sep-Pak C18 cartridges [185–187]. Blood samples collected in chilled 7 ml lavender stoppered tubes containing EDTA are centrifuged at 4°C, 1000 ¥ g (3000 rpm in a usual laboratory centrifuge) for 20 minutes. This 20-minute centrifugation is mandatory for obtaining platelet-poor plasma samples, since a large fraction of the circulating vasopressin is associated with the platelets in humans [77,188]. The tubes may be kept for 2 hours on slushed ice prior to centrifugation. Plasma is then separated, frozen at -20°C, and extracted within 6 weeks of sampling. Details for sample preparation and assay procedure can be found in the articles of Bichet and colleagues [76,77]. An AVP radioimmunoassay should be validated by demonstrating: (i) a good correlation between plasma sodium or osmo-

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lality and plasma AVP during dehydration and infusion of hypertonic saline solution (see Fig. 7.7); and (ii) the inability to obtain detectable values of AVP in patients with severe central diabetes insipidus. It is unlikely that this complicated radioimmunoassay procedure will be replaced by other sensitive methods. A cytochemical assay to measure human plasma AVP, based on the stimulation of Na+-K+ ATPase activity in the outer medulla of the rat kidney, has been published [189]. Unfortunately, during an infusion of hypertonic saline in six normal volunteers, plasma osmolality increased from 286.8 ± 1.7 to 307.6 ± 7.6 mmol/kg, and immunoreactive AVP increased from 1.3 ± 0.2 to 17.7 ± 3.6 pmol/l, but no change in plasma AVP concentrations was observed (2.1 ± 0.9 and 1.9 ± 1.3 pmol/l) [189]. In pregnant patients, the blood contains high concentrations of cystine aminopeptidase which can (in vitro) inactivate enormous quantities (ng ml-1 min-1) of AVP. However, phenanthroline effectively inhibits these cystine aminopeptidases [123]. Urinary AVP has also been shown to correlate to plasma osmolality during hypertonic saline infusion experiments in humans, and similar osmotic thresholds for AVP release have been obtained [190]. Radioimmunoassay measurements of plasma oxytocin have been described by McNeilly et al. [191], Stricker et al. [192] and Jenkins et al. [193]. Plasma concentrations of oxytocin are increased by hypertonicity in rats [194], but not in humans [195,196]. Radioimmunoassays for individual rat neurophysins [197] provided an index of the activity of the magnocellular neurons in a series of experiments by Cheng and North [198–200], but similar extensive evaluation through neurophysin measurements have not been done in humans. HYPOTHALAMIC DIABETES INSIPIDUS Diabetes insipidus is a disorder characterized by the excretion of abnormally large volumes (>30 mL/kg of body weight per day) of dilute urine (<250 mmol/kg). Four basic defects can be involved. The most common, a deficient secretion of the antidiuretic hormone AVP, is referred to as hypothalamic diabetes insipidus. Diabetes insipidus can also result from renal insensitivity to the antidiuretic effect of AVP, which is referred to as nephrogenic diabetes insipidus. Excessive water intake can result in polyuria, which is referred to as primary polydipsia. Finally, increased metabolism of vasopressin during pregnancy is referred to as gestational diabetes insipidus.

Clinical Characteristics of Hypothalamic Diabetes Insipidus Common Forms

Failure to synthesize or secrete vasopressin normally limits maximal urinary concentration and, depending on the severity of the disease, causes varying degrees of polyuria and polydipsia. Experimental destruction of the vasopressinsynthesizing areas of the hypothalamus (supraoptic and para-

ventricular nuclei) causes a permanent form of the disease. Similar results are obtained by sectioning the hypophyseal hypothalamic tract above the median eminence. Sections below the median eminence, however, produce only transient diabetes insipidus. Lesions to the hypothalamicpituitary tract are frequently associated with a three-stage response both in experimental animals and in humans [201]. 1. An initial diuretic phase lasting from a few hours to 5 to 6 days 2. A period of antidiuresis unresponsive to fluid administration. This antidiuresis is probably due to vasopressin release from injured axons and may last from a few hours to several days. Since urinary dilution is impaired during this phase, continued water administration can cause severe hyponatremia 3. A final period of diabetes insipidus. The extent of the injury determines the completeness of the diabetes insipidus, and as already discussed, the site of the lesion determines whether the disease will or will not be permanent. A detailed assessment of water balance following transsphenoidal surgery has been reported [202]. One hundred and one patients who underwent transsphenoidal pituitary surgery at the National Institutes of Health Clinical Center were studied. Twenty five percent of the patients developed spontaneous isolated hyponatremia, 20% developed diabetes insipidus and 46% remained normonatremic. Normonatremia, hyponatremia and diabetes insipidus were associated with increasing degrees of surgical manipulation of the posterior lobe and pituitary stalk during surgery. The etiologies of central diabetes insipidus in adults and in children are listed in Table 7.4 [203,204]. No underlying pathologic condition (idiopathic form) could be recognized in 12 to 29% of the child and adult cases. Rare causes of central diabetes insipidus include leukemia, thrombotic thrombocytopenic purpura, pituitary apoplexy, sarcoidosis and Wegener’s granulomatosis [205]. A distinctive syndrome Table 7.4. Etiology of hypothalamic diabetes insipidus in children and adults*

Primary brain tumor Before surgery After surgery Idiopathic (isolated or familial) Histiocytosis Metastatic cancer Trauma Postinfectious disease

Children (%)

Adults (%)

49.5 33.5 16.0 29.0 16.0 – 2.2 2.2

30 13 17 25 – 8 17 –

* Data from Czernichow et al. [203], Greger et al. [204], and Moses et al. [205]. See also [381].

Chapter 7

characterized by early diabetes insipidus with subsequent progressive spastic cerebellar ataxia has also been described [206]. Five patients who all presented with central diabetes insipidus and hypogonadism as first manifestations of neurosarcoidosis have been reported [207]. Finally, circulating antibodies to vasopressin do not play a role in the development of diabetes insipidus [208]. Antibodies to vasopressin occasionally develop during treatment with ADH and, when they do, almost always result in secondary resistance to its antidiuretic effect [208,209]. Rare Forms: Autosomal Dominant Central Diabetes Insipidus and the DIDMOAD Syndrome (Wolfram Syndrome)

In 1945, Forssman described a “pituitrin-sensitive” familial polyuric state with X-linked inheritance [210,211]. However, no other cases of familial X-linked hypothalamic diabetes insipidus have been described. Most of the reported cases of familial central diabetes insipidus were transmitted through an autosomal dominant pattern [211,212]. As discussed earlier, mutations in the AVP-NPII gene are responsible for the AVP deficiency (see expression of the vasopressin gene in autosomal dominant and autosomal recessive diabetes insipidus in humans, pp. 281–284). In autosomal dominant central diabetes insipidus, the polyuria– polydipsia symptoms usually occur after the first year of life, and some limited capacity to release vasopressin can be demonstrated. As a consequence, no severe episodes of dehydration have been described in the affected individuals during their first year of life. The physical and mental development of the affected children are normal. These characteristics are in sharp contrast to those of congenital nephrogenic diabetes insipidus, an X-linked disorder, which can lead to repeated episodes of severe dehydration and eventual mental retardation if left untreated. Young children with autosomal recessive central diabetes insipidus are also at risk for early dehydration episodes [64]. The acronym DIDMOAD describes the following clinical features of a syndrome: diabetes insipidus, diabetes mellitus, optic atrophy, sensorineural deafness [213,214]. An unusual incidence of psychiatric symptoms has also been described in these subjects [215]. These included paranoid delusions, auditory or visual hallucinations, psychotic behavior, violent behavior, organic brain syndrome typically in the late or preterminal stages of their illness, progressive dementia, severe learning disabilities or mental retardation or both. The syndrome is an autosomal recessive trait, the diabetes insipidus is usually partial and of gradual onset [214], and the polyuria can be wrongly attributed to poor glycemic control. Furthermore, a severe hyperosmolar state can occur if untreated diabetes mellitus is associated with an unrecognized pituitary deficiency. The dilatation of the urinary tract observed in the DIDMOAD syndrome may be secondary to chronic high urine flow rates and, perhaps, to some degenerative aspects of the innervation of the urinary tract [213]. Wolfram syndrome (OMIM 222300) [36] is secondary to mutations in the WFS1 gene (chromosome

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region 4p16), which codes for a transmembrane protein expressed in various tissues including brain and pancreas [216–218]. Syndrome of Hypernatremia and Hypodipsia

Some patients with the hypernatremia and hypodipsia syndrome may have partial central diabetes insipidus [219]. These patients also have persistent hypernatremia, which is not due to any apparent extracellular volume loss; absence or attenuation of thirst; and a normal renal response to AVP. In almost all the patients studied to date, the hypodipsia has been associated with cerebral lesions in the vicinity of the hypothalamus. It has been proposed that in these patients there is a “resetting” of the osmoreceptor, because their urine tends to become concentrated or diluted at inappropriately high levels of plasma osmolality. However, by using the regression analysis of plasma AVP concentration versus plasma osmolality, it has been possible to show that in some of these patients the tendency to concentrate and dilute urine at inappropriately high levels of plasma osmolality is due solely to a marked reduction in sensitivity or a gain in the osmoregulatory mechanism. This finding is compatible with the diagnosis of partial central diabetes insipidus. In other patients, however, plasma AVP concentrations fluctuate randomly, bearing no apparent relationship to changes in plasma osmolality. Such patients frequently display large swings in serum sodium concentrations and frequently exhibit hypodipsia. It appears that most patients with essential hypernatremia fit one of these two patterns (Fig. 7.13). Both of these groups of patients consistently respond normally to nonosmolar AVP release signals, such as hypotension, emesis, or hypoglycemia or all three. These observations suggest that the osmoreceptor may be anatomically as well as functionally separate from the nonosmotic efferent pathways and neurosecretory neurons for vasopressin. Furthermore, a hypothalamic lesion may impair the osmotic release of AVP while the nonosmotic release of AVP remains intact, and the osmoreceptor neurons that regulate vasopressin secretion are not totally synonymous with those that regulate thirst, although they appear to be anatomically close if not overlapping.

Differential Diagnosis of Polyuric States The first step in the action of AVP on water excretion is its binding to V2 receptors on the basolateral membrane of the collecting duct cells. The human V2 receptor gene, AVPR2, is located in chromosome region Xq28 and has three exons and two small introns [156,220]. The sequence of cDNA predicts a polypeptide of 371 amino acids with a structure typical of guanine-nucleotide (G) protein-coupled receptors with seven transmembrane, four extracellular, and four cytoplasmic domains [166]. The activation of the V2 receptor on renal collecting tubules stimulates adenylyl cyclase via the stimulatory G protein (Gs) and promotes the cAMP mediated incorporation of water pores into the

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luminal surface of these cells. This is the molecular basis of the AVP-induced increase in the osmotic water permeability of the apical membrane of the collecting tubule. Nephrogenic Diabetes Insipidus (NDI)

In NDI, the kidney is unable to concentrate urine despite normal or elevated concentrations of the antidiuretic hormone arginine vasopressin (AVP). In congenital NDI, the obvious clinical manifestations of the disease, that is polyuria and polydipsia, are present at birth and need to be immediately recognized to avoid severe episodes of dehy-

dration. Most (>90%) of congenital NDI patients have mutations in the AVPR2 gene, the Xq28 gene coding for the vasopressin V2 (antidiuretic) receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive inheritance and mutations have been identified in the aquaporin-2 gene (AQP2) located in chromosome region 12q13, i.e. the vasopressin-sensitive water channel. Eighty-five different putative disease-causing mutations in the AVPR2 gene have now been published in 123 unrelated families with X-linked nephrogenic diabetes insipidus (Fig. 7.14). When studied in vitro, most AVPR2 mutations

FIGURE 7.13. Plasma vasopressin as a function of “effective” plasma osmolality in two patients with adipsic hypernatremia. Unfilled circles indicate values obtained on admission; filled squares indicate those obtained during forced hydration; filled triangles indicate those obtained after 1 to 2 weeks of ad libitum water intake. Shaded areas indicate range of normal values. From Robertson [346].

FIGURE 7.14. Schematic representation of the V2 receptor and identification of 85 AVPR2 mutations which include 42 missense, 11 nonsense, 23 frameshift, three inframe deletions, one splice-site, and five large deletion mutations. The five large deletions (240, 352, 353) are incompletely characterized and are not included in the figure. Predicted amino acids are given as the one letter code. Solid symbols indicate the predicted location of the mutations; a number indicates more than one mutation in the same codon. The names of the mutations were assigned according to the conventional nomenclature. The extracellular, transmembrane and cytoplasmic domains are defined according to Mouillac et al. [Mouillac, 1995 #22]. The extracellular (EI to EIV), cytoplasmic (CI to CIV) and transmembrane domains (TMI to TMVII) are labeled from the N-terminus to the C-terminus according to Sharif and Hanley [354]. EI: 85delC (codon changed is S5) [249]. 97-24del69;97-59ins6;34bp inv (codon changed is A9) [355]. 97ins28 (previously labelled 98ins28, codon changed is A9) [356, 357]. 98del28 (codon changed is A9) [356]. 113delCT (codon changed is P14) [240]. TMI: L43P [249], L44F [358], L44P [359], L53R [356]. CI: 253del35 (codon changed is A61) [240], L62P [358], 255del9 (codon changed is L62) [240], 273insG (previously called 274insG, codon changed is R68) [240], W71X [238, 239]. TMII: H80R [249, 360], 314ins9 (codon changed is C82) [355], L83P [356], D85N [250, 358], V88M [240, 353, 358], 337delCT (codon changed is A89) [352], P95L [356]. EII: R106C [240], G107E [249]. TMIII: 402delCT (codon changed is L111) [240], C112R [240], R113W [238, 358, 361, 362], 409delG (codon changed is R113) [355], Q119X [363], Y124X [240], S126F [240], Y128S [240, 363, 364]. CII: A132D [365], R137H [238, 240, 366], R143P [367], A147V [240, 249], 528delG (codon changed is G153) [360], 528del7 (codon changed is G153) [358]. TMIV: W164S [240], S167L [240, 356, 358], S167T [359]. EIII: R181C [240, 358, 363], G185C [368], W193X [249], R202C [240, 249, 362, 368, 369], T204N [358], 684delTA (codon changed is Y205) [240], Y205C [249, 356, 368, 370]. TMV: V206D [358], T207N [355], L219R [352], L219P [355], Q225X [358]. CIII: 753insC (codon changed is I228) [371], E231X [357], 763delA (codon changed is E231) [363], 786delG (codon changed is G239) [372], E242X [356], 804delG (codon changed is G245) [365], 803insG (previously called 804insG, codon changed is G245) [224, 240, 367], 834delA (codon changed is S255) [356], 855delG (codon changed is V262) [373]. TMVI: V277A [362], DV278 [364, 366, 367], Y280C [362, 374], 911del5 (codon changed is A285) [355], W284X [240], A285P [240], P286R [363], P286L [364], L292P [362], W293X [240]. TMVII: 977delG (codon changed is L302) [358], 982-2A Æ G (first codon changed is G304) [356], L309P [366], 1001delC (codon changed is L310) [375], L312X [238], P322S [249, 372], P322H [372], W323R [356]. CIV: R337X [240, 249, 358, 362]. Whereas deletions and insertions can be attributed to slipped mispairing during DNA replication favored by direct repeats, complementary repeats and symmetric sequences in the vicinity of the mutation, more than 50% of the single base substitutions can be explained by mutations in CpG dinucleotides, which are hot spots for genetic disease and which are relatively common in the human V2 receptor gene [240]. See also http://www.medicine.mcgill.ca/nephros/.

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lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A minority of the mutant receptors reach the cell surface but are unable to bind AVP or to trigger and intracellular cAMP signal. Similarly AQP2 mutant proteins are trapped intracellularly and cannot be expressed at the luminal membrane. AVPR2 and AQP2-trafficking defects are correctable, at least in vitro, by pharmacological or chemical chaperones [63,221,222]. Loss of Function Mutations of the AVPR2

X-linked nephrogenic diabetes insipidus (OMIM 304800) [36] is secondary to AVPR2 mutations which result in a loss of function or dysregulation of the V2 receptor [223]. Males who have an AVPR2 mutation have a phenotype characterized by early dehydration episodes, hypernatremia and hyperthermia as early as the first week of life. Dehydration episodes can be so severe that they lower arterial blood pressure to a degree that is not sufficient to sustain adequate oxygenation to the brain, kidneys, and other organs. Mental and physical retardation and renal failure are the classical “historic” consequences of a late diagnosis and lack of treatment. Heterozygous females exhibit variable degrees of polyuria and polydipsia because of skewed X chromosome inactivation [224]. Clinical Characteristics The “historic” clinical characteristics include hypernatremia, hyperthermia, mental retardation, and repeated episodes of dehydration in early infancy [225–228]. Mental retardation, a consequence of repeated episodes of dehydration, was prevalent in the Crawford and Bode study [225], in which only nine of 82 patients (11%) had normal intelligence. Early recognition and treatment of X-linked NDI with an abundant intake of water allows a normal lifespan with normal physical and mental development [229]. Two characteristics suggestive of X-linked NDI are the familial occurrence and the confinement of mental retardation to male patients. It is then tempting to assume that the family described in 1892 by McIlraith [230] and discussed by Reeves and Andreoli [231] was an X-linked NDI family. The early symptoms of the nephrogenic disorder and its severity in infancy is clearly described by Crawford and Bode [225]. The first manifestations of the disease can be recognized during the first week of life. The infants are irritable, cry almost constantly, and, although eager to suck, will vomit milk soon after ingestion unless prefed with water. The history given by the mothers often includes persistent constipation, erratic unexplained fever, and failure to gain weight. Even though the patients characteristically show no visible evidence of perspiration, increased water loss during fever or in warm weather exaggerates the symptoms. Unless the condition is recognized early, children experience frequent bouts of hypertonic dehydration, sometimes complicated by convulsions or death; mental retardation is a frequent consequence of these episodes.

The intake of large quantities of water, combined with the patient’s voluntary restriction of dietary salt and protein intake, lead to hypocaloric dwarfism beginning in infancy. Frequently, lower urinary tract dilatation and obstruction, probably secondary to the large volume of urine produced [232], develop in affected children. Dilatation of the lower urinary tract is also seen in primary polydipsic patients and in patients with neurogenic diabetes insipidus [233, 234]. Chronic renal insufficiency may occur by the end of the first decade of life and could be the result of episodes of dehydration with thrombosis of the glomerular tufts [225]. Rareness and Diversity of AVPR2 Mutations We estimated the incidence of X-linked NDI in the general population from patients born in the province of Quebec (Canada) during the 10-year period, 1988–97, to be approximately 8.8 per million (SD = 4.4 per million) male live births [235]. Thus, X-linked NDI is generally a rare disorder. By contrast, NDI was known to be a common disorder in Nova Scotia (Canada) [236]. Thirty affected males who resided mainly in two small villages with a total population size of 2500 [237] are descendants of members of the Hopewell pedigree studied by Bode and Crawford [236] and carry the nonsense mutation, W71X [238,239]. This is the largest known pedigree with X-linked NDI and has been referred to as the Hopewell kindred, named after the Irish ship Hopewell, which arrived in Halifax in 1761 [236]. Descendants of Scottish Presbyterians, who migrated to the Ulster Province of Ireland in the 17th century, emigrated from Ireland in 1718 and settled in northern Massachusetts. A later group of immigrants were passengers on the ship Hopewell and settled in Colchester County, Nova Scotia. Members of the two groups were subsequently united in Colchester County [236]. Thus, it is likely that Ulster Scot immigrants, perhaps on more than one occasion, brought the W71X mutation to North America. To date, we have identified the W71X mutation in 38 affected males who predominantly reside in the Maritime provinces of Nova Scotia and New Brunswick. We estimated the incidence in these two Maritime provinces to be 6/104,063 or approximately 58 per million (SD = 24 per million) male live births for the 10-year period, 1988–97. We have identified 82 different mutations in 117 NDI families referred to our laboratory [235]. Half of the mutations are missense mutations. Frameshift mutations due to nucleotide deletions or insertions (27%), nonsense mutations (11%), large deletions (5%), inframe deletions or insertions (4%), splice-site mutations (2%), and one complex mutation account for the remainder of the mutations. Mutations have been identified in every domain, but on a per nucleotide basis, about twice as many mutations occur in transmembrane domains compared to the extracellular or intracellular domains. We previously identified private mutations, recurrent mutations and mechanisms of mutagenesis [240,241]. The 10 recurrent mutations (D85N,V88M, R113W,Y128S,

Chapter 7

R137H, S167L, R181C, R202C, A294P, and S315R) were found in 35 ancestrally independent families [235]. The occurrence of the same mutation on different haplotypes was considered as evidence for recurrent mutation. In addition, the most frequent mutations D85N,V88N, R113W, R137H, S167L, R181C, and R202C occurred at potential mutational hotspots (a C-to-T or G-to-A nucleotide substitution occurred at a CpG dinucleotide). The diversity of AVPR2 mutations found in many ethnic groups (Caucasians, Japanese, Afro-Americans, Africans) and the rareness of the disease is consistent with an X-linked recessive disease that in the past was lethal for male patients and was balanced by recurrent mutations. In X-linked NDI, loss of mutant alleles from the population occurs because of the higher mortality of affected males compared with healthy males, whereas gain of mutant alleles occurs by mutation. If affected males with a rare X-linked recessive disease do not reproduce and if mutation rates are equal in mothers and fathers, then, at genetic equilibrium, onethird of new cases of affected males will be due to new mutations. Expression Studies The classification of defects of mutant V2 receptors is based on that of the LDL receptors [242]. Type 1 receptors reach the cell surface but have impaired binding; consequently, they are unable to induce normal cAMP stimulation. The presence of mutant V2 receptors on the cell surface of the transfected cells is usually demonstrated by transiently transfecting mammalian cells with an expression vector containing an epitope-tagged receptor cDNA. This epitope-tagging allows easy immunodetection of the expressed receptors by immunofluorescence in whole-cell studies or by immunoblot analysis of membrane preparations. The binding of tritiated AVP to mutant V2 receptors expressed on the cell membrane has been used to assess the number of receptors transfected and their binding affinities compared to that of normal receptors. Type 2 mutant receptors have defective intracellular transport. This is indirectly demonstrated by their absence on the plasma membrane in addition to the identification and quantification of abnormal species membrane preparations. It is likely that this group of mutant receptors accumulates in a pre-Golgi compartment, are degraded, and do not reach the cell surface. Type 3 mutant receptors are ineffectively transcribed. This subgroup seems to be rare, since Northern blots usually reveal normal and mutant V2 receptor mRNA to be of identical sizes and similar amount. Most of the mutant V2 receptors tested were not transported to the cell membrane and were thus retained within the intracellular compartment (type 2). For example, of the 12 mutants that we tested (N55H, L59P, L83Q, V88M, 497CCÆGG, DR202, I209F, 700delC, 908insT, A294P, P322H, P322S) only three (DR202, P322S and P322H) were detected on the cell surface. Similarly, the 10 mutant receptors (Y128S, E242X, 803insG, 834delA, DV278, Y280C, W284X, L292P, W293X, L312Y) tested by Schöneberg et

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al. [243,244] did not reach the cell membrane and were trapped in the interior of the cell. Similar results for the following mutants were obtained: L44F, L44P, W164S, S167L, S167T [245]; R143P, DV278 [246]; Y280C, L292P, R333X [247]. Schöneberg et al. [243,244] pharmacologically rescued truncated or missense V2 receptors by coexpression of a polypeptide consisting of the last 130 amino acids of the V2 receptor in COS-7 cells. Four of the six truncated receptors (E242X, 804delG, 834delA and W284X) and the missense mutant Y280C, regained considerable functional activity, as demonstrated by an increase in the number of binding sites and stimulation of adenylyl cyclase activity but the absolute number of expressed receptors at the cell surface remained low and the precise mechanism of the rescue phenomenon (dimerization?) [248] was unclear. Most of the loss-of-function mutations secondary to AVPR2 missense mutations are unlikely to be improved by this coexpression strategy and delivery of the gene transfer vehicle is a major unresolved problem. We have shown that selective, non-peptide V2 receptor antagonists dramatically increased cell surface expression and rescued the function of eight different mutant V2 receptors by promoting their proper folding and maturation [222]. Pharmacological chaperones may offer a new therapeutic approach to several different diseases resulting from errors in protein kinesis [63]. Only three AVPR2 mutations (D85N, G201D, P322S) have been associated with a mild phenotype [249,250]. In general, the male infants bearing these mutations are identified later in life and the “classical” episodes of dehydration are less severe. This mild phenotype is also found in expression studies: the mutant proteins are expressed on the plasma membrane of cells transfected with these mutants and demonstrate a stimulation of cAMP for higher concentrations of agonists [250,251]. Benefits of Genetic Testing and the Difficult First Two Years of Males Bearing AVPR2 Mutations The identification of the molecular defect underlying X-linked NDI is of immediate clinical significance because early diagnosis and treatment of affected infants can avert the physical and mental retardation resulting from repeated episodes of dehydration. Diagnosis of X-linked NDI was accomplished by mutation testing of chorionic villous samples (n = 4), cultured amniotic cells (n = 5) or cord blood (n = 17). Three infants who had mutation testing done on amniotic cells (n = 1) or chorionic villous samples (n = 2) also had their diagnosis confirmed by cord blood testing. Of the 23 offspring tested, 12 were found to be affected males, seven were unaffected males and four were non-carrier girls (Bichet et al. unpublished). The affected males were immediately treated with abundant water intake, a low sodium diet and hydrochlorothiazide. They have not experienced severe episodes of dehydration and their physical and mental development remains normal, however, their urinary output is only decreased by 30% and a normal growth curve is still difficult to reach during the

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first 2 to 3 years of their life, despite the above treatments and intensive attention! Water should be offered every 2 hours day and night, and temperature, appetite and growth should be monitored. Admission to hospital may be necessary for continuous gastric feeding. The voluminous amounts of water kept in patients’ stomachs will exacerbate physiologic gastrointestinal reflux as an infant and toddler, and many affected boys frequently vomit and have a strong positive “Tuttle test” (esophageal pH testing). These young patients often improve with the absorption of an H-2 blocker and with metoclopramide (which could induce extrapyramidal symptoms) or with domperidone, which seems to be better tolerated and efficacious. Loss of Function Mutations of AQP2 (OMIM 107777) (36)

On the basis of phenotypic characteristics of both males and females affected with NDI and dDAVP infusion studies, a non-X-linked form of NDI with a postreceptor defect was suggested [252–254]. In contrast to males affected with Xlinked NDI [255,256], two males and two females with NDI experienced a normal increase, for example, two- to threefold, in plasma concentrations of factor VIII and von Willebrand factor after dDAVP infusion, but urinary osmolality remained low [257]. X-linked NDI was excluded for two sisters with vasopressin-resistant hypotonicity because they inherited different alleles of an Xq28 marker from their mother; autosomal recessive inheritance was suggested on the basis of gender, parental consanguinity, and normal urine concentration in the parents [253]. In 1993, the cloning of the cDNA that encodes a water channel in the rat and its exclusive expression in the collecting duct provided a strong candidate gene for non X-linked NDI [258]. The cDNA and gene of the human homologue, designated AQP2, was cloned and two missense mutations were found in a male NDI patient [259–261]. The AQP2 gene is located in chromosome region 12q13. Males and females affected with congenital NDI have been described who are homozygous for a mutation in the AQP2 gene or carry two different mutations ([249,260,262–265]; Fig. 7.15). The oocytes of the African clawed frog Xenopus have provided a most useful test bed for looking at the functioning of many channel proteins. Oocytes are large cells which are just about to become mature eggs ready for fertilization. They have all the normal translation machinery of living cells and so they respond to the injection of mRNA

by making the protein for which it codes. Functional expression studies showed that Xenopus oocytes injected with mutant cRNA had abnormal coefficient of water permeability, whereas Xenopus oocytes injected with both normal and mutant cRNA had coefficient of water permeability similar to that of normal constructs alone. These findings provide conclusive evidence that NDI can be caused by homozygosity for mutations in the AQP2 gene. A patient with a partial phenotype has also been described to be a compound heterozygote for the L22V and C181W mutations [265]. Immunolocalization of AQP2-transfected CHO cells showed that the C181W mutant had an endoplasmic reticulum-like intracellular distribution, whereas L22V and wild-type AQP2 showed endosome and plasma membrane staining. The authors suggested that the L22V mutation was key to the patient’s unique response to dDAVP. The leucine 22 residue might be necessary for proper conformation or for binding of another protein important for normal targeting and trafficking of the molecule. More recently, we obtained evidence to suggest that both autosomal dominant and autosomal recessive NDI phenotypes could be secondary to novel mutations in the AQP2 gene [266]. Reminiscent of expression studies done with AVPR2 proteins, Mulders, Deen, Tamarappo and Verkman also demonstrated that the major cause underlying autosomal recessive NDI is the misrouting of AQP2 mutant proteins [221,264,267]. To determine whether the severe AQP2-trafficking defect observed with the naturally occurring mutations T126M, R187C, and A147T is correctable, cells were incubated with the chemical chaperone glycerol for 48 hours. Redistribution of AQP2 from the ER to the membrane–endosome fractions was observed by immunofluorescence. This redistribution was correlated to improved water permeability measurements [221]. It will be important to correct this defective AQP2-trafficking in vivo. In contrast to the AQP2 mutations in autosomal recessive NDI, which are located throughout the gene, the dominant mutations are predicted to affect the carboxyl terminus of AQP2 [268] (DG Bichet unpublished data). One dominant mutation, E258K, has been analyzed in detail in vitro; AQP2-E258K reduced water permeability compared to wild-type AQP2 [266]. In addition, AQP2-E258K was retained in the Golgi apparatus, which differs from mutant AQP2 in recessive NDI that is retained in the endoplasmic reticulum. The dominant action of AQP2 mutations can be

FIGURE 7.15. (a) Schematic representation of the aquaporin-2 protein and identification of 14 AQP2 mutations. A monomer is represented with six stretches of hydrophobic sequences that are suggestive of six transmembrane helices. The MIP proteins (see text) share an NPA (Asn-Pro-Ala) motif in each of the two prominent loops. AQP1 (and by analogy AQP2) is a homotetramer containing four independent aqueous channels. The location of the protein kinase A phosphorylation site is indicated. This site is possibly involved in the vasopressin-induced trafficking of AQP2 from intracellular vesicles to the plasma membrane and in the subsequent stimulation of endocytosis [376,377]. The extracellular, transmembrane and cytoplasmic domains are defined according to Deen et al. (260). Similar to Fig. 7.3, solid symbols indicate the predicted location of the mutations. TMI: L22V [265], CII: G64R [262], N68S [264], R85X [249]. TMIII: G100X [263]. EII: 369delC [262], T126M [264]. TMIV: A147T [264]. TMV: V168M [249]. EIII: C181W [265], R187C [260, 262], W202C [375]. TMVI: S216P [249, 260]. CIV: E258K [266]. (b) A surface-shaded representation of the six-helix barrel of the AQP1 protein viewed parallel to the bilayer (modified from [378], with permission). For a description of new mutations see [379].

(a)

(b)

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explained by the formation of heterotetramers of mutant and wild-type AQP2 that are impaired in their routing after oligomerization [269]. Acquired

The acquired form of nephrogenic diabetes insipidus is much more common than the congenital form of the disease, but it is rarely severe. The ability to elaborate a hypertonic urine is usually preserved despite the impairment of the maximal concentrating ability of the nephrons. Polyuria and polydipsia are therefore moderate (3–4 L/day). The more common causes of acquired nephrogenic diabetes insipidus are listed in Table 7.5. Lithium administration has become the most common cause of nephrogenic diabetes insipidus. Boton et al. [270] reported that this abnormality was estimated to be present in at least 54% of 1105 unselected patients on chronic lithium therapy. Nineteen percent of these patients had Table 7.5. insipidus

Acquired causes of nephrogenic diabetes

Chronic renal disease

Polycystic disease Medullary cystic disease Pyelonephritis Ureteral obstruction Far-advanced renal failure

Electrolyte disorders

Hypokalemia Hypercalcemia

Drugs

Alcohol Phenytoin Lithium Demeclocycline Acetohexamide Tolazamide Glyburide Propoxyphene Amphotericin Methoxyflurane Norepinephrine Vinblastine Colchicine Gentamicin Methicillin Isophosphamide Angiographic dyes Osmotic diuretics Furosemide and ethacrynic acid

Sickle cell disease Dietary abnormalities

Miscellaneous

Excessive water intake Decreased sodium chloride intake Decreased protein intake Multiple myeloma Amyloidosis Sjogren’s disease Sarcoidosis

polyuria, as defined by a 24-hour urine output exceeding 3 liters. The mechanism whereby lithium causes polyuria has been extensively studied. Lithium has been shown to inhibit adenylate cyclase in a number of cell types, including renal epithelia [271,272]. The concentration of lithium in the urine of patients on well-controlled lithium therapy (i.e., 10–40 mmol/l) is sufficient to inhibit adenylate cyclase. Measurements of adenylate cyclase activity in membranes isolated from a cultured pig kidney cell line (LLC-PK1) revealed that lithium in the concentration area of 10 mmol/l interfered with the hormone-stimulated guanyl nucleotide regulatory unit (Gs) [273]. The effect of chronic lithium therapy has been studied in rat kidney membranes prepared from the inner medulla. It caused a marked downregulation of AQP2, only partially reversed by cessation of therapy, dehydration or dDAVP treatment, consistent with clinical observations of slow recovery from lithium-induced urinary concentrating defects [274]. Downregulation of AQP2 has also been shown to be associated with the development of severe polyuria due to other causes of acquired NDI (hypokalemia [275], release of bilateral ureteral obstruction [276], and hypercalciuria [277]). Thus, AQP2 expression is severely downregulated in both congenital [278] and acquired NDI. More studies will be needed to determine whether non-peptide vasopressin agonists, permeable cAMP-like compounds or other signaling molecules will be able to restore AQP2 expression and function. In patients receiving long-term lithium therapy, amiloride has been proposed to prevent the uptake of lithium in the collecting ducts. Amiloride may thus prevent the inhibitory effect of intracellular lithium on water transport [279]. Primary Polydipsia

Primary polydipsia, a state of hypotonic polyuria secondary to excessive fluid intake, was extensively studied by Barlow and de Wardener in 1959 (280). However, the understanding of the pathophysiology of this disease has made little progress over the past 30 years. Barlow and de Wardener described seven women and two men who were compulsive water drinkers; their ages ranged from 48 to 59 years except for one patient aged 24. Eight of these patients had histories of psychological disorders which ranged from delusions, depression, and agitation to frank hysterical behavior. The other patient appeared normal. The consumption of water fluctuated irregularly from hour to hour or from day to day; in some patients there were remissions and relapses lasting several months or longer. In eight patients, the mean plasma osmolality was significantly lower than normal. Vasopressin tannate in oil made most of these patients feel ill; in one, it caused overhydration. In four patients the fluid intake returned to normal after electroconvulsive therapy or a period of continuous narcosis; the improvement in three was transient, but in the fourth patient it lasted 2 years. Compulsive water drinking can also occur in infants and leads to a partial nephrogenic diabetes pattern [281]. Psychotic patients with polydipsia and hyponatremia will be

Chapter 7

described later in this chapter (Table 7.8). At present, there are no clinical or biologic features in patients with primary polydipsia that could be used diagnostically. Therefore, the diagnosis of compulsive water drinking must still be done by exclusion. Polyuric States During Pregnancy

Pregnancy in a Patient Known to have Diabetes Insipidus An isolated deficiency of vasopressin without a concomitant loss of hormones in the anterior pituitary does not result in altered fertility and, with the exception of polyuria and polydipsia, gestation, delivery and lactation are uncomplicated [282]. Treated patients may require increasing dosages of dDAVP. The increased thirst may be due to a resetting of the thirst osmostat [123]. Increased polyuria also occurs during pregnancy in patients with partial nephrogenic diabetes insipidus. These patients may be heterozygous for an AVPR2 mutation [235] or may have autosomal dominant AQP2 mutation ([266], DG Bichet, personal observation). Syndromes of Diabetes Insipidus that Begin During Gestation and Remit after Delivery

Barron and coworkers [283] described three pregnant women in whom transient diabetes insipidus developed late in gestation and remittted postpartum. In one of these patients dilute urine was present despite high plasma concentrations of AVP. Hyposthenuria in all three patients was resistant to administered aqueous vasopressin. Since excessive vasopressinase activity was not excluded as a cause of this disorder, Barron and colleagues labeled the disease vasopressin resistant rather than nephrogenic diabetes insipidus. A well-documented case of enhanced activity of vasopressinase involved a woman in the third trimester of a previously uncomplicated pregnancy [284]. She had massive polyuria and markedly elevated plasma vasopressinase activity. The polyuria did not respond to large intravenous doses of AVP but responded promptly to dDAVP, a vasopressinaseresistant analogue of AVP. The polyuria vanished with the disappearance of the vasopressinase [284]. Finally, unmasking of subclinical forms of both nephrogenic and hypothalamic diabetes insipidus has been described during pregnancy [285]. It is suggested that pregnancy is associated with several different forms of diabetes insipidus, including hypothalamic, nephrogenic and vasopressinase mediated. Dipsogenic Diabetes Insipidus

GL Robertson has described a selective defect in the osmoregulation of thirst [286]. Under basal conditions of ad libitum water intake, all three patients had thirst, polydipsia and polyuria. Urine output ranged from 6 to 17 L/day and urine osmolality was appropriately low. However, basal plasma osmolality and sodium were not suppressed, as might be expected in primary polydipsia. When treated with dDAVP, water intake decreased slightly less than urine volume. As a consequence, all three patients went into

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positive water balance as evidenced by an excessive fall in plasma osmolality and a rise in body weight. In each case, these changes significantly exceeded those observed under identical conditions of treatment in patients with uncomplicated neurogenic diabetes insipidus. During a standard waterload (20 mL/km) and hypertonic saline infusion, all the patients demonstrated a normal stimulation of AVP. However, the osmotic threshold for thirst was abnormally low. In each case, this estimated osmotic threshold for water intake was well below that found for AVP release and lower than that found in patients with uncomplicated neurogenic diabetes insipidus. It is of interest that out of the 129 patients with polyuria and polydipsia studied by Robertson, dipsogenic diabetes insipidus has been diagnosed in eight and suspected in another seven who had thirst, polyuria and polydipsia in the absence of any significant defect in either the secretion or action of vasopressin.

Testing Plasma sodium and osmolality are maintained within normal limits (136–143 mmol/l for plasma sodium, 275– 290 mmol/km for plasma osmolality) by a thirst-ADH-renal axis. Thirst and ADH, both stimulated by increased osmolality, have been termed a “double-negative” feedback system [287]. Thus, even when the ADH limb of this “doublenegative” regulatory feedback system is lost, the thirst mechanism still preserves the plasma sodium and osmolality within the normal range but at the expense of pronounced polydipsia and polyuria. Thus, the plasma sodium concentration or osmolality of an untreated patient with diabetes insipidus may be slightly higher than the mean normal value, but since the values usually remain within the normal range, these small increases have no diagnostic significance. Theoretically, it should be relatively easy to differentiate between central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia. A comparison of the osmolality of urine obtained during dehydration from patients with central diabetes insipidus or nephrogenic diabetes insipidus with that of urine obtained after the administration of AVP should reveal a rapid increase in osmolality only in the patients with central diabetes insipidus. Urinary osmolality should increase normally in response to moderate dehydration in patients with primary polydipsia. However, these distinctions may not be as clear as expected because of several factors [288]. First, chronic polyuria of any etiology interferes with the maintenance of the medullary concentration gradient, and this “washout” effect diminishes the maximum concentrating ability of the kidney. The extent of the blunting varies in direct proportion to the severity of the polyuria and is independent of its cause. Hence, for any given level of basal urine output, the maximum urinary osmolality achieved in the presence of saturating concentrations of AVP is depressed to the same extent in patients with primary polydipsia, central diabetes insipidus and nephrogenic diabetes insipidus (Fig. 7.16).

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Second most patients with central diabetes insipidus maintain a small, but detectable, capacity to secrete AVP during severe dehydration, and urinary osmolality may then rise above plasma osmolality. Third, many patients with acquired nephrogenic diabetes insipidus have an incomplete deficit in AVP action, and concentrated urine could again be obtained during dehydration testing. Finally, all polyuric states (whether central, nephrogenic or psychogenic) can induce large dilatations of the urinary tract and bladder [233,234]. As a consequence, the urinary bladder of these patients may contain an increased residual capacity, and changes in urinary osmolalities induced by diagnostic maneuvers might be difficult to demonstrate.

FIGURE 7.16. The relationship between urine osmolality and plasma vasopressin in patients with polyuria of diverse etiology and severity. Note that for each of the three categories of polyuria—neurogenic diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia—the relationship is described by a family of sigmoid curves that differ in height. These differences in height reflect differences in maximal concentrating capacity owing to “washout” of the medullary concentration gradient. They are proportional to the severity of the underlying polyuria (indicated in liters per day at the right end of each plateau) and are largely independent of the etiology. Thus, the three catagories of diabetes insipidus differ principally in the submaximal or ascending portion of the dose-response curve. In patients with partial neurogenic diabetes insipidus, this part of the curve lies to the left of normal, reflecting increased sensitivity to the antidiuretic effects of very low concentrations of plasma arginine vasopressin (AVP). In contrast, in patients with partial nephrogenic diabetes insipidus, this part of the curve lies to the right of normal, reflecting decreased sensitivity to the antidiuretic effects of normal concentrations of plasma AVP. In primary polydipsia, this relationship is relatively normal. From Robertson [288].

Indirect Test The measurement of urinary osmolality after dehydration or vasopressin administration is usually referred to as indirect testing, since vasopressin secretion is indirectly assessed through changes in urinary osmolalities. The patient is maintained on a complete fluid restriction regimen until urinary osmolality reaches a plateau, as indicated by an hourly increase of less than 30 mmol/kg for at least 3 successive hours. After the plasma osmolality is measured, 5 units of aqueous vasopressin, or 4 mg of dDAVP, are administered subcutaneously. Urinary osmolality is measured 30 and 60 minutes later. That last urinary osmolality value obtained before the vasopressin injection and the highest value obtained after the injection are compared. The patients are then separated into five categories according to previously published criteria (Table 7.6) [289]. Direct Test The two approaches of Zerbe and Robertson are used [290]. In the first approach, plasma is collected and assayed for vasopressin during the dehydration test. The results are plotted on a nomogram depicting the normal relationship between plasma sodium or osmolality and plasma AVP in normal subjects (see Fig. 7.7). If the relationship between plasma vasopressin and osmolality falls below the normal range, the disorder is diagnosed as central diabetes insipidus. “Platelet-fraction” [77] AVP measurements also easily differentiate hypothalamic from nephrogenic diabetes insipidus [80].

Table 7.6. Urinary responses to fluid deprivation and exogenous vasopressin in recognition of partial defects in antidiuretic hormone secretiona

Normal subjects Complete central diabetes insipidus Partial central diabetes insipidus Nephrogenic diabetes insipidus Compulsive water drinking a b

Data from Miller et al. [289]. Urinary osmolality (Uosm) in mmol/kg.

Number of cases

Maximum Uosmb

Uosm after vasopressin

Percent change (Uosm)

Uosm increase after vasopressin

9 8 11 2 7

1068 ± 69 168 ± 13 438 ± 34 123.5 738 ± 73

979 ± 79 445 ± 52 549 ± 28 174.5 780 ± 73

-9 ± 3 183 ± 41 28 ± 5 42 5.0 ± 2.2

<9% >50% >9% <50% <50% <9%

Chapter 7

In the second approach, partial nephrogenic diabetes insipidus and primary polydipsia are differentiated by analyzing the relationship between plasma AVP and urinary osmolality at the end of the dehydration period (see Figs 7.7 and 7.16). However, a definitive differentiation between these two disorders might be impossible, since a normal or even supranormal AVP response to increased plasma osmolality occurs in polydipsic patients. None of the patients with psychogenic or other forms of severe polydipsia studied by Robertson have ever shown any evidence of pituitary suppression [288]. Benefits of Direct Test Zerbe and Robertson [290] found that in the differential diagnosis of polyuria, all seven cases of severe neurogenic diabetes insipidus diagnosed by the standard indirect test were confirmed when diagnosed by the plasma vasopressin assay. However, two of six patients diagnosed by the indirect test as having partial neurogenic diabetes insipidus had normal vasopressin secretion as measured by the direct assay; one was found to have primary polydipsia and the other nephrogenic diabetes insipidus. Moreover, three of 10 patients diagnosed as having primary polydipsia by the indirect test had clear evidence of partial vasopressin deficiency by the direct assay [290]. These patients were thus wrongly diagnosed as being primary polydipsic. A combined direct and indirect testing of the AVP function has been recommended by Stern and Valtin [291]; measurements of AVP cannot be used in isolation but must be interpreted in the light of four other factors: (i) clinical history, (ii) concurrent measurements of plasma osmolality and of (iii) urinary osmolality and (iv) urinary response to exogenous vasopressin in reference to the basal urinary flow. Therapeutic Trial In selected patients with an uncertain diagnosis, a closely monitored therapeutic trial of dDAVP (10 mg intranasally twice a day) may be used to distinguish partial nephrogenic diabetes insipidus from partial neurogenic diabetes insipidus and primary polydipsia. If dDAVP at this dosage causes a significant antidiuretic effect, nephrogenic diabetes insipidus is effectively excluded. If polydipsia as well as polyuria are abolished and plasma sodium does not fall below the normal range, the patient probably has central diabetes insipidus. Conversely, if dDAVP causes a reduction in urine output without a reduction in water intake and hyponatremia appears, the patient probably has primary polydipsia. Since fatal water intoxication is a remote possibility, the dDAVP trial should be done with close monitoring. Recommendations Table 7.7 lists recommendations for obtaining a differential diagnosis of diabetes insipidus. Plasma Sodium, Plasma, and Urinary Osmolality Measurements Measurements of plasma sodium, plasma and urinary osmolality should be immediately available at various intervals during dehydration procedures. Plasma sodium is easily measured by flame photometry or with a

Table 7.7. 1

2

3

4

5

6

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Differential diagnosis of diabetes insipidus*

Measure plasma osmolality and/or sodium concentration under conditions of ad libitum fluid intake. If they are above 295 mmol/kg and 143 mmol/L, the diagnosis of primary polydipsia is excluded and the workup should proceed directly to step 5 and/or 6 to distinguish between neurogenic and nephrogenic diabetes insipidus. Otherwise, Perform a dehydration test. If urinary concentration does not occur before plasma osmolality and/or sodium reach 295 mmol/kg or 143 mmol/L, the diagnosis of primary polydipsia is again excluded and the workup should proceed to step 5 and/or 6. Otherwise, Determine the ratio of urine to plasma osmolality at the end of the dehydration test. If it is less than 1.5, the diagnosis of primary polydipsia is again excluded and the workup should proceed to step 5 and/or 6. Otherwise, Perform a hypertonic saline infusion with measurements of plasma vasopressin and osmolality at intervals during the procedure. If the relationship between these two variables is subnormal, the diagnosis of diabetes insipidus is established. Otherwise, Perform a vasopressin infusion test. If urine osmolality rises by more than 150 mosmol/kg above the value obtained at the end of the dehydration test, nephrogenic diabetes insipidus is excluded. Alternately, Measure urine osmolality and plasma vasopressin at the end of the dehydration test. If the relationship is normal, the diagnosis of nephrogenic diabetes insipidus is excluded.

* From Robertson [345].

sodium-specific electrode [292]. Plasma and urinary osmolalities are also reliably measured by freezing-point depression instruments with a coefficient of variation of less than 1% at 290 mmol/kg. In our clinical research unit, plasma sodium and plasma and urinary osmolalities are measured at the beginning of each dehydration procedure and at regular intervals (usually hourly) thereafter, depending on the severity of the polyuric syndrome explored. Great care should be taken to avoid any severe hypertonic state arbitrarily defined as a plasma sodium greater than 155 mmol/l. At variance with published data [290,293], we have found that plasma and serum osmolalities are equivalent (i.e., similar values are obtained). Blood taken in heparinized tubes is easier to handle than blood taken without an anticoagulant as the plasma can be more readily removed after centrifugation. The green-stopper tube used contains a minuscule concentration of lithium and sodium, but these do not interfere with the plasma sodium or osmolality measurements. Treatment

In most patients with complete hypothalamic diabetes insipidus, the thirst mechanism remains intact [294]. Thus, these patients do not develop hypernatremia and suffer only from the inconvenience associated with marked polyuria and polydipsia. If hypodipsia develops or access to water is limited, then severe hypernatremia can supervene. The treatment of choice for patients with severe hypothalamic diabetes insipidus is dDAVP, a synthetic, long-acting vaso-

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pressin analogue, with minimal vasopressor activity but a large antidiuretic potency [219]. The usual intranasal daily dose is between 5 and 20 mg. To avoid the potential complication of dilutional hyponatremia, which is exceptional in these patients due to an intact thirst mechanism, dDAVP can be withdrawn at regular intervals to allow the patients to become polyuric. Aqueous vasopressin (Pitressin) or dDAVP (4.0 mg/1 mL ampule) can be used intravenously in acute situations such as after hypophysectomy or for the treatment of diabetes insipidus in the brain dead organ donor [295]. Pitressin tannate in oil and nonhormonal antidiuretic drugs are somewhat obsolete and now rarely used. For example, chlorpropamide (250–500 mg daily) appears to potentiate the antidiuretic action of circulating AVP [219], but troublesome side effects of hypoglycemia and hyponatremia do occur. The treatment of congenital nephrogenic diabetes insipidus has been recently reviewed [296–298]. SYNDROME OF INAPPROPRIATE SECRETION OF THE ANTIDIURETIC HORMONE (SIADH) Hyponatremia (defined as a plasma sodium below 130 mmol/l) is the most common disorder of body fluid and electrolyte balance encountered in clinical practice of medicine, with incidences ranging from 1% to 2% in both acutely and chronically hospitalized patients [299–301]. Because a defect in renal water excretion, as reflected by hypoosmolality, may occur in the presence of an excess or deficit of total body sodium or nearly normal total body sodium, it is useful to classify the hyponatremic states accordingly [302,303]. Moreover, since total-body sodium is the primary determinant of the extracellular fluid (ECF) volume, bedside evaluation of the ECF volume allows for a convenient means of classifying hyponatremic patients [302,303]. Patients with hyponatremia who show no evidence of either hypovolemia or edema constitute a select group. Although many of these patients may have SIADH (this syndrome is so named because the secretion of AVP cannot be accounted for by recognized osmotic or nonosmotic stimuli), endocrine disorders such as hypoparathyroidism, hypopituitarism with glucocorticoid deficiency, various pharmacological agents and emotional and physical stress may also cause euvolemic hyponatremia [303]. Psychotic patients with polydipsia and hyponatremia are also classified in this group of hyponatremic patients with normal total body sodium [304,305]. The diagnosis of SIADH is made primarily by excluding other causes of hyponatremia. It should be considered in the absence of hypovolemia, edematous disorders, endocrine dysfunction (including primary and secondary adrenal insufficiency and hypothyroidism), renal failure and drugs, all of which impair water excretion. Psychotic patients with polydipsia and hyponatremia have multiple disturbances in water regulation including alteration in osmoreceptor function, inappropriate thirst response, renal hypersensitivity to vasopressin and

vasopressin-independent perturbation of urinary dilution. Thus, we recommend that these patients should not be classified as presenting SIADH. An animal model of antidiuretic-induced hyponatremia closely resembling clinical SIADH has been developed by Verbalis and coworkers using a continuous subcutaneous infusion of dDAVP in combination with dextrose drinking or the self-ingestion of a concentrated, nutritionally balanced liquid diet [306–308]. A chronic, severe hyponatremia accompanied by an antidiuretic effect was obtained. Multiple hemodynamic and hormonal adaptive responses were also observed [307,309]. Since 1957 when Schwartz et al. [310] first described SIADH in two patients with bronchogenic carcinoma who were hyponatremic, clinically euvolemic with normal renal and adrenal function, and who had less than maximally dilute urine with appreciable urinary sodium concentrations (greater than 20 mmol/l), SIADH has been recognized in a variety of pathological processes. Various diseases which may be accompanied by SIADH are listed in Table 7.8. These diseases generally fall into three categories: (i) malignancies; (ii) pulmonary disorders; and (iii) central nervous system disorders. Human immunodeficiency virus (HIV) infection forms a new category of patients with SIADH, with as many as 35% of hospitalized patients affected. In these patients, Pneumocystics carinii pneumonia, CNS infections and malignancies play a role in the development of SIADH [311]. Tumors can synthesize and secrete AVP. Many tumors contain typical secretory granules and cultured tumor tissue has been shown to synthesize not only AVP but also the entire AVP precursor peptide, propressophysin [10,312]. Furthermore, tumor extracts have been found to contain AVP bioactivity and immunologically recognizable AVP [313]. Numerous reports have called attention to a rare tumor, olfactory neuroblastoma, which is frequently associated with chronic, occasionally symptomatic, hyponatremia [314–318]. In our laboratory, we have demonstrated the presence of AVP mRNA in this rare tumor [319]. In spite of the hyponatremia, patients with SIADH have a concentrated urine in which the urinary sodium concentration closely parallels the sodium intake, i.e., it is usually above 20 mmol/l. However, in the presence of sodium restriction or volume depletion these patients can conserve sodium normally and decrease their urinary sodium concentration to less than 10 mmol/l [320]. Serum uric acid has been found to be reduced in SIADH patients, whereas patients with other causes of hyponatremia have normal concentrations of serum uric acid [321].Uric acid and phosphate clearances were found to be increased in patients with SIADH as the consequence of volume expansion and decreased tubular reabsorption [322]. Similarly, low serum blood urea nitrogen concentrations have been found in SIADH [323]. This is probably due to an increase in total body water, where urea is normally distributed, but a decrease in protein intake could also contribute. Plasma atrial natriuretic factor concentration has been found to be

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305

Table 7.8. Disorders associated with syndrome of inappropriate secretion of the antidiuretic hormone (SIADH) Carcinomas

Small-cell carcinoma of the lung Carcinoma of the duodenum Carcinoma of pancreas Thymoma Carcinoma of the ureter Lymphoma Ewing’s sarcoma Mesothelioma Carcinoma of the bladder Prostatic carcinoma Olfactory neuroblastoma

Central nervous system disorders

Encephalitis (viral or bacterial) Meningitis (viral, bacterial, tuberculous, fungal) Head trauma Brain abscess Brain tumors Guillain–Barré syndrome Acute intermittent porphyria Subarachnoid hemorrhage of subdural hematoma Cerebellar and cerebral atrophy Cavernous sinus thrombosis Neonatal hypoxia Hydrocephalus Shy–Drager syndrome Rocky Mountain spotted fever Delirium tremens Cerebrovascular accident (cerebral thrombosis or hemorrhage) Acute psychosis Peripheral neuropathy Multiple sclerosis

Pulmonary disorders

Viral pneumonia Bacterial pneumonia Pulmonary abscess Tuberculosis Aspergillosis Positive-pressure breathing Asthma Pneumothorax Cystic fibrosis

increased in patients with SIADH and to correlate with urinary sodium excretion [324–326]. Dillingham and Anderson [327] observed a direct inhibition of the renal epithelial water transport in rabbit collecting tubules perfused in vitro with 2 nmol of atriopeptin III. Nonoguchi et al. [328] found that physiological concentrations of atrial natriuretic factor caused an inhibition of vasopressinstimulated osmotic water permeability in the rat terminal inner medullary collecting duct. Thus, although atrial natriuretic factor may antagonize the hydrosmotic effect of vasopressin, SIADH may nevertheless occur in the presence of increased plasma atrial natriuretic hormone concentrations.

FIGURE 7.17. Plasma vasopressin as a function of plasma osmolality during the infusion of hypertonic saline in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). From Robertson [346].

Abnormal osmoregulation of vasopressin has been studied in 79 patients with SIADH [329] (Fig. 7.17). These patients underwent either hypertonic saline or water loading or both and four patterns of responses were identified. The type I pattern, observed in 37% of the patients studied, consisted of large, erratic changes in plasma vasopressin concentrations with no relationship to the plasma osmolality. In type II (33% of the patients), the release of vasopressin was found, as in normal subjects, to correlate closely with the plasma osmolality; however, the osmotic threshold for vasopressin release was abnormally low. Theoretically, this group could correspond to the previously described patients with a “reset osmostat” which enabled the urine of these patients to become maximally dilute if they were sufficiently hyponatremic [330–333]. Unfortunately, Zerbe et al. [329] did not publish any water load studies for these patients. Thus the ability of this group of SIADH patients to excrete a water load normally at a reduced osmotic threshold remains to be documented. In the type III patients, a constant, nonsuppressible basal “leak” of vasopressin with an otherwise normal osmotic release of vasopressin was observed. In type IV patients (14%), no detectable abnormalities in vasopressin secretion were observed (Fig. 7.17). This suggested either a nonvasopressin-mediated mechanism or an increased sensitivity to normal amounts of vasopressin. These four types of SIADH did not correlate with the underlying clinical problems (Table 7.9). For example, bronchogenic carcinoma, a disorder that might be expected to feature ectopic production of vasopressin, was associated with all four categories of SIADH. The clinical relevance of this categorization of SIADH therefore remains to be elucidated.

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Table 7.9. Principal clinical diagnoses in each of the four types of syndrome of inappropriate secretion of the antidiuretic hormone (SIADH) identified by saline infusion in 25 patients* Type I

II

III

IV

Number of patients 2 1 1 1 1 4 2 1 1 1 3 2 1 1 1 1

Diagnoses Acute respiratory failure Bronchogenic carcinoma Pulmonary tuberculosis Schizophrenia Rheumatoid arthritis Bronchogenic carcinoma Cerebrovascular disease Tuberculous meningitis Acute respiratory disease Carcinoma of pharynx Central nervous system disease Bronchogenic carcinoma Pulmonary tuberculosis Schizophrenia Bronchogenic carcinoma Diabetes mellitus, arteriosclerosis

* Data from Robertson [346].

SIGNS, SYMPTOMS AND TREATMENT OF HYPONATREMIA The majority of the manifestations of hyponatremia are of a neuropsychiatric nature and include lethargy, psychosis, seizures and coma [334]. Elderly and young children with hyponatremia are most likely to become symptomatic. The degree of the clinical impairment is not strictly related to the absolute value of the lowered serum sodium concentration, but, rather, it relates to both the rate and the extent of the fall of ECF osmolality [334]. The mortality rate from acute symptomatic hyponatremia is difficult to determine. Arieff quotes a mortality rate of approximately 50% [335,336]. On the other hand, none of the 10 acutely hyponatremic patients reported by Sterns had permanent neurologic sequelae [337]. As Berl [338] commented, the 50% mortality rate might be an exaggeration, but estimates suggesting that acute hyponatremia is a benign condition greatly underevaluate this potentially catastrophic electrolyte disturbance. Most patients who have seizures and coma have plasma sodium concentrations less than 120 mmol/l. The signs and symptoms are most likely related to the cellular swelling and cerebral edema that are associated with hyponatremia. Patients with SIADH whose plasma sodium concentrations are usually greater than 125 mmol/l rarely have significant symptoms related to hyponatremia itself and may not require specific treatment to raise their plasma sodium. The treatment of symptomatic hyponatremic patients has been the subject of a large scale debate in the literature. This debate has been prompted by the description of both

Table 7.10. hyponatremia

A prudent approach of the treatment of

Guiding principles in the treatment of hyponatremia 1 Neurologic disease can follow both the failure to promptly treat and the injudicious rapid treatment of hyponatremia 2 The presence or absence of significant neurologic signs and symptoms must guide the treatment 3 The acuteness or chronicity of the electrolyte disturbance influences the rate at which the correction should be undertaken Acute symptomatic hyponatremia 1 The risk of the complications of cerebral edema are greater than the risk of the complications of the treatment 2 Treat with furosemide and hypertonic NaCl until convulsions subside Asymptomatic hyponatremia 1 Almost always chronic 2 Treat with water restriction regardless of how low the serum sodium concentration is Symptomatic hyponatremia (chronic or unknown duration) 1 Increase serum sodium promptly by 10%, that is, approximately 10 mEq/liters, and then restrict water intake 2 Do not exceed a correction rate of 2 mEq/liter/hr at any given time 3 Do not increase serum sodium by more than 20 mEq/day

pontine (central pontine myelinolysis (CPM)) and extrapontine demyelinating lesions in patients whose hyponatremia has been treated [337,339–342]. Numerous experiments (reviewed by Berl [338]) have demonstrated that hyponatremia per se is not the underlying cause of CPM, but that the corrections of hyponatremia of greater than 24-hour duration, may play a central role in the development of CPM. The critical rate and the magnitude of the correction have been addressed and a “prudent” approach to the treatment has been published [311,338] (Table 7.10). The use of non-peptide vasopressin receptor antagonists holds great promise in the treatment of SIADH [180,181].

ACKNOWLEDGMENTS The studies from the author’s laboratory reported in this chapter were supported by the Canadian Kidney Foundation, the Canadian Institutes of Health Research (MOP8126), and the Fondation J. Rodolphe-La Haye. Dr Daniel G Bichet is a career investigator of Le Fonds de la recherche en santé du Québec. The manuscript and illustrations were prepared by Danielle Binette.

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Chapter 7 215 Swift RG, Sadler DB, Swift M. Psychiatric findings in Wolfram syndrome homozygotes. Lancet 1990;336:667–669. 216 Inoue H, Tanizawa Y, Wasson J et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nature Genet 1998;20:143–148. 217 Strom TM, Hortnagel K, Hofmann S et al. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet 1998;7:2021–2028. 218 Hardy C, Khanim F, Torres R et al. Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. Am J Hum Genet 1999;65:1279–1290. 219 Howard RL, Bichet DG, Schrier RW. Hypernatremic and polyuric states. In: Seldin DW, Giebisch G, eds. The kidney: physiology and pathophysiology 2nd ed., New York: Raven Press, 1992:1753–1778. 220 Seibold A, Brabet P. Rosenthal W et al. Structure and chromosomal localization of the human antidiuretic hormone receptor gene. Am J Hum Genet 1992;51:1078–1083. 221 Tamarappoo BK, Verkman AS, Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J Clin Invest 1998;101:2257–2267. 222 Morello JP, Salahpour A, Laperrière A et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 2000;105:887–895. 223 Oksche A, Rosenthal W. The molecular basis of nephrogenic diabetes insipidus. J Mol Med 1998;76:326–337. 224 Nomura Y, Onigata K, Nagashima T et al. Detection of skewed X-inactivation in two female carriers of vasopressin type 2 receptor gene mutation. J Clin Endocrinol Metab 1997;82:3434–3437. 225 Crawford JD, Bode HH. Disorders of the posterior pituitary in children. In: Gardner LI, eds. Endocrine and genetic diseases of childhood and adolescence 2nd ed., Philadelphia: WB Saunders, 1975:126–158. 226 Forssman H. On the mode of hereditary transmission in diabetes insipidus. Nordisk Medicine 1942:16:3211–3213. 227 Waring AG, Kajdi L, Tappan V. Congenital defect of water metabolism. Am J Dis Child 1945;69:323–325. 228 Williams RM, Henry C. Nephrogenic diabetes insipidus transmitted by females and appearing during infancy in males. Ann Int Med 1947;27: 84–95. 229 Niaudet P, Dechaux M, Trivin C et al. Nephrogenic diabetes insipidus: clinical and pathophysiological aspects. Adv Nephrol Necker Hosp 1984;13:247–260. 230 McIlraith CH. Notes on some cases of diabetes insipidus with marked family and hereditary tendencies. Lancet 1892;2:767–768. 231 Reeves WB, Andreoli TE. Nephrogenic diabetes insipidus. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease 7th ed., New York: McGraw-Hill, 1995:3045–3071. 232 Streitz JMJ, Streitz JM. Polyuric urinary tract dilatation with renal damage. J Urol 1988;139:784–785. 233 Boyd SD, Raz S, Ehrlich RM. Diabetes insipidus and nonobstructive dilatation of urinary tract. Urology 1980;16:266–269. 234 Gautier B, Thieblot P, Steg A. Mégauretère, Mégavessie et diabète insipide familial. Sem Hop 1981;57:60–61. 235 Arthus M-F, Lonergan M, Crumley MJ et al. Report of 33 novel AVPR2 mutations and analysis of 117 families with X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 2000;11:1044–1054. 236 Bode HH, Crawford JD. Nephrogenic diabetes insipidus in North America: the Hopewell hypothesis. N Engl J Med 1969;280:750–754. 237 Bichet DG, Hendy GN, Lonergan M et al. X-linked nephrogenic diabetes insipidus: from the ship Hopewell to restriction fragment length polymorphism studies. Am J Hum Genet 1992;51:1089–1102. 238 Bichet DG, Arthus M-F, Lonergan M et al. X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. J Clin Invest 1993;92:1262–1268. 239 Holtzman EJ, Kolakowski LF, O’Brien D et al. A null mutation in the vasopressin V2 receptor gene (AVPR2) associated with nephrogenic diabetes insipidus in the Hopewell kindred. Hum Mol Genet 1993;2:1201–1204. 240 Bichet DG, Birnbaumer M, Lonergan M et al. Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus. Am J Hum Genet 1994;55:278–286. 241 Fujiwara TM, Morgan K, Bichet DG. Molecular analysis of X-linked nephrogenic diabetes insipidus. Eur J Endocrinol 1996;134:675–677. 242 Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 1990;24:133–170.

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243 Schöneberg T, Yun J, Wenkert D, Wess J. Functional rescue of mutant V2 vasopressin receptors causing nephrogenic diabetes insipidus by a coexpressed receptor polypeptide. EMBO J 1996;15:1283–1291. 244 Schöneberg T, Sandig V, Wess J et al. Reconstitution of mutant V2 vasopressin receptors by adenovirus-mediated gene transfer. J Clin Invest 1997;100: 1547–1556. 245 Oksche A, Schulein R, Rutz C et al. Vasopressin V2 receptor mutants that cause X-linked nephrogenic diabetes insipidus: analysis of expression, processing, and function. Mol Pharmacol 1996;50:820–828. 246 Tsukaguchi H, Matsubara H, Taketani S et al. Binding-, intracellular transport-, and biosynthesis-defective mutants of vasopressin type 2 receptor in patients with X-linked nephrogenic diabetes insipidus. J Clin Invest 1995;96: 2043–2050. 247 Wenkert D, Schoneberg T, Merendino JJ Jr et al. Functional characterization of five V2 vasopressin receptor gene mutations. Mol Cell Endocrinol 1996;124: 43–50. 248 Schulz A, Grosse R, Schultz G et al. Structural implication for receptor oligomerization from functional reconstitution studies of mutant V2 vasopressin receptors. J Biol Chem 2000;275:2381–2389. 249 Vargas-Poussou R, Forestier L, Dautzenberg MD et al. Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 families with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 1997;8:1855–1862. 250 Sadeghi H, Robertson GL, Bichet DG et al. Biochemical basis of partial NDI phenotypes. Mol Endocrinol 1997;11:1806–1813. 251 Ala Y, Morin D, Mouillac B et al. Functional studies of twelve mutant V2 vasopressin receptors related to nephrogenic diabetes insipidus: molecular basis of a mild clinical phenotype. J Am Soc Nephrol 1998;9:1861–1872. 252 Knoers N, Monnens LA. A variant of nephrogenic diabetes insipidus: V2 receptor abnormality restricted to the kidney. Eur J Pediatr 1991;150:370–373. 253 Langley JM, Balfe JW, Selander T et al. Autosomal recessive inheritance of vasopressin-resistant diabetes insipidus. Am J Med Genet 1991;38:90–94. 254 Lonergan M, Birnbaumer M, Arthus M-F et al. Non-X-linked nephrogenic diabetes insipidus: phenotype and genotype features. J Am Soc Nephrol 1993;4:264A. 255 Bichet DG, Razi M, Lonergan M et al. Hemodynamic and coagulation responses to 1-desamino[8-D-arginine]vasopressin (dDAVP) infusion in patients with congenital nephrogenic diabetes insipidus. N Engl J Med 1988;318: 881–887. 256 Bichet DG, Razi M, Arthus M-F et al. Epinephrine and dDAVP administration in patients with congenital nephrogenic diabetes insipidus. Evidence for a pre-cyclic AMP V2 receptor defective mechanism. Kidney Int 1989;36:859–866. 257 Brenner B, Seligsohn U, Hochberg Z. Normal response of factor VIII and von Willebrand factor to 1-deamino-8D-arginine vasopressin in nephrogenic diabetes insipidus. J Clin Endocrinol Metab 1988;67:191–193. 258 Fushimi K, Uchida S, Hara Y et al. Cloning and expression of apical membrane water channel of rat kidney collecting tubule. Nature 1993;361: 549–552. 259 Uchida S, Sasaki S, Furukawa T et al. Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla [published erratum appears in J Biol Chem 1994 Jul 22;269(29): 19192]. J Biol Chem 1993;268:3821–3824. 260 Deen PMT, Verdijk MAJ, Knoers NVAM et al. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 1994;264:92–95. 261 Sasaki S, Fushimi K, Saito H et al. Cloning, characterization, and chromosomal mapping of human aquaporin of collecting duct. J Clin Invest 1994;93: 1250–1256. 262 van Lieburg AF, Verdijk MAJ, Knoers NVAM et al. Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene. Am J Hum Genet 1994;55:648–652. 263 Hochberg Z, van Lieburg A, Even L et al. Autosomal recessive nephrogenic diabetes insipidus caused by an aquaporin-2 mutation. J Clin Endocrinol Metab 1997;82:686–689. 264 Mulders SB, Knoers NVAM, van Lieburg AF et al. New mutations in the AQP2 gene in nephrogenic diabetes insipidus resulting in functional but misrouted water channels. J Am Soc Nephrol 1997;8:242–248. 265 Canfield MC, Tamarappoo BK, Moses AM et al. Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response. Hum Mol Genet 1997;6:1865–1871. 266 Mulders SM, Bichet DG, Rijss JPL et al. An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the golgi complex. J Clin Invest 1998;102:57–66.

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267 Deen PMT, Croes H, van Aubel RAMH et al. Water channels encoded by mutant aquaporin-2 genes in nephrogenic diabetes insipidus are impaired in their cellular routing. J Clin Invest 1995;95:2291–2296. 268 van Os CH, Deen PM. Aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus. Proc Assoc Am Physicians 1998;110:395–400. 269 Kamsteeg EJ, Wormhoudt TA, Rijss JP et al. An impaired routing of wild-type aquaporin-2 after tetramerization with an aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus. Embo J 1999;18: 2394 –2400. 270 Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 1987;10:329–345. 271 Christensen S, Kusano E, Yusufi AN et al. Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats. J Clin Invest 1985;75:1869–1879. 272 Cogan E, Svoboda M, Abramow M. Mechanisms of lithium-vasopressin interaction in rabbit cortical collecting tubule. Am J Physiol 1987;252: F1080–1087. 273 Goldberg H, Clayman P, Skorecki K. Mechanism of Li inhibition of vasopressin-sensitive adenylate cyclase in cultured renal epithelial cells. Am J Physiol 1988;255:F995–1002. 274 Marples D, Christensen S, Christensen EI et al. Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla. J Clin Invest 1995;95:1838–1845. 275 Marples D, Frokiaer J, Dorup J et al. Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex. J Clin Invest 1996;97:1960–1968. 276 Frokiaer J, Marples D, Knepper MA et al. Bilateral ureteral obstruction downregulates expression of vasopressin-sensitive AQP-2 water channel in rat kidney. Am J Physiol 1996;270:F657–F668. 277 Sands JM, Flores FX, Kato A et al. Vasopressin-elicited water and urea permeabilities are altered in IMCD in hypercalcemic rats. Am J Physiol 1998;274:F978–985. 278 Kanno K, Sasaki S, Hirata Y et al. Urinary excretion of aquaporin-2 in patients with diabetes insipidus [see comments]. N Engl J Med 1985;332: 1540–1545. 279 Batlle DC, von Riotte AB, Gaviria M et al. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med 1985;312:408–414. 280 Barlow ED, de Wardener HE. Compulsive water drinking. Q J Med New Series 1959;28:235–258. 281 Moses AM, Scheinman SJ, Oppenheim A. Marked hypotonic polyuria resulting from nephrogenic diabetes insipidus with partial sensitivity to vasopressin. J Clin Endocrinol Metab 1984;59:1044–1049. 282 Amico JA. Diabetes insipidus and pregnancy. In: Czernichow P, Robinson AG, eds. Frontiers of hormone research, vol 13, Diabetes insipidus in man. Basel: Switzerland, Karger, 1985:266–277. 283 Barron WM, Cohen LH, Ulland LA et al. Transient vasopressin-resistant diabetes insipidus of pregnancy. N Engl J Med 1984;310:442–444. 284 Durr JA, Hoggard JG, Hunt JM, Schrier RW. Diabetes insipidus in pregnancy associated with abnormally high circulating vasopressinase activity. N Engl J Med 1987;316:1070–1074. 285 Iwasaki Y, Oiso Y, Kondo K et al. Aggravation of subclinical diabetes insipidus during pregnancy [see comments]. N Engl J Med 1991;324:522–526. 286 Robertson GL. Dipsogenic diabetes insipidus: a newly recognized syndrome caused by a selective defect in the osmoregulation of thirst. Trans Assoc Am Physicians 1987;100:241–249. 287 Leaf A. Neurogenic diabetes insipidus. Kidney Int 1979;15:572–580. 288 Robertson GL. Diagnosis of diabetes insipidus. In: Czernichow P, Robinson AG, eds. Frontiers of hormone research, vol 13, Diabetes insipidus in man. Basel: Karger, 1985:176–189. 289 Miller M, Dalakos T, Moses AM et al. Recognition of partial defects in antidiuretic hormone secretion. Ann Intern Med 1970;73:721–729. 290 Zerbe RL, Robertson GL. A comparison of plasma vasopressin measurements with a standard indirect test in the differential diagnosis of polyuria. N Engl J Med 1981;305:1539–1546. 291 Stern P, Valtin H. Verney was right, but . . . [editorial]. N Engl J Med 1981;305:1581–1582. 292 Maas AH, Siggaard-Andersen O, Weisberg HF, Zijlstra WG. Ion-selective electrodes for sodium and potassium: a new problem of what is measured and what should be reported. Clin Chem 1985;31:482–485. 293 Redetzki HM, Hughes JR, Redetzki JE. Differences between serum and plasma osmolalities and their relationship to lactic acid values. Proc Soc Exp Biol Med 1972;139:315–318.

294 Thompson CJ, Baylis PH. Thirst in diabetes insipidus: clinical relevance of quantitative assessment. Q J Med 1987;65:853–862. 295 Debelak L, Pollak R, Reckard C. Arginine vasopressin versus desmopressin for the treatment of diabetes insipidus in the brain dead organ donor. Transplant Proc 1990;22:351–352. 296 Knoers N, Monnens LA. Nephrogenic diabetes insipidus: clinical symptoms, pathogenesis, genetics and treatment. Pediatr Nephrol 1992;6:476–482. 297 Bichet DG, Oksche A, Rosenthal W. Congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 1997;8:1951–1958. 298 Bichet DG, Fujiwara TM. Nephrogenic diabetes insipidus. In: Scriver CR, Beaudet AL, Sly WS et al., eds. The metabolic and molecular bases of inherited disease 8th ed., New York: McGraw-Hill, 2001. 299 Anderson RJ. Hospital-associated hyponatremia [clinical conference]. Kidney Int 1986;29:1237–1247. 300 Anderson RJ, Chung HM, Kluge R, Schrier RW. Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med 1985;102:164–168. 301 Verbalis JG. Hyponatremia. In: Alberti KG, Besser GM, Bierich JR et al., eds. Baillière’s Clinical Endocrinology and Metabolism. vol 3, Water and Salt Homeostasis in Health and Disease. London: Baillière Tindall, 1989:499–530. 302 Berl T, Anderson RJ, McDonald KM, Schrier RW. Clinical disorders of water metabolism. Kidney Int 1976;10:117–132. 303 Bichet DG, Kluge R, Howard RL, Schrier RW. Hyponatremic states. In: Seldin DW, Giebisch G, eds. The kidney: physiology and pathophysiology 2nd ed., New York: Raven Press, 1992:1727–1751. 304 Berl T. Psychosis and water balance [editorial]. N Engl J Med 1988;318: 441–442. 305 Goldman MB, Luchins DJ, Robertson GL. Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Engl J Med 1988;318:397–403. 306 Verbalis JG. An experimental model of syndrome of inappropriate antidiuretic hormone secretion in the rat. Am J Physiol 1984;247:E540–E553. 307 Verbalis JG, Drutarosky MD. Adaptation to chronic hypoosmolality in rats. Kidney Int 1988;34:351–360. 308 Verbalis JG, Drutarosky MD, Ertel RJ, Vollmer RR. Adaptive responses to sustained volume expansion in hyponatraemic rats. J Endocrinol 1989;122: 421–431. 309 Verbalis JG. The syndrome of inappropriate antidiuretic hormone secretion and other hypoosmolar disorders. In: Schrier RW, Gottschalk CW, eds. Diseases of the kidney 6th ed., vol III. Boston: Little, Brown and Company, 1997: 2393–2427. 310 Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957;23:529–542. 311 Berl T, Kumar S. Disorders of water metabolism. In: Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. London: Mosby, 2000:9.1–9.20. 312 Smitz S, Legros JJ, Franchimont P, le Maire M. Identification of vasopressinlike peptides in the plasma of a patient with the syndrome of inappropriate secretion of antidiuretic hormone and an oat cell carcinoma. Acta Endocrinol (Copenh.) 1988;119:567–574. 313 Verbalis JG. Tumoral hyponatremia [editorial]. Arch Intern Med 1986;146: 1686–1687. 314 Cullen MJ, Cusack DA, O’Briain DS et al. Neurosecretion of arginine vasopressin by an olfactory neuroblastoma causing reversible syndrome of antidiuresis. Am J Med 1986;81:911–916. 315 Osterman J, Calhoun A, Dunham M et al. Chronic syndrome of inappropriate antidiuretic hormone secretion and hypertension in a patient with olfactory neuroblastoma. Evidence of ectopic production of arginine vasopressin by the tumor. Arch Intern Med 1986;146:1731–1735. 316 Schwaab G, Micheau C, Le Guillou C et al. Olfactory esthesioneuroma: a report of 40 cases. Laryngoscope 1988;98:872–876. 317 Singh W, Ramage C, Best P, Angus B. Nasal neuroblastoma secreting vasopressin. A case report. Cancer 1980;45:961–966. 318 Srigley JR, Dayal VS, Gregor RT et al. Hyponatremia secondary to olfactory neuroblastoma. Arch Otolaryngol 1983;109:559–562. 319 Houde I, René de Cotret P, Zingg H, Bichet DG. Messenger RNA (mRNA) for arginine-vasopressin (AVP) in an olfactory neuroblastoma, a rare tumor associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Kidney Int 1990;37:266A. 320 Nolph KD, Schrier RW. Sodium, potassium and water metabolism in the syndrome of inappropriate antidiuretic hormone secretion. Am J Med 1970;49:534–545. 321 Beck LH. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 1979;301:528–530.

Chapter 7 322 Falardeau P, Proulx J, Nawar T et al. Clinical and biochemical profiles of inappropriate secretion of antidiuretic hormone. Proceedings of the Seventh International Congress of Nephrology 1978:D-32. 323 Decaux G, Genette F, Mockel J. Hypouremia in the syndrome of inappropriate secretion of antidiuretic hormone. Ann Intern Med 1980;93:716–717. 324 Cogan E, Debieve MF, Pepersack T, Abramow M. Natriuresis and atrial natriuretic factor secretion during inappropriate antidiuresis. Am J Med 1988;84:409–418. 325 Manoogian C, Pandian M, Ehrlich L et al. Plasma atrial natriuretic hormone levels in patients with the syndrome of inappropriate antidiuretic hormone secretion. J Clin Endocrinol Metab 1988;67:571–575. 326 Kamoi K, Ebe T, Kobayashi O et al. Atrial natriuretic peptide in patients with the syndrome of inappropriate antidiuretic hormone secretion and with diabetes insipidus. J Clin Endocrinol Metab 1990;70:1385–1390. 327 Dillingham MA, Anderson RJ. Inhibition of vasopressin action by atrial natriuretic factor. Science 1986;231:1572–1573. 328 Nonoguchi H, Sands JM, Knepper MA. Atrial natriuretic factor inhibits vasopressin-stimulated osmotic water permeability in rat inner medullary collecting duct. J Clin Invest 1988;82:1383–1390. 329 Zerbe R, Stropes L, Robertson G. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med 1980;31:315–327. 330 DeFronzo RA, Goldberg M, Agus ZS. Normal diluting capacity in hyponatremic patients. Reset osmostat or a variant of the syndrome of inappropriate antidiuretic hormone secretion. Ann Intern Med 1976;84: 538–542. 331 Michelis MF, Fusco RD, Bragdon RW, Davis BB. Reset of osmoreceptors in association with normovolemic hyponatremia. Am J Med Sci 1974;267: 267–273. 332 Penney MD, Murphy D, Walters G. Resetting of osmoreceptor response as cause of hyponatraemia in acute idiopathic polyneuritis. Br Med J 1979;2:1474–1476. 333 Skowsky WR, Kikuchi TA. The role of vasopressin in the impaired water excretion of myxedema. Am J Med 1978;64:613–621. 334 Arieff AI, Llach F, Massry SG. Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes. Medicine (Baltimore) 1976;55:121–129. 335 Arieff AI. Hyponatremia associated with permanent brain damage. Adv Intern Med 1987;32:325–344. 336 Arieff AI. Osmotic failure: physiology and strategies for treatment. Hosp Pract (Off Ed) 1988;23:173–178, 183–174, 187–179 passim. 337 Sterns RH. Severe symptomatic hyponatremia: treatment and outcome: a study of 64 cases. Ann Intern Med 1987;107:656–664. 338 Berl T. Treating hyponatremia: damned if we do and damned if we don’t [clinical conference]. Kidney Int 1990;37:1006–1018. 339 Kleinschmidt-DeMasters BK, Norenberg MD. Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis. Science 1981;211:1068–1070. 340 Norenberg MD, Leslie KO, Robertson AS. Association between rise in serum sodium and central pontine myelinolysis. Ann Neurol 1982;11: 128–135. 341 Sterns RH. Unsafe at any speed? Am Kidney Fund Lett 1989;6:1–10. 342 Sterns RH, Riggs JE, Schochet SS Jr. Osmotic demyelination syndrome following correction of hyponatremia. N Engl J Med 1986;314: 1535–1542. 343 Antonarakis S. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat 1998;11:1–3. 344 Baylis PH. Vasopressin and its neurophysin. In: DeGroot LJ, Besser JM, Cahill GFJ et al., eds. Endocrinology. 2nd ed, vol 1. Philadelphia: WB Saunders, 1989:213–229. 345 Robertson GL. Diseases of the posterior pituitary. In: Felig D, Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and Metabolism, New York: McGraw-Hill, 1981:251–277. 346 Robertson GL. The physiopathology of ADH secretion. In: Tolis G, Labrie F, Martin JB et al., eds. Clinical neuroendocrinology: A pathophysiological approach. New York: Raven Press, 1979:247–260. 347 Richter D, Schmale H. Molecular aspects of the expression of the vasopressin gene. In: Czernichow P, Robinson AG, eds. Frontiers of hormone research, vol 13, Diabetes insipidus in man. Basel: S. Karger, 1985:37–41. 348 Zerbe RL, Robertson GL. Disorders of ADH. Med North America 1984;13: 1570–1574. 349 Vokes T, Robertson GL. Physiology of secretion of vasopressin. In: Czernichow P, Robinson AG, eds. Diabetes insipidus in man, Basel: S. Karger, 1985.

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350 Robertson GL. Regulation of vasopressin secretion. In: Seldin DW, Giebisch G, eds. The kidney: physiology and pathophysiology, New York: Raven Press, 1985:869–884. 351 Chini B, Mouillac B, Ala Y et al. Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor. Embo J 1995;14: 2176–2182. 352 van Lieburg AF, Verdijk MAJ, Schoute F et al. Clinical phenotype of nephrogenic diabetes insipidus in females heterozygous for a vasopressin type 2 receptor mutation. Hum Genet 1995;96:70–78. 353 Jinnouchi H, Araki E, Miyamura N et al. Analysis of vasopressin receptor type II (V2R) gene in three Japanese pedigrees with congenital nephrogenic diabetes insipidus: identification of a family with complete deletion of the V2R gene. Eur J Endocrinol 1996;134:689–698. 354 Sharif M, Hanley M. Stepping up the pressure. Nature 1992;357: 279–280. 355 Cheong HI, Park HW, Ha IS et al. Six novel mutations in the vasopressin V2 receptor gene causing nephrogenic diabetes insipidus. Nephron 1997;75: 431–437. 356 Wildin RS, Antush MJ, Bennett RL et al. Heterogeneous AVPR2 gene mutations in congenital nephrogenic diabetes insipidus. Am J Hum Genet 1994;55:266–277. 357 Holtzman EJ, Kolakowski LFJ, Geifman-Holtzman O et al. Mutations in the vasopressin V2 receptor gene in two families with nephrogenic diabetes insipidus. J Am Soc Nephrol 1994;5:169–176. 358 Knoers NV, van den Ouweland AM, Verdijk M et al. Inheritance of mutations in the V2 receptor gene in thirteen families with nephrogenic diabetes insipidus. Kidney Int 1994;46:170–176. 359 Oksche A, Dickson J, Schülein R et al. Two novel mutations in the vasopressin V2 receptor gene in patients with congenital nephrogenic diabetes insipidus. Biophys Biochem Res Com 1994;205:552–557. 360 Yuasa H, Ito M, Oiso Y et al. Novel mutations in the V2 vasopressin receptor gene in two pedigrees with congenital nephrogenic diabetes insipidus. J Clin Endocrinol Metab 1994;79:361–365. 361 Holtzman EJ, Harris HWJ, Kolakowski LFJ et al. Brief report: a molecular defect in the vasopressin V2-receptor gene causing nephrogenic diabetes insipidus. N Engl J Med 1993;328:1534–1537. 362 Wenkert D, Merendino JJJ, Shenker A et al. Novel mutations in the V2 vasopressin receptor gene of patients with X-linked nephrogenic diabetes insipidus. Hum Mol Genet 1994;3:1429–1430. 363 Pan Y, Metzenberg A, Das S et al. Mutations in the V2 vasopressin receptor gene are associated with X-linked nephrogenic diabetes insipidus. Nat Genet 1992;2:103–106. 364 Faa V, Ventruto ML, Loche S et al. Mutations in the vasopressin V2-receptor gene in three families of Italian descent with nephrogenic diabetes insipidus. Hum Mol Genet 1994;3:1685–1686. 365 Rosenthal W, Seibold A, Antaramian A et al. Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature 1992;359:233–235. 366 Shoji Y, Takahashi T, Suzuki Y et al. Mutational analyses of AVPR2 gene in three Japanese families with X-linked nephrogenic diabetes insipidus: two recurrent mutations, R137H and delta V278, caused by the hypermutability at CpG dinucleotides. Hum Mutat 1998;Suppl 1:S278–S283. 367 Tsukaguchi H, Matsubara H, Aritaki S et al. Two novel mutations in the vasopressin V2 receptor gene in unrelated Japanese kindreds with nephrogenic diabetes insipidus. Biochem Biophys Res Commun 1993;197: 1000–1010. 368 van den Ouweland AM, Dreesen JC, Verdijk M et al. Mutations in the vasopressin type 2 receptor gene (AVPR2) associated with nephrogenic diabetes insipidus. Nat Genet 1992;2:99–102. 369 Tsukaguchi H, Matsubara H, Inada M. Expression studies of two vasopressin V2 receptor gene mutations, R202C and 804insG, in nephrogenic diabetes insipidus. Kidney Int 1995;48:554–562. 370 Yokoyama K, Yamauchi A, Izumi M et al. A low-affinity vasopressin V2receptor gene in a kindred with X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 1996;7:410–414. 371 Merendino JJJ, Speigel AM, Crawford JD et al. Brief report: a mutation in the vasopressin V2-receptor gene in a kindred with X-linked nephrogenic diabetes insipidus. N Engl J Med 1993;328:1538–1541. 372 Tajima T, Nakae J, Takekoshi Y et al. Three novel AVPR2 mutations in three Japanese families with X-linked nephrogenic diabetes insipidus. Pediatr Res 1996;39:522–526. 373 Pan Y, Wilson P, Gitschier J. The effect of eight V2 vasopressin receptor mutations on stimulation of adenylyl cyclase and binding to vasopressin. J Biol Chem 1994;269:31933–31937.

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374 Friedman E, Bale AE, Carson E et al. Nephrogenic diabetes insipidus: an X chromosome-linked dominant inheritance pattern with a vasopressin type 2 receptor gene that is structurally normal. Proc Natl Acad Sci USA 1994;91: 8457–8461. 375 Oksche A, Moller A, Dickson J et al. Two novel mutations in the aquaporin-2 and the vasopressin V2 receptor genes in patients with congenital nephrogenic diabetes insipidus. Hum Genet 1996;98:587–589. 376 Fushimi K, Sasaki S, Marumo F. Phosphorylation of serine 256 is required for cAMP-dependent regulatory exocytosis of the aquaporin-2 water channel. J Biol Chem 1997;272:14800–14804. 377 Katsura T, Gustafson C, Ausiello D, Brown D. Protein kinase A phosphorylation is involved in regulated exocytosis of aquaporin-2 in transfected LLC-PK1 cells. Am J Physiol 1997;272:F817–F822. 378 Cheng A, van Hoek AN, Yeager M et al. Three-dimensional organization of a human water channel. Nature 1997;387:627–630.

379 Burbach JP, Luckman SM, Murphy D, Gainer H. Gene regulation in the magnocellular hypothalamo-neurohypophysial system. Physiol Rev 2001;81: 1179–1267. 380 Abbes AP, Bruggerman B, van Den Akker EL. Identification of two distinct mutations at the same nucleotide position, concomitantly with a novel (polymorphism in the vasopressin-neurophysin II gene (AVP-NP II) in two dutch families with familiarl neurohypophyseal (diabetes insipidus Clin Chem 2000;46:1699–1702. 381 Maghnie M, Cosi G, Genovese E et al. Central diabetes insipidus in children and young adults. N Engl J Med 2000;343:998–1007. 382 Kuwahara M, Iwai K, Ooeda T et al. Three families with autosomal dominant nephrogenic diabetes insipidus cansed by aquaporin-2 mutations in the C-terminus. Am J Hum Genet 2001;69:738–748.

S e c t i o n 2

Hypothalamic–Pituitary Dysfunction

C h a p t e r

8 The Hypothalamus Glenn D. Braunstein

ANATOMY The hypothalamus is one of the major portions of the diencephalon, and is situated at the base of the brain below the thalamus and above the pituitary (Figs 8.1 and 8.2). The anterior margin of the optic chiasm forms the anterior boundary of the hypothalamus, while the posterior margins of the mamillary bodies delineate the posterior boundary. The lateral borders are less well defined and vary at different levels. They are composed of the optic tracts, internal capsule, pes pedunculi, globus pallidus, and ansa lenticularis [1]. Between the chiasm and the mamillary bodies on the ventral surface is the tuber cinereum from which the pituitary stalk arises. The third ventricle lies in the center of the hypothalamus, and is connected to the lateral ventricles through the foramen of Monro, and to the fourth ventricle by the aqueduct of Sylvius. The overall dimensions of the hypothalamus are aproximately 1.5 (top-to-bottom) ¥ 1.5 (front-to-back) ¥ 1.3 (side-to-side) cm, and the weight is about 2.5 g [2]. This relatively small structure is packed with groups of nerve cell bodies which form distinct nuclei (see Figs 8.1 and 8.2). These nuclei can be divided into three zones (periventricular, medial, lateral) or four regions moving anterior to posterior (preoptic, supraoptic, tuberal, and mamillary) (Table 8.1) [3–5]. In addition to the nuclei, numerous afferent and efferent fibers connect the hypothalamus to the cerebral cortex and the brain stem.

HYPOTHALAMIC FUNCTIONS A number of functions have been ascribed to the hypothalamus based upon animal studies, clinical observations of disease states involving the hypothalamus, and electrical stimulation or destruction of hypothalamic regions in

humans. Because of the close association of hypothalamic nuclei to afferent and efferent tracts from cortical, thalamic, limbic, midbrain, and spinal regions, it has been difficult to localize precisely specific functions to specific nuclei in the hypothalamus. A lesion in a nucleus may also damage or interrupt transmissions from adjacent nerve fibers. Indeed, the nucleus may only serve as a synaptic junction for neural transmissions that begin and terminate elsewhere. In addition, many nuclei appear to subserve multiple functions, and more than one pair of nuclei may be involved with the same function. For example, the ventromedial nucleus is involved in appetite control, emotional expression, and short-term memory retention. The following sections summarize the current concepts regarding the normal functions of the hypothalamus. The reader is referred to several publications which review the clinical and experimental evidence upon which these summaries are based [3,6–9].

Water Metabolism Antidiuretic hormone (ADH; arginine vasopressin) is synthesized in the nerve cell bodies of the magnocellular neurons of the supraoptic and paraventricular nuclei. The hormone is packaged in secretory granules with a specific neurophysin and transported through axoplasmic streaming down long axons that terminate in the pituitary stalk and posterior pituitary. ADH is released into the blood when serum osmolarity increases or vascular volume decreases. Blood volume status is monitored by stretch receptors present in the left atrium and large pulmonary veins, while serum osmolarity changes are detected by peripheral and hypothalamic osmoreceptors. Increased serum osmolarity is the dominant stimulus for ADH release, and this is mediated primarily through the hypothalamic osmoreceptors located in the medial preoptic anterior hypothalamic region. 317

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Table 8.1.

Hypothalamic–Pituitary Dysfunction

Major hypothalamic nuclei Zone

Region

Periventricular

Medial

Lateral

Preoptic

Medial preoptic nucleus

Lateral preoptic nucleus

Mamillary

Posterior hypothalamic nucleus

Anterior hypothalamic nucleus Medial portion of supraoptic nucleus Dorsomedial hypothalamic nucleus Ventromedial hypothalamic nucleus Premamillary nucleus Medial mamillary nucleus

Lateral portion of supraoptic nucleus

Tuberal

Preoptic periventricular nucleus Anterior periventricular nucleus Suprachiasmatic nucleus Paraventricular nucleus Arcuate (infundibular) nucleus

Supraoptic

Lateral hypothalamic nucleus Lateral mamillary nucleus Intercalatus nucleus

Modified from [3–5].

their water permeability, allowing water to be reabsorbed from the urine into the hypertonic renal medullary interstitial region, from which it reenters the bloodstream. This reabsorbed water along with the water ingested in response to activation of the thirst mechanism reestablishes volume and decreases osmolarity, closing the feedback loop. Other factors that stimulate the release of ADH include hypotension, nausea, vomiting, nicotine, hypoglycemia, hypoxia, barbiturates, b-adrenergic drugs, morphine, tricyclic antidepressants, cholinergic drugs, and angiotensin II infusions. ADH release is inhibited by ethanol, atropine, aadrenergic drugs, diphenylhydantoin, and chlorpromazine [10].

Temperature Regulation

FIGURE 8.1 Schematic representation of lateral brain section demonstrating hypothalamic nuclei. Dashed lines represent the frontal (coronal) section planes illustrated in Figs. 8.2 and 8.3. Key to numbers: 1, preoptic nucleus; 2, paraventricular nucleus; 3, anterior hypothalamic area; 4, supraoptic nucleus; 5, arcuate nucleus; 6, dorsal hypothalamic area; 7, dorsomedial nucleus; 8, ventromedial nucleus; 9, posterior hypothalamic area; 10, mamillary body; 11, optic chiasm; 12, optic nerve.

The preoptic anterior hypothalamus harbors receptors for warmth (“warm receptors”), as well as “cold receptors” that respond to cold. When peripheral warm receptors are stimulated by a rise in ambient temperature, and the hypothalamic adrenergic warm receptors are activated by an increase in the temperature of the blood, efferent signals are transmitted to the lateral portion of the posterior hypothalamus via the median forebrain bundle. This leads to activation of the heat dissipating responses of vasodilatation and sweating. In contrast, activation of peripheral cold receptors through a decrease in environmental temperature, or activation of the serotonergic hypothalamic cold receptors, leads to medially placed neurons in the posterior hypothalamus activating the heat production and conservation mechanisms of shivering and vasoconstriction [6,7].

Appetite Control Osmoreceptors located in the lateral preoptic anterior hypothalamic region stimulate thirst in response to increased serum osmolarity [6]. Hypovolemia and hypotension also stimulate thirst. Under the influence of the secreted ADH, the distal tubules and collecting ducts of the kidneys increase

The physiology of caloric homeostasis is poorly understood. Feeding behavior involves cerebral cortical, limbic, and hypothalamic input. Animal studies have defined the ventromedial medial nucleus as the “satiety center”, which inhibits feeding when stimulated, and leads to hyperphagia

FIGURE 8.2 Frontal (coronal) sections of the hypothalamic regions. (a) represents the preoptic region (frontal section plane 1 in Fig. 8.1); (b) represents the supraoptic region (frontal section plane 2 in Fig. 8.1); (c) represents the tuberal region (frontal section plane 3 in Fig. 8.1); (d) represents the mamillary region (frontal section plane 4 in Fig. 8.1)

Chapter 8 The Hypothalamus

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when destroyed. In addition, a “feeding center” is present in the lateral hypothalamus, whereby stimulation leads to hyperphagia and destruction to hypophagia [11,12]. The mechanisms by which the body monitors caloric balance are unknown. Peripheral lipid sensors, intestinal mechanoreceptor, hepatic glucoreceptors, and hypothalamic glucoreceptors have been proposed [7]. The hypothalamus does contain glucoreceptors, and hypoglycemia can stimulate them to increase feeding behavior, but these receptors do not appear to be of physiologic importance [7].

Sleep–wake Cycle and Circadian Rhythm Control The most important area governing wakefulness is the reticular activating system of the brain stem. Lesions in this area result in coma, a state in which the individual cannot be aroused, even with noxious stimuli. The anterior hypothalamus contains a “sleep center,” stimulation of which leads to inhibition of the reticular activating system and sleep, from which, in contrast to coma, the animal or individual can be aroused. Stimulation of the posterior hypothalamus (“wakefulness center”) leads to wakefulness and arousal. The normal sleep–wake cycle may reflect the integrative activities of these two centers; alternatively, the cycle may be entrained in other regions such as the brain stem [6,7]. The suprachiasmatic nuclei control the circadian rhythms in anterior pituitary hermone release, as well as other physiologic rhythms [13,14]. Many of these rhythms are entrained through the visual system via the retinohypothalamic tract [15].

the medial tuberal region [3], increased motility activity of the gastrointestinal tract with stimulation of the preoptic anterior hypothalamus and posterior dorsolateral regions, and reduced bowel motility with ventromedial hypothalamic stimulation [3,7,16]. Gastric juice volume, acidity and pepsin content are increased with stimulation of the anteromedial hypothalamus, as well as the tegmentum of the brain stem [6,17].

Emotional Expression and Behavior Through the use of electrode stimulation or production of lesions in various hypothalamic regions of animals, as well as clinical observations on humans with hypothalamic diseases, the ventromedial nucleus has been found to play an important role in integrating cortical input with regard to behavior. Lesions in this area lead to rage with aggressive, often violent behavior, associated with activation of the sympathetic nervous system [7]. This behavior is referred to as “sham rage” to distinguish it from voluntary or cortical rage. The autonomic response is probably mediated through activation of the posterior hypothalamic sympathetic area. In man, electrical stimulation of the medial or posterior hypothalamus results in the sensations of fear or horror, while apathy and reduced activity is found with destructive lesions in these areas [8,18,19]. Lesions in the limbic system in the region of the caudal hypothalamus have been associated with aggressive, hypersexual behavior [20]. A “pleasure center” located in the medial forebrain bundle in the lateral hypothalamus of rats has been described [6], as has a “nourishing region” around the septal area, stimulation of which leads to lapping, licking, and chewing [3].

Regulation of Visceral (Autonomic) Functions Integration of sympathetic and parasympathetic autonomic nervous system activity is an important function of the hypothalamus. Stimulation of the “sympathetic region” in the posteromedial hypothalamus results in activation of the thoracolumbar autonomic response and a “fight-or-flight” reaction with pupillary dilatation, a rise in blood pressure, tachycardia, increased cardiac output, tachypnea, piloerection, vasoconstriction of the a-adrenergic receptor visceral vascular beds, and vasodilatation of the b-adrenergic responsive blood vessels in skeletal muscle [8]. Stimulation of the “parasympathetic region” in the preoptic anterior hypothalamus leads to increased vagal and sacral autonomic response with pupillary constriction, bradycardia, hypotension, increased blood flow in the visceral vascular bed, and decreased flow in the muscle blood vessels [7,8,16]. Because of the multitude of autonomic fibers running through the hypothalamus, stimulation of one area may result in a sympathetic response, while a parasympathetic type of response may be found with stimulation of an adjacent area. Other types of autonomic function that have been described in nonhuman animal studies include stimulation of micturition and defecation with electrical stimulation of

Memory Memory is a complex process that requires an intact brain stem reticular formation, limbic system, and hypothalamus. Short-term or recent memory requires intact ventromedial nuclei and hippocampus [6,7]. The role of the mamillary nuclei and dorsal medial nucleus in short-term memory is presently unclear [21].

Control of Anterior Pituitary Function The hypothalamus synthesizes and secretes several hypophysiotropic releasing and inhibitory hormones that regulate anterior pituitary function. The physiologic and pharmacologic factors that control the hypothalamic– pituitary–target organ axes are described in detail elsewhere in this volume. Several immunohistochemical studies have localized the various factors in the hypothalamus. Although the nerve cell bodies in which the factors are synthesized are widely distributed throughout the hypothalamus, the axons converge at the median eminence (neurovascular zone) as part of the tuberoinfundibular system and terminate on or near the hypothalamohypophysial portal vessels in

Chapter 8

which they discharge the hypophysiotropic substances under appropriate stimulation [22]. The highest concentrations of nerve cell bodies for gonadotropin-releasing hormone (GnRH) are located in the medial basal hypothalamus and preoptic areas [23]. Thyrotropin-releasing hormone (TRH) neurons are found in the suprachiasmatic, preoptic medial, and paraventricular nuclei [24], while corticotropin-releasing hormone (CRH) has been localized to the paraventricular nucleus [25]. Growth hormone-releasing hormone (GHRH)-containing neurons are found in the arcuate nucleus [26], as are neurons synthesizing somatostatin [27]. Dopaminergic neurons, which presumably inhibit prolactin secretion through dopamine release into the hypothalamohypophysial portal vessels, are found primarily in the arcuate nucleus, with smaller amounts found in the dorsomedial, ventromedial, periventricular, paraventricular nuclei, and median forebrain bundle [28]. In addition to the peptides and amines with established physiologic pituitary regulatory functions, the hypothalamus is replete with a large number of biologically active substances, many of which are located in the same neurons that harbor the hypophysiotropic factors (Table 8.2). PATHOPHYSIOLOGICAL PRINCIPLES Considering the large number of important physiologic functions that depend upon the integrity of the hypothalamus, the close proximity of the nuclei and tracts, and the small overall size of the structure, one would anticipate that diseases involving the hypothalamus would give rise to a plethora of clinical syndromes. Indeed, this is the case, but despite the diversity of findings from patient to patient, several general principles regarding the pathophysiology of signs and symptoms of hypothalamic dysfunction have been established through careful clinical observation [6,7, 29–33]. 1. The spectrum of diseases that can affect the hypothalamus is large, and different lesions may produce identical signs and symptoms of hypothalamic damage. Multiple pathologic processes in each of the major disease categories can involve the hypothalamus (Table 8.3). Bauer reviewed 60 patients with hypothalamic involvement by a variety of diseases documented by autopsy [29,30]. Despite the diversity of pathologic abnormalities, 78% had neuroophthalmologic abnormalities (in 13% these were the first manifestations), 75% developed pyramidal tract or sensory nerve involvement, 65% had headaches, 62% showed extrapyramidal cerebellar signs, and 40% exhibited recurrent vomiting. Findings more specific to the hypothalamus included precocious puberty in 40% (undoubtedly reflecting a selection bias due to the types of case reports in which autopsies were performed), diabetes insipidus in 35%, hypogonadism in 32%, somnolence in 30%, dysthermia in 28%, and obesity

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Table 8.2. Biologically active substances present in paraventricular and arcuate nucleus neurons Paraventricular nucleus Magnocellular division Angiotensin II Cholecystokinin Glucagon Oxytocin Peptide 7B2 Proenkephalin B (dynorphin, rimorphin, a-neoendorphin) Vasopressin Parvocellular division Angiotensin II Atrial natriuretic factor Cholecystokinin Corticotropin-releasing hormone Dopamine Follicle-stimulating hormone-releasing factor g-Aminobutyric acid Galanin Glucagon Neuropeptide Y Neurotensin Peptide 7B2 Proenkephalin A (methionine enkephalin, leucine enkephalin, BAM 22P, metorphamide, [Met]enkephalin-Arg6-Phe7-Leu8, [Met]enkephalin-Arg6Gly7-Leu8) Somatostatin Thyrotropin-releasing hormone Vasopressin Vasoactive intestinal polypeptide/Peptide histidine isoleucine Arcuate nucleus Acetylcholine Dopamine Galanin g-Aminobutyric acid Growth hormone-releasing hormone Neuropeptide Y Neurotensin Pancreatic polypeptide Proenkephalin A Prolactin Proopiomelanocortin (adrenocorticotropic hormone, b-lipotropin, g-melanocyte-stimulating hormone, b-endorphin) Somatostatin Substance P From Lechan [22].

or emaciation in 25%. Although most of the different hypothalamic syndromes can result from a large proportion of the disease listed in Table 8.3, some pathologic processes result in a restricted number of syndromes. For instance, the gliosis of the supraoptic and paraventricular nuclei that occurs in familial or idiopathic diabetes insipidus has diabetes insipidus as its only hypothalamic

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Table 8.3.

Hypothalamic–Pituitary Dysfunction

Etiologies of hypothalamic dysfunction

Congenital Acquired Developmental malformations Anencephaly Porencephaly Agenesis of the corpus callosum Septooptic dysplasia Suprasellar arachnoid cyst Colloid cyst of the third ventricle Hamartoma Aqueductal stenosis Trauma Intraventricular hemorrhage Genetic (Familial or sporadic cases) Hypothalamic hypopituitarism Familial diabetes insipidus Prader–Willi syndrome Bardet–Biedl syndrome Wolfram’s syndrome Pallister–Hall syndrome Tumors Primary intracranial tumors Angioma of the third ventricle Craniopharyngioma Ependymoma Ganglioneuroma Germ cell tumors Glioblastoma multiforme Glioma Hamartoma Hemangioma Lipoma Lymphoma Medulloblastoma Meningioma Neuroblastoma Pinealomas Pituitary tumors Plasmacytoma Sarcoma Metastatic tumors Infiltrative Histiocytosis Leukemia Sarcoidosis Immunologic Idiopathic diabetes insipidus Paraneoplastic syndrome

Nutritional/metabolic Anorexia nervosa Kernicterus Wernicke–Korsakoff syndrome Weight loss Degenerative Glial scarring Parkinson’s Infectious Bacterial Meningitis Mycobacterial Tubrculosis Spirochetal Syphilis Viral Cytomegalovirus Encephalitis Jakob–Creutzfeldt Kuru Poliomyelitis Varicella Vascular Aneurysm Arteriovenous malformation Pituitary apoplexy Subarachnoid hemorrhage Vasculitis Trauma Birth injury Head injury Postneurosurgical Functional Diencephalic epilepsy Drugs Hayek–Peake syndrome Idiopathic SIADH Kleine–Levin syndrome Periodic syndrome of Wolff Psychosocial deprivation syndrome Other Radiation Porphyria Toluene exposure

manifestation. Similarly, hamartomas have precocious puberty and galastic seizures as their primary manifestations, due to their endocrine activity and/or their specific location in the tuber cinereum. Many of the pathologic processes have characteristic appearances on

magnetic resonance imaging that are helpful diagnostically [34]. 2. As a general rule, patients with systemic illnesses such as sarcoidosis, histiocytosis, and infections that involve the hypothalamus usually, but not uniformly, have nonhypothalamic manifestations of the disease process. Isolated sarcoid lesions may be found in the hypothalamus, but more commonly ophthalmologic and extracranial disease coexists. Unifocal eosinophilic granulomas have been described in the hypothalamus, but usually such involvement reflects disseminated histiocytosis and bony lesions generally are present also. Tuberculous meningitis, neurosyphilis, and viral illnesses are rarely confined to the hypothalamus, although hypothalamic symptoms may be early manifestations of the disease. 3. The site of a lesion causing a dysfunction does not necessarily correspond to the site from which the function emanates. As noted above, the hypothalamic nuclei are closely packed and interspersed among various fiber tracts whose origins or destinations may be the cerebral cortex, midbrain, thalamus, limbic system, spinal cord, or even other nuclei within the hypothalamus. Since disease processes involving the hypothalamus tend to be rather large in relation to the size of the hypothalamus, it is rare to find a lesion involving only one nucleus or a single tract. Therefore, it is not surprising that in Bauer’s series most patients had mixtures of neurologic or neuroophthalmologic signs and symptoms in addition to endocrine abnormalities [29,30]. 4. The clinical manifestations depend in part upon the rate of progression of the disease process. Patients with small, rapidly progressive lesions often develop symptoms early, while slowly progressive lesions may remain asymptomatic for long periods, allowing some to obtain relatively immense size before clinical evidence of the disease becomes apparent. Presumably in the latter instance, the slow growth allows for the other areas of the hypothalamus or extrahypothalamic regions to compensate for the deficits induced by the lesion. Acute insults, such as vascular accidents or trauma, tend to result in decreased consciousness, hyperthermia, and diabetes insipidus which may be transient if the patient survives the initial injury. Chronic lesions tend to alter cognitive ability and endocrine function, and are not reversible. 5. Although lesions that involve a single, unilateral area of the hypothalamus may result in symptoms, most lesions resulting in chronic hypothalamic syndromes are bilateral, though not necessarily symmetrical. Since most of the hypothalamic functions are controlled by one or more pairs of nuclei, destruction of a single nucleus usually is not sufficient to result in a clinical syndrome. From a pathophysiologic standpoint, this implies that pathologic processes that are multiple (i.e., metastatic

Chapter 8

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tumors, granulomatous diseases), arise in or around the third ventricle (colloid cysts), cause enlargement of the third ventricle (pinealomas, germ cell tumors, midbrain gliomas, aqueductal stenosis), or impinge upon or invade the floor of the hypothalamus (craniopharyngiomas, optic gliomas, pituitary adenomas) will be more likely to result in clinical signs and symptoms of hypothalamic disease than will diseases that affect the lateral portions of the hypothalamus. 6. Lesions involving hypothalamic nuclei may give different syndromes depending upon whether the lesion results in stimulation or destruction of the nuclei. Thus, stimulatory lesions in the tuberal area may result in precocious puberty, while destructive lesions may lead to hypogonadism. Hyperthermia is associated with stimulation of the preoptic region, while hypothermia is the clinical consequence of destruction of the same area. 7. The clinical manifestations of hypothalamic disease depends upon the age of onset. As a rule, the hypothalamus of neonates is quite immature, and diseases afflicting the neonatal or infant hypothalamus present different symptoms than the same disease affecting the same region in an older child or an adult. The diencephalic syndrome of infancy due to a glioma involving the anterior hypothalamus is an example of this phenomenon. The affected infants eat seemingly adequate quantities of food, yet lose weight. They tend to be hyperactive and euphoric. After the age of two years, the surviving infants undergo a dramatic change by gaining weight, becoming obese, and displaying irritable behavior [7]. Another type of age-related disease manifestation is the effect of hypopituitarism due to hypothalamic abnormalities. Gonadotropin deficiency that occurs before puberty will result in a lack of pubertal changes with maintenance of the sexually infantile state. Acquired hypothalamic hypogonadism that has its onset in an adult may lead to some regression of secondary sexual characteristics, but such individuals do not appear sexually infantile. GH deficiency due to hypothalamic disease in a prepubertal individual is associated with short stature, while a similar deficiency in an adult is clinically inapparent.

Manifestations of Hypothalamic Disease Keeping the above general principles in mind, and based upon careful pathologic studies of patients with hypothalamic diseases, a topographic map of the hypothalamus which correlates clinical findings with anatomic sites of lesions can be constructed [35–44] (Fig. 8.3).

Disorders of Water Metabolism Central Diabetes Insipidus

This condition results from a partial or complete absence of ADH. Without sufficient ADH, the distal tubules and

FIGURE 8.3 Clinical findings associated with hypothalamic lesions located at various anatomical sites. Clinicopathologic correlation based upon multiple studies [31–40]. (a) corresponds to region depicted in Fig. 8.2a; (b) corresponds to region depicted in Fig. 8.2c; (c) corresponds to section depicted in Fig. 8.2d.

collecting ducts of the kidneys are unable to adequately reabsorb water, leaving the urine inappropriately hypotonic relative to the plasma osmolarity. The persistent diuresis leads to polyuria (up to 10–12 l/day) and nocturia, which in turn stimulates the thirst mechanism to bring about water-seeking behavior and polydipsia. If the osmoreceptor mechanism is intact and the patient is conscious and has

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access to fluids, the plasma osmolarity may be maintained within the normal range. However, if the osmoreceptors of the thirst center are damaged, or if the patient is unable to ingest adequate quantities of water, hypernatremic dehydration may occur and result in rapid deterioration of the sensorium from lethargy to stupor to coma. Patients with lesser deficiencies of ADH may release enough of the hormone to maintain adequate water balance under basal conditions. In contrast to patients with complete diabetes insipidus, patients with partial diabetes insipidus may increase their urine osmolarity to a level above their plasma osmolarity during dehydration. However, in both conditions, the administration of exogenous vasopressin to a dehydrated patient will result in a further increase in urine osmolarity, while dehydrated normal individuals will show little or no further increase in urine osmolarity after a standard dehydration test. Diabetes insipidus results from lesions involving the magnocellular neurons of the supraoptic and paraventricular nuclei or that interrupt the supraopticohypophysial tracts that terminate in the pituitary stalk or posterior pituitary. Such lesions are commonly found in patients with hypothalamic disorders. Transient diabetes insipidus may be found in individuals with posterior pituitary or low pituitary stalk lesions, or in patients with acute, reversible hypothalamic lesions. In Bauer’s series of anatomically proven chronic hypothalamic lesions, 21 (35%) of the patients had diabetes insipidus at some time during the course of their illness [29,30]. Although it was the second-most frequent manifestation of hypothalamic disease, in only 3% of cases was diabetes insipidus the initial manifestation. Diabetes insipidus is often associated with hypogonadism and obesity, reflecting the anterior, medial hypothalamic localization of lesions affecting the supraoptic and paraventricular nuclei. The spectrum of pathologic lesions accounting for diabetes insipidus from two large series is shown in Table 8.4. Idiopathic diabetes insipidus comprises the largest single category of causes and over a third of these patients have circulating vasopressin cell antibodies suggesting an autoimmune etiology [48]. In this condition, loss of magnocellular nerve cell bodies and gliosis is found in the supraoptic and paraventricular nuclei [49]. The same pathologic findings are present in patients with familial central diabetes insipidus but these patients do not have anti-ADH antibodies. Rather, mutations in the vasopressin precursor molecule gene have been found in some families [50]. Both sex-linked recessive and autosomal dominant forms of this latter condition have been described. An autosomal recessive form (Wolfram’s syndrome) exists, composed of central diabetes insipidus, insulin-dependent diabetes mellitus, primary optic atrophy, bilateral sensorineural deafness, and in some families, autonomic neurogenic bladder and ataxia [51]. Degeneration of the paraventricular and, to a lesser extent, the supraoptic nuclei have been noted in this syndrome, as has atrophy of the posterior pituitary [52].

Table 8.4.

Etiologies of diabetes insipidus

Etiology

Number of patients

Percentage

Idiopathic/familial Neoplasm Primary intracranial Metastatic Lymphoma Leukemia Trauma Histiocytosis Infectious Neurosyphilis Meningitis Postencephalitic Sarcoidosis Other*

138

42

71 15 3 3 18 23

21 5 1 1 5 7

9 3 5 4 40

3 1 2 1 11

Total

332

100

* Cerebral atherosclerosis, birth injury, postvaccinal, giant cell granuloma, systemic illness, postirradiation, congenital malformation, and postoperative. Adapted from [45–47].

Deficiency of ADH is frequently seen with hypothalamic involvement by suprasellar germinomas (85%) [53,54], pineal germinomas (40%) [53,55], the chronic disseminated form of histiocytosis (50%) [56], and sarcoidosis (58%) [57–60]. Diabetes insipidus may also be found in patients with septooptic dysplasia (23%) [61–64], pinealomas (18%) [55], hypothalamic gliomas (17%) [65,66], and craniopharyngiomas (14%) [53]. Adipsic or Essential Hypernatremia (Cerebral Salt Retention Syndrome)

Damage to the osmoreceptors in the anterior medial and anterior lateral preoptic regions of the hypothalamus may bring about essential hypernatremia which is characterized by chronic, fluctuating elevations of serum sodium (and chloride), often to dangerously high levels, despite the spontaneous ingestion of amounts of fluid (1–2 l/day) that are capable of maintaining appropriate plasma osmolarity in otherwise normal adults. Affected individuals have an impaired thirst mechanism, demonstrating hypodipsia or adipsia despite the marked elevations in serum sodium. Nevertheless, these patients have a normal volume of extracellular fluid and are not dehydrated, and, therefore, maintain a normal blood pressure, pulse rate, blood–urea nitrogen, serum creatinine, and creatinine clearance. Since vascular volume status also regulates ADH release, these patients can release ADH and concentrate their urine with volume depletion. However, even while hypernatremic, an oral or intravenous intake of a large volume of water only results in inhibition of ADH release due to increased volume, culminating in the excretion of a dilute urine. Most

Chapter 8

of these patients do have partial diabetes insipidus, as their urine osmolarity does increase with exogenous administration of ADH [7,29,30,32,67,68]. Clinically, few symptoms reflecting hypernatremia are found with serum sodium concentrations below 160 mmol/l. Above this level, patients develop fatigue, lethargy, weakness, muscle tenderness and cramps, anorexia, depression, and irritability. Stupor and frank coma may be found with sodium concentrations greater than 180 mmol/l. Although the pituitary gland at autopsy is normal, anterior pituitary hormone deficiencies are found in 71% of patients, reflecting the hypothalamic etiology of the hypopituitarism [67]. Obesity has been noted also in 43% of the patients. Additionally, hypertriglyceridemia has been found in five of six subjects (83%) in whom this measurement has been reported [67]. The pathologic processes that have been associated with essential hypernatremia include suprasellar germinomas, histiocytosis, sarcoidosis, craniopharyngiomas, ruptured aneurysms, optic nerve gliomas, pineal tumors, trauma, hydrocephalus, cysts, inflammatory conditions, and toluene exposure [69]. Recently a few children have been described with essential hypernatremia but without a structural hypothalamic defect being found (Hayek–Peake syndrome). They demonstrate recurrent hypernatremia, hypodipsia, obesity, hyperprolactinemia, hypothyroidism, hyperlipidemia, lethargy, increased perspiration, and in some cases, central hypoventilation [20,21]. The findings suggest a functional derangement in the anterior medial hypothalamic region with involvement of the osmoreceptors and the ventral medial nucleus. Syndrome of Inappropriate Secretion of ADH (SIADH)

This condition is characterized by serum hypoosmolarity and hyponatremia, an inappropriately concentrated urine for the low serum osmolarity, continued urinary excretion of sodium despite the low serum sodium, and hypouricemia in a patient with normal renal, adrenal, and thyroid function, and who does not exhibit findings of extracellular fluid volume expansion (i.e., no evidence of congestive heart failure, cirrhosis, or other edematous states). This condition may be due to drugs, activation of peripheral volume receptors, peripheral neuropathies, ectopic production of ADH from neoplasms, or intracranial processes. In some individuals the syndrome is due to a decrease in the setpoint for the serum osmolarity release of ADH. Indeed, SIADH may occur, usually transiently, following head trauma, intracranial bleeds, meningitis, encephalitis, transsphenoidal pituitary surgery, and other neurosurgical procedures. It has also been noted in some patients with hydrocephalus, craniopharyngiomas, germinomas, pinealomas, central pontine myelinolysis, and acute intermittent porphyria [53]. In the latter situation it is not clear whether this is a reflection of a hypothalamic lesion or the result of a peripheral neuropathy [7,32]. An idiopathic, cyclic form of the syndrome has been found in young women with menstrual irregu-

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larities, and enlarged lateral ventricles. No hypothalamic pathology has been identified in patients with the idiopathic variety [10]. Besides symptoms from the underlying disease, these patients demonstrate the clinical findings of water intoxication. Mild decrements in serum sodium, between 130 and 120 mmol/l, generally result in weight gain without edema, anorexia, nausea, vomiting, headache, weakness, withdrawal, and lethargy. Mental confusion is common at concentrations below 120 mmol/l, and seizures and coma may also develop, especially if the decrease in sodium occurs rapidly.

Dysthermia Hyperthermia

Acute injury to the anterior hypothalamic and preoptic areas from intracranial bleeds, neurosurgical procedures in the region of the floor of the third ventricle, or trauma may result in temperature elevations up to 41°C, tachycardia, and unconsciousness that generally lasts for less than 2 weeks if the patient survives. With such lesions, heat production continues, while the heat-dissipating mechanisms fail to respond appropriately. The pulse rate in patients with hyperthermia due to hypothalamic lesions is not increased to the same extent for a given elevation in temperature as is the pulse rate in patients with fever from infections or inflammatory processes [3,6,7,29,30]. Acute hyperthermia to 41°C or greater is a characteristic of the neuroleptic malignant syndrome. This syndrome develops in susceptible individuals over 24 to 72 hours following exposure to phenothiazines, butyrophenones, thioxanthenes, or ioxapine. The potential for development of the syndrome roughly parallels the antidopaminergic D2 receptor potency of the neuroleptic drug. It has been hypothesized that the syndrome results from basal ganglia dopamine D2 receptor blockade which activates heat generation through muscle contraction, impairment of heat dissipation through hypothalamic injury, and inhibition of diaphoresis through a peripheral anticholinergic effect of the neuroleptics [72]. Autopsy studies have shown injury in the preoptic medial and tuberal nuclei [72]. Other clinical characteristics of the syndrome include hypertonicity of the skeletal muscles with “lead-pipe” type of rigidity, fluctuating consciousness varying from agitation to stupor to coma, and instability of the autonomic nervous system reflected by pallor, diaphoresis, wide swings in blood pressure, tachycardia and arrhythmias, tremors, and akinesis. Leukocytosis, elevations of serum creatine phosphokinase, and nonspecific encephalopathic findings on electroencephalography (EEG) are also found [73]. The syndrome lasts 5 to 10 days and currently carries a 20–30% mortality rate [74]. Sustained or chronic hyperthermia is found with lesions in the tuberoinfundibular region. Ten percent of the patients in Bauer’s series exhibited chronic hyperthermia

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[29,30], which may result from loss of heat-dissipating mechanisms, stimulation of the heat-conservation mechanisms, or elevation of the setpoint for activation of the heat dissipation [7]. Patients with chronic hypothalamic hyperthermia do not exhibit the generalized malaise that accompanies elevated temperatures due to infections, and also have paradoxical peripheral vasoconstriction with cold, clammy extremities. The hyperthermia may respond to sedatives or anticonvulsant medications, but not to salicylates [29,30]. Spontaneous paroxysmal hyperthermia of probable hypothalamic origin but without pathologic lesions in the hypothalamus has been described in a few patients. In most individuals, the episodes occur sporadically and are characterized by shaking chills, fever, hypertension, vomiting, and peripheral vasoconstriction. Resolution over minutes to hours is accompanied by vasodilatation and diaphoresis. A similar syndrome occurring at regular 3-week intervals was described by Wolff, and may represent a form of diencephalic epilepsy [7,75,76]. Hypothermia

Chronic hypothermia with temperatures below 32°C was present in 12% of the patients described by Bauer [29,30], and this finding was usually associated with large lesions involving the anterior and/or posterior hypothalamus. Destruction of the thermoregulatory mechanisms by such lesions results in an inability to generate heat through shivering and vasoconstriction. Hypothermia has been noted in third-ventricular and large hypothalamic neoplasms, poliomyelitis, neurosyphilis, sarcoidosis, multiple sclerosis, gliosis of the anterior hypothalamus, posterior hypothalamic neuronal pyknosis in Parkinson’s disease, and with the periventricular and mamillary body destruction seen with Wernicke’s encephalopathy [57,76–81]. Episodic or paroxysmal hypothermia, also known as diencephalic autonomic epilepsy, is a distinct syndrome in which body temperatures abruptly decrease, often to 32°C or lower, over a period of minutes to days, associated with a variety of signs and symptoms of autonomic nervous system dysfunction [7,35,82–88]. The frequency of attacks varies from daily to decades apart. Patients experience flushing, diaphoresis, fatigue, hypotension, bradycardia, salivation, lacrimation, pupillary dilatation, Cheyne–Stokes respirations, nausea, vomiting, asterixis, ataxia, and obtundation. Thus, during the episodes heat generation is impaired and heat loss is increased due to the vasodilatation and sweating. EEG slowing occurs during the episodes. Recovery occurs spontaneously over hours to days, and is associated with heat generation through shivering and vasoconstriction. Attacks often begin in the teenage years and the frequency and duration of attacks may increase as the patient ages. Some degree of thermal regulation is maintained during the episodes, since experimentally lowering the temperature further results in shivering and vasoconstriction, suggesting that there is a resetting of the thermostat during the episodes

[87]. This syndrome has been found in some patients with tumors involving the floor and lower walls of the third ventricle [35,82]. In others, gliosis and loss of the arcuate nucleus and the premamillary area have been noted at autopsy. In addition, approximately half of the patients with episodic hypothermia have an agenesis of the corpus callosum, a combination given the eponym “Shapiro’s syndrome” [83,84]. Such patients may also have hypogonadism, precocious puberty, diabetes insipidus, reset osmostat, and GH deficiency [83,86,87]. Poikilothermia

This condition – the tendency of the individual to assume the ambient temperature – results from loss of both heat conservation and heat-loss homeostatic mechanisms. Wide fluctuations of temperature are seen, and affected patients do not experience thermal discomfort, nor attempt to alter their environment to maintain their core body temperature. This condition, noted in 1.7% of the patients in Bauer’s series, is found with large lesions involving the posterior hypothalamus and rostral mesencephalon, as well as in patients with both anterior and posterior hypothalamic destruction [7,29,30]. Poikilothermia may also be found in Wernicke’s encephalopathy [7].

Disorders of Caloric Balance Hypothalamic Obesity

Obesity is a common finding in patients with hypothalamic diseases, occurring in approximately 25% of individuals with anatomically proven lesions, although rarely is it the initial manifestation of hypothalamic dysfunction [29,30]. Most patients with hypothalamic obesity have large lesions or extensive involvement of multiple areas of the hypothalamus. Nevertheless, based upon careful study of the few patients with well-described, discrete lesions, it is clear that bilateral destruction of the ventromedial nucleus results in obesity in man, as it does in experimental studies in animals [3,11,29,30,37,38,42]. In patients with documented structural involvement, close to 90% have a neoplasm, most often a craniopharyngioma (approximately 60%) [11]. Approximately 6% are the result of inflammatory or granulomatous processes including sarcoidosis, tuberculosis, arachnoiditis, and encephalitis, 5% are posttraumatic, and 2% are due to leukemic infiltration [11]. As would be anticipated from the location of the lesions that lead to obesity, other clinical findings are commonly present. In a series of 69 patients analyzed by Bray and Gallagher, 72% had headaches, 72% had decreased vision or visual field abnormalities, 56% exhibited reproductive dysfunction such as amenorrhea, impotence, or diminished libido, 35% had disordered water metabolism with diabetes insipidus, polyuria, and/or polydipsia, 40% were somnolent, 20% had behavioral abnormalities, and 7% had seizures [11]. The association between obesity and hypogonadism has long

Chapter 8

been noted since Froehlich described his patient, who was subsequently found to have a craniopharyngioma, with “dystrophic adiposogenitalis.” The affective disorders that coexist with hypothalamic obesity vary from antisocial behavior to sham rage [38]. The obesity is clearly the result of hyperphagia. In many instances the abnormality appears to reflect a resetting of the satiety setpoint. This is best seen in patients with obesity that develops following trauma. Most affected individuals gain weight for approximately 6 months following the trauma, followed by a period of stabilization as the energy expenditure equals the caloric content of the ingested food, with a subsequent gradual decrease in food intake and a loss of weight [11]. Similarly, patients with tumor destruction of the ventromedial nuclei may develop hyperphagia and a rapid gain in weight, followed by a plateau, and then a further weight gain as the neoplasm grows [7]. Some patients display an indiscriminate food intake and even will ingest left-over scraps destined for the garbage, while others will show a finickiness that closely resembles that seen in rats with bilateral lesions in the ventromedial nuclei [11]. These patients have hyperinsulinemia to a greater extent than do patients with essential obesity, and it has been proposed that this is due to enhanced insulin secretion through stimulation of the vagus nerve, as increased vagal firing rate has been noted in animals with ventromedial nucleus lesions [12]. Hypothalamic Cachexia in Adults

In Bauer’s series, 18% of the patients exhibited substantial weight loss, 7% had anorexia, and 8% were bulimic [29,30]. Destruction of both the ventromedial nuclei and the lateral hypothalamus leads to anorexia and emaciation, as do lesions isolated to the lateral hypothalamus [37,38,41]. The features of the lateral hypothalamic syndrome include rapid weight loss, muscle wasting, decreased activity, and hypophagia leading to cachexia and death. The most common lesions accounting for this syndrome are neoplasms, although cysts, and malignant multiple sclerosis also have been described as causes [37,41]. Diencephalic Syndrome of Infancy

In 1951, Russell described an unusual syndrome in infants with hypothalamic tumors of severe emaciation despite an apparently good food intake, associated with an alert appearance and euphoric affect, and nystagmoid eye movements [89]. The majority (80%) of these infants have been found to have low-grade hypothalamic or optic nerve gliomas that destroy the ventromedial nuclei [6,7,90]. Rarely ependymomas, gangliogliomas, and dysgerminomas give rise to the syndrome [90]. The infants appear normal at birth and demonstrate normal feeding and developmental parameters during the first 3–12 months. Towards the end of the first year of life, the infants begin to lose weight and subcutaneous fat, show signs of hyperactivity and a cheerful, happy

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affect, but continue to grow normally. They exhibit an alert appearance secondary to eyelid retraction (Collier sign) [90]. Other findings including nystagmus, pallor, vomiting, tremor, and optic atrophy may be present (Table 8.5). Endocrine evaluation is generally normal, although absent diurnal variation in plasma cortisol concentrations, and elevated basal serum GH levels with a paradoxical rise following a glucose load, have been found [32]. The elevated GH levels are not specific to these patients, since other illnesses associated with weight loss, such as anorexia nervosa, also are accompanied by such elevations. Usually the infants succumb to the tumor and emaciation by the age of 2 years. Paradoxically, infants who survive beyond age 2, either due to spontaneous stabilization or therapy, often maintain their good appetite, gain weight, and become obese. In addition, their pleasant personality is replaced by irritability and rage, and they may develop somnolence and precocious puberty [6,90,91]. This syndrome nicely illustrates the fact that the manifestations of hypothalamic disease are related in part to the age of patient and maturity of the hypothalamus. Anorexia Nervosa

The typical patient with anorexia nervosa is a young, white female from a middle to upper socioeconomic background who inappropriately views herself as obese, and, therefore, severely restricts her food intake, exercises excessively, and may engage in bulimic binges with self-induced vomiting, and diuretic and cathartic abuse. The typical age of onset is less than 25 years, the patients lose more than 15% of their weight, and are usually 25% below their ideal body weight.

Table 8.5. Clinical findings in 67 patients with diencephalic syndrome of infancy Feature Emaciation Alert appearance Increased vigor and/or hyperkinesis Vomiting Euphoria Pallor Hydrocephalus Nystagmus Irritability Optic atrophy Tremor Sweating Large hands/feet Large genitalia Polyuria Papilledema Endocrine abnormalities From Burr et al. [90].

Percentage 100 87 72 68 59 55 33 55 32 23 23 15 <5 <5 <5 <5 90

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Amenorrhea is a characteristic finding and often precedes the weight loss, and may persist even after the patient regains her weight [92]. A number of endocrine abnormalities have been noted. A prepubertal pattern of gonadotropin release is characteristically present with low basal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations, a prepubertal, apulsitile 24-hour LSsecretory pattern, a diminished LH response to GnRH, and a loss of the positive feedback effect of estrogen on LH secretion [93]. With weight gain, the patients enter a “second puberty,” developing nocturnal secretory pulses of LH, and eventually an adult pattern of pulsatile LH release throughout the day and night [93]. The GnRH response also returns to normal. Basal serum GH levels are normal or elevated, and rise paradoxically following a glucose load. The GH response to GHRH is normal, but the response to l-dopa and apomorphine is impaired [93]. A rise in serum GH levels may also occur following an injection of TRH, a response also found in patients with acromegaly, depression, chronic renal failure, and cirrhosis [93]. The major mediator of GH action, insulin-like growth factor-I (IGF-I, somatomedin-C), is low, suggesting that the elevations in serum GH are due to decreased feedback inhibition by IGF-I. A reduction in tonic inhibition of GH secretion through a lowering of somatostatin has been suggested following the finding of decreased somatostatin levels in the cerebrospinal fluid [93]. The GH abnormalities revert to normal with weight gain. Patients with anorexia nervosa also exhibit abnormalities in the hypothalamic–pituitary–adrenal axis. Plasma adrenocorticotropic hormone (ACTH) concentrations are diminished, while plasma cortisol levels are elevated, reflecting a decrease in the clearance of cortisol, since the cortisol production rate remains normal [92,93]. As is found in patients with Cushing’s syndrome, depression, and obesity, the reduction in plasma or serum cortisol is inadequate following the administration of dexamethasone. An attenuated response to a bolus injection of CRH has also been found. The abnormalities return to normal following weight gain. These individuals share many clinical features with hypothyroid patients, including dry skin with a yellowish hue due to hypercarotinemia, scalp hair loss, bradycardia, and hypothermia. Their thyroid function tests are similar to those seen in patients with the “sick euthyroid syndrome.” Thus, serum thyroxine levels are in the low normal or frankly low range, the triiodothyronine concentrations are low, the reverse triiodothyronine levels are elevated, and the thyroid stimulating hormone (TSH) concentrations are in the low normal range. The serum TSH response to TRH is either normal or shows a delayed rise with a peak at 45 or 60 minutes, characteristic of hypothalamic hypothyroidism. As with the other hormonal abnormalities, the thyroid dysfunction resolves with weight gain. Although most patients with classical anorexia nervosa do not have hypothalamic anatomic abnormalities, there is

convincing evidence that this disorder has a component of hypothalamic dysfunction. In addition to the neuroendocrine abnormalities noted above, these patients may have hyperprolactinemia with galactorrhea, a poikilothermic type of thermal dysregulation, and a partial diabetes insipidus [94]. It is unknown whether the hypothalamic abnormalities reflect a primary hypothalamic etiology of pathophysiologic importance to the genesis of anorexia nervosa, or whether the dysfunction is an epiphenomenon of a major psychiatric derangement and the associated weight loss. Diencephalic Glycosuria

Transient hyperglycemia and glycosuria may occur following hypothalamic injury that results in lesion of the tuberoinfundibular region [3,95]. This has been most commonly noted after basal skull fractures, intracranial hemorrhage, or surgery near the floor of the third ventricle. Although each of these entities is associated with elevated concentrations of ACTH, glucocorticoids, GH, and catecholamines, which have insulin-contraregulatory effects, the occurrence of hyperglycemia with injuries to the tuberoinfundibular region and not with injuries to other areas of the hypothalamus which may also be associated with elevations of the same hormones, suggests that other factors are involved. This may be analogous to pique hyperglycemia found with brain stem lesions.

Sleep–wake Cycle Second Circadian Abnormalities Alterations in consciousness and the sleep–wake cycle rhythm are relatively common in patients with hypothalamic disease. Somnolence is most often seen, is found in 30% of patients, and is the presenting symptom in about 10% of individuals with proven hypothalamic disease [29,30]. Acute injury to the hypothalamus may result in coma, as can lesions involving the periaqueductal gray matter, mamillary bodies, or the mid-brain reticular activating system [6,7,95]. Drowsiness, hypersomnolence, and emotional lethargy frequently accompany posterior hypothalamic lesions, often in association with hypothermia [3,7,16]. Historically, hypothalamic hypersomnia was commonly seen in the 1918 pandemic of Von Economo’s encephalitis and as a manifestation of thiamine deficiency as part of Wernicke’s encephalopathy [3,6,7]. Neoplasms account for the majority of documented cases at present. Hypersomnia, drowsiness or stupor is found in approximately 24% of patients with craniopharyngiomas [96], 15% of patients with suprasellar germinomas, and 26% of patients with nongerminomatous pineal tumors [55]. Approximately 40% of patients with hypersomnolence also have hypothalamic obesity [11]. Insomnia is an infrequent manifestation of hypothalamic disease. Hyperactivity and diminished duration of sleep has been noted in patients with anterior and preoptic hypothalamic lesions [97]. More commonly, anterior hypothalamic or anterior tuberal lesions result in alterations of the

Chapter 8

sleep–wake cycle, with daytime somnolence and nocturnal hyperactivity [7,43,97]. This is especially common with cystic craniopharyngiomas, and may resolve with drainage of the cyst fluid. Lesions in the tuberal region also have been associated with a syndrome resembling akinetic mutism in which the patient is mute, shows little spontaneous movement, is not responsive to verbal stimuli, and yet appears awake [97]. A hypothalamic etiology for narcolepsy has been suggested because the syndrome has been found following encephalitis, third ventricular tumors, multiple sclerosis, and head injuries, although the majority are idiopathic without a demonstratable pathologic basis [3]. Narcolepsy most commonly occurs in obese males with an onset in the teenage years, and is characterized by sudden attacks of falling asleep for minutes to hours [3]. Unlike normal sleep, these patients enter the stage of rapid eye movement sleep immediately and do not pass through the nonrapid eye movement stage [3,98]. Lesions that damage the suprachiasmatic region are associated with disordered circadian rhythms of the sleep– wake cycle, and body temperature and cognitive functioning [99].

Behavioral Abnormalities Lesions involving the ventromedial nuclei are associated with rage reactions with emotional lability, agitation, and aggressive and destructive behavior that occur spontaneously [7,16,43]. During the episodes, there is usually activation of the autonomic nervous system with tachycardia, a rise in blood pressure, diaphoresis, and pupillary dilatation. Similar sham rage reactions are found with lesions of the medial temporal lobes or orbitofrontal cortex [7]. Medial posterior hypothalamic lesions or destruction of the mamillary bodies is characteristically associated with apathy, somnolence, hypoactivity, and general indifference. Vocal and auditory unresponsiveness and akinetic mutism have also been noted with lesions in this region [3,7]. Confabulation and short-term memory deficits are characteristic of Korsakoff ’s psychosis due to Wernicke’s encephalopathy, which is associated with widespread lesions involving the mamillary bodies, periaqueductal gray matter, and thalamus. These abnormalities appear to be the result of damage to the medial dorsal thalamus rather than the hypothalamus, although ependymal cysts and gliomas involving the third ventricle may be associated with similar findings, possibly through compression of the thalamus [3,6,7]. Sexual dysfunction occurs commonly with hypothalamic disorders. Hypogonadism was present in 32% of the patients analyzed by Bauer, with the majority of the lesions located around the floor of the third ventricle and involving the anterior hypothalamus, ventromedial nuclei, and the tuberoinfundibular regions [29,30]. Symptoms include decreased libido and impotence in men, and amenorrhea in

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women. The pathogenesis most likely is due to abnormalities in GnRH secretion. Hypersexual behavior may accompany lesions in the limbic system, medial temporal lobe, and the caudal hypothalamus [100]. The Kline–Levin syndrome is speculated to be the result of a functional abnormality – possibly reduced dopaminergic tone – in the hypothalamus [101]. The syndrome usually involves adolescent boys who exhibit recurrent episodes of somnolence, with periodic arousal associated with irritability, incoherent speech, hallucinations, forgetfulness, compulsive gorging of food (megaphagia), masturbation, and other sexual activity. The symptoms generally develop over a 2- to 4-day period with a vague sensation of malaise and headache. The episodes occur at 3- to 6-month intervals, and usually last 5 to 7 days, although they may last for several weeks. Spontaneous resolution is the rule in late adolescence or early adulthood. The syndrome also occurs in adolescent girls linked to their menstrual cycles [3,102].

Diencephalic Epilepsy Diencephalic epilepsy broadly encompasses any seizure activity arising from the hypothalamus, although the term was originally used by Penfield in his description of a patient with a third ventricular cholesteatoma and periodic hypothermia and associated autonomic discharge [82]. Periodic hypothermia with absence of the corpus callosum (Shapiro’s syndrome) and periodic hyperthermia (Wolff ’s syndrome) also are forms of diencephalic epilepsy. Gelastic or laughing seizures are seen primarily in children with hamartomas of the tuber cinereum (50%) and other lesions near the floor of the third ventricle and extending to the mamillary region [103]. During a typical seizure the child stops his activity, makes laughing, giggling, or bubbling noises, and develops a grimacing appearance from unilateral or bilateral clonic movements of the ocular, palpebral, and/or buccal muscles [104]. During the episode the child does not lose consciousness, although the gelastic seizure may be followed by a grand mal or petit mal seizure [105]. The diagnosis is established by stereotyped recurrences, absence of precipitating factors, concomitance of other ictal manifestations, epileptiform abnormalities on EEG, and no other obvious cause for pathologic laughter [103,104]. It is unclear whether the seizure is the consequence of compression of the mamillary region, interference with the neural connections with the limbic system, or reflects associated cerebral malformations [104]. NEUROGENIC (CUSHING’S) ULCERS Since stimulation of the preoptic and anterior medial hypothalamic areas in animals results in enhanced secretion of gastric acid and pepsin, it has been proposed that the neurogenic ulcers found with acute hypothalamic lesions may be a consequence of irritation of the diencephalic

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parasympathetic center and subsequent vagus nerve activation [17]. Indeed, vagotomy abolishes the occurrence of experimental neurogenic ulcers [7]. However, neurogenic ulcers, which can occur anywhere in the gastrointestinal tract, and gastric hemorrhages from superficial erosive gastritis, are found with a wide variety of central nervous system (CNS) problems including trauma, infections, vascular accidents, multiple sclerosis, and intracranial surgery. In addition to vagal activation which may occur at levels other than in the hypothalamus, the lesions may also activate the sympathetic nervous system with enhanced catecholamine secretion, and the hypothalamic–pituitary–adrenal axis with resulting hypercortisolemia. These factors, along with drugs used to treat CNS diseases (e.g., glucocorticoids), may increase the likelihood of nonspecific gastrointestinal tract ulceration. DISORDERED CONTROL OF ANTERIORPITUITARY FUNCTION Hyperfunction Syndromes

Precocious Puberty Sexual precocity is considered to be present when secondary sexual development begins below the age of 8 years in girls and 9 years in boys. Isosexual precocious puberty due to CNS mechanisms is called true or complete precocious puberty, while that due to primary gonadal or adrenal abnormalities, or tumors that produce human chorionic gonadotropin (hCG) ectopically is referred to as incomplete precocious puberty. In Bauer’s series of patients with pathologically proven hypothalamic lesions, true precocious puberty was noted in 24 of the 60 cases (40%), most often due to neoplasms (60%), especially those located in the posterior hypothalamus at or near the mamillary bodies, or hamartomas in the region of the tuber cinereum (20%) [29,30]. However, Bauer’s series overrepresents the true frequency of hypothalamic neoplasms and hamartomas, since 80% of the affected individuals with central precocious puberty are girls, and idiopathic precocious puberty is the diagnosis in close to 70% [106]. There is a marked gender difference in the underlying etiologies accounting for central precocious puberty. While the majority of girls have idiopathic early activation of the hypothalamic–pituitary–ovarian axis, idiopathic precocious puberty accounts for only 10% of the cases in boys [106]. Approximately half of the boys, and only 16% of the girls have hypothalamic hamartomas, while 35% of the boys and 7% of the girls have benign or malignant neoplasms [106]. The spectrum of etiologies responsible for central precocious puberty is shown in Table 8.6. At the onset of normal puberty the hypothalamus appears to become less sensitive to the inhibitory influences of the gonadal steroids on the arcuate nucleus, which controls the pulsatile release of GnRH. This leads to enhanced secretion of pituitary gonadotropins which in turn leads to enhanced gonadal steroid secretion, and the appearance of secondary sexual characteristics. The process continues until adult levels

Table 8.6.

Causes of central precocious puberty

Idiopathic Congenital abnormalities Hypothalamic hamartoma Arachnoid cyst Myelomeningocele Aqueductal stenosis with hydrocephalus Tuberous sclerosis Congenital optic nerve hypoplasia Congenital adrenal hyperplasia McCune–Albright syndrome

Inflammatory conditions Tuberculosis Sarcoidosis Meningoencephalitis Subdural hematoma Primary hypothyroidism

Neoplasms Optic nerve glioma Hypothalamic glioma Neurofibroma Astrocytoma Ependymoma Infundibuloma Pinealoma Neuroblastoma Germinoma Craniopharyngioma Data compiled from [63,64,106–112].

of gonadotropins and sex steroid hormones are achieved. Patients with idiopathic precocious puberty go through the same sequence, and this condition presumably represents a premature activation of the normal gonadotropin regulatory system. The finding that some patients without structural lesions in the central nervous system have a family history of early puberty or even precocious puberty supports this hypothesis. Patients with neoplasms, inflammatory conditions, or conditions associated with increased intracranial pressure also may have premature activation of the normal pubertal maturation process due to the mass, pressure, or irritative effects on the basal hypothalamus. In addition, germinomas may secrete hCG which may directly stimulate the gonads to secrete sex steroid hormones. Premature activation of the normal process is seen in some patients who initially have incomplete precocious puberty due to congenital adrenal hyperplasia or the McCune–Albright polyostotic fibrous dysplasia syndrome in which the hypothalamus is bathed with sex steroid hormone concentrations that are elevated for the patient’s chronologic age. In susceptible individuals lowering of the sex hormone levels through adrenal or gonadal suppression may be followed by the appearance of central precocious puberty, presumably due to functional hypothalamic alterations from the previously elevated sex steroid hormone levels. The precocious puberty found in patients with hypothalamic hamartomas may be the result of premature activation of the normal pubertal mechanisms or secondary to direct secretion of GnRH from the hamartoma, since GnRH is present in neurons that

Chapter 8

comprise the hamartoma [113,114]. The cause of the precocious puberty in children with primary hypothyroidism and galactorrhea with elevated levels of TSH and prolactin (the Van Wyk–Grumbach syndrome) is unknown, but is probably not due to premature activation of the normal hypothalamic–pituitary–gonadal axis, since treatment of such patients with thyroxine results in cessation of further progression of precocious puberty. Acromegaly As discussed elsewhere in this book, over 98% of patients with acromegaly have a pituitary adenoma. Rarely, GH itself is secreted ectopically [115]. A small number of acromegalics have ectopic production of GHRH from benign or malignant carcinoid or pancreatic islet cell tumors, adrenal adenoma, pheochromocytoma, or lung carcinoma [116]. Acromegaly has also been found in patients with hypothalamic hamartomas, gangliocytomas, gliomas, and choristomas which contain and presumably secrete excessive quantities of GHRH [116–119]. Most of these tumors have extended into or been located within the sella turcica in close proximity to the anterior pituitary. Of interest, the predominant anterior pituitary lesion is a pituitary adenoma, and not pituitary hyperplasia [120,121]. Since the hypothalamus is the physiologic source of GHRH, it is reasonable to speculate that GH-producing pituitary adenomas actually represent neoplastic transformation secondary to excessive stimulation of the somatotropes to high concentrations of hypothalamc GHRH. Support for this hypothesis includes the unconfirmed finding of nonsuppressed plasma GHRH concentrations in a series of patients with GH-secreting pituitary adenomas [122]; the paradoxical increase in serum GH following a bolus injection of TRH in acromegalics with typical pituitary adenomas, similar to the response that is found in patients with GHRHsecreting neoplasms [116]; the recurrence of GH hypersecretion and acromegaly following apparently successful transsphenoidal removal of an adenoma, presumably reflecting the development of a second adenoma; and the finding that some patients have a favorable therapeutic response to progestogens or chlorpromazine which probably have a hypothalamic locus of action [123]. Cushing’s Disease This refers to the pituitary-dependent form of Cushing’s syndrome associated with bilateral adrenal cortical hyperplasia, excessive secretion of ACTH and cortisol, and the presence of a pituitary adenoma. This form must be differentiated from the pituitary-dependent variety that is secondary to excessive ectopic production of CRH, and the pituitary independent ectopic ACTH syndrome, adrenal neoplasms, and bilateral micronodular adrenal hyperplasia. A hypothalamic etiology for Cushing’s disease has long been suggested, and the hypersecretion of ACTH may reflect an altered setpoint for feedback inhibition at the hypothalamus by circulating glucocorticoids [124] patients with Cushing’s disease demonstrate a loss of the circadian periodicity of GH, PRI, and ACTH, as well as sleep, abnor-

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malities that remain following correction at the hypercortisolism [124]. Historically, many patients with Cushing’s disease recount a severe emotional stress, such as a death in the family or a separation, that immediately precedes the onset of the disease [125]. In addition, although over 80% of patients with Cushing’s disease are found to have a pituitary adenoma at the time of surgery, cortisol hypersecretion may persist after apparently successful removal of the neoplasm or an adenoma may recur after transsphenoidal adenomectomy, despite initial postoperative reestablishment of normal hypothalamic–pituitary–adrenal dynamics [126,127]. A number of the pituitary adenomas have been found to secrete ACTH in vitro in response to CRH [124]. Cyproheptadine, a serotonin antagonist, bromocriptine, a dopamine receptor agonist, and sodium valproate, which increases gamma aminobutyric acid concentrations, lower ACTH and cortisol concentrations and reverse the clinical manifestations in some patients with Cushing’s disease, possibly through a hypothalamic rather than direct pituitary action [128–131]. Finally, Cushing’s disease has been associated with an intrasellar gangliocytoma which produced CRH, indicating that these neural neoplasms have the capacity to directly stimulate the corticotropes [132]. However, the clonal origin of corticotrope adenomas, the presence of a discrete adenoma rather than hyperplasia at surgery, the high cure rate following transsphenoidal removal of the adenoma, and the low concentration of CRH in the CSF at patients with Cushing’s disease strongly suggest a somatic mutation is responsible for corticotrope adenoma formation, although hypothalamic factors many be needed for promoting clonal expansion of the abnormal corticotrope cell [124,133,134]. Hyperprolactinemia Since the lactotropes in the anterior pituitary are normally under tonic inhibition by dopamine synthesized and secreted by the hypothalamus, it is common for hyperprolactinemia to be present in patients with structural abnormalities of the hypothalamus. Amenorrhea and galactorrhea in women, and impotence in men, are present to a variable extent. The menstrual abnormalities, libido, and potency problems are difficult to assess because of the high frequency of concomitant gonadotropin deficiency. Most patients have serum prolactin concentrations below 70 ng/ml, although an occasional patient will have a level up to 150 ng/ml [135]. In a series of patients with hypothalamic tumors, Imura and coworkers found hyperprolactinemia in 36% of patients with craniopharyngiomas, in 79% of patients with suprasellar germinomas, and in 14% of patients harboring a pineal germinoma [55]. Galactorrhea was less frequently seen, being found in 4, 3, and 0% of patients with the three types of tumor, respectively [55]. Prolactin-secreting microadenomas of the pituitary may be caused by a hypothalamic dopamine deficiency with resultant disinhibition of the lactotropes leading to lactotrope hyperplasia and neoplasia. In support of this hypothesis is

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the finding of such hyperplasia of the lactotropes in some patients with prolactin-secreting adenomas, and the recurrence of adenomas following successful removal of microadenomas as assessed by a return to normal of prolactin dynamics in response to provocative tests [136,137]. A large group of patients with hyperprolactinemia do not have obvious structural abnormalities in the hypothalamus or pituitary microadenomas visualized by computed tomography (CT) or magnetic resonance imaging (MRI) scans. The serum prolactin in response to provocative and inhibitory agents in patients with idiopathic hyperprolactinemia is qualitatively indistinguishable from that in patients with prolactin-secreting microadenomas. Indeed, some patients with idiopathic hyperprolactinemia when followed over time will develop a microadenoma, adding support to the concept that idiopathic hyperprolactinemia and prolactin-secreting pituitary tumors are on a continuum, with hypothalamic dopamine deficiency being the etiology of both conditions. Hypofunction Syndromes

Acquired Hypogonadotropic Hypogonadism This condition is commonly found in patients with organic lesions in the hypothalamus. Almost one-third of the patients in Bauer’s series had hypogonadism, with 84% of the lesions located in the floor of the third ventricle involving the tuberoinfundibular and more anterior regions of the hypothalamus [29,30]. The etiology is probably multifactorial in most instances. The mechanisms include destruction of GnRH-secreting neurons, disruption of the median eminence where the GnRH peptidergeric axons converge, interference with the “pulse generator” that is responsible for the normal pulsatile release of LH and FSH, damage to the hypothalamohypophysial portal system, and/or hyperprolactinemia. Patients with neoplasms and inflammatory conditions have a high frequency of neuroophthalmologic abnormalities (52%), diabetes insipidus (47%), and obesity (42%) [29,30]. Hypothalamic hypogonadism with prepubertal onset results in a lack of pubertal development. Thus, both sexes will have diminished growth of axillary and pubic hair, unless ACTH deficiency coexists in which case pubic and axillary hair will be absent because of the lack of adrenal androgens. Males will not develop chin, sideburn, moustache, chest, abdominal, or back terminal hair growth; nor will the voice deepen or muscles develop into the adult pattern. The testicles will remain small and the penis does not enlarge. Females will not experience breast development, uterine enlargement, vaginal cornification and adult mucous production, or menstruation. If GH secretion remains normal, affected individuals may continue to grow and acquire eunuchoidal proportions in which the upper segment (crown to pubis) to lower segment (pubis to floor) ratio is less than 1, and the arm span exceeds total height by 5 cm or more. This occurs because the cartilaginous epiphyseal growth plates of the long bones grow under the

influence of GH and do not fuse, as this requires pubertal levels of androgens and estrogens. Acquired hypogonadism developing postpubertally results in amenorrhea, vaginal dryness, and some regression of breast glandular tissue in women. Men experience gradual loss of body and pubic hair, decreased muscular development, testicular atrophy, decreased libido, and impotence. With long-standing hypogonadism, both sexes may develop fine wrinkling around the corners of the eyes and lips, and osteopenia. The characteristic hormonal findings are low levels of LH and FSH in association with low concentrations of gonadal steroids. The gonadotropin response to a single bolus injection of GnRH may be normal or low, but characteristically increases if the patient receives multiple priming doses given every 90 minutes. Males have a low seminal plasma volume and oligo- or azoospermia. Congenital (Idiopathic) Gonadotropin Deficiency Deficiency of LH may occur alone or together with FSH resulting in hypogonadotropic hypogonadism, and gonadotropin deficiency may be present as part of the multiple tropic hormone deficiencies that are seen in idiopathic panhypopituitarism. The most common form of isolated gonadotropin deficiency is Kallmann’s syndrome, also known as olfactory–genital dysplasia. This syndrome, which occurs sporadically or as an X-linked dominant or autosomal dominant trait with incomplete penetrance, is due to a defect in hypothalamic GnRH synthesis or secretion. The X-chromosome linked syndrome is due to defects in the KAL gene which results in a failure of the GnRH neurons to migrate to the hypothalamus from the olfactory placode [138]. Males are affected more frequently than females. Cryptorchidism and microphallus may be present at birth owing to the lack of normal fetal testicular testosterone production in late gestation as a result of deficient fetal gonadotropin secretion. Puberty fails to occur at all in the severe, complete form of the syndrome, or may be markedly delayed and incomplete in the partial form [92]. In addition to the gonadal abnormalities, other defects are present. The most common associated problem is hyposmia or anosmia due to agenesis or hypoplasia of the olfactory bulbs. Color blindness, nerve deafness, cleft palate, exostosis, and renal abnormalities may also be present. In addition to the prepubertal levels of LH, FSH, and sex steroids, these patients exhibit a deficient release of LH or FSH following a bolus injection of GnRH. After several weeks of priming the pituitary gonadotropes with pulsatile boluses of GnRH given at 90-minute intervals, the gonadotropin response to a bolus injection of GnRH approaches normal, indicating that the initial inadequate gonadotrope response represented secondary atrophy of the gonadotrope due to the lack of endogenous GnRH secretion. Full fertility in these patients may be achieved with small doses of GnRH given by infusion pump every 90 minutes [138]. Idiopathic hypogonadotropic hypogonadism may also occur without hyposmia, anosmia or the other midline

Chapter 8

structural defects, either sporadically or through an autosomal recessive genetic pattern. LH deficiency, with normal levels of FSH, has been termed the “fertile eunuch syndrome” since these patients have hypogonadism with prepubertal levels of testosterone, deficient secondary sexual development, and large testes with evidence of spermatogenesis. Unlike the small, prepubertal testes seen in patients with combined gonadotropin deficiency, these patients experience testicular growth because of normal serum concentrations of FSH which stimulate the growth of the seminiferous tubules that normally account for 85% of the adult testicular volume. Gonadotropin deficiency is also present in patients with complex, presumably hypothalamic, syndromes including the Prader–Willi, Laurence–Moon, and Bardet–Biedl syndromes. Acquired Hypothalamic GH Deficiency Growth failure due to structural abnormalities in the hypothalamus is common, and may be multifactorial in origin including deficiency of GH, thyrotropin, and gonadotropins, as well as nutritional abnormalities. Growth retardation is present in about one-third of children with craniopharyngiomas [53,110,138], 40% of patients with the chronic disseminated form of histiocytosis [56], and 10–40% of individuals with suprasellar germinomas [53,55,138]. Formal testing for GH secretory response in patients with hypothalamic disease yields an even higher frequency of abnormalities. For instance, 85–95% of patients with craniopharyngioma, have an inadequate rise in serum GH following provocative stimuli [138,139]. In these patients, the GH deficiency is presumed due to inadequate synthesis, release, or transmission of GHRH to the somatotropes. Indeed, many patients with hypothalamic structural abnormalities demonstrate a rise in serum GH following a bolus injection of GHRH, indicating the presence of functional somatotropes [140]. Congenital GH Deficiency Congenital absence of GH due to hypothalamic structural or functional abnormalities is seen in several midline developmental abnormalities including anencephaly, holoprosencephaly, transsphenoidal encephalocele, septooptic dysplasia, and some patients with simple cleft lip and palate [51]. In most affected patients GH deficiency coexists with deficiencies of one or more of the other tropic hormones. Recent studies have suggested that approximately one third of these patients develop their hormone abnormalities due to a traumatic transection of the pituitary stalk during delivery, while the remainder have a defective induction of the mediobasal brain structures, which results in a failure of the pituitary lobes to fuse, and an absence or hypoplasia of the pituitary stalk [141,142]. GH deficiency occurs on a familial basis, either as part of familial panhypopituitarism or as an isolated defect. In panhypopituitarism, GH deficiency is the most common abnormality, followed by gonadotropin, then ACTH, and

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finally TSH deficiency or deficiencies. Both autosomal recessive and X-linked recessive transmission have been described, although most cases appear to be sporadic [51]. Most of these patients exhibit a rise in anterior pituitary hormones following bolus injections of the releasing hormones, but not in response to provocative stimuli that work through the release of endogenous hypothalamicreleasing hormones. Monotropic growth hormone deficiency may be found in patients with abnormalities in the GH gene family found on chromosome 17, in which case the pituitary is unable to produce GH or secretes a biologically inactive form. However, the majority of patients with monotropic GH deficiency actually have a hypothalamic etiology, with an absence of appropriate secretion of GHRH. These patients have GH containing somatotropes in their anterior pituitary, but are unable to secrete adequate quantities because of inadequate stimulation from the hypothalamus. Most are capable of releasing GH following the exogenous administration of GHRH. Clinically, patients with congenital GH deficiency have normal birth length and weight. Males may exhibit micropenis, especially if gonadotropin deficiency coexists. Growth retardation generally becomes apparent during the latter part of the first year, and both height age and bone age are delayed. Untreated patients develop proportional short stature, an increase in subcutaneous fat, a “pinched facies” with a high forehead, and fine wrinkling of the skin around the corners of the mouth and eyes. Hypoglycemia may occur during infancy, since GH is an insulin antagonist, but later insulin deficiency may develop resulting in abnormal glucose tolerance. Puberty may be delayed even in the absence of gonadotropin deficiency. Exogenous GH replacement therapy stimulates linear growth, restores normal glucose tolerance, and allows puberty to progress normally [51]. Hypothalamic Hypoadrenalism

Abnormalities of the hypothalamic–pituitary–adrenal cortex axis, as revealed by blood or urine steroid measurements or provocative tests, are relatively common in patients with congenital or acquired structural disorders of the hypothalamus. Even with normal baseline corticosteroids, abnormalities in the normal circadian variation of these steroids are frequently seen [143]. Over half of patients with craniopharyngiomas, suprasellar germinomas, and septooptic dysplasia demonstrate deficient glucocorticoid levels or ACTH responses to stimuli that function via the hypothalamus [54,61–64,138,139,144]. CRH administration to patients with hypothalamic structural abnormalities does result in the release of ACTH from the pituitary. Congenital monotropic ACTH deficiency is rare, and theoretically could result from either an abnormality in CRH production or secretion or a defect in the corticotrope cells in the pituitary. There is at present insufficient information available to localize the locus of abnormality in these patients. A hypothalamic etiology of the ACTH deficiency found in some patients with

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congenital panhypopituitarism is implied by the finding that these patients can release other “deficient” anterior pituitary hormones with hypothalamic-releasing factors. The clinical manifestations of tertiary adrenal insufficiency include hypoglycemia in childhood, especially if GH deficiency coexists, and occasionally hypotension. Acute adrenocortical insufficiency rarely occurs spontaneously, but may be precipitated with stresses such as surgery, infections, or trauma. In this situation nausea, vomiting, and hypotension may be found. Unlike patients with primary adrenocortical insufficiency, hyperpigmentation and the electrolyte abnormalities that reflect aldosterone deficiency (hyponatremia and hyperkalemia) are not seen.

Table 8.7. Complex syndromes of presumed hypothalamic origin or with hypothalamic involvement Syndrome Congenital Prader–Willi

SPECIFIC HYPOTHALAMIC DISORDERS A number of syndromes have been described in which affected patients exhibit abnormalities in hypothalamic function, but do not have obvious structural defects in the hypothalamus (Table 8.7). Some, like the Prader–Willi, Bardet–Biedl, and Laurence–Moon syndromes, may be congenital with fixed defects, while others, such as anorexia nervosa (discussed above) or the emotional deprivation syndrome, are acquired and reversible.

Pigmentary retinopathy Obesity Mental retardation Polydactyly Hypogonadism

Wolfram

Central diabetes insipidus Insulin-dependent diabetes mellitus Optic atrophy Sensorineural deafness

Hayek–Peake

Adipsia or hypodipsia Recurrent hypernatremia Obesity Hyperprolactinemia Hypothyroidism Hypertriglyceridemia Central hypoventilation

Septooptic-pituitary dysplasia

Absent septum pellucidum Optic nerve hypoplasia Agenesis of corpus callosum Visual defects Mental retardation Short stature Hypothalamic hypopituitarism

Acquired Anorexia nervosa

Anorexia Weight loss Behavioral abnormalities Bradycardia Hypogonadism Thermal dysregulation Partial diabetes insipidus Hyperprolactinemia

Environmental deprivation

Short stature Polydipsia Polyphagia Bizarre behavior Emotional/mental retardation

Pseudocyesis

Amenorrhea Symptoms of pregnancy Abdominal distension Hyperprolactinemia Persistent corpus luteum

Prader–Willi Syndrome In 1956, Prader, Labhart, and Willi described a syndrome whose major features were fetal hypotonia, hyperphagia, obesity, short stature, mental retardation, and hypogonadism [146]. Since that time several hundred patients have been described, and the prevalence of the syndrome has been estimated to be approximately 1 per 10–15,000 live births [147]. The major clinical features derived from three series of studied patients are tabulated in Table 8.8. The clinical manifestations begin before birth with reduced fetal move-

Hypotonia Hyperphagia Obesity Short stature Mental retardation Hypogonadism

Bardet–Biedl

Hypothalamic Hypothyroidism

Tertiary hypothyroidism is found in one-third to one-half of patients with craniopharyngiomas, suprasellar germinomas, and septooptic dysplasia [53,54,62–64,138,139]. Characteristically these patients have low serum concentrations of free thyroxine; normal, low, and occasionally slightly elevated levels of serum TSH (the latter possibly representing a TSH molecule with reduced biologic activity) [145]; and a quantitatively normal or exaggerated, but delayed peak in serum TSH concentrations following a bolus injection of TRH [53,54,63,64]. Normally, the highest concentrations of TSH are found between 15 and 30 minutes after TRH, while in patients with hypothalamic hypothyroidism, peak levels are found between 90 and 120 minutes. The clinical manifestations of hypothalamic hypothyroidism are similar, but less severe than those found with primary hypothyroidism and include thyroid gland atrophy, lethargy, cold intolerance, dry skin with a pasty, yellow hue, hypothermia, bradycardia, constipation, and weight gain.

Major manifestations

Chapter 8 Table 8.8. Clinical features of 73 patients with the Prader–Willi syndrome Percentage affected

Developmental period

Abnormality

Gestational/birth

Poor fetal vigor Nonterm delivery Breech presentation Low birth weight (<2.27 kg)

Neonatal/infancy

Hypotonia Feeding problems Delayed milestones Acromicria Cryptorchidism Strabismus

100 99 99 90 85 63

Childhood/adulthood

Hyperphagia Obesity Mental retardation Hypogonadism Short stature Personality problems Delayed bone age Seizures

100 100 97 93 92 68 66 18

81 40 34 26

Adapted from Bray et al. [147].

ment, an increased incidence of breech presentation and prematurity, and low birth weight. Profound muscle hypotonia may be present at birth resulting in a poor sucking response, often necessitating gavage feeding. The affected infants may exhibit multiple somatic anomalies including a narrow bitemporal diameter of the cranium, strabismus, hypertelorism, almond-shaped eyes, upslanting palpebral fissure, low-set ears, micrognathism, an ogival palate, clinodactyly, and small hands and feet [147–150]. During late infancy or early childhood, hyperphagia develops, with often indiscriminate food-seeking behavior, resulting in obesity, which reaches morbid proportions in many individuals. These patients also have short stature, which during childhood and adolescence is associated with a delayed bone age. In the series of patients studied by Bray and associates, the mean height was 149 cm and the mean weight 114 kg [147]. Mental and developmental retardation is almost always present, and personality problems, such as stubbornness, temper tantrums, and inadequate peer interactions have been noted in over two-thirds of such individuals [149]. Hypogonadism is a prominent feature, especially in males. Cryptorchidism and scrotal hypoplasia is generally present at birth, undoubtedly due to inadequate fetal testicular androgen production; the penis is small and the testes immature [147]. Labial hypoplasia has been noted in affected females [149]. There is a variable degree of sexual maturation that occurs during adolescence or adulthood, and even precocious puberty has been noted in a few patients [147].

The Hypothalamus

335

Endocrine studies have demonstrated normal thyroid function tests, including normal responses to TRH, normal ACTH and cortisol dynamics in response to provocative stimuli, and normal prolactin concentrations [147]. GH responses to various secretagogues have been blunted, but resemble the response seen in patients with simple obesity. Although, early reports suggested that type II diabetes mellitus was frequently present in these patients [150], more recent studies have shown that the glucose intolerance and insulin resistance is identical to that found in weightmatched subjects with simple obesity [147]. The hypogonadism is associated with low testosterone in males and low estradiol in females, and low basal serum LH and FSH concentrations [147]. GnRH tests are abnormal in most of the patients, with a marked blunting of the gonadotropin response, reflecting a long-standing GnRH deficiency. Indeed, chronic treatment with GnRH will increase the LH and FSH response to a bolus injection of GnRH. Treatment of patients with clomiphene citrate, a competitive inhibitor of estradiol, has been found to increase basal LH, FSH, and sex steroid hormones, and to restore the gonadotropin response to GnRH to normal [147]. Collectively, these results indicate that the hypogonadotropism is hypothalamic in origin. There is little information available about nonendocrine hypothalamic function. Some patients have been noted to have abnormalities in temperature control and heat generation, also pointing to a hypothalamic abnormality [147]. Most patients with the Prader–Willi syndrome develop it sporadically, although a few familial cases have been reported [149]. The syndrome is due to an abnormality in genomic imprinting. Most affected patients have a deletion of the paternally contributed chromosome 15q11–q13 which is normally the active gene at this site [148,151]. The few autopsy studies that have been carried out have failed to demonstrate any histopathologic abnormalities in the hypothalamus [147].

Bardet–Biedl Syndrome The cardinal features of this syndrome are tapetoretinal degeneration, obesity, mental retardation, polydactyly, and hypogonadotropic hypogonadism (Table 8.9). In over twothirds of the patients, an extra digit is found in one or more of the extremities (hexadactyly), while other digital abnormalities such as syndactyly and/or brachydactyly are seen in 10–15% of individuals [152]. The retinopathy, which in the early stages may not be pigmentary, begins in early childhood and is associated with night blindness, decreased visual acuity, and an abnormal electroretinogram response. By age 20, almost three-fourths of the patients are blind or near blind, and this figure rises to 86% by age 30 [152]. Obesity and associated glucose intolerance begin in early childhood. Variable degrees of mental retardation are present, with 36% being classified as mild, 12% moderate, and 9% severe [152]. In addition, a variety of behavioral abnormalities have been

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Table 8.9.

Hypothalamic–Pituitary Dysfunction

Clinical features of the Bardet–Biedl syndrome

Table 8.10. Clinical, anatomic, and biochemical features of septo-optic–pituitary dysplasia

Percentage affected

Abnormality Pigmentary retinopathy and other ocular manifestations Obesity Mental retardation Polydactyly Hypogonadism

Men (n = 188)

Number abnormal/ number studied

Percentage abnormal

Anatomic Hypoplastic optic nerves Absent septum pellucidum Agenesis of corpus callosum

67/67 64/99 4/54

100 64.6 7.4

Clinical: nonendocrine Visual problems Mental retardation Cerebral palsy Nystagmus Seizures Neonatal jaundice Neonatal hypoglycemia

25/32 36/51 29/51 36/67 19/51 10/44 12/60

78.1 70.6 56.9 53.7 37.3 22.7 20

Clinical: endocrine Short stature Decreased growth rate Diabetes insipidus Precocious puberty

41/61 41/67 34/130 1/51

67.2 61.2 26.2 2

108/126

79.4

54/120

45

25/124

20.2

11/18

61.1

3/11 5/24 52/111

27.2 20.8 46.8

Women (n = 133)

93.6

92.5

89.4 86.7 76.1 76.1

94.7 85.0 73.7 51.9

Adapted from Klein and Ammann [152].

noted including emotional lability and short attention span. The hypogonadism affects males more frequently than females (see Table 8.9). Other associated abnormalities noted include nerve deafness (9%), renal abnormalities (glomerulosclerosis, mesangial proliferation, renal cysts; 13%), brachycephaly (50%), and rarely diabetes insipidus and hyperlipidemia [91,152]. The disorder is transmitted in an autosomal recessive fashion, with a prevalence of 1 per 160 000 births [152]. Although the hypothalamic hypogonadism, obesity, and occasional coexistence of central diabetes insipidus strongly suggest hypothalamic involvement, the few pathologic studies performed to date have not demonstrated a histopathologic abnormality in the hypothalamus [153]. The pathogenesis of the presumed hypothalamic dysfunction may involve a transient internal hydrocephalus during the eighth to ninth embryonic week, resulting in an enlargement of the third ventricle causing a diencephalic lesion [152]. Several other syndromes that resemble Bardet–Biedl syndrome have been described. The Laurence–Moon syndrome includes retinal pigmentary degeneration, mental retardation, hypogonadism, progressive spastic paraparesis and distal muscle weakness, but no polydactyly [154]. The Biemond syndrome, also inherited as an autosomal recessive condition, consists of hypogonadotropic hypogonadism, mental retardation, polydactyly or brachydactyly, obesity, and iris coloboma, rather than retinitis pigmentosa [152,155]. The Alstrom–Hallgren syndrome, transmitted as an autosomal recessive defect, is associated with atypical tapetoretinal degeneration, obesity, diabetes mellitus, nerve deafness, acanthosis nigricans, and hypogonadism. In contrast to Bardet–Biedl syndrome, the hypogonadism is due to primary gonadal failure, rather than to hypothalamic dysfunction [152,155]. At least three other syndromes with overlapping features with the above disorders have been described by other authors [155]. It is likely that they represent heterogenous expression of the same or a closely related genetic abnormality.

Feature

Endocrine testing Human growth hormone deficiency Adrenocorticotropic hormone deficiency Thyroid stimulating hormone deficiency Abnormal thyrotropinreleasing hormone test Gonadotropin deficiency Hyperprolactinemia Multiple hormone deficiencies Compiled from [61– 64,158].

Septo-optic–pituitary Dysplasia The cardinal features of the septo-optic–pituitary dysplasia syndrome (De Morsier syndrome) are anterior midline prosencephalic developmental defects including an absent septum pellucidum and/or agenesis of the corpus callosum, bilateral or unilateral optic nerve hypoplasia, and hypothalamic hypopituitarism (Table 8.10) [61–64,156–158]. In addition to the above anatomic defects, other defects and dysmorphic features may be present. These include cleft palate, syndactyly, low-set ears, misshapened pinnae, hypertelorism, mongoloid slants of the palpebral fissures, micropenis, and agenesis of the olfactory nerves. The optic nerve atrophy is manifest by a small optic disc, one-third to one-half the normal size, and variable degrees of visual impairment [61–64].

Chapter 8

The syndrome occurs sporadically, and the etiology is unknown. The affected individuals are usually the first-born of a young woman whose pregnancy may have been complicated by toxemia [63]. Birth weight is normal, but the infants demonstrate poor feeding, vomiting, prolonged neonatal hyperbilirubinemia, and hypoglycemia. Cerebral palsy with hemiplegia, diplegia or quadriplegia is relatively common, as is mental retardation, and seizures [63]. The most common endocrine abnormality is short stature associated with GH deficiency. Clinically this is followed by ACTH deficiency, diabetes insipidus, and hypothyroidism, although abnormalities in the hypothalamic–pituitary– thyroid axis can be demonstrated in over 60% of patients by TRH testing [61–64]. The relatively low frequency of hypogonadism reported in these patients undoubtedly reflects the fact that the mean age of diagnosis of the disorder is 4.9 years [61–64], which is too young to detect hypogonadotropic hypogonadism. However, some children have been noted to have micropenis, which may be a reflection of prenatal fetal hypogonadotropism [62]. Examination of the hypothalamus at autopsy has demonstrated absence of the supraoptic and paraventricular nuclei, hypoplasia of the posterior pituitary, ependymal scars around the third ventricle, and a normal anterior pituitary, supporting the hypothalamic locus of the hypopituitarism [157].

Environmental Deprivation Syndrome (Psychosocial Dwarfism) Children presenting with this unusual, reversible syndrome have a constellation of signs and symptoms that suggest hypothalamic dysfunction. These include short stature, polydipsia, polyphagia, emotional or mental retardation, and bizarre behavior (Table 8.11). The majority of children have the onset of the syndrome before the age of 2, and over half have a social history of divorced or separated parents, or significant marital strife at home resulting in a disturbed parent–child relationship. Males are more frequently affected than females. Short stature is generally the presenting complaint and is associated with a retarded bone age and inadequate GH response to insulin hypoglycemia. The upper-to-lower body size ratio is normal for age, as is tooth eruption. Body weight is low for the chronologic age and in most instances for the height age. Polydipsia and polyphagia are uniformly present. Indeed, these children have been noted to eat two- to three-times the amount of food compared to their siblings. Bulky, foul-smelling stools have been noted in many of the subjects, which together with the polyphagia, low weight, and short stature, often leads to an evaluation for malabsorption, which is not present in these children. Bizarre behavior is a common concomitant of the syndrome. The patients often steal food and hide it around their houses, and most have been discovered to have eaten food retrieved from garbage cans. They also drink water from toilet bowls and stagnant pools, and tend to wander at night in search of food or water. Emotional retardation is

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Table 8.11. Clinical features of 13 patients with environmental deprivation syndrome Feature Short stature Retarded bone age Low weight for height Abnormal human growth hormone dynamics Polydipsia Polyphagia Gorging and vomiting Foul-smelling stools Bizarre behavior Food-stealing Eating from garbage cans Nocturnal wandering Drinking from toilet bowl Emotional/mental retardation Low IQ Retarded speech Playing alone Shy Temper tantrums Protuberant abdomen Depressed (infantile) nasal bridge

Percentage 100 77 85 75* 100 100 69 62 100 92 85 54 46 100 100† 85 69 69 69 100 100

* Based on eight patients. † Based on IQ testing of eight children “who were easily distracted during the test period.” From Powell et al. [159,160].

clearly present manifest by shyness and a tendency to play alone, temper tantrums, delayed toilet training, and retarded speech [159,160]. Endocrine testing reveals normal urine-concentrating ability, normal thyroid function in most patients, inadequate adrenocortical response to provocative testing, along with the poor GH responses to stimuli. Thus, these patients appear to have a form of idiopathic hypopituitarism. However, when they are removed from their home environment, their polydipsia, polyphagia, and food-stealing rapidly cease. They gain weight, and some even become obese. In addition, they exhibit rapid linear growth, showing a “catch-up” growth phenomenon, and return of the GH abnormalities to normal. If they are once again placed in their home environment, growth rapidly ceases. The pathogenesis of this complex syndrome is unclear, but it is likely that it represents a psychophysiologic reaction to the adverse environment.

Pseudocyesis Pseudocyesis or false pregnancy represents a hysterical conversion reaction in a woman who either desperately wishes to conceive, or is extremely fearful of becoming pregnant. The woman develops amenorrhea, progressive abdominal

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distension, morning sickness, sensations of fetal activity, breast engorgement with a prominent venous pattern, and, at times, galactorrhea [161–164]. Hyperprolactinemia is present in the majority of women, and may be of pathophysiologic significance, in that its luteotropic activity may be the cause of the persistent corpus luteum found in these individuals. In addition, LH levels may be elevated which also may account for maintenance of the corpus luteum [161]. When confronted with the diagnosis, some women experience a rapid decrease in abdominal girth, which was due to gaseous distension of the intestine, cessation of galactorrhea, and resumption of menses. This syndrome, along with anorexia nervosa and the environmental deprivation syndrome illustrate the profound influence that the cerebral cortex has on the hypothalamus.

Hypothalamic Hamartoma Hamartomas are benign heterotrophic hyperplastic malformations composed of a fibrous glial matrix with mature ganglion cells and occasional myelinated nerve fibers [104,165]. They range in size between a few millimeters and 3.5 cm, with the majority being less than 1.5 cm, and usually are located in the posterior hypothalamus between the tuber cinereum and the mamillary bodies [104,165]. They are felt to represent a midline dysraphic syndrome with displacement of cells from the mamillary region as the infundibulum moves behind the notochord [104]. As indicated in Table 8.12, a little more than half of the affected individuals are males, and most patients present before the age of 2 years [103,105,113,166–169]. Close to 90% of the patients develop precocious puberty with pubertal or adult concentrations of sex steroid hormones and gonadotropins [105,167]. Over half have neurodevelopmental delay with low intelligence quotient and seizures. Often the seizures are gelastic or laughing seizures with brief lapses without loss of consciousness [103,105,113]. Emotional lability and sham rage may also be present. Gross neurologic abnormalities are usually absent, although large hamartomas may be associated with ataxia and nystagmus due to pontine compression [165]. There is also a tendency for the patients to become obese in late childhood and adolescence [165]. Three hypotheses have been proposed to explain the precocious puberty in these patients. First, the hamartoma may mechanically stimulate the median eminence to secrete GnRH. Support for this explanation is the finding that some hamartomas associated with precocious puberty are devoid of nerve cell bodies, and that precocious puberty is also found in some patients with suprasellar arachnoid cysts and craniopharyngiomas located in the same region, suggesting that pressure on the median eminence is of etiologic significance. Alternatively, these lesions may interrupt interneuronal pathways that tonically inhibit the GnRHsecreting neurons in the median eminence, allowing these neurons to be disinhibited and begin secreting GnRH [104].

Table 8.12. hamartomas

Clinical features of patients with hypothalamic

Feature

Number abnormal/ number studied

Percentage

Sex Male Female

53/98 45/98

54.1 45.9

Age of onset Birth <2 years (including at birth) 2–4 years 5–8 years

10/69 46/69 13/69 5/69

14.5 66.7 18.8 7.2

Age at diagnosis <2 years 2–4 years 5–8 years

25/51 19/51 7/51

49 37.2 13.7

43/50 17/21 9/9 7/9 23/27

86.0 80.9 100 77.7 85.2

14/29

48.3

24/40 39/74 26/74 5/24

60.0 52.7 35.1 20.8

Assessment of sexual precocity Precocious puberty present Tanner stage 3 or more (males) Tanner stage 3 or more (females) Menses Bone age > chronologic age by 3 + years Height age > chronologic age by 3 + years Development and neurologic assessment Neurodevelopmental delay Seizures Hyperactivity/tremors/laughing spells Signs of increased intracranial pressure

Data are combined from [103,105,113,166–169].

The finding that an occasional patient with precocious puberty may actually have a hamartoma that is not attached to the hypothalamus, argues against precocious puberty being the direct result of hypothalamic pressure [120,171]. The third suggestion is that the hamartoma acts as an “accessory hypothalamus” directly secreting GnRH, which in turn stimulates the gonadotropes to secrete gonadotropins [113,114,172]. Indeed, several of these hamartomas have been found to contain GnRH, and cerebrospinal fluid GnRH concentrations in patients with hypothalamic hamartoma-associated precocious puberty have been found to be elevated [113,114,172]. That GnRH is involved in the pathogenesis of the precocious puberty is evidenced by the pubertal or adult gonadotropin response to a bolus injection of GnRH [105,167], and the response to the therapeutic administration of long-acting analogs of GnRH, which act directly on

Chapter 8

the gonadotropes to down-regulate the GnRH receptors. This results in a lowering of basal levels of sex steroid hormones and gonadotropins, inhibition of the gonadotropin response to a bolus injection of GnRH, a cessation of menses, and a deceleration of the advancing bone age and growth rate [106,167]. Indeed, treatment of the precocious puberty with GnRH analogs is the therapy of choice for this disorder, since in most instances, the hamartoma does not appear to progress, and attempts at total neurosurgical removal in the past have been associated with high operative or postoperative mortalities and neurologic disabilities [113]. Although more recent neurosurgical data suggests that over half of the patients undergoing complete removal of the hamartoma have some degree of improvement [168], surgery should be restricted to those patients who have signs of increased intracranial pressure or neurologic deterioration from progressive growth of the hamartoma. The Pallister–Hall syndrome is a complex autosomal dominant disorder which includes hypothalamic hamartoma, which often occupies the space between the optic chiasm and interpeduncular fossa, and pituitary dysplasia with hypopituitarism [173–176]. The hypopituitarism is manifest by micropenis and cryptorchidism in affected males and the presence of hypoadrenalism. Associated craniofacial malformations include large fontanelles, a shortened midface, short nose with long philtrum, posteriorly rotated ears, cleft uvula and palate, microglossia, cleft larynx, hypoplasia of the epiglottis, and occasional natal teeth or buccal frenula. Limb abnormalities such as postaxial polydactyly, syndactyly, nail dysplasia, clinodactyly of the fifth fingers, shortened fourth metacarpals and/or metatarsals, and pes cavus are commonly found. Other anomalies noted with this syndrome are congenital heart disease, hypoplastic renal dysplasia, abnormal lung segmentation, and imperforate anus. The genetic basis of this disorder is unknown, but it is linked to 7p13 [177].

Germ Cell Tumors Germ cell tumors are broadly classified into germinomas (seminomas; 65% of intracranial germ cell neoplasms) and nongerminomatous germ cell tumors. The latter group includes teratomas, embryonal carcinomas, endodermal sinus tumors, and choriocarcinomas, which account for 18, 5, 7, and 5%, respectively, of the germ cell tumors [55]. The incidence of these neoplasms in Western countries is between 0.4 and 3.4% of primary intracranial neoplasms, while the incidence in the Far East is several-fold higher [55,178]. Germinomas and nongerminomatous germ cell tumors differ with regard to their age of onset, sex ratio, site of primary neoplasm, and prognosis. The peak age of diagnosis is 10–12 years, with patients with nongerminomatous tumors generally presenting earlier than individuals with germinomas. The male/female sex ratio is 1.88 : 1 for patients with germinoma, and 3.25 : 1 for those with nongerminomatous germ cell tumor [55]. Ninety-five

339

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Table 8.13. Clinical features and pituitary function evaluation in patients with suprasellar germ cell tumors

Feature Diabetes insipidus Clinical hypopituitarism Chiasmal visual field defect Headache Emaciation Growth failure Adipsia/hypernatremia Delayed or regression of sexual development Nausea/vomiting Obesity Precocious puberty Hormonal evaluation Abnormal growth hormone dynamics Abnormal response to gonadotropinreleasing hormone Hyperprolactinemia Abnormal adrenocorticotropic hormone dynamics Low thyroxine or abnormal thyrotropin-releasing hormone response

Number abnormal/ number studied

Percentage

104/112 34/43 48/81 13/28 17/50 24/81 9/42 6/44

92.8 79.1 59.3 46.4 34 29.6 21.4 13.6

4/28 7/60 2/41

14.3 11.7 4.9

40/41 30/34

97.6 88.2

47/62 20/30

75.8 66.7

34/42

81

Data are restricted to tumors involving the suprasellar region and do not include germ cell tumors of the pineal. Data are compiled from [53,54,178–182].

percent of patients with intracranial germ cell neoplasms have the primary lesion located in the region of the third ventricle, between the suprasellar cistern and the pineal gland, with the majority of the germinomas being found in the suprasellar region and most of the nongerminomatous tumors located in the pineal area [55]. The cardinal clinical features of suprasellar germ cell tumors are listed in Table 8.13. The triad of diabetes insipidus, visual field abnormalities, and clinical and/or biochemical evidence of anterior pituitary hormone deficiency is present in many patients, reflecting the anatomic involvement of the optic chiasm, median eminence, and region of the third ventricle. Some patients with occult intracranial germinomas present with diabetes insipidus and pituitary stalk thickening [183]. Other manifestations of hypothalamic dysfunction include abnormalities in appetite control with both emaciation and obesity being found, and the adipsia/hypernatremia syndrome characterized by severe proximal muscle weakness; polyuria, adipsia or hypodipsia, hypernatremia, and hypertriglyceridemia [53,179]. In an exhaustive review of a large number of patients with germ cell tumors, Jennings and colleagues noted that patients with

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germinomas, most of whom had primary lesions in the suprasellar region, exhibited a variety of neurologic abnormalities including hydrocephalus (21%), obtundation (15%), Parinaud’s sign (paralysis of the upward gaze, 14%), pyramidal tract signs (11%), ataxia (9%), diplopia (10%), seizures (3%), choreoathetosis (2%), dementia (2%), and psychosis (1%) [55]. In contrast, patients with nongerminomatous germ cell tumors, usually involving the pineal gland, tended to demonstrate more neurologic abnormalities due to obstruction of the third ventricle and aqueduct of Sylvius and less endocrine disturbances [184]. Thus, 47% had hydrocephalus, 34% Parinaud’s sign, 26% obtundation, 21% pyramidal tract signs, 19% ataxia, 18% diabetes insipidus, and only 19% had evidence of hypothalamic–anterior pituitary failure [55]. Of interest, approximately 5% of patients with intracranial germ cell tumors develop precocious puberty [53–55,179,180]. This may occur as a pressure effect of the neoplasm on the median eminence, or, alternatively, as a result of the production of hCG by the neoplasm [185]. Choriocarcinomas or the syncytiotrophoblastic giant cells present in the other types of germ cell neoplasms secrete hCG, which directly stimulates the Leydig cells of the testes to produce androgens, resulting in sexual precocity. The testes of affected individuals show Leydig cell hyperplasia with no spermatogenesis since FSH levels are suppressed [185]. Precocious puberty is extremely rare in girls with germ cell tumors, probably because of the requirement of FSH for ovarian estradiol production [186]. Intracranial germ cell neoplasms spread by direct invasion of the hypothalamus or through seeding into the ventricles or subarachnoid pathways [55]. Poor prognostic features include neoplastic involvement of the hypothalamus, third ventricle, or spinal cord, and histologic tumor type, with germinomas having the best prognosis, choriocarcinomas the worst, and the other varieties falling in between [55]. The mainstay of therapy for these neoplasms has been radiation therapy, with the best results being seen in patients with germinomas who receive 5000–6000 rads to the tumor. Extirpative surgery and chemotherapy are generally reserved for patients with aggressive, radioresistant tumors [55].

Optic Chiasm and Hypothalamic Gliomas Gliomas of the optic pathways tend to be low-grade pilocytic astrocytomas, occurring primarily in children, with close to 40% being found in those under 2 years of age and 80% under 10 [65,66,187–191]. These tumors account for 1–3% of brain tumors in children and adolescents [65]. Approximately one-fourth of optic pathway gliomas are intraorbital, while three-fourths arise in the optic chiasm, optic tract, or hypothalamus. Tumors of the chiasm and hypothalamus are grouped together because they tend to infiltrate and involve both structures, and it is often impossible to differentiate between tumors originating in one

structure or the other. Von Recklinghausen’s neurofibromatosis is a major predisposing factor for the development of these tumors and is present in 20–25% of patients with gliomas of the optic pathways [66,108,188]. Intraorbital optic nerve gliomas rarely involve the hypothalamus or pituitary. The major clinical manifestations are unilateral visual loss, proptosis of the ipsilateral eye, papilledema, strabismus, and nystagmus [66,188,192,193]. In contrast, optic chiasm/hypothalamic gliomas are associated with endocrine disturbances, visual field abnormalities, diabetes insipidus, hydrocephalus, and the diencephalic syndrome of infancy, in addition to decreased visual acuity, optic atrophy, and papilledema (Table 8.14). Therapy of these tumors has been controversial. Some authorities have argued that these tumors are indolent and behave more like hamartomatous lesions than neoplasms, and, therefore, do not require therapy unless they continue to grow and cause neurologic dysfunction [192]. Others have advocated radiation therapy, citing improvement or stabiliza-

Table 8.14. Clinical features of patients with optic chiasm/hypothalamic glioma

Feature Sex Male Female Age of onset <2 years of age Associated neurofibromatosis Decreased visual acuity Optic atrophy Anterior pituitary dysfunction Growth retardation Precocious puberty Delayed puberty Hypothyroidism Panhypopituitarism Hypothalamic involvement Papilledema/increased intracranial pressure Hydrocephalus Visual field abnormalities Microcephaly Diencephalic syndrome Headache Ataxia/hemiparesis Nausea/vomiting Diabetes insipidus Seizures Exophthalmos Behavioral abnormalities Data are compiled from [65,66,187–190].

Number abnormal/ number studied

Percentage

95/164 69/164 28/73 20/112 83/125 54/101 23/48 7/32 11/76 8/56 2/33 2/33 23/68 23/69

57.9 42.1 38.4 17.9 66.4 53.5 47.9 21.9 14.5 14.3 6 6 33.8 33.3

29/92 24/80 5/24 11/53 23/116 9/57 5/33 9/61 4/52 4/68 1/24

31.5 30 20.8 20.8 19.8 15.8 15.2 14.8 7.7 5.9 4.2

Chapter 8

tion of the visual abnormalities and inhibition of tumor growth, or a delayed time to recurrence [65,187,190,193]. From a prognostic standpoint, patients with intraorbital gliomas have a considerably better prognosis than do patients with chiasmatic/hypothalamic gliomas. In one long-term study, 85% of patients with optic nerve gliomas survived 17 years, while only 44% of patients with chiasmatic/ hypothalamic lesions lived 19 years [188]. There is also evidence that optic pathway gliomas in patients with neurofibromatosis behave in more benign fashion than do gliomas in patients without neurofibromatosis [188,192].

Craniopharyngioma Craniopharyngiomas are benign neoplasms derived from cell rests of Rathke’s pouch origin, that often behave in a malignant fashion due to local growth and infiltration of surrounding tissue [110]. They account for approximately 2.5% of brain tumors, and 5–10% of brain neoplasms in children [138,194]. The male/female sex ratio is 1.2–1.4 : 1 [195,196]. Almost half the patients present before the age of 20, with the median age of 22 years [196]. Most of the tumors are cystic or partially cystic, while 15% are solid [110]. The clinical presentation and prognosis depends upon the age of the patient, the location of the neoplasm, and its size [138,195]. Children generally present with signs and symptoms of increased intracranial pressure including headache (often occurring intermittently in the morning), vomiting (occasionally in a projectile fashion), papilledema (31%), and hydrocephalus [110,138,191,194,197]. Decreased visual acuity and visual field abnormalities are also common. Short stature due to GH deficiency is the most prevalent hormonal abnormality, being found in close to 43% of the children, with diabetes insipidus being the second most common clinical endocrinologic disorder (22%) although endocrine abnormalities are the presenting complaint in less than 15% of the patients [198]. Abnormalities of the sleep–wake cycle and excessive somnolence occur more frequently in children than in adults [110,138,195,196,199]. In contrast, visual abnormalities, especially a progressive diminution of vision and an asymmetric bitemporal hemianopsia, are the most common presenting symptoms in adults [110,195,199]. Other prominent symptoms in this group are headache, deterioration of cognitive abilities, personality change, vomiting, weight gain, and hypogonadism [110,195,199]. In addition to the signs and symptoms of raised intracranial pressure, visual abnormalities, hypothalamic dysfunction, and deficiencies of the anterior pituitary tropic hormones, a variety of additional neurologic findings may be present in both children and adults. Lateral extension of the neoplasm into the cavernous sinus may damage cranial nerves III, IV, and VI, which results in diplopia and abnormalities of the extraocular muscles, and a portion of cranial nerve V, which leads to facial pain. Temporal lobe involvement is associated with temporal lobe seizures, while

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posterior extension to the midbrain may give rise to cerebellar ataxia and pyramidal tract findings [110,191,196]. The clinical and biochemical features of craniopharyngiomas derived from several series of patients are summarized in Table 8.15. Children with craniopharyngiomas differ from adults in several other respects. They are more likely to have an enlarged sella turcica on skull roentgenography (64% vs 27%) [196], calcification of the tumor on skull X-ray (76% vs 21%) [196], larger tumors (91%
3 cm in children vs 60% in adults [195], and a better prognosis [195]. The therapy of these neoplasms has been a matter of controversy for decades. In the past, radical excision carried unacceptably high mortality and morbidity rates [194,196]. However, recent studies using modern microsurgical techniques, including approaching the tumors through the transsphenoidal route, have claimed excellent results although there remains a 25% recurrence rate [194,197,199–201]. The most conservative approach balancing the associated risks with radical, total resection, and the need for local control of tumor growth is to partially resect the tumor and deliver

Table 8.15 Clinical and biochemical features of patients with craniopharyngioma

Feature

Number abnormal/ number studied

Percentage

269/296 39/42 39/191 37/44 168/609 34/44

91 93 20.4 84.1 27.6 77.3

Anterior pituitary dysfunction Gonadotropin deficiency* Clinical hypogonadism Growth hormone deficiency* Short stature/delayed bone age Adrenocorticotropic hormone deficiency* Thyroid-stimulating hormone deficiency Multiple hormone deficiency Hyperprolactinemia* Galactorrhea Precocious puberty

20/46

53.5

246/296 116/296 12/296 21/363

83 39.2 4 5.8

Decreased visual acuity/visual field defect Headache Obesity Vomiting Mental deterioration Diabetes insipidus Papilledema Hydrocephalus Somnolence Ataxia Pyramidal tract signs

468/639 314/449 207/489 103/367 106/382 215/902 33/149 16/102 6/67 9/149 4/67

73.2 69.9 42.3 28.1 27.7 23.8 22.1 15.7 8.9 6 6

* Results from biochemical testing. Data are compiled from [53,110,138,139,144,194 –197].

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5000–6000 rads of postoperative radiation to the residual neoplasm [195,202]. This carries a 21% recurrence rate [197]. Following surgery, one-half or more of the patients develop hyperplasia, obesity, hyperinsulinemia, and normal growth despite growth hormone deficiency, possibly reflecting damage to the ventromedial hypothalamus [203].

Suprasellar Meningiomas Meningiomas arising from the tuberculum sellae and planum sphenoidale may encroach upon, but not invade, the hypothalamus. These benign neoplasms have a male/ female sex ratio of 1 : 3, and become symptomatic in adults. The peak incidence is between the ages of 40 to 50 years [110,204]. Over 80% of the patients present with a complaint of slow loss of vision in one eye, and over 90% have objective evidence of diminished visual acuity. Other neuroophthalmologic signs and symptoms include poor color perception, an afferent pupillary light defect, abnormal visual fields (80%), pallor of the optic discs (83%), the Foster–Kennedy syndrome (7.2%), and abnormal extraocular movements (3.6%) [204]. Headache is also common, being found in 54% of the patients. It generally is of poor localizing value, although some patients will have ipsilateral orbital pain. Deterioration of cognitive function, confusion, and memory loss may be found in approximately 20% of patients [204]. Endocrine abnormalities have been found in 22% of patients, most commonly hypogonadism (13%), hypothyroidism (14%), and diabetes insipidus (4.8%). Close to 40% of the patients are obese [204]. These tumors contain estrogen receptors and may increase in size during pregnancy or even during the menstrual cycle [110,138]. The latter feature may account for some of the fluctuation in the signs and symptoms noted in patients with these tumors. Surgical resection is the treatment of choice for these lesions, and results in improved vision in about 60% of patients, and stabilization of the visual defect in an additional 30% [204].

Suprasellar Arachnoid Cyst Developmental defects in the arachnoid membrane in the suprasellar region may allow for the development of a large, fluid-filled closed cyst that causes symptoms through a mass effect. The majority (70%) of patients with this congenital anomaly present before 5 years of age [205,206]. The major findings are related to hydrocephalus with increased intracranial pressure from obstruction to cerebrospinal fluid flow through the foramen of Monro (Table 8.16). Symptoms and signs related to compression of the brain stem, thalamus, and the optic tracts are also common. GH and ACTH deficiency, and precocious puberty are the primary endocrinologic problems encountered in children affected with this rare abnormality. The treatment is surgical decompression. Although a number of procedures have been developed, percutaneous

Table 8.16. Clinical features of patients with suprasellar arachnoid cysts Number abnormal/ number studied

Percentage

Hydrocephalus Increased head size Headache/papilledema Drowsiness/vomiting

21/25 17/25 5/25 2/25

84 68 20 8

Brain stem/thalamic compression Spasticity Ataxia Tremor Head bobbing

14/20 11/20 6/20 4/20 12/106

70 55 30 20 11

Hypothalamic–pituitary dysfunction Growth hormone deficiency Adrenocorticotropic hormone deficiency Precocious puberty

9/18 4/18 4/18

50 22 22

4/18

22

Optic nerve/chiasm compression Optic pallor Visual acuity/field defect

9/25 7/25 6/25

36 28 24

Feature

From Pierre-Khan et al. [205,207].

ventriculocystostomy appears to be an effective technique with lowest morbidity [205]. Following the procedure, the elevated intracranial pressure returns to normal and there is an increase in the IQ of the child [205].

Colloid Cyst of the Third Ventricle Colloid cysts are usually located in the roof of the third ventricle or rarely in the area of the septum pellucidum [208]. They generally present clinically between the ages of 25 and 50 years, and there is a male/female sex ratio of 2–3 : 1 [209,210]. There are three major clinical presentations that these patients exhibit [210]. A little over one-third will have symptoms and signs of increased intracranial pressure, complaining of a nonspecific headache and vomiting, and exhibiting papilledema. Approximately 20% will develop a fluctuating or progressive dementia, often with gait disturbance and urinary incontinence, a combination that closely resembles normal pressure hydrocephalus. Another 20% will present with a history of intermittent attacks of headache, vomiting, and visual disturbances, followed by loss of consciousness for a variable period, and then recovery. The headache is often of sudden onset with a frontal localization, usually precipitated by head movement such as lying down. The pain intensity rises rapidly, and the patient develops nausea and vomiting until he or she loses consciousness [210]. This “classical” presentation is due to the cyst acting

Chapter 8

as a ball-valve obstructing the foramen of Monro or the aqueduct of Sylvius. A similar mechanism is probably responsible for the drop attacks that can occur abruptly in these patients. Approximately 10–20% of patients in several series suffer sudden death, presumably from acute obstruction to the flow of cerebrospinal fluid [209,210].

Infiltrative Disorders

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343

hypothalamic involvement is growth retardation, found in 40% of patients with prepubertal onset of disease, due to abnormalities in the formation and/or release of GHRH by the hypothalamus [56,140,221]. Hyperprolactinemia, hypothalamic hypogonadism, and disorders of thirst are also seen in some patients. Low-dose radiation therapy and chemotherapy have been utilized to treat the disease, but have not been successful in reversing the diabetes insipidus or growth retardation [56].

Hypothalamic–Pituitary Sarcoidosis

Sarcoidosis involves the intracranial central nervous system in 1.35% of patients with the disease, and affects the hypothalamic–pituitary region in 0.53% of cases [211]. The sarcoid granulomas have a predilection for the basal hypothalamus and floor of the third ventricle, as well as the posterior, but not the anterior, pituitary [60,212]. Both sexes are equally involved, and over 80% of the patients have evidence of systemic involvement with sarcoidosis, especially hilar adenopathy, which is present on chest X-rays in twothirds of cases [57,58]. The common clinical manifestations in these patients are diabetes insipidus (37.5%), visual acuity and/or visual field abnormalities (53%), other dysfunction of other cranial nerves (especially VII, I, V, and VIII; 44%), and evidence of other central nervous system involvement (71%) [57,58,60,213–215]. In addition to the diabetes insipidus, hypothalamic involvement is manifest by thermal dysregulation (hypothermia, hyperthermia, and poikilothermia), somnolence, personality changes, abnormalities of thirst with resetting of the osmostat, and obesity [57,58,212–214,216]. Hypothalamic hypopituitarism is also present in virtually all of the patients with hypothalamic involvement. GH deficiency is the most common abnormality (92%), followed by gonadotropin deficiency (79%), ACTH deficiency (58%), hyperprolactinemia (20%), and hypothyroidism (6%) [58–60,217]. Following a bolus injection of TRH the patients who have hypothyroidism associated with a low basal TSH have a rise in TSH. Similarly, the hypogonadal patients show a rise in gonadotropins following GnRH infusion [58]. Most patients with sarcoidosis involving the CNS, including the hypothalamus, receive therapeutic doses of glucocorticoids. Several authors have described improvement in some of the clinical manifestations of hypothalamic–pituitary sarcoidosis, especially the visual dysfunction, following such therapy, although it is uncommon for long-standing abnormalities, especially diabetes insipidus to improve [57,58,60,217–219]. Histiocytosis

Hypothalamic involvement with Langerhans’ cell histiocytosis occurs primarily in the chronic, disseminated form, Hand–Schuller–Christian disease, and occasionally by a unifocal eosinophilic granuloma [56,220]. The classical triad of Hand–Schuller–Christian disease consists of exophthalmos, lytic lesions of the membranous bones, and diabetes insipidus. Diabetes insipidus is found in close to one-half of the patients [56]. The other common clinical manifestation of

Leukemia

Diabetes insipidus due to leukemic infiltration or thrombosis of the small vessels of the hypothalamus or posterior pituitary is a rare manifestation of acute leukemia. Close to three-quarters of the patients have acute nonlymphoblastic leukemia, 14% have acute lymphoblastic leukemia, 10% chronic myelocytic leukemia, and 3% have chronic lymphocytic leukemia [222]. Antileukemic therapy generally fails to resolve the diabetes insipidus. The relatively low frequency of acute lymphoblastic leukemia associated with diabetes insipidus may reflect the prophylactic central nervous system radiation and intrathecal chemotherapy these patients receive [222]. Paraneoplastic Syndrome

Lymphocytic and histiocytic infiltration of the hypothalamus in patients with non-metastatic neural crest tumors can result in a syndrome of hypersomnia, hyperphagia, obesity, polyuria, respiratory irregularity, and aggressive behavior [223].

Effect of Brain Irradiation on Hypothalamic Function It has been known for decades that patients who receive therapeutic irradiation to the pituitary–hypothalamic region for the treatment of pituitary adenomas or primary suprasellar neoplasms may develop hypopituitarism, either as a direct result of the radiation or as a consequence of the mass effects of the neoplasm. Nevertheless, it commonly was felt that the normal hypothalamus and pituitary is relatively radioresistant. However, histologic studies have shown areas of necrosis in the hypothalamus following cranial irradiation and it is now being increasingly recognized that hypothalamic pituitary and especially dysfunction may be a longterm, adverse consequence of irradiation to the head and neck for disease outside of the sellar region. Thus, wholebrain irradiation for acute lymphoblastic leukemia or primary brain tumors, or more localized radiation for the treatment of nasopharyngeal cancer, paranasal sinus tumors, and other head and neck neoplasms have been found to be associated with hypothalamic and pituitary dysfunction and decreased pituitary gland height on magnetic resonance imaging [224–231]. The risk factors that have been identified include the dose of irradiation, with higher doses being associated with a higher risk, the interval over which the

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Figure 8.4. The earliest abnormality was found with GH secretion, with onset of the dysfunction being documented a mean of 2.6 years following therapy, and the last abnormality to be detected involved ACTH secretion, which was found a mean of 6 years following the therapy [227]. Younger patients tended to have more GH deficiency than adults, while adults tended to have a greater frequency of ACTH and LH deficiency than did younger individuals. Serial serum prolactin levels appear to be a relatively sensitive and easy means to detect hypothalamic–pituitary dysfunction in patients who receive head and neck irradiation [227,228]. Other manifestations of hypothalamic dysfunction that have been noted in patients that received wholebrain irradiation include alterations in personality, appetite, thirst, and sleep–wake cycle [230]. REFERENCES

FIGURE 8.4 Percentages of 166 patients with head and neck irradiation who have abnormal hormonal levels following radiotherapy. Data from Samaan et al. [227]. In this group of patients the thyroid-stimulating hormone (TSH) tended to be elevated, reflecting primary hypothyroidism secondary to the head and neck radiation. ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; PRL, prolactin.

radiotherapy is delivered, the age of the patient, with children and adolescents being more susceptible than adults, and the interval following completion of the radiation therapy and the time that the patient is specifically tested for damage [230,232]. Many of the early series of patients studied were referred for evaluation of short stature or hypothalamic dysfunction; objective endocrine abnormalities were quite common in these cases [226,228,230]. One of the most important studies that examined the topic is the investigation by Samaan and colleagues [227]. They studied 166 patients who received a median of 5000 rads to the hypothalamus and 5700 rads to the pituitary during treatment of nasopharyngeal carcinoma and paranasal sinus tumors [227]. These patients were not selected because of signs or symptoms of hypothalamic or pituitary disease, and studies in 65 of the patients were performed prospectively. They found that 66.8% of the patients had one or more hormonal abnormalities that suggested a hypothalamic lesion, while 40% had evidence of primary pituitary dysfunction. The prevalence of the various anterior pituitary hormone abnormalities was directly related to the number of years between completion of the therapy and the evaluation, as shown in

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Chapter 8 140 Borges JLC, Blizzard RM, Gelato MC et al. Effects of human pancreatic tumour growth hormone releasing factor on growth hormone and somatomedin C levels in patients with idiopathic growth hormone deficiency. Lancet 1983;ii:119–124. 141 Carlier R, Monnet O, Idir ABC et al. Anterior and posterior hypopituitarism with pituitary stalk abnormalities. J Neuroradiol 1991;18:49–60. 142 Triulzi F, Scotti G, di Natale B et al. Evidence of a congenital midline brain anomaly in pituitary dwarfs: a magnetic resonance imaging study in 101 patients. Pediatrics 1994;93:409–416. 143 Krieger DT, Krieger HP. Circadian variation of the plasma 17hydroxycorticosteroids in central nervous system disease. J Clin Endocrinol Metab 1966;26:929–940. 144 Korsgaard O, Lindholm J, Rasmussen P. Endocrine function in patients with suprasellar and hypothalamic tumours. Acta Endocrinol 1976;83:1–8. 145 Beck-Peccoz P, Amr S, Menezes-Ferreira M, Faglia G, Weintraub BD. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. N Engl J Med 1985;312:1085–1090. 146 Prader A, Labhart A, Willi H. Ein syndrome von adipositas, Kleinwuchs, Kryptorchismus, und Oligophrenie nach myotonieartigen Zustand im Neugeborenenalter. Schweiz Med Wochenschr 1956;86:1260–1261. 147 Bray GA, Dahms WT, Swerdloff RS, Fiser RH, Atkinson RL, Carrel RE. The Prader–Willi syndrome: a study of 40 patients and a review of the literature. Medicine 1983;62:59–80. 148 Cassidy SB. Prader–Willi syndrome. J Med Genet 1997;34:917–923. 149 Sapienza C, Hall JG. Genetic imprinting in human disease. In: Scriver CR, Beaudet AR, Sly WS, eds. The metabolic and molecular basis of inherited disease, vol. 1. New York: McGraw-Hill Inc, 1995:437–458. 150 Rimoin DL, Schimke RN. Genetic Disorders of the Endocrine Glands. St Louis: C V Mosby Co, 1971:189–191. 151 Cassidy SB, Schwartz S. Prader–Willi and Angelman syndromes: disorders of genomic imprinting. Medicine 1998;77:140–151. 152 Klein D, Ammann F. The syndrome of Laurence–Moon–Bardet–Biedl and allied diseases in Switzerland. Clinical, genetic and epidemiological studies. J Neuro Sci 1969;9:479–513. 153 Stiggelbout W. The Bardet–Biedl syndrome. Including Hutchinson–Laurence–Moon syndrome. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, vol. 13. Amsterdam: North-Holland, 1972: 380–413. 154 Beales PL, Warner AM, Hitman GA et al. Bardet-Biedl syndrome: A molecular and phenotypic study of 18 families. J Med Genet 1997;34:922–928. 155 Edwards JA, Sethi PK, Scoma AJ, Bannerman RM, Frohman LA. A new familial syndrome characterized by pigmentary retinopathy, hypogonadism, mental retardation, nerve deafness and glucose intolerance. Amer J Med 1976;60:23–32. 156 Morishima A, Aranoff GS. Syndrome of septo-optic–pituitary dysplasia: the clinical spectrum. Brain Dev 1986;8:233–239. 157 Roessmann U, Velasco ME, Small EJ, Hori A. Neuropathology of “septo-optic dysplasia” (de Morsier syndrome) with immunohistochemical studies of the hypothalamus and pituitary gland. J Neuropath Exp Neurol 1987;46:597–608. 158 Yukizane S, Kimura Y, Yamashita Y et al. Growth hormone deficiency of hypothalamic origin in septo-optic dysplasia. Eur J Pediatr 1990;150:30–33. 159 Powell GF, Brasel JA, Blizzard RM. Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. I. Clinical evaluation of the syndrome. N Engl J Med 1967;276:1271–1278. 160 Powell GF, Brasel JA, Raiti S, Blizzard RM. Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. II. Endocrinologic evaluation of the syndrome. N Engl J Med 1967;276:1279–1283. 161 Yen SSC, Rebar RW, Quesenberry W. Pituitary function in pseudocyesis. J Clin Endocrinol Metab 1976;43:132–136. 162 Zuber T, Kelly J. Pseudocyesis. Am Fam Phys 1984;30:131–134. 163 Small GW. Pseudocyesis: an overview. Canadian J Psych 1986;31:452–457. 164 Bray MA, Muneyyirci-Delale A, Kofinas GD, Reyes FI. Circadian, ultradian, and episodic gonadotropin and prolactin secretion in human pseudocyesis. Acta Endocrinol 1991;124:501–509. 165 List CF, Dowman CE, Bagchi BS, Bebin J. Posterior hypothalamic hamartomas and gangliogliomas causing precocious puberty. Neurology 1958;8:164–174. 166 Diebler C, Ponsot G. Hamartomas of the tuber cinereum. Neuroradiology 1983;25:93–101. 167 Comite F, Pescovitz OH, Rieth KG. Luteinizing hormone-releasing hormone analog treatment of boys with hypothalamic hamartoma and true precocious puberty. J Clin Endocrinol Metab 1984;59:888–892. 168 Sato M, Ushio Y, Arita N, Mogami H. Hypothalamic hamartoma: report of two cases. Neurosurgery 1985;16:198–206.

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169 Valdueza JM, Cristante L, Dammann O et al. Hypothalamic hamartomas: with special reference to gelastic epilepsy and surgery. Neurosurgery 1994;34: 949–958. 170 Northfield DWC, Russel DS. Pubertas praecox due to hypothalamic hamartoma: report of two cases surviving surgical removal of the tumor. J Neurol Neurosurg Psychiat 1967;30:166–173. 171 Ilgren E, Briggs M, Anysly-Green A. Precocious puberty in a 3-year-old girl associated with parasellar ganglionic hamartoma. Clin Neuropathol 1983;2: 95–98. 172 Bierich JR. Sexual precocity. J Clin Endocrinol Metab 1975;44:107–142. 173 Hall JG, Pallister PD, Clarren SK et al. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly – a new syndrome? Part I: Clinical, causal, and pathogenetic considerations. Am J Med Gen 1980;7:47–74. 174 Clarren SK, Alvord EC Jr, Hall JG. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly – a new syndrome? Part II: Neuropathological considerations. Am J Med Gen 1980;7: 75–83. 175 Biesecker LG, Abbott M, Allen J et al. Report from the workshop on Pallister–Hall syndrome and related phenotypes. Am J Med Genet 1996;65:76–81. 176 Biesecker LG, Graham JM Jr. Pallister–Hall syndrome. J Med Genet 1996;33:585–589. 177 Kang S, Allen J, Graham JM Jr et al. Linkage mapping and phenotypic analysis of autosomal dominant Pallister–Hall syndrome. J Med Genet 1997;34: 441–446. 178 Takeuchi J, Handa H, Nagata I. Suprasellar germinoma. J Neurosurg 1978;49: 41–48. 179 Sklar CA, Grumbach MM, Kaplan SL, Conte FA. Hormonal and metabolic abnormalities associated with central nervous system germinoma in children and adolescents and the effect of therapy: report of 10 patients. J Clin Endocrinol Metab 1981;52:9–16. 180 Simson LR, Lampe I, Abell MR. Suprasellar germinomas. Cancer 1968;22: 533–544. 181 Aida T, Abe H, Fujieda K, Matsuura N. Endocrine functions in children with suprasellar germinoma. Neurol Med Chir 1993;33:152–157. 182 Nishio S, Inamura T, Takeshita I et al. Germ cell tumor in the hypothalamo–neurohypophysial region: clinical features and treatment. Neurosurg Rev 1993;16:221–227. 183 Mootha SL, Barkovich AJ, Grumbach MM et al. Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab 1997;82: 1362–1367. 184 Nichols CR, Fox EP. Extragonadal and pediatric germ cell tumors. Hemat/Oncol Clinics N Amer 1991;5:1189–1209. 185 Navarro C, Corretger JM, Sancho A, Rovira J, Morales L. Paraneoplastic precocious puberty. Report of a new case with hepatoblastoma and review of the literature. Cancer 1985;56:1725–1729. 186 Kubo O, Yamasaki N, Kamijo Y, Amano K, Kitamura K, Demura R. Human chorionic gonadotropin produced by ectopic pinealoma in a girl with precocious puberty. J Neurosurg 1977;47:101–105. 187 Packer RJ, Sutton LN, Bilaniuk LT et al. Treatment of chiasmatic/ hypothalamic gliomas of childhood and chemotherapy: an update. Ann Neurol 1988;23:79–85. 188 Rush JA, Younge BR, Campbell RJ, MacCarty CS. Optic glioma. Long-term follow up of 85 histopathologically verified cases. Ophthalmology 1982;89: 1213–1219. 189 Helcl F, Petraskova H. Gliomas of visual pathways and hypothalamus in children – a preliminary report. Acta Neurochir 1985;35(suppl.):106–110. 190 Rodriguez LA, Edwards MSB, Levin VA. Management of hypothalamic gliomas in children: an analysis of 33 cases. Neurosurgery 1990;26:242–247. 191 Rogol AD. Pituitary and parapituitary tumors of childhood and adolescence. In: Givens JR, Kitabchi AE, Robertson JT, eds. Hormone-secreting pituitary tumors. Chicago: Year Book Medical Publishers, Inc., 1981:349–375. 192 Alshail E, Rutka JJ, Becker LE, Hoffman HJ. Optic chiasmatic-hypothalamic glioma. Brain Pathol 1997;7:799–806. 193 MacCarty CS, Boyd AS Jr, Childs DS Jr. Tumors of the optic nerve and optic chiasm. J Neurosurg 1970;33:439–444. 194 Kjellberg RN. Craniopharyngiomas. In: Tindall GT, Collins WF, eds. Clinical management of pituitary disorders. New York: Raven Press, 1979:373– 388. 195 Wen B-C, Hussey DH, Staples J et al. A comparison of the roles of surgery and radiation therapy in the management of craniopharyngiomas. Int J Rad Oncol Bio Phys 1989;16:17–24.

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196 Randall RV, Laws ER Jr, Abboud CF. Clinical presentation of craniopharyngiomas. A brief review of 300 cases. In: Givens JR, Kitabchi AE, Robertson JT, eds. The hypothalamus. Chicago: Year Book Medical Publishers, Inc., 1984:321–333. 197 Sanford RA, Muhlbauer MS. Craniopharyngioma in children. Neurologic Clinics 1991;9:453–465. 198 Sklar CA. Craniopharyngioma: endocrine abnormalities at presentation. Pediatr Neurosurg 1994;21(suppl 1):18–20. 199 Yasargil MG, Curcic M, Kis M, Siegenthaler G, Teddy PJ, Roth P. Total removal of craniopharyngiomas. Approaches and long-term results in 144 patients. J Neurosurg 1990;73:3–11. 200 Laws ER Jr, Randall RV, Abboud CF, Hayles AB. Craniopharyngioma. The transsphenoidal microsurgical approach. In: Givens JR, Kitabchi AE, Robertson JT, eds. The hypothalamus. Chicago: Year Book Medical Publishers, Inc., 1984:335–347. 201 Samii M, Tatagiba M. Surgical management of craniopharyngiomas: a review. Neurol Med Chir 1997;37:141–149. 202 Fischer EG, Welch K, Shillito J Jr, Winston KR, Tarbell NJ. Craniopharyngiomas in children. Long-term effects of conservative surgical procedures combined with radiation therapy. J Neurosurg 1990;73:534–540. 203 Sklar CA. Craniopharyngioma: Endocrine sequelae of treatment. Pediatr Neurosurg 1994;21:120–123. 204 Finn JE, Mount LA. Meningiomas of the tuberculum sellae and planum sphenoidale. A review of 83 cases. Arch Ophthalmol 1974;92:23–27. 205 Pierre-Kahn A, Capelle L, Brauner R et al. Presentation and management of suprasellar arachnoid cysts. Review of 20 cases. J Neurosurg 1990;73:355–359. 206 Harsh GR IV, Edwards MSP, Wilson CB. Intracranial arachnoid cysts in children. J Neurosurg 1986;69:835–842. 207 Rappaport ZH. Suprasellar arachnoid cysts: options in operative management. Acta Neurochir 1993;122:71–75. 208 Martin JB, Reichlin S. Clinical Neuroendocrinology. Philadelphia: FA Davis Co., 1987:534. 209 Little JR, MacCarty CS. Colloid cysts of the third ventricle. J Neurosurg 1974;39:230–235. 210 Kelly R. Colloid cysts of the third ventricle. Analysis of twenty-nine cases. Brain 1951;74:23–65. 211 Silverstein A, Feuer MM, Siltzbach LE. Neurologic sarcoidosis. Arch Neurol 1965;12:1–11. 212 Stuart CA, Neelon FA, Lebovitz HE. Disordered control of thirst in hypothalamic–pituitary sarcoidosis. N Engl J Med 1980;303:1078–1082. 213 Winnacker JL, Becker KL, Katz S. Endocrine aspects of sarcoidosis. N Engl J Med 1968;278:427–434. 214 Winnacker JL, Becker KL, Katz S. Endocrine aspects of sarcoidosis (concluded). N Engl J Med 1968;278:483–492.

215 Bell NH. Endocrine complications of sarcoidosis. Endocrinol Metab Clin N Am 1991;20:645–654. 216 Vesely DL. Hypothalamic sarcoidosis: a new cause of morbid obesity. South Med J 1989;82:758–761. 217 Nakao K, Noma K, Sato B, Yano S, Yamamura Y, Tachibana T. Serum prolactin levels in eighty patients with sarcoidosis. Europ J Clin Invest 1978;8:37–40. 218 Scott IA, Stocks AE, Saines N. Hypothalamic/pituitary sarcoidosis. Aust NZ J Med 1987;17:243–245. 219 Hidaka N, Takizawa H, Miyachi S, Hisatomi T, Kosuda T, Sato T. Case report: a case of hypothalamic sarcoidosis with hypopituitarism and prolonged remission of hypogonadism. Am J Med Sci 1987;294:357–363. 220 Ober KP, Alexander E Jr, Challa VR, Ferree C, Elster A. Histiocytosis X of the hypothalamus. Neurosurgery 1989;24:93–95. 221 Braunstein GD, Kohler PO. Pituitary function in Hand–Schuller–Christian disease. Evidence for deficient growth-hormone release in patients with short stature. N Engl J Med 1972;286:1225–1229. 222 Ra’anani P, Shpilberg O, Berezin M, Ben-Bassat I. Acute leukemia relapse presenting as central diabetes insipidus. Cancer 1994;73:2312–2316. 223 Ouvrier R, Nunn K, Sprague T et al. Idiopathic hypothalamic dysfunction: a paraneoplastic syndrome? Lancet 1995;346:1298. 224 Littley MD, Shalet SM, Beardwell CG. Radiation and hypothalamic–pituitary function. Bailliere’s Clin Endocrinol Metab 1990;4:147–175. 225 Constine LS, Woolf PD, Cann D et al. Hypothalamic–pituitary dysfunction after radiation for brain tumors. N Engl J Med 1993;328:87–94. 226 Richards GE, Wara WM, Grumbach MM, Kaplan SL, Sheline GE, Conte FA. Delayed onset of hypopituitarism: sequelae of therapeutic irradiation of central nervous system, eye, and middle ear tumors. J Pediatr 1976;89:553– 559. 227 Samaan NA, Schultz PN, Yang K-PP et al. Endocrine complications after radiotherapy for tumors of the head and neck. J Lab Clin Med 1987;109: 364–372. 228 Mechanick JI, Hochberg FH, LaRocque A. Hypothalamic dysfunction following whole-brain irradiation. J Neurosurg 1986;65:490–494. 229 Lam KSL, Tse VKC, Wang C, Yeung RTT, Ma JTC, Ho JHC. Early effects of cranial irradiation on hypothalamic–pituitary function. J Clin Endocrinol Metab 1987;64:418–424. 230 Costin G. Effects of low-dose cranial radiation on growth hormone seretory dynamics and hypothalamic–pituitary function. Amer J Dis Child 1988;142: 847–852. 231 Pääkkö E, Talvensaari K, Pyhtinen J, Lanning M. Decreased pituitary gland height after radiation treatment to the hypothalamic–pituitary axis evaluated by MR. Am J Neuroradiol 1994;15:537–541. 232 Shalet SM. Radiation and pituitary dysfunction. N Engl J Med 1993;328: 131–133.

C h a p t e r

9 Anterior Pituitary Failure Charles F. Abboud

an identifiable structural abnormality. All intrinsic pituitary and all extrinsic disorders are structural; however, hypothalamic disorders can be either functional or structural.

INTRODUCTION Hypopituitarism is the clinical syndrome which results from failure of the anterior pituitary gland to produce one, more than one, or all of its hormones. The anterior lobe of the pituitary gland, the adenohypophysis, is a complex endocrine gland which has five types of endocrine cells which produce, at least, eight identifiable hormones. It is under the control of the hypothalamic regulatory hormones which are synthesized and secreted by the neuroendocrine cells of the hypophysiotropic area of the hypothalamus. These hypothalamic hormones are transported to the anterior pituitary gland through the hypothalamic–pituitary portal system. The anterior pituitary cells, their hormones and their hypothalamic regulatory hormones are outlined in Table 9.1. ETIOLOGY Hypopituitarism can result from: (i) intrinsic or primary pituitary disease associated with absence, destruction or dysfunction of the hormone-secreting cells of the anterior pituitary gland; (ii) intrinsic hypothalamic or secondary pituitary disease which leads to a deficiency or loss of the hypothalamic regulatory hormones, with resultant impairment of anterior pituitary hormone synthesis and secretion; and (iii) extrinsic extrasellar or parasellar disease which impinges on and displaces, or infiltrates and destroys, the hypothalamic–pituitary endocrine unit. Disorders of the hypothalamic–pituitary unit can be classified into “structural or organic” disorders where a structural disorder is identifiable, and “functional” disorders where a potentially reversible dysfunction occurs in the absence of

Structural Disorders Hypopituitarism can result from identifiable structural developmental, traumatic, inflammatory, degenerative, vascular or neoplastic disorders [1–9,20]. Developmental Disorders

The adenohypophysis develops from Rathke’s pouch which originates in the nasopharynx and migrates to its normal location in the sella turcica. Congenital absence of the hypophysis is a rare abnormality which results from abnormal development of Rathke’s pouch, and may be complete (aplasia), or partial (hypoplasia) [10–12]. Absence of the hypophysis is often accompanied by other malformations, including anencephaly and holoprosencephaly, a spectrum of developmental anomalies associated with failure of complete midline cleavage of the embryonic forebrain. Pituitary hypoplasia is a constant finding in patients with anencephaly. The anterior lobe, which is devoid of neurohumoral regulation, is reduced in size and has well-developed adenohypophyseal cell types except for a decrease in the number of corticotrophs. Many of these malformations are lethal, but if with less severe malformations the newborn survives, varying degrees of hypopituitarism develop depending on the degree of the pituitary maldevelopment. The genetic disorders, familial or sporadic, which affect the anterior pituitary cells and their endocrine functions are discussed separately under the sections dealing with individual hormone deficiency states. Ectopic Pituitary The gland’s migration may be arrested anywhere along its path of development. Hypopituitarism 349

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Table 9.1. Anterior pituitary hormones and their hypothalamic regulators Anterior pituitary cell

Anterior pituitary hormone(s)

Hypothalamic regulatory hormone(s)

Somatotrope

Somatotropin or growth hormone

Growth hormone release inhibiting hormone (somatostatin) Growth hormone-releasing hormone

Lactotrope

Lactotropin or prolactin

Prolactin inhibiting hormone (dopamine) Vasoactive intestinal peptide

Thyrotrope

Thyrotropin or thyroid-stimulating hormone

Thyrotropin-releasing hormone Somatostatin

Gonadotrope

Follicle-stimulating hormone Luteinizing hormone

Gonadotropin-releasing hormone

Corticotrope

Corticotropin or adrenocorticotropic hormone b-Lipotropin b-Endorphin

Corticotropin-releasing hormone

ensues because of absence of the hypothalamic vascular connections and endocrine control. Developmental Cysts [13] Cystic mass lesions may be present in or around the pituitary gland. They may present as a sellar or extrasellar mass and cause hypopituitarism by compression of the pituitary gland or of the hypothalamus and pituitary stalk. Rathke’s Cleft Cyst [14–18,20] Believed to arise from remnants of Rathke’s pouch, they consist of a thin-walled cyst of variable size, lined by cuboidal or columnar ciliated epithelium and containing mucoid fluid. Most of these slow-growing cysts are intrasellar in location, small in size, and found incidentally at autopsy with an estimated incidence of 12% to 22%. Some may be large and have sellar and suprasellar components, and few are entirely suprasellar in location [18]. Arachnoid Cysts [19,20] Extremely rare and occur predominantly in childhood, they arise from the arachnoid membrane and may be located in the suprasellar subarachnoid space, in the third ventricle or rarely within the sella. Epidermoid Cysts [1,21] Representing 0.2% to 1% of intracranial tumors, with a third of them being situated in the parasellar region, they are slow-growing, unilocular cysts lined by laminated squamous epithelium and usually pre-

senting in the second decade. Very rarely, epidermoid cysts may undergo malignant transformation. Dermoid Cysts [1,22] Uncommon in the sellar region and usually presenting in the first two decades of life, they have a firm fibrous capsule and are filled with yellow greasy material and hair. Microscopically, cutaneous adnexal structures such as hair follicles, sweat and sebaceous glands, may be seen embedded in dermal connective tissue. Peripheral calcifications may be evident. Dermoid cysts rarely undergo malignant change. “Traumatic” Disorders

Accidental Head Trauma [23–25] May lead to pituitary damage because of a direct fracture of the sella turcica [26] and hemorrhage within the gland or damage to the hypothalamus, rupture of the pituitary stalk [27,28] or ischemic pituitary infarction due to interruption of blood supply, vasospasm, or shock. Hypopituitarism may result from anterior pituitary and/or hypothalamic injury [29–32], may be multihormonal or selective [33,34] and may be transient or permanent [35,36]. Neurosurgical Trauma Neurosurgical therapy directed at management of pituitary tumors or tumors of neighboring structures, either by transsphenoidal or transcranial approach, can lead to damage of the pituitary gland, its stalk, or the hypothalamus. Diabetes insipidus and variable degrees of hypopituitarism may occur, usually in close proximity in time to surgical procedure, and may be transient or permanent [37–52]. Radiation Therapy [53–69] The pituitary gland is irradiated in the course of radiotherapy of pituitary adenomas [53–61] and of regional neoplasms [62–69]. When exposed to sufficient doses of radiation, the gland undergoes progressive coagulative necrosis. The neurohypophysis rarely shows morphologic or functional evidence of injury. Atrophy and fibrosis are the end result of the radiation insult, substantial atrophy occurs, a secondary empty sella may ensue. Vascular Disorders

Pituitary infarction is a noninflammatory coagulative necrosis of the pituitary gland caused by ischemia secondary to interruption of the hypothalamic–hypophyseal portal system. Small adenohypophyseal infarcts remain clinically silent and are found in approximately 1% to 6% of unselected adult autopsies. Postpartum pituitary necrosis (Sheehan’s syndrome) [71,72,108,109] occurs in women who experience severe blood loss and hypovolemic shock about the time of delivery, often because of placenta previa or retained placenta. Normally, the pituitary gland is markedly increased in size during pregnancy, primarily because of the hyperplasia and

Chapter 9

hypertrophy of the lactotroph cells resulting from the influence of rising estrogen secretion. In association with severe hemorrhage and hypotension in the immediate postpartum period, vasospasm of the hypophyseal vessels is believed to occur, leading to ischemic necrosis of the pituitary gland. The degree of necrosis depends on the severity of the hemorrhage. Clinical hypopituitarism does not occur until about 70% to 75% of the anterior pituitary is destroyed, and complete hypopituitarism requires at least 90% loss of glandular tissue. As many as 30% of women experiencing hemorrhage and vascular collapse during delivery will develop some degree of hypopituitarism. This entity is less commonly encountered at present due to significant improvements in obstetrical care. Pituitary infarction usually spares the posterior lobe and the hypophyseal stalk because of their rich arterial blood supply. Necrotic foci may, however, occur in these structures [75,76] leading to the development of diabetes insipidus. Fibrous atrophy is the end result of ischemic necrosis, the necrotic areas being replaced by fibrous tissue; a secondary empty sella may ensue [73,74]. Adenohypophyseal necrosis may also occur, though less frequently, in “nonobstetric” shock [77]. Pituitary infarcts of varying sizes can be found in patients with diabetes mellitus [78,79], traumatic head injury [26] and disruption of the pituitary stalk [27,28], cerebrovascular accident, obstructive hydrocephalus, epidemic hemorrhagic fever, vasculitis, and in terminal patients maintained on mechanical respirators. Pituitary hemorrhages are rare. Most commonly, they develop in patients with pituitary adenomas; the tumor may outgrow its blood supply, leading to areas of degeneration and necrosis with subsequent hemorrhage. The hemorrhage is variable in extent, may be small and clinically silent, or rapid and severe resulting in the syndrome of pituitary apoplexy [80–83]. Such apoplexy occurs most often in growth hormone cell adenomas and silent corticotroph cell adenomas. Most patients will recover spontaneously and eventually have anterior pituitary failure [84–87], though posterior pituitary function is almost always preserved. Gross cystic changes in large adenomas or formation of a secondary empty sella may follow the occurrence of hemorrhage into a pituitary tumor. Functioning pituitary tumors can be destroyed by such hemorrhage resulting in amelioration of the hypersecretory clinical syndromes. Pituitary apoplexy may occur in both untreated and irradiated adenomas. Aneurysms [88–93] of the cavernous sinus segment of the internal carotid artery or of the circle of Willis may expand into the sella, mimicking a pituitary adenoma, and impinge on or compress the sellar contents leading to hypopituitarism. Intra-aneurysmal thrombosis may occur and prevent angiographic recognition of the aneurysmal sac. In addition, aneurysms can occur in presumably coincidental association with pituitary adenoma [94,95].

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Inflammatory Disorders

Acute infections of the pituitary gland occur infrequently. They result from either direct extension of infection from the neighboring structures, such as osteomyelitis of the sphenoid bone, purulent sphenoid sinusitis, bacterial meningitis, purulent otitis media, or suppurative thrombophlebitis of the cavernous sinus. Acute infections may also occur in the course of septicemia. Purulent hypophysitis and abscess may result; suppuration may also occur in pituitary tumors or cysts or may occur uncommonly as a postoperative complication [96–101]. Septic shock may be associated with pituitary infarction. Granulomatous infections are uncommon and include tuberculosis, syphilis, and fungal infections. Tuberculosis of the pituitary [1,4,7,8,102] is rare and is always secondary to hematogenous dissemination from an extrapituitary tuberculous lesion, most commonly from the lung, but it may also occur from direct extension from the nearby structures. Syphilis [1,4,8] occurs as a gummatous lesion or a diffuse inflammatory scarring. Fungal infections [102,103,104] of the pituitary caused by histoplasmosis, coccydiosis, etc., have been reported, usually in association with disseminated diseases as with immunosuppression, or with sinonasal infections. Parasitic infections of the pituitary are extremely rare. Viral infections may cause actual necrosis of the gland or may alter pituitary function and have been caused by any of the herpes viruses, influenza, measles, mumps, polio, and epidemic hemorrhagic fever. Histopathologic abnormalities of the pituitary gland have been described rarely in the acquired immune deficiency syndrome or associated cytomegalovirus disease and toxoplasmosis [102]. Hypopituitarism can also result from congenital toxoplasmosis. Lymphocytic hypophysitis [106–109] is an increasingly recognized distinct clinicopathologic entity which occurs almost exclusively in women, with the majority of cases temporally related to pregnancy or the postpartum state. It is presumed to be autoimmune in etiology, based on characteristic cellular infiltrate, association with other autoimmune endocrinopathies or other recognized autoimmune disorders, and demonstration of antipituitary antibodies in some affected patients. Focal lymphocytic infiltrates are observed in about one-third of pituitaries at autopsy without any identifiable endocrine disease in life. When the lesion is widespread, the gland is enlarged and shows diffuse infiltration of its parenchyma by lymphocytes and plasma cells; the adenohypophyseal cells are decreased in number. Later in the course of the disease, atrophy occurs; a secondary empty sella may result. Lymphocytic hypophysitis usually presents with manifestations of a mass effect and/or of hypopituitarism. Spontaneous resolution of the inflammatory process, and recovery of pituitary function may occur, though infrequently [110,111]. Sarcoidosis of the central nervous system is rare [112–115]; frequent among its manifestations are adhesive arachnoiditis

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and granulomatous involvement of the hypothalamic– pituitary area. The noncaseating granulomas, which consist of giant cells, lymphocytes, and epithelial macrophages, usually involve the hypothalamus [112], pituitary stalk [117], and posterior lobe, and rarely the anterior lobe. Occasionally, infiltrative nodules may appear and present as a suprasellar [116] or sellar mass. Hypopituitarism is usually due to hypothalamic involvement. The course of hypothalamic– pituitary sarcoidosis may be either self-limited or progressive, leading to fibrosis and scarring and rarely to a secondary empty sella [96]. Central nervous system (CNS) sarcoidosis is usually associated with other extra-CNS manifestations of the disease and may appear early or late in the course of the illness. Occasionally, it may be the only manifestation of the disease [118]. Sarcoidosis may cause osteolytic lesions in the calvarium. Giant cell granuloma [119,120] is a rare granulomatous disorder which primarily affects the adenohypophysis and usually in adults. It consists of noncaseating giant cell granulomas which may destroy large areas of the pituitary and lead to fibrosis. The pathogenesis is unknown; immune mechanisms have been proposed. In contrast to sarcoidosis, it does not usually involve other organs; rarely, the adrenals may be the site of granuloma formation. It differs from lymphocytic hypophysitis by the later age of onset, the lack of sex predilection, and the lack of association with pregnancy. Rarely, the hypothalamic pituitary area is involved in histiocytosis X or Hand–Schuller–Christian disease [42,64]. Although the anterior lobe may be involved, it is the hypothalamus, pituitary stalk, and posterior lobe that bear the brunt of involvement by tissue infiltration with macrophages, histiocytes, eosinophils, and lymphocytes [121–126]. Extensive tissue destruction may occur. Hypopituitarism is usually due to hypothalamic involvement. In hemochromatosis and hemosiderosis [127], iron pigment may be deposited in the cytoplasm of the adenohypophyseal cells, predominantly in the gonadotrophs, and may be accompanied by fibrosis, leading to hypopituitarism. Neoplastic Disorders

Pituitary tumors [1,3,4,5,6,41,42,43] are commonly occurring neoplasms, being reported in 6% to 23% of unselected adult autopsies and representing 10% to 15% of clinical intracranial tumors. They are variable in size: microadenomas measure less than, macroadenomas more than, 10 mm in diameter. The vast majority of these tumors are benign, slow growing, and confined to the sella turcica. Some exhibit a more rapid rate of growth, extend outside the sellar confines, and compress neighboring structures. Although they can occur at any age, they are most commonly diagnosed in adults, particularly in middle-aged and elderly patients, and are rarely diagnosed before puberty. The sex distribution is about equal. The majority of pituitary adenomas synthesize and release one or more of the anterior pituitary hormones, leading to characteristic biochemical

and clinical hyperfunctioning endocrine syndromes. Less than 20% are clinically and endocrinologically silent. Pituitary tumors usually occur in isolation; infrequently, they may be a part of the syndrome of multiple endocrine neoplasia (MEN) type I, which is a familial syndrome inherited in an autosomal dominant fashion. In MEN I, hyperplasia/neoplasia affects the anterior pituitary, parathyroid and endocrine pancreas, and rarely other endocrine glands, singly or in combination. Numerous modes of classification of pituitary tumors have been proposed. The most useful from a clinical standpoint have been classifications unifying the characteristics of size, growth pattern, cytogenesis, cellular composition, ultrastructural features, hormone content, and endocrine function. The reader is referred to a number of excellent reviews of such modes of classification [3–6]. Pituitary tumors are the most common cause of hypopituitarism in the adult. Variable degrees of hypopituitarism usually result from impingement on or compression and destruction of the anterior pituitary gland, and infrequently from damage to the hypothalamus or the pituitary stalk by suprasellar extension of the tumor. Hypopituitarism occurs characteristically in patients with pituitary macroadenomas, and very rarely, in those with microadenomas. In addition, hypopituitarism can result from surgical [36–40,44–52] or radiation therapy [53–69] applied in the management of pituitary tumors. Hypopituitarism, which is associated with pituitary tumors, may be reversible after medical or surgical management of these tumors [128–131]. Pituitary carcinomas [1,3,5,6] are rare functioning or nonfunctioning pituitary tumors with wide clinical and pathologic variation. Some are malignant histologically and show distant metastases; others may exhibit histologic signs of malignancy, but without evidence of metastases; still others may show benign histologic features and have distant metastases. In general, these tumors grow faster and infiltrate surrounding structures. Clinically, the diagnosis of malignancy is made only in the presence of recognizable metastases. If metastases are not found, these aggressive tumors are classified as invasive. Sarcomas [1,3,5,6] of the adenohypophysis include fibrosarcoma, osteosarcoma, and undifferentiated sarcoma. These very rare tumors occur mainly in patients who have undergone radiation therapy to the pituitary area several years before the development of the sarcoma. Sarcomas are rapidly growing tumors which are pleomorphic and show areas of hemorrhages and foci of necrosis. Other primary neoplasms [1,4,7,8] occurring rarely in and around the sella include fibroma, angioma, glioma, meningioma, granular cell tumors, cholesteatomas, paragangliomas, chordomas, and teratomas. Craniopharyngioma [132–135] a slow growing, encapsulated, squamous cell tumor that is believed to arise from Rathke’s pouch remnants, is the most common hypothalamic–pituitary region tumor in children. The peak incidence of craniopharyngioma is in the second decade, but more than 50% of patients are over 20 years in age. Two-thirds of

Chapter 9

these tumors are suprasellar or parasellar in location; only one-third originate within or extend into the sella. Most are cystic, but some are solid or mixed, and have a propensity toward calcification (Fig. 9.1). Hypopituitarism resulting from craniopharyngioma is usually secondary to hypothalamic involvement, but may be the result of primary pituitary compression or destruction. Metastatic neoplasms [136–139] of the pituitary region occur in 1% to 5% of cancer patients. Carcinoma of the breast is the most common source; other primary sources include the bronchus, colon, prostate, kidney, malignant melanoma, and hematologic malignancies. Most often, metastatic neoplasms are clinically inert and are found incidentally at autopsy. Although metastatic deposits usually occur first in the pituitary stalk and posterior lobe and only later involve the anterior lobe either by direct extension or via the portal circulation, isolated metastasis may occur in the adenohypophysis. Infiltration of the pituitary stalk portal vessels may, however, lead to ischemic pituitary infarcts, but these are seldom large enough to cause hypopituitarism. Clinical hypopituitarism from metastatic disease is a rare development because patients rarely live long enough for manifestations of hypopituitarism to be expressed. When it occurs, however, it is usually due to hypothalamic–pituitary stalk damage and rarely to anterior pituitary destruction. Very rarely, a solitary pituitary metastasis may present as a sellar mass [140,141].

Functional Disorders The functional hypothalamic disorders outlined in Table 9.2 are frequent causes of hypopituitarism and are discussed elsewhere in this book (see Chapter 8) and under the separate hormonal deficiency states outlined later in this chapter. Characteristically, no identifiable structural abnormality in the hypothalamic–pituitary unit is delineated, and the disorders are potentially reversible.

FIGURE 9.1. Craniopharyngioma—autopsy findings revealing the suprasellar mass with solid and cystic components.

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CLINICAL MANIFESTATIONS OF HYPOPITUITARISM For the purposes of description in this chapter, the clinical features of hypopituitarism will be discussed under selective anterior pituitary hormone deficiencies.

Gonadotropin Deficiency Gonadotropin deficiency is commonly encountered as part of the clinical syndrome of hypopituitarism. It may be

Table 9.2.

Etiology of hypopituitarism

Primary: pituitary Developmental Aplasia, hypoplasia Ectopia Rathke’s cleft cyst Arachnoid cyst Epidermoid cyst Dermoid cyst Traumatic Neurosurgical Radiotherapeutic Pituitary tumors Other head and neck tumors Accidental Inflammatory or infiltrative Infectious, e.g., tuberculosis, syphilis, fungal Sarcoidosis, hemochromatosis Autoimmune hypophysitis Histiocytosis X Vascular Ischemic necrosis Postpartum pituitary necrosis (Sheehan’s syndrome) Diabetes mellitus Temporal arteritis Sickle cell disease and trait Eclampsia Pituitary apoplexy Neoplastic Primary Pituitary tumors Craniopharyngiomas Metastatic Miscellaneous Primary empty sella Idiopathic Occasionally familial, frequently monohormonal Secondary: hypothalamic Destruction of pituitary stalk Trauma Neurosurgical Compression by tumor or aneurysm

Hypothalamic or other central nervous system disease Functional Stress—psychogenic Nutritional Starvation Obesity Anorexia nervosa Systemic disease Renal, hepatic failure Uncontrolled diabetes mellitus Drugs, e.g., vincristine Hormones Glucocorticoids Gonadal steroids Thyroid hormones Organic Developmental Traumatic Neurosurgery Irradiation Inflammatory/infiltrative Sarcoidosis Histiocytosis X Neoplastic Primary Gliomas Ectopic pinealoma Craniopharyngioma Metastatic Lymphoma and leukemia Idiopathic Extrasellar disease Parasellar neoplasms Meningioma Optic nerve glioma Chordoma Cysts, e.g., arachnoid Nasopharyngeal carcinoma Sphenoid sinus mucocele Aneurysm of internal carotid Cavernous sinus thrombosis

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isolated or selective for gonadotropin deficiency (referred to as isolated gonadotropin deficiency or IGD) or it may be a part of global anterior pituitary hormone deficiencies which involve many or all of the other facets of pituitary function. Basically, gonadotropin failure may result from decrease in number or absence of functioning gonadotropes due to either an intrinsic pituitary disease or to a hypothalamic disorder interfering with availability of gonadotropin-releasing hormone (GnRH). Etiology (see Table 9.3)

Congenital Isolated Hypogonadotropic Hypogonadism IHH is believed to be related to an isolated defect in GnRH secretion. Evidence supporting this hypothesis includes: (i) complete or partial absence of any GnRHinduced LH pulsations; (ii) normalization of pituitary and gonadal function in response to physiologic regimens of exogenous GnRH replacement; (iii) normal other pituitary functions; and (iv) absence of evidence of structural disease on radiographic imaging of the hypothalamic–pituitary region. Familial clustering of IHH suggests a variety of inheritance patterns, and, to date, six different genetic mutations which cause IHH have been identified [142]: (i) X-linked

Table 9.3.

Etiology of gonadotropin deficiency

Structural Genetic/familial Hypothalamic KAL gene defect—Kallman’s syndrome AHC gene defect—adrenal hypoplasia congenital syndrome Leptin and leptin-receptor defects Pituitary GnRH-receptor defect PROP1-gene defect FSHb defect LHb defect Acquired (See Table 9.2) Traumatic Inflammatory Degenerative Vascular Neoplastic Functional Exercise Nutritional disorders Use of anabolic agents Chronic illness Critical illness Hyperprolactinemia Hyperandrogenic states Hypothyroid state Chronic glucocorticoid therapy Use of GnRH agonists

recessive mutations of the KAL gene or the AHC gene leading respectively to Kallman’s syndrome [145,152–153] or adrenal hypoplasia congenita/hypogonadotropic hypogonadism [155–157]; these mutations affect only males; (ii) autosomal recessive mutations in the GnRH-receptor [143,144]; (iii) autosomal recessive mutations in the leptin receptor [160]; (iv) autosomal recessive mutations in leptin [158,159]; (v) autosomal recessive mutations in Prop1 gene [161,211–215]; and (vi) autosomal recessive isolated deficiencies of the gonadotropin beta subunits [162–165]. It is important to note that the molecular basis for the inherited forms of hypogonadotropic hypogonadism is understood in only about 10% of cases and that most cases of hypogonadotropic hypogonadism are sporadic. Several families with compound heterozygous mutations in the GnRH-receptor gene have been described [143,144]. The severity of the phenotypic expression varies in different families [144]. Some patients have complete hypogonadotropic hypogonadism and do not have any pubertal development; others with partial defect may show an arrested puberty. All the patients are infertile, do not respond to pulsatile GnRH administration, but can respond to gonadotropin therapy. Kallman’s syndrome, an X-linked recessive disorder, is characterized by hypogonadotropic hypogonadism and anosmia (see Fig. 9.2) [145–153]. Other anomalies such as renal agenesis, midline facial clefts, neurologic disorders such as synkinesia and oculomotor dysfunction, and pes cavus may be present. Mutations in the KAL gene are believed to be

FIGURE 9.2. A 23-year-old man with Kallmann’s syndrome depicting the sexual infantalism, prepubertal external genitalia, absence of masculine secondary sex characteristics, and eunuchoid body proportions.

Chapter 9

the cause of the syndrome [146–148]. The KAL gene, located on the pseudoautosomal region of the X chromosome, encodes a neural cell adhesion molecule that is necessary for olfactory neurons to synapse with the mitral cells of the olfactory bulb, and for GnRH cells in the olfactory placode to migrate to the hypothalamus [149–151]. If the gene is defective, this protein is deficient, and hypogonadotropic hypogonadism and anosmia result. The gene is also expressed in the kidney, oculomotor nucleus, retina, cerebellum, spinal cord, limb buds, and facial mesenchyme, explaining some of the associated anomalies that are seen in patients with the syndrome. Although patients with Kallmann’s syndrome and IHH have typically been distinguished by the presence or absence of anosmia, respectively, both of these presentations (i.e., with and without anosmia) can occur in the same family with this disorder, thus underscoring the variability of that trait. More than 50 mutations have been described to date for the X-linked recessive mutations of AHC gene encoding the DAX1 protein, an orphan steroid receptor localized to the X chromosome, which is expressed phenotypically as adrenal hypolasia and hypogonadotropic hypogonadism [155–157]. In the neonatal period or early childhood, males with this syndrome present with adrenal insufficiency. Those who are treated successfully and survive show hypogonadotropic hypogonadism at puberty. Leptin gene mutations [158,159] have been identified in two families with extreme obesity, very low serum leptin concentrations, and pubertal hypogonadotropic hypogonadism. A similar phenotype is produced by the autosomal recessive leptin-receptor gene mutations; however, in this syndrome of leptin resistance, the serum leptin concentrations are elevated. Autosomal recesive mutations in the PROP1 gene [161], a transcription factor important in pituitary development, results in combined pituitary deficiency syndrome, consisting of deficiency of growth hormone prolactin, TSH and gonadotropins. The phenotypic expression is one of severe shortness of stature and delayed puberty. In contrast, the autosomal dominant Pit-1 gene mutation spares the gonadotropins and is expressed as growth hormone, prolactin and TSH deficiency (see under Growth hormone deficiency, Chapter 3). One mutation in the luteinizing hormone (LH) -b gene [162], a homozygous autosomal recessive mutation, has been described in a male with delayed puberty, low serum testosterone concentrations, and elevated serum LH concentrations, and whose serum testosterone concentrations responded normally to human chorionic gonadotropin (hCG). LHb gene mutations have not as yet been described in females. Isolated follicle-stimulating hormone (FSH) deficiency, resulting from autosomal recessive deletions or mutations in FSHb, has been described in both males and females [163–165]. In the male, the phenotypic expressions are those of azospermia with or without delayed puberty, low serum

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FSH concentrations, and increased levels of serum LH [165]. In the female, the phenotypic expression is with delayed puberty, absent breast development, primary amenorrhoea, low or undetectable serum FSH concentrations, increased serum LH concentrations, and low serum testosterone concentrations [164]. The latter finding suggests that FSH may be necessary for androgen production in women. No mutations of the a-subunit gene have been identified in humans. The fertile eunuch syndrome [166–168] thought to represent an incomplete form of GnRH deficiency, is expressed as partial pubertal development, with impaired virilization, development of spermatogenesis and near-normal testes size. It is believed that the impaired GnRH secretion in this syndrome, which is inadequate to produce full virilization, is sufficient to achieve the intratesticular testosterone concentrations needed to initiate and support spermatogenesis and testicular growth. Fertile eunuchs are distinguished by the preservation of spermatogenesis and the achievement of fertility with testosterone or hCG therapy alone. In patients with isolated GnRH deficiency, there is often a history of partial progression through puberty followed by a permanent arrest of sexual maturation. Less well-appreciated is the frequent history of delayed but otherwise normal puberty in the families of patients with IHH or Kallmann’s syndrome [169,170]. Adult-onset idiopathic hypogonadotropic hypogonadism is a distinct disorder that is important to recognize since it is potentially treatable [171]. A recent report investigated 10 men with normal sexual maturation, idiopathic infertility, sexual dysfunction, low serum testosterone concentrations, and apulsatile secretion of luteinizing hormone due to isolated GnRH deficiency. Long-term GnRH therapy was given to five of these patients; all had a reversal of hypogonadism with the restoration of fertility. Other Developmental and Hereditary Disorders Associated with Hypgonadotropism Other causes of gonadotropin lack include sporadic or autosomal recessive disorders with associated somatic and genital abnormalities but with normal sense of smell. The Prader–Lebhert–Willi syndrome [172–175] is characterized by hypogonadism, hypotonia, obesity, mental retardation, short stature, and adult-onset diabetes mellitus. Other anomalies may include acromicria (small hands and feet), micrognathia, strabismus, clinodactyly, and absence of auricular cartilage. Bilateral cryptorchidism and a small flat scrotum are characteristic. Recently a chromosomal defect consisting of deletion or translocation of chromosome 15 has been described in a significant proportion of patients [176]. Although few patients have been shown to have hypergonadotropic hypogonadism, the hypogonadism in most patients is, however, hypogonadotropic in type and may be partial to severe in degree. Few older patients who have had partial hypogonadotropism have responded

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to clomiphine with onset of spontaneous puberty. The diagnosis rests on the characteristic clinical stigmata. Laurence–Moon–Biedl syndrome [177,178] is a rare syndrome characterized by hypogonadotropic hypogonadism in association with retinitis pigmentosa, obesity, mental retardation, and polydactylism. It seems to be inherited as an autosomal recessive disorder. A minority of patients have primary testicular failure as a cause of their hypogonadism. In prepubertal boys, microphallus, hypospadius, and undescended testes are common. Endocrine evaluation demonstrates the hypogonadotropism to be clomiphine unresponsive. Hypogonadotropism may also be associated with multiple lentigines syndrome [179], congenital ichthyosis, Rud syndrome, Allstrom Hallgren syndrome, cerebellar ataxia [182], and other inherited disorders [180,181]. The diagnosis is made by the recognition of the associated congenital anomalies. Gonadotropin resistance has been reported in patients with pseudohypoparathyroidism [183,184]. Acquired Hypogonadotropism Hypogonadotropic hypogonadism may also be caused by organic or functional impairment of the hypothalamic–pituitary unit. The functional disorders [185–196] will be discussed under hypothalamic disorders in Chapter 8. In organic hypogonadotropism, other features may include additional pituitary dysfunction and features of the underlying disease. Craniopharyngioma is the most common space-occupying lesion leading to sexual infantilism; other parasellar tumors such as germinoma, glioma, and astrocytoma may occur. Pituitary tumors, though rare in children, are the most common cause of hypogonadotropism in the adult. Other etiologic factors include CNS disorders such as histiocytosis X, sarcoidosis, postinfectious inflammatory lesions, trauma, or cranial irradiation. Functional Disorders These refer to those disorders which are characterized by transient reversible hypogonadotropic hypogonadism and the absence of structural disease in the hypothalamic–pituitary unit [185]. They may be seen in the following settings: • Hypothalamic amenorrhea may be precipitated by factors such as significant weight loss [186], exercise [187], or stress. • Moderate-to-severe dietary restriction in otherwise healthy men lowers testosterone levels by impairing secretion of GnRH [189,192]. In addition, some, but not all, studies have shown that strenuous physical exercise may adversely affect testosterone concentrations [193]. • The use of anabolic steroids by athletes, more commonly men, may result in a functional type of hypogonadotropic hypogonadism, decreased concentrations of both testosterone and

•

•

•

• • • • •

dihydrotestosterone, and marked impairment of spermatogenesis [195]. Suppression of the hypothalamic–pituitary gonadotropin axis may be seen in thyroid disorders, hyperprolactinemic states, hyperandogenic states, and in chronic debilitating diseases. Any critical illness, such as surgery, myocardial infarction, or head trauma can cause hypogonadotropic hypogonadism; the degree of hypogonadism is directly related to the severity of the illness [196]. Several chronic, systemic illnesses, including cirrhosis, chronic renal failure, and AIDS, cause hypogonadism by a combination of primary and secondary effects. Chronic treatment with glucocorticoids. Hyperprolactinemic states, of diverse etiologies. Hyperandrogenic states. Primary hypothyroidism. Prolonged administration of GnRH analogs, as commonly used in the treatment of prostate cancer.

Clinical Features [153,154,156,169]

Adolescent Hypogonadotropism Although the most common presentation is with the classic findings of complete failure of pubertal development, few patients have postpubertal loss of GnRH function and give a history of partial pubertal development. A fewer number of patients give a history indicating normal complete pubertal development with subsequent and, as yet unexplained, isolated loss of gonadotropic function between the ages of 20 and 35 years. Classically, male patients present in their adolescent years with sexual infantilism. The patient does not display the expected postpubertal sex drive, and erections are absent or infrequent as are nocturnal emissions. The penis remains small and is often buried in the fat pad of the mons and the scrotum is small, smooth, and hairless. The testes remain small, usually less than 2 ml in volume, and are characteristically soft. Cryptorchidism is occasionally present. The prostate remains infantile. Secondary sex characteristics are absent. Eunuchoidism is a characteristic feature, the eunuchoid proportions resulting from delayed closure of epiphyseal junctions with continuation of longitudinal growth which is disproportionately marked in the extremities; the span exceeds the height and the upper to lower body segment ratio is less than 1. The skeleton is slender and genovulgam is common. Often there are striking leg varicosities. The voice maintains a childish high-pitched quality and the characteristic male Adam’s apple is not apparent. True gynecomastia is, however, rare. The skin is delicate and pale and in older individuals may show a characteristic fine wrinkling. Patients have a tendency towards obesity with pads of fat around the hips, epigastric area, and unlike those patients with constitutional delay and those with growth hormone deficiency, patients with isolated gonadotropin deficiency are of normal height until adoles-

Chapter 9

cence; in the teenage years and because of lack of pubertal growth spurt, these patients grow at a rate less than that of a normal pubertal individual. However, they reach a normal adult height because their epiphyses are not closed at the normal age and they continue to grow beyond the normal age of epiphyseal fusion. Osteopenia may be present in the adult with isolated gonadotropin deficiency (IGD). The psychologic effects of sexual infantilism are pronounced; characteristically the patients are introverted, passive, and self conscious. In those individuals with partial or complete pubertal development, the size of the testes, the growth of the external genitalia, and development of secondary sex characteristics show a spectrum that extends from minimal to complete physical and sexual development. IGD of both sporadic and familial types is less common in women than in men. The clinical picture of IGD in the female reflects failure of maturation of the endocrine and gametogenic functions of the ovary. The classical features are primary amenorrhea, sexual infantilism of the female external and internal genitalia, and failure of development of female secondary sex characteristics. Most of the patients have axillary and pubic hair, and some may show some evidence of mammary development. The body proportions are eunuchoidal with the upper segment to lower segment ratio being less than 1 and the span exceeding the height; however, eunuchoidism is usually modest. Important extragonadal abnormalities are found in association with IHH [153]. These include anosmia/hyposmia; craniofacial midline defects including cleft lip or palate; skeletal deformities including short fourth metacarpals, spina bifida, hypoplasia of the first rib, and fibrous dyplasia of the sphenoid; congenital deafness; color blindness, syndactyly, and various neurologic abnormalities. Of these, only anosmia/hyposmia is common, occurring in about one-third to one-half of patients with IHH. Adult Hypogonadotropism Hypogonadism is the most common clinical presentation of hypopituitarism in the adult. In premenopausal women, the resulting decrease in ovarian function is manifested by oligomenorrhea, amenorrhea, infertility, and hypoestrogenic manifestations that include decreased vaginal secretion, dyspareunia, decreased libido, breast atrophy, and osteoporosis. Gonadotropin deficiency, in postmenopausal women, is not associated with clinical manifestations. In the adult male, the resulting decrease in testicular function is manifested by decreased libido, potency impairment, decrease in ejaculate volume, infertility, decreased beard and body hair growth, fine wrinkling of the facial skin, muscle weakness, and fatigue (Fig. 9.3). The testes may be small and soft, and the prostate may be flat. Diagnosis and Laboratory Evaluation

The tests which are employed in the assessment of the hypothalamic–pituitary–gonadal axis and their interpretations are outlined in Tables 9.4, 9.5 and 9.6. The diagnostic approach is outlined in Figure 9.4.

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FIGURE 9.3. A 56-year-old man with panhypopituitarism— fine wrinkling, sparsity of facial sexual hair, and loss of outer third of eyebrows.

Delayed Puberty in the Male The objectives of the diagnostic approach to delayed puberty in the male are to determine whether delayed puberty is present, and if present, to determine its underlying cause. The first step in the diagnostic approach is a careful assessment of testicular volume. For this measurement, one can use the Prader orchidometer (which consists of a series of plastic ellipsoids ranging in volume from 1 to 25 ml). Each testis is compared to the appropriate ellipsoid. A testicular volume greater than 4 ml usually indicates that the testes are gonadotropin-stimulated and that puberty has already started. A testicular volume less than 4 ml indicates that the patient is prepubertal, and the differential diagnosis here is between primary gonadal disease, hypogonadism caused by hypothalamic pituitary disease, and constitutional delay in puberty. The required tests are measurements of serum testosterone, LH, and FSH concentrations. Primary gonadal failure should be considered if the testes are difficult to palpate and if somatic abnormalities are evident. It is confirmed by a low serum testosterone and a high serum LH and FSH. The history and physical examination, buccal smear, and karyotype will point to the cause. A low serum testosterone and an inappropriately low serum LH and FSH indicate hypogonadotropic hypogonadism. Olfactory testing is mandatory because anosmia or hyposmia may not have been noted by the patient. The presence of hyposmia or anosmia, other midline defects, and a positive family history point to isolated hypogonadotropic hypogonadism (IHH). Assessment of the clinical setting should be made for evidence of systemic disease, weight loss, anorexia nervosa, and primary thyroid abnormalities to rule out functional hypothalamic hypogonadism. The presence of chronic disease is generally evident on history and physical examin-

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Ta b l e 9 . 4 .

Hypothalamic–Pituitary Dysfunction

Laboratory tests in assessment of male gonadal axis

Tests

Determinant(s)

Male hypogonadism

Comments

Semen analysis

Hypothalamic–pituitary–testicular endocrine function and normal genital duct system

Abnormal in male hypogonadism

Normal semen analysis implies normal hypothalamic–pituitary–testicular axis and normal genital ducts

Serum T Normal, 300–1200 ng/dl (RIA)

Normal hypothalamic–pituitary–testicular endocrine function. Normal SHBG Serum T measures total T: protein-bound T (>98%) and free biologically active T (<2%) Endocrine hypothalamic–pituitary–testicular function. Measures free biologically active fraction

Low in male hypogonadism, but may be normal in hypogonadal patients with increased SHBG (e.g., hyperthyroidism)

Serum T may be low in eugonadal patients with decreased SHBG (hypothyroidism, obesity, acromegaly)

Low in male hypogonadism

Not affected by conditions that decrease SHBG

Serum estradiol (E2) Normal, 1–5 ng/dl (RIA)

Endocrine testicular function

Low-normal or increased in primary testicular failure; low in hypogonadism due to hypothalamic–pituitary disease; high in hypogonadism due to estrogen-producing tumor

Serum LH and FSH FSH: normal, <22 IU/l LH: normal, 4–24 IU/l (RIA)

Hypothalamic–pituitary–gonadal endocrine function

Always evaluate serum LH and FSH in relation to serum T or semen analysis; in hypogonadal males, high values point to primary testicular disease, while low or normal values point to hypogonadism due to hypothalamic–pituitary disease

Serum prolactin Normal, 0–20 ng/ml (RIA)

Endocrine function of the lactotroph of the anterior pituitary

Hyperprolactinemia may be the cause of hypogonadism due to hypothalamic– pituitary disease

hCG stimulation test

hCG has biologic activity similar to LH. The test is used as a stimulation test for testicular function; 4000 IU are given intramuscularly daily for 4 days. Serum T is measured before and on the fourth day of administration

No change in serum T in primary gonadal failure Qualitatively normal response in secondary gonadal failure

Used in the differential diagnosis of cryptorchidism (normal response) vs anorchia (no response)

Buccal smear

Scraping from the buccal mucosa stained with appropriate dyes and examined for Barr bodies (represent inactive X chromosome; number of Barr bodies is 1 < number of X chromosomes) and for Y fluorescence

Useful in differential diagnosis of primary gonadal failure due to sex chromosome abnormalities

Presence of Barr bodies in 15% or greater of mucosal cells in a male confirms presence of extra X chromosome (Klinefelter’s syndrome) and its variants). May be negative in Klinefelter’s mosaics

Karyotype

Chromosomal analysis

Identifies sex chromosomal anomalies, including mosaicism, causing male hypogonadism

May not show mosaicism present in tissues other than those examined

Serum free T Normal, 9–30 ng/dl (RIA)

LH and FSH are secreted in pulsatile fashion. In borderline cases, obtain 3 samples at 30–40 minute intervals and assay LH and FSH in pooled sample Low value may be seen in eugonadal due to insensitivity of the assay

FSH, follicle-stimulating hormone: hCG, human chorionic gonadotropin; LH, luteinizing hormone; RIA, radioimmunoassy; SHBG, sex hormone-binding globulin; T, testosterone.

ation, but occasional disorders, such as malabsorption syndrome resulting from Crohn’s or celiac disease, may be relatively asymptomatic and go unrecognized. If present, the functional disease should be treated and the cause removed. Restoration of normal gonadal function and the initiation of puberty points to functional hypogonadotropism as the cause. If the sense of smell is normal and the functional causes have been excluded, the next step is to rule out organic hypothalamic–pituitary disease. Evaluation of other pituitary functions including serum prolactin and assessment of

growth hormone (GH), adrenocorticotropic hormone (ACTH), TSH, and antidiuretic hormone (ADH) axes, ophthalmologic evaluation for chiasmal syndrome, and imaging of the hypothalamic–pituitary region by CT or MR imaging are in order. If these tests are abnormal, they point to organic hypothalamic pituitary disease, and the diagnosis of its cause is based on the evaluation of the clinical setting, on the results of laboratory and radiologic studies, and occasionally on the results of surgical intervention. If these studies are normal, the differential diagnosis is

Chapter 9 Table 9.5.

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Laboratory tests in assessment of female gonadal axis

Tests

Determinant(s)

Hypogonadism

Comments

Serum estradiol Normal: 3–40 ng/dl Postmenopausal females: 0–3 ng/dl

Hypothalamic–pituitary– ovarian endocrine function

Low in hypogonadism; cannot differentiate between hypogonadism caused by ovarian disease from that caused by hypothalamic– pituitary disease

Serum LH and FSH Normal FSH: <20 IU/l Normal LH: <30 IU/l (except at mid cycle = 30–150 IU/l Postmenopausal normal FSH: >40 IU/l; and LH: >30 IU/l

Hypothalamic–pituitary– ovarian function

Always evaluate in relation to menstrual function and serum E2. In hypogonadal female, high values indicate primary ovarian failure, while “normal or inappropriately low” values indicate hypogonadism due to hypothalamic–pituitary disease. High LH/FSH ratio in amenorrheic females suggests polycystic ovaries

Secreted in pulsatile fashion. Draw samples every 30–40 minutes three times and assay LH and FSH in pooled sample. “Low” levels may be found in normal eugonadal females because of insensitivity of assays

Serum prolactin Normal, 0–23 ng/ml

Pituitary lactotroph function

Hyperprolactinemia is a common cause of hypogonadism; points to hypothalamic– pituitary dysfunction as the cause

Should be measured in all hypogonadal females

Progesterone test

10 mg medroxyprogesterone acetate orally for 5 days or 200 mg progesterone in oil intramuscularly

Withdrawal bleeding implies: 1 Normal outflow genital tract 2 An intact endometrium exposed to adequate estrogen levels; points, therefore, to anovulation as the cause of amenorrhea

No withdrawal bleeding can occur in: 1 Pregnancy 2 Hypoestrogenic state 3 Intrinsic endometrial disease 4 Obstruction of outflow tract

Estrogen/progesterone test

Ethinyl estradiol, 0.1 mg or conjugated estrogen, 1.25 mg daily for 20 days followed by medroxyprogesterone acetate, 10 mg orally for 5 days

Absence of withdrawal bleeding points to a diagnosis of endometrial failure. Presence of withdrawal bleeding points to: 1 Normal outflow tract 2 Impaired hypothalamic–pituitary–ovarian axis as the cause of amenorrhea

Should be done in patients with amenorrhea who have a history suggestive of outflow or uterine endometrial impairment

Buccal smear

Normal females will have Barr bodies in at least 25% of nuclei and no fluorescent Y

In an amenorrheic patient, Barr-body negative, Y chromosome negative suggests 45/XO; Barr-body negative, Y positive suggests 46/XY or gonadal dysgenesis mosaics; Barr-body positive, Y negative suggests 46/XX or gonadal dysgenesis mosaics

Karyotype

Chromosomal analysis

Determines chromosomal constitution in tissue studied

May not show chromosomal abnormalities if present in tissues not studied

FSH, follicle-stimulating hormone; LH, luteinizing hormone.

between isolated hypogonadotropism and constitutional delay in puberty. The diagnosis of IHH in a hypogonadotropic patient is straightforward if olfactory disturbances, other congenital midline defects, or a positive family history of such defects are present. The demonstration of extragonadal clinical abnormalities provides the best means of confirming the diagnosis of IHH. Anosmia/hyposmia is particularly useful because of its frequency in patients or their relatives. If associated congenital anomalies or a positive family history are not present, the only definitive way to make the diagnosis of IHH is to pursue long-term observation. Most of the patients with constitutional delay in puberty will have undergone pubertal changes by age 20; persistence of

hypogonadotropism beyond this age, with rare exception, will point to IHH. Primary Amenorrhoea Approximately 40% of patients with primary amenorrhoea have gonadal dysgenesis, usually classical Turner’s syndrome (45XO), 10% have developmental abnormalities of the Mullerian system, uterus, or vagina, and the rest will have functional or structural abnormalities of the hypothalamic–pituitary unit. The first challenge the physician must face is to decide whether or not the complaint of amenorrhoea warrants study. As a general rule, a girl should be evaluated by age 14 if there is no other evidence of pubertal development, or by age 16 if other pubertal changes have occurred.

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Table 9.6.

Hypothalamic–Pituitary Dysfunction

Gonadotropins (LH-FSH) provocative tests

Provocative test GnRH Can be done at any time of the day. Administer a bolus of 100 mg of GnRH intravenously. Measure LH and FSH at 0 minutes and 30–60 minutes after administration of GnRH

Clomiphene citrate Clomiphene citrate is a sex steroid receptor competitive inhibitor at the hypothalamic level. In men, administer 10 mg orally twice a day for 10 days. Measure serum LH, FSH, and testosterone before and on the tenth day of drug administration. In women, administer 50–100 mg/day orally for 5 days. Measure serum LH and FSH before the test and on the fifth, tenth, and fifteenth days

Response

Comments

Normal responses vary widely, in correlation with the age and sex of the patient and the phase of menstrual cycle in women. Each laboratory should standardize its normal response. In eugonodal subjects, serum LH increases rapidly and reaches maximal levels at 30 minutes, whereas serum FSH increases more slowly and peaks at about 60 minutes. The elevation in LH is generally more than 3 times the basal level, and in women is greater in the luteal phase than in the follicular phase of the menstrual cycle; the increase in FSH is from 1–12 to 2 times the basal level

No side-effects and no contraindications. In a single test, absence of response cannot distinguish pituitary from hypothalamic hypogonadism. Normal response does not exclude pituitary disease

In men, increase in LH (50–250%), FSH (30–200%), and testosterone (30–200%) occurs on day 10 of drug administration. In women, a similar increase in LH and FSH occurs on day 5, followed by another surge of LH on day 10 or 15. Variables of ovulation should also be considered. A normal response implies normal hypothalamic–pituitary gonadotropic axis

No risks in men. In women, risks include hyperstimulation syndrome and multiple ovulation. No contraindications. Impaired response occurs in hypothalamic and pituitary diseases

FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

FIGURE 9.4. hypogonadism.

In the sexually developed patient, pregnancy, though unusual in a girl presenting for evaluation of primary amenorrhoea, should always be considered and excluded. The presence of normal secondary sex characteristics implies adequate estrogen production and therefore a normal hypothalamic–pituitary–gonadal axis; it should prompt the

Diagnostic approach to

physician to consider outflow tract disorders, uterine anomalies, and testicular feminization. Presence of sexual infantilism implies estrogen lack and denotes either a gonadal or hypothalamic–pituitary endocrine dysfunction. The necessary investigation here will be measurement of the serum concentrations of LH and particularly FSH. An increased

Chapter 9

serum FSH concentration points to hypergonadotropic hypogonadism and should prompt consideration of a karyotype analysis. In hypogonadotropic hypogonadism, an attempt to rule out functional causes by a detailed history, physical examination, and appropriate studies, a search for other evidence of anterior pituitary endocrine dysfunction, especially hyperprolactinemia, and an imaging study (MR or CT), to rule out a space-occupying disorder in the hypothalamic–pituitary region, are in order. The Adult Male The central objectives of the diagnostic approach is to ascertain the presence of hypogonadism, to determine whether hypogonadism is due to primary gonadal disorder or secondary to hypothalamic– pituitary–gonadotroph failure, and to determine the nature of the underlying cause. The diagnosis depends on clinical assessment, knowledge of the likely differential diagnosis, and selection and interpretation of laboratory and radiologic diagnostic studies. The first step in the diagnostic approach is to obtain, if possible, a semen analysis. A normal semen analysis generally implies a normal hypothalamic–pituitary–gonadal axis. If the semen analysis is abnormal, or if semen cannot be obtained for analysis, the next step is measurement of concentrations of serum testosterone, LH, and FSH. In hypergonadotropic failure, the cause is usually apparent after a careful history and physical examination. A buccal smear and karyotype may be needed for diagnosis of sex chromosome abnormalities. The presence of hypogonadotropism should prompt a careful assessment of potential functional causes. If a functional cause is present, an attempt at its reversal is made. Restoration of normal gonadal function as a result of removal of the functional cause points to functional hypogonadotropism. Further testing is indicated if no functional cause is found, a functional cause is found but cannot be reversed, or if hypogonadotropism persists after the removal of the functional cause. Additional tests should include an assessment of other pituitary function, of ophthalmologic evaluation to rule out chiasmal defects, and a CT or MRI examination of the hypothalamic–pituitary area. Abnormalities in these additional tests point to organic hypothalamic– pituitary disease. If these additional tests are negative, the patient is described as having hypogonadotropism of indeterminate origin. Such patients should be followed at regular intervals because an organic cause may become identifiable in the course of follow-up. Secondary Amenorrhoea Secondary amenorrhea is present when there is persistent absence of periods for at least 3 months in a woman with previously established menstrual function. The most common causes of secondary amenorrhea are pregnancy, functional hypothalamic disorders, hyperprolactinemia and other hypothalamic–pituitary diseases, and polycystic ovarian syndrome. The most common cause of secondary amenorrhea is pregnancy. A pregnancy test should be the first step in the

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laboratory evaluation. If the patient has manifestations of androgen excess, the work-up proceeds in an attempt to outline ovarian or adrenal causes. Assessment of the anatomic integrity for the uterine endometrium is important if the patient’s history, such as history of pelvic infection, trauma, overzealous D&C, or abnormal pelvic examination, implies endometrial disease as the cause of secondary amenorrhea. The next step is to assess the hypothalamic–pituitary–gonadal axis by measurement of serum estradiol, LH, and FSH. The discussion of primary gonadal failure is beyond the scope of this chapter. “Normal” (inappropriately low in the face of hypoestrogenism) or “low” gonadotropins point to hypothalamic– pituitary disease. Consideration of the various causes of functional secondary hypothalamic amenorrhea are in order; correction of the cause and resumption of menstrual function confirm functional hypogonadotropism. Organic hypothalamic–pituitary disease is suspected if evaluation is negative for functional causes, amenorrhea persists despite elimination of a recognizable functional cause, and other suggestive symptoms of hypothalamic–pituitary diseases are present. Serum prolactin, other pituitary function tests, CT or MRI of the hypothalamic-pituitary region, and visual fields are obtained. If the investigations are negative, hypogonadotropism is labeled as being of “indeterminate cause.” Careful follow-up is important if amenorrhea persists. Periodic assessment of the hypothalamic–pituitary unit is in order because an organic lesion may become recognizable at some future date.

Somatotropin, Growth Hormone Deficiency GH deficiency is probably the most common endocrine expression of hypopituitarism. Its recognition in childhood is of paramount importance because of its profound effect on linear growth and the potential of deployment of GH therapy. GH deficiency in childhood is a rare disorder; estimates of its incidence approach 1 : 5000 to 1 : 10,000 children [442]. In the adult, it is generally accepted that growth hormone deficiency is the earliest and most common endocrine abnormality in organic hypopituitarism, especially in evolving space-occupying lesions. Its true incidence in the adult had not been established because of inconvenience and cost of diagnostic steps, and, until the 1990s, the apparent lack of indication and availability of GH therapy. The era of recombinant GH therapy and early reports of beneficial effects of such therapy in GH-deficient adults will lead to renewed efforts at early detection and therapy of GH deficiency in the adult. GH deficiency may be isolated or a part of a more global hypopituitarism, may be functional or organic, idiopathic or related to a specific hypothalamic pituitary disorder, congenital or acquired, and familial or sporadic. Basically, GH deficiency can result from decreased GH production because of hypothalamic regulatory disorder (GHRH deficiency or somatostatin excess) or from primary

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pituitary disease, from the production of a biologically inactive GH or from tissue resistance to the actions of GH. The etiology of GH deficiency is outlined in Table 9.7. Growth Hormone Deficiency (GHD) in the Child

Etiology Genetic/Familial GHD [197–200] A genetic/familial association is present in as many as 3% to 30% of children with GHD. Several causes have been described: • Mutations of the GHRH receptor [201]: GHRH stimulates GH transcription and secretion, and also somatotroph proliferation. The GHRH receptor is a cell surface-associated, seven membrane-spanning domain protein linked to a G protein (Gs) which, after ligand-induced activation, stimulates intracellular cAMP production. The gene for the GHRH-receptor is located on chromosome 7. GHRH receptor gene defects cause undetectable GH release during standard provocative tests and after exogenous GHRH administration, but the children respond to GH treatment. • Mutations in Pit-1 gene [202–210,435]: Pit-1 is a transcription factor which is the product of a gene located on chromosome 3p11. It binds to DNA receptors located in the nuclei of somatotrophs, lactotrophs and thyrotrophs, and is responsible for their development and function. At least seven recessive and three dominant types of PIT1 abnormality have been recognized in sporadic and familial multiple hormone deficiency syndromes. Patients with Pit-1 gene mutations have absent or impaired GH responses to GHRH stimulation, and prolactinand TSH- responses to TRH. Clinically, these patients

Table 9.7.

Etiology of growth hormone deficiency

Structural Genetic/familial Pituitary hypolasia/aplasia Defects in: PIT-1 gene PROP1 gene GHRH-receptor gene GH-1 gene Syndrome of bioinactive GH Genetic GH insensitivity [GHI] Acquired See Table 9.2 Functional Obesity Undernutrition Chronic Illness Glucocorticoid excess Hypothyroidism

present with growth failure and variable severity of hypothyroidism; they may experience delayed puberty because of delay in T4 or GH treatment; however, they eventually undergo normal sexual maturation and are fertile. Anterior pituitary size, as assessed by magnetic resonance imaging, is small or normal in persons with PIT1 mutations, and there is no consistent relationship between the size of the pituitary and the age of the patient or the type of Pit-1 mutation. • Mutations in PROP 1 gene [211–215,436]: PROP 1 is a transcription factor of a gene located on chromosome 5q. This transcription factor precedes, and is a prerequisite for the expression of Pit-1. PROP1 in humans is an abbreviation for “prophet of Pit-1”. At least seven human autosomal recessive mutations have been recognized since 1998. In humans, the hormonal phenotype involves deficiencies of LH and FSH, as well as GH, prolactin (PRL), and TSH. Most persons with PROP1 mutations have small or normal size anterior pituitary glands; the pituitary stalk is normal, and the posterior pituitary is not ectopic. There have been reports of families with PROP1 mutations and striking enlargement of the anterior pituitary [215]. In some there has been progression from a large and full sella turcica to suprasellar extension of a pituitary mass, followed by areas of cystic change, loss of contrast enhancement of the mass, and eventual regression leaving a large and nearly empty sella with a rim of anterior pituitary tissue. The clinical expression of GH and TSH in childhood is variable in onset and severity. Hypogonadism, which represents a major difference between the phenotypes produced by PIT1 and PROP1 mutations, also shows variability in clinical and hormonal expressions. Most fail to enter puberty and show consistently low LH and FSH responses to LHRH stimulation. Most patients with PROP1 abnormalities do not have abnormalities of the adrenal axis. Some, however, show diminished cortisol responses to ACTH late in the course of their disease. • Mutations of the GH-1 gene [219]: the human GH gene family comprises five distinct genes, all on chromosome 17q22. GH-1 is the gene encoding GH, located on chromosome 17. Gene deletions, gene frameshift, and nonsense mutations of the GH-1 gene have been described as causes of familial GHD. • Syndrome of bioinactive GH [220]: a diagnosis of the syndrome of bioinactive GH has been proposed for short children with a phenotype that resembles that of isolated GHD, with normal or slightly elevated basal GH levels in combination with low IGF-1 concentrations that increase after treatment with exogenous GH. • Genetic GH insensitivity (GHI) [221–224]: GHI is a group of inherited disorders where there is a

Chapter 9

reduction or absence of the biologic effects of GH in the presence of normal or elevated circulating serum GH levels, with low IGF-1 and IGF-BP3 levels. The classic GHI syndrome is also known as Laron syndrome. About 30 different homozygous or heterozygous exonic and intronic mutations of the receptor have been described, most of which are found in its extracellular ligand-binding domain of the receptor. Mutation in the IGF-1 gene has also been described [225]. Other developmental pituitary disorders may occur as isolated congenital defects or in association with other embryologic defects [226]. Pituitary dysgenesis is a very uncommon cause of hypopituitarism. Aplasia is usually incompatible with life. Hypoplasia has a spectrum ranging from severe to mild deficiency. Very rarely, failure of migration of the anterior pituitary from the nasopharynx results in lodging of the pituitary in a number of ectopic sites extending from the submucosa of the nasopharynx, the so-called pharyngeal pituitary, to the base of the brain. Affected patients have shallow development or absence of the sella turcica. Although sporadic cases have been reported, a significant number of patients have familial pituitary dysgenesis that appears to be inherited as autosomal recessive characteristics. The main presentations are severe hypoglycemia and adrenal crisis. Anencephaly and holoprosencephaly are usually incompatible with life and are associated with either pituitary aplasia or hypoplasia. Death usually occurs from adrenal insufficiency. Optic nerve hypoplasia, DeMorsier’s syndrome, (septo-optic dysplasia) [216–218,227–231,241] is a sporadic defect in which there is hypoplasia of the optic chiasm and optic nerves with or without abnormalities of the septum pellucidum or corpus callosum. Hypothalamic function is frequently impaired leading to various combinations of pituitary hormone deficiencies. The developmental anatomic abnormality and the associated hormone deficiencies are variable. Growth failure and hypopituitarism occur in 60% of cases. Other endocrine manifestations include hyperprolactinemia and diabetes insipidus. Simple cleft lip and palate may also be associated with growth hormone deficiency [232,233]. In single upper central incisor abnormalities of nasal development and impaired pituitary function have been described. Sporadic empty sella is rare in childhood, most of the reported cases have associated cranial defects [234]. Familial empty sella in association with Rieger’s anomaly of the anterior chamber of the eye has been reported as an autosomal dominant trait [235,236]. In the Pallister-Hall syndrome [237] polydactyly with nail dysplasia, short nose with flat nose bridge, low-set ears, renal, pulmonary, cardiac abnormalities, micropenia; undescended or hypoplastic testes, varying degrees of pituitary hypoplasia and hypopituitarism, and hypothalamic hamartoblastoma may be present. GH deficiency has also been associated with the ectrodactyly, ectodermal dysplasia-clefting (EEC) syndrome [238,239], and Fanconi’s anemia.

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A number of other anomalies of craniofacial area may coexist with hypopituitarism. In the syndrome of basal encephalocele [240] and hypothalamic pituitary dysfunction, patients have nasopharyngeal mass or unexplained “nasal polyp.” The diagnosis should be considered when a “nasal mass” is seen in conjunction with associated findings of hypertelorism, optic atrophy, or congenital disc abnormalities, broad nasal root, and midline facial defects. Acquired Growth Hormone (GH) Deficiency • Structural GH disorders: the reader is referred to the section on Etiology for a detailed discussion of the acquired etiologic disorders. The so-called idiopathic hypopituitarism is associated with a history of inordinately high perinatal complications including breech and face presentations, intrapartum asphyxia or hypoxia, and precipitant labor. In many such patients, MR imaging has shown transection of the pituitary stalk with an ectopic posterior lobe visualized at the proximal stump of the transected stalk. The pituitary gland itself may be normal in size or hypoplastic and associated with secondary empty sella [244–248]. Accidental trauma or child abuse may lead to bleeding into the hypothalamic area or disruption of the stalk and variable degrees of hypopituitarism. Irradiation for tumors of the head and neck or as prophylaxis in leukemia carries a high risk of impaired pituitary function. Children who have received cranial irradiation evaluation for GH deficiency should be pursued when height velocity becomes subnormal. ACTH and TSH are usually preserved, and little is known at this time about the gonadotropin status in these patients. A recent report revealed that hypogonadotropism was present in 5.8% of children with intracranial tumors who had received cranial and spinal radiotherapy and adjuvant chemotherapy and who reached pubertal age. Infiltrative diseases, whether infectious or granulomatous, including histiocytosis X, and sarcoidosis, may cause hypopituitarism. Several different tumors in the hypothalamic–pituitary region may interfere with hypothalamic and/or pituitary function. By far the most common tumor in children is craniopharyngioma. Others include germinomas, gliomas, meningiomas, colloid cysts of the third ventricle, and rarely a pituitary tumor. GH deficiency and abnormalities of gonadotropin function are the most common endocrine manifestations of these space-occupying lesions; deficiency of ACTH, TSH, and ADH are seen less often. Autoimmune hypophysitis has rarely been observed as a cause of GH deficiency in childhood. • Functional GH disorders: transient reversible defects in GH secretion or action can occur in primary hypothyroidism, glucocorticoid excess, psychosocial dwarfism, in the “lazy pituitary syndrome,” and in

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some patients with isolated ACTH deficiency. In primary hypothyroidism [250], treatment with thyroid hormone normalizes GH responses to provocative stimuli, and allows catch-up growth. GH secretory testing in hypothyroid children should be postponed until they have been rendered euthyroid by T4 replacement. Cessation of growth is an expression of glucocorticoid excess of any etiology, exogenous or endogenous Cushing’s syndrome [380–385]. Glucocorticoids exert multiple growth-suppressing effects interfering with endogenous growth hormone secretion, generation of IGF-1 and antagonizing the peripheral growth-promoting effects of GH. In addition, glucocorticoids interfere with bone formation, nitrogen retention, and collagen formation. Transient GH deficiency has been documented in prepubertal males, the so-called lazy pituitary syndrome [251]. As puberty develops, GH responses to provocative stimuli are restored. Transient GH deficiency, in association with isolated ACTH deficiency, is reversed by glucocorticoid therapy. Deprivational or psychosocial dwarfism [242,252,254,255] is believed to be a facet of the syndrome of child abuse and neglect and is characterized by growth failure and abnormalities of pituitary function, emotional disturbances, and behavioral aberrations, all of which are transient and reversed by modifications in the child’s environment. These patients are normal in length and weight at birth. Their growth failure has a variable age of onset. They present with short stature and growth failure. Growth curves cannot be distinguished from that seen in acquired GH deficiency. Disturbed behavior is centered around eating, drinking, and sleeping. Patients exhibit sleep disturbance with nighttime roaming and foraging, bizarre eating and drinking habits, and difficulty with bladder and bowel training. An apparent retardation of intellectual development and speech is frequent. The syndrome usually affects one child in a family. The family’s social situation appears to be disorganized and disrupted. The pathogenic link between environmental deprivation and GH deficiency remains obscure; pathogenic mechanisms may include dysfunction of central neurotransmitter function, malnutrition, and sleep disturbances. The diagnosis is clinical and depends primarily on past history and subsequent clinical course. It is based upon the history and observation of the child’s home environment, the documentation of growth failure and GH deficiency, and confirmation of the transient and reversible nature of the disorder by removing the child from the environment and observing restoration of weight gain and growth rate and normalization of GH and ACTH reserve. This may occur within days or weeks of the change of

the environment. Returning to the home environment can cause the syndrome to recur. Long-term psychologic therapy for the child and parents may be needed. Clinical Features [256–261] Both organic and idiopathic GH deficiency are seen twice as often in boys as in girls. Children with GH deficiency are short and fail to grow at a normal rate, and their growth curve is characterized by progressive deviation away from normal. Since GH appears not to be essential for intrauterine growth, children with congenital GH a normal weight and length at birth. Growth failure is usually noted by 12 to 18 months of age, although it may be present as early as 3 to 6 months of age. The growth curve of patients with acquired GH deficiency is typical of acquired growth failure; after a period of normal growth there is a break in the curve with subsequent deviation of height away from the mean. The overall appearance has been described as “doll-like” or “cherubic.” Patients tend to be overweight for their height. The excess fat deposition has a frequent predilection to the chest and abdomen. The children are normally proportioned; their upper to lower segment ratio and the arm span height ratio normal. Frontal bossing is a common feature. The face may appear small. Dentition is delayed. The voice is usually highpitched and squeaky. GH deficiency may first become manifest in early infancy and childhood as symptomatic hypoglycemia with convulsions. This presentation is seen more commonly when there is maldevelopment of the anterior pituitary or idiopathic hypopituitarism with GH and ACTH deficiencies. Affected infants may also have manifestations of TSH deficiency; congenital gonadotropin deficiency may lead to micropenis and underdeveloped scrotum and cryptorchildism. Multiple pituitary hormone deficiencies should be considered in a male infant who shows microgenitalia and hypoglycemia. In general, as the growth hormone deficient child grows older, the frequency and severity of hypoglycemic episodes diminish and tendency to spontaneous hypoglycemia disappears by age 5. It may, however, reappear if a severe illness prevents oral intake for prolonged periods. Intellectual development is normal; however, patients frequently lag behind in social adjustment and psychologic maturation as a result of the psychologic burden of their short stature. Midline developmental abnormalities such as cleft lip and palate, septooptic dysplasia, and congenital roaming nystagmus, a single upper central incisor, that are associated with GH deficiency, can usually be recognized before growth failure is noted. In addition, neurologic, visual, and endocrine abnormalities associated with the causative lesion may be noted. Symptoms may include impairment of vision and visual field defects, manifestations of increased intracranial pressure, failure of pubertal development and clinical manifestations of ACTH, TSH, and ADH lack and hypothalamic vegetative dysfunction. In adults GH deficiency is usually clinically silent. It may, however, contribute to decreased muscle

Chapter 9

mass, increased adiposity, fatigue, and a general feeling of ill-health. Diagnosis The indications for assessment of the GH axis include either clinical evidence in a child suggestive of GH deficiency, or the presence of congenital or acquired disorders, at any age, known to have the potential of inducing GH deficiency, e.g., perinatal trauma, cranial irradiation, tumors of the hypothalamic–pituitary area, etc [249]. In the child, clinical evidence suggestive of GH deficiency includes shortness of stature with normal body proportions (height greater than 2.5 SD below the mean), abnormal growth velocity for the chronologic age (less than 7 cm per year below the age of 3; less than 4 to 5 cm per year from age 3 to the onset of puberty; and less than 5.5 to 6 cm per year during the pubertal years), delayed skeletal maturation (bone age greater than 2 SD below mean for chronologic age), deceleration of linear growth even if height is within the normal range, and the presence of hypoglycemia. (See diagnostic approach in Fig. 9.5.) In interpreting basal serum GH values [262–267], it is important to remember the effects of the episodic and labile GH secretion and the limitation of the radioimmunoassay, since presently available assays cannot distinguish between low-normal and low values seen in hypopituitarism. The diagnosis of GH deficiency requires provocative tests to document decreased GH reserve. The failure to induce a rise in GH secretion in response to provocative tests is the most common endocrine abnormality in hypothalamic pituitary disease. The provocative tests which are available for the assessment of the GH axis and their implications are outlined in Table 9.8. These tests can be classified either as screening or definitive tests.

FIGURE 9.5. Diagnostic approach to growth hormone deficiency (GHD) in the child.

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Screening tests are based on the known physiologic effects of exercise and sleep in enhancing GH release. The exercise test has the advantage of simplicity. It can be easily performed during routine office hours, requires only one or two blood samples, and does not need the administration of medications which may have unpleasant effects. GH response to sleep is less optimal than that seen with exercise; it is less convenient, and the responses are variable and are more difficult to assess. Definitive provocative tests of GH secretion are indicated in a patient with suspected GH deficiency who fails to show a GH response to one of the screening tests [268–275]. Confirmation of the diagnosis of GH deficiency requires documentation of failure to respond to two provocative tests. These may include the insulin test, the arginine test [281,282], the l-dopa test [283], glucagon test, [285–287] or clonidine test [284]. The insulin-hypoglycemia test [276–280] is considered by most centers to be the test of choice for the diagnosis of GHD. The Anginine-GHRH test [282] is considered to be an effective alternative in provocative testing for patients in whom the insulinhypoglycemia test is contraindicated. The GH responses to this test do not overlap with the responses of healthy individuals and they do not show inter- or intra-individual variability. Values less than 9 ul/L are thought to be indicative of GH deficiency. There are several important considerations in interpreting GH response to provocative tests [243]. All tests should be performed in the fasting state because postprandial hyperglycemia may suppress GH release. Also GH responses to all provocative tests may be impaired in patients with significant hypothyroidism or hypocortisolism. In the hypopituitary patient with TSH and ACTH deficiencies, GH stimulation tests should be performed after adequate thyroid and cortisol substitution therapy. The absence of a normal GH response to various provocative tests does not necessarily indicate an intrinsic hypothalamic pituitary disease [278]. Interpretation of the results of provocative tests should include consideration of the many nonpituitary influences known to impair the GH responses: obesity, primary hypothyroidism, thryotoxicosis, primary hypogonadism, Kallman syndrome, Cushing’s syndrome, and the use of glucocorticoids, alpha adrenergic agonists, B adrenergic agonists, serotonin agonists, and dopamine antagonists. By virtue of its prevalence, obesity poses the most serious problem in the interpretation of abnormal responses. Serum insulin-like growth factor (IGFs) [270,271] constitute a family of GH-dependent insulin-like peptides which mediate the growth-promoting actions of GH, and also perhaps many of its metabolic actions. There are at least two distinct circulating insulin-like growth factor: IGF-1 and insulin-like growth factor 2 (IGF-2). These IGFs circulate in the blood complexed to specific binding proteins, and their serum levels remain relatively status constant throughout the day. Of the two, IGF-1 is more

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Table 9.8.

Hypothalamic–Pituitary Dysfunction

GH provocative tests

Provocative test

Response

Comments

Definitive tests Insulin-induced hypoglycemia After an overnight fast, administer a bolus of regular crystalline insulin 0.1–0.15 IU/kg intravenously (in patients with hypopituitarism, 0.05 IU/kg; if insulin resistance is present, e.g., obesity, Cushing’s syndrome, or acromegaly, 0.15 to 0.3 IU/kg). Measure plasma glucose and serum GH (and plasma cortisol, if needed; see p. 378) at 0, 30, 60, 90, and 120 minutes

A normal response is an increase in serum GH > 5 ng/ml or to a level >10 ng/ml (10–15% of normal subjects may not respond). A normal response indicates an intact hypothalamic–pituitary GH axis. An impaired response cannot distinguish a hypothalamic from a pituitary GH disorder and may occur in nonpituitary disorders such as obesity, primary hypothyroidism, thyrotoxicosis, primary hypogonadism, and Cushing’s syndrome

For effective challenge, plasma glucose levels should decrease by at least 50% to a level below 40 mg/dl or to symptomatic hypoglycemic levels. If these criteria are not reached, repeat insulin dose in 45–60 minutes. Severe hypoglycemia may develop in association with ischemic cardiovascular and cerebrovascular symptoms, lethargy, stupor, or seizures. A physician should be present throughout the test. If serious hypoglycemic symptoms develop, 50% glucose should be given promptly. The test is contraindicated in patients with convulsive disorders, those with ischemic cardiovascular disorders, those with ischemic cardiovascular and cerebrovascular disease, and elderly persons

The values that indicate a normal response are as listed under the insulin test. In 10–20% of normal subjects, response may be impaired

Nausea, vomiting, weakness, pallor, and apprehension may occur

Same as for insulin test. About 10–20% of normal have no GH response

Transient nausea, vomiting, vertigo, and hypotension may occur. Keep patient recumbent during test

Same as for insulin test. About 30–35% of normal subjects have no response

No side-effects; contraindicated in patients with severe renal or liver failure

Same as for insulin test. Of normal individuals, 90–95% have GH response

Postural hypotension and drowsiness may occur because of central a-adrenergic effects

GHRH is available only as an investigational drug in the USA. Peak levels of GH occur at 15–30 minutes and range from 10 to >50 ng/ml; responses are slightly higher in women than in men, and decrease with age in both sexes. Diminished responses occur in pituitary diseases. A GH response usually occurs in patients with GH deficiency secondary to hypothalamic disease

Mild, transient flushing may occur. There are no significant risks. The test is only of use to delineate level of defect in GH deficiency, in the assessment of GH secretory reserve and in the selection of potential candidates for GHRH therapy. Response may be blunted in hypothyroidism and in Cushing’s syndrome

Glucagon Glucagon is given in a dose of 0.03 mg/kg up to 1.0 mg intramuscularly or subcutaneously. Samples for GH are obtained every hour for 3 hours L-dopa

After an overnight fast, administer 500 mg of L-dopa orally (in children, 10 mg/kg to a maximum of 500 mg). Measure serum GH at 0 time and hourly for 3 hours Arginine After an overnight fast, administer L-arginine (0.5 g/kg to a maximal dose of 30 g) intravenously over 30 minutes or 2 hours. Measure serum GH at 0 time and every 30 minutes for 2 hours Clonidine A dose of 0.15 mg (150 mg/m2) is administered orally. Serum GH is measured at 0 and every 30 minutes or 2 hours GHRH test A dose of 1 mg/kg is injected intravenously and blood samples are obtained at 0, 15, 30, and 60 minutes

GH-dependent on GH, and its levels reflect cumulative effects of the daily GH production. Circulating IGF-1 is synthesized mainly in the liver. IGF-1 is also synthesized locally by all GH-dependent tissues and serves an autocrine and paracrine function in regulating the response of tissues to GH. IGF-1 can be measured at any time of the day using available sensitive radioimmunoassays.

A number of factors, other than GH, influence serum IGF-1 levels. These must be taken into consideration in assessing the specificity of serum IGF-1 levels in the diagnosis of GH deficiency. The most important normal determinants of IGF-1 levels are age and pubertal status. IGF-1 levels are relatively low in infancy and childhood, increase progressively during childhood, and show a three- to four-

Chapter 9 Table 9.8.

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Continued

Provocative test Screening tests Exercise screening test (a) Omit food for 3–4 hours; after 30 minutes of test, walk briskly for 15 minutes. Then up and down one flight of stairs for 5 minutes; Obtain blood samples for serum GH pre- and postexercise (b) After overnight fast, perform 20 minutes of supervised vigorous exercise of patient’s preference. Obtain postexercise blood for GH Sleep Measure serum GH 60 and 90 minutes after clinically evident deep sleep

Response

Comments

Between 80 and 95% of normal children respond with a rise similar to that seen with insulin hypoglycemia test

Same as for insulin test. Incidence of response in normal subjects is 20–90%

Safe test. Useful as screening test in children

Pretreatment with propranolol (or sex steroid) may enhance GH response to stimulatory tests. Propranolol is given as 20 mg for children weighing <20 kg or 40 mg for heavier individuals. GH, growth hormone; GHRH, growth hormone releasing hormone.

fold increase by the time of puberty; after puberty, the levels decrease to the normal adult range and show a further decrease at senescence. IGF-1 assays have to be reflective of these age and sex differences. Normal IGF-1 levels in the younger and in the older age groups tend to overlap with values characteristic of GH deficiency. Fasting, malnutrition, primary hypothyroidism and chronic renal failure can decrease IGF-1 levels. Despite these limitations, IGF-1 measurements can also be useful adjuncts to the GH provocative tests in the assessment of GH axis, especially in the older age child. Of the six IGFBPs, serum IGF binding potein-3 (IGFBP3) [272–275] is the major serum carrier for IGF- peptides, and the most GH-dependent. The serum IGF-BP3 concentrations are less nutritionally dependent, and their normal range varies only modestly with age. Experience to date shows, in general, good correlations between serum concentrations of IGFBP-3 and GH status as determined by provocative GH testing. Serum IGF-1 and IGFBP-3 concentrations are invariably reduced in the patient with unequivocal GHD. Twenty-four hour measurement of GH secretion is not practical for clinical use, requires hospitalization, is tedious and labor intensive; in addition, substantial overlap in values exists between normal individuals and patients with growth hormone deficiency. Measurements of urinary GH vary significantly between individuals and within individuals from day to day. However, such measurements may be helpful if other biochemical markers, e.g. IGF-1, are measured as well. Based on the above considerations, at present the acceptable criteria for the diagnosis of GH deficiency are as follows: the presence of short stature, growth failure, delayed

bone age, normal body proportions, absence of significant underlying illness or emotional deprivation, low circulating levels of IGF-1 and IGF-BP3, and impaired GH responses to at least two provocative stimuli for GH release. Other Tests

Once the diagnosis of GH deficiency is established, additional tests are indicated which include endocrine assessment of the other pituitary functions, imaging study of the hypothalamic pituitary region, and, if necessary, neuro-ophthalmologic evaluation. Growth Hormone Deficiency (GHD) in the Adult [288,289,291]

Etiology Growth hormone deficiency is encountered in two settings: 1. Adults with acquired hypothalamic–pituitary disease. This group represents most of the adults with GHD encountered in clinical practice. In these patients, GHD usually occurs as a part of multiple pituitary hormonal deficiencies, but infrequently, it can occur as an isolated deficiency. 2. Young adults who have had childhood-onset GH deficiency, and who show evidence of persistent GHD when retested in young adulthood (see below). Clinical Features The clinical presentations of GHdeficiency in the adult are a composite of the features of GH deficiency, those of associated other pituitary deficiencies and their treatment, and those of the underlying disease (Fig. 9.6) [288–291].

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• Increased insulin resistance [319] • Increased risk of hypertension. A number of changes in cardiac structure and function have been noted [314–317]: • Decreased LV wall thickness, and interventricular septal thickness • Impaired cardiac function • Reduction in maximal oxygen uptake • Decreased maximal heart rate (20%) • Decreased cardiac output at rest and during exercise • Decreased LV systolic function. Diagnosis The diagnostic approach to GH deficiency in the adult is shown in Figure 9.7. The presence of GHD in the adult should be suspected in the following clinical settings.

FIGURE 9.6. A 37-year-old man with childhood idiopathic hypopituitarism—shortness of stature, hypothyroid facies, and sexual infantilism.

The symptoms of GH deficiency are nonspecific and include fatigue, decreased energy and stamina, increased weight and adiposity (dominantly abdominal) [292–294], decreased muscle bulk and strength [295], osteopenia [306–309] and increased risk of fragility fractures [296–305], decreased sense of well-being, moodiness, depression, and increased sense of social isolation [310–312]. GHD impacts negatively on muscle strength and exercise performance: • Reduced lean body mass and isometric strength • Reduced maximal heart rate and reduced cardiac output during exercise (20%) • Reduced exercise capacity (20%) • Decreased sweating and ability to lose heat, which results in impaired thermoregulation and heat intolerance. GHD is associated with several changes in the cardiovascular risk profile: • Increased total cholesterol and LDL-cholesterol, increased triglycerides and decreased HDLcholesterol and variable impact on Lp(a) [299,300–304] • Increased risk of arterial thrombosis which is related to increased fibrinogen, increased plasminogenactivator inhibitor, and impaired fibrinolysis [318] • Increased abdominal fat which is a marker of insulin resistance and an established risk factor of cardiovascular disease

Patients with Known Hypothalamic–Pituitary Disorders Over 90% of adult-onset GHD is seen in patients with known pituitary tumors. GH deficiency results from either direct effect of the tumor or from the effects of surgical or radiotherapeutic management, history of cranial irradiation, history of head trauma or patients with hypopituitarism. In patients with organic hypothalamic–pituitary disease, the likelihood of GH deficiency increases with the increasing number of pituitary hormone deficits from approximately 45%, if no other deficits are present, to nearly 100%, if two or more pituitary hormone deficiencies are present. Patients with a History of Childhood-Onset GH Deficiency It is important to remember that 33% of children with “idiopathic” GH deficiency show normal GH secretory function when retested in young adulthood. Childhoodonset GHD usually persists especially in those with organic identifiable disease in the hypothalamic–pituitary region [322]. Untreated thyroid, adrenal or gonadal deficiency decrease GH response to provocative tests. It is, therefore, important at the outset to evaluate other pituitary functions, document other hormonal deficiencies, and provide, when necessary, appropriate replacement therapy for these deficiencies. In most patients, basal GH measurements are not helpful. GH secretion is normally pulsatile, with a greater amplitude of pulses at night, resulting in undetectable GH serum concentrations during a very sizable portion of the day [321]. Therefore, low basal levels may be seen in normal people, and cannot be taken as indicative of growth hormone deficiency. A high basal GH level, however, excludes GH deficiency. Serum IGF-1 measurements have not proven to be reliable indicators of GH deficiency. IGF-1 concentrations are widely variable in healthy adults, and are affected by factors such as age, sex and nutritional state. In addition, there is inconsistency and variability among different assays. A

Chapter 9

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GH secretion, e.g. aging. Furthermore, the benefits of treatment of partial GH deficiency remain to be established. GHD must be distinguished from: 1. The reduced GH secretion of aging [323–325]: daily GH secretory rates decline from a peak of about 150 mg/kg during puberty to about 25 mg/kg by age 55 years; this decline parallels the age-related decline in body mass index. Serum IGF-1 levels and IGFBP3 measurements, GH responsiveness to provocative stimuli also decline with age. Agerelated IGF-1 levels must be used as reference. 2. The reduced GH secretion in obesity: obesity is associated with decreased spontaneous GH secretion and subnormal GH responses to provocative tests. Serum IGF-1 concentrations are normal in obesity, but this is not very helpful in differentiation between obesity and growth hormone deficiency because over 50% of patients with growth hormone deficiency have normal IGF-1 concentrations. In the obese patient, however, GH secretory abnormalities are reversible with weight loss. FIGURE 9.7. Diagnostic approach to growth hormone deficiency (GHD) in the adult.

normal IGF-1 level is seen in greater than 50% of patients with growth hormone deficiency and, therefore, cannot be used to exclude GH deficiency. A low IGF-1 level, in the appropriate clinical context, and particularly in the presence of other pituitary hormone deficiencies, and in the absence of other factors known to reduce IGF-1 levels, can be very helpful in making the diagnosis. The use of measurements of IGF-BP3 or acid labile IGF-1 fragments, whose levels are modulated by GH, have also been found to be unhelpful in the diagnosis of growth hormone deficiency in the adult because of considerable overlap in values between patients with GHD and healthy individuals. The definitive diagnosis of GHD in the adult requires the demonstration of impaired GH responses to provocative tests [278]. At present there is no consensus regarding which provocative test is preferred for the diagnosis of growth hormone-deficiency, but, in most centers, the insulin hypoglycemia test is considered to be the provocative test of choice [279]. It is to be noted that age- and gender-related normal ranges for GH responses to provocative stimuli have not been clearly defined and that the diagnostic accuracy of these provocative tests in adults has not been ascertained. Two provocative tests are required in the patient in whom GHD is suspected; however, one provocative test is considered adequate for diagnosis of GHD in the patient who has other pituitary hormone deficiencies or who has a history of childhood-onset GH deficiency. Partial GH deficiency exists, but additional research is needed to distinguish it from physiologic causes of reduced

Corticotropin (ACTH) Deficiency ACTH deficiency state can result from ACTH underproduction or tissue resistance; decreased production may be due to intrinsic pituitary disease (secondary) or may result from deficiency of CRH because of a hypothalamic disorder (tertiary). ACTH deficiency can be congenital or acquired, familial or sporadic, and partial or complete. It may occur as an isolated deficiency or as a part of a more global hypopituitarism. Etiology (see Table 9.9)

Genetic/Familial [328] No abnormalities within the CRH gene have yet been reported in either animal models or humans. At the pituitary level, gene defects may lie in the CRH receptor or the POMC gene. Dissociation of the pituitary responsiveness to lysine vasopressin and CRH has been reported leading to the hypothesis that ACTH deficiency might, in some cases, be caused by a defect in the CRH receptor. However, no abnormalities in the CRH receptor gene in isolated ACTH deficiency have been reported. A very rare autosomal recessive disorder, characterized by ACTH deficiency, early onset of obesity, and red hair, is caused by homozygous or compound heterozygous mutations in the pro-opiomelanocortin (POMC) gene [329,330]. The defect in POMC processing affects the hypothalamus, pituitary and epidermal hair follicle cells leading to the manifestations of the syndrome. Several POMC mutations and polymorphisms have also been detected in a number of extremely obese children and adolescents [330], and thin patients with undernutrition and anorexia nervosa [330].

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Table 9.9.

Hypothalamic–Pituitary Dysfunction

Etiology of corticotropin deficiency

Structural Genetic/familial Defects in the CRH receptor (?) Mutations in the POMC-gene Defects in POMC-processing Late in the course of PROP1 Gene mutations ACTH-receptor defects (ACTH-resistance) Familial glucocorticoid deficiency Without ACTH receptor-defect Triple A (Allgrove) syndrome Acquired (see Table 9.2) Traumatic Inflammatory Degenerative Vascular Neoplastic Functional Glucocorticoid therapy After treatment of Cushing’s syndrome Megestrol therapy Acute illness in the elderly

A defect in posttranslational processing of POMC has been reported [331]. This defect has been proposed to explain rare cases of congenital ACTH deficiency in which ACTH deficiency was associated with low concentrations of serum ACTH and b-LPH, and with preservation of the ability to synthesize and secrete ACTH-precursors. The secretion of these ACTH precursors was responsive to stimulation by CRH. Most patients with PROP1 gene defects also have a normal ACTH axis [211–215] but some patients, late in the course of their disease, do show diminished cortisol responses to ACTH. In patients with Pit-1 gene defects, the ACTH axis is normal [332]. ACTH Resistance Syndromes Resistance to ACTH is characterized by glucocorticoid deficiency, without deficiency of mineralocorticoids, in the presence of inappropriately elevated circulating levels of ACTH. The zona fasciculata and reticularis are atrophied, while the zona glomerulosa is preserved. Two rare autosomal recessive disorders have been described: (i) familial glucocorticoid deficiency (FGC); and (ii) the triple A syndrome. These syndromes are believed to result from genetic defects in the ACTH receptor. More than 70 patients with FGD have been described [333–335,337–339]. This autosomal recessive disorder, which is transmitted as autosomal recessive fashion, presents in the first year of life with severe hypoglycemic episodes, failure to thrive and frequent and severe infections; death may occur in early childhood. A number of defects of the

ACTH receptor have been described related to a homozygous or compound heterozygous mutations in the ACTHreceptor gene. FGD has been reported in families in whom no mutations within the coding region of the ACTH receptor could be identified. Triple A syndrome (Allgrove’s syndrome) [336,340–345] is an autosomal recessive familial disorder, characterized by the triad of ACTH-resistant adrenal insufficiency, achalasia of the cardia and alacrima [336]. The features usually appear during the first decade of life. Mineralocorticoid deficiency appears in about 15% of cases. The molecular defect is still unknown; no mutation in the ACTH receptor has been detected as yet. Acquired ACTH Deficiency Structural Disorders The reader is referred to the section on Etiology for a detailed discussion of the various structural disorders. Tumors of the hypothalamic–pituitary region are the most common spontaneous cause of ACTH deficiency. Such deficiency results from direct invasion, infiltration, or compression of the hypothalamic–pituitary axis or secondarily as a consequence of ablative surgical or radiotherapeutic treatment modalities. In such patients, ACTH deficiency is virtually always accompanied by deficiency of other pituitary hormones. In hypopituitarism caused by these tumors, GH and LH/FSH are usually lost first, followed by loss of ACTH and finally of TSH. Other organic causes of the hypopituitary syndrome are less common etiologies of ACTH deficiency and have been outlined in the pathology section. In lymphocytic hypophysitis, ACTH lack may occur as an isolated abnormality or as a part of more global hypopituitarism. Hypothalamic causes of ACTH deficiency may be either organic or functional in nature. The most common causes of ACTH deficiency encountered in clinical practice are those disorders associated with functional suppression of the CRH-ACTHcortisol axis. Such a suppressed axis is encountered in glucocorticoid pharmacologic therapy, after the cure of endogenous Cushing’s syndrome, during and after megestrol therapy [327]. The pathologic anatomy of the pituitary and hypothalamus in isolated ACTH deficiency [346–348] has not been fully characterized. Total or partial reduction in basophil cells have been reported. Birth trauma may be etiologic in some children. Secretion of the other pituitary hormones, by definition, is normal except for other POMC-derived peptides. There is increasing recognition of the association of autoimmunity with isolated ACTH deficiency; however, it is not clear yet that such autoimmunity plays a role in the pathogenesis of the syndrome in most of these patients. Isolated ACTH deficiency has been reported in patients with type I diabetes mellitus [356–360], in lymphocytic hypophysitis [355,362], and most commonly with primary thyroid failure [349,352–354]. It is not known whether

Chapter 9

ACTH deficiency is due to a pituitary etiology or results from defective hypothalamic secretion of CRH [350,351]. Most of these patients were presumed to have a selective hypothalamic dysfunction, but recent data with the use of CRH provocative tests seem to point to primary pituitary corticotrope failure [369]. Most patients with isolated ACTH deficiency are between the ages of 30 and 50 years. There is no clear sex predominance. Neuropsychiatric behavior abnormalities [363], weakness or symptomatic hypoglycemia, adrenal crisis [364], or hyponatremia [365,366], are often the presenting complaints. Gynecomastia may occur which resolves with glucocorticoid therapy [367]. Pitfalls in the diagnosis of isolated ACTH include: (i) the potential to overlook the clinical diagnosis because of nonspecific symptoms; (ii) omitting partial ACTH deficiency from consideration because of normal ACTHcosyntropin test responses; and (iii) discordance between finding of low basal cortisol and normal responsiveness to provocative tests [368,370]. Characteristically patients with isolated ACTH deficiency have a low or low-normal plasma cortisol level, low urinaryfree cortisol, or 17 hydroxy-corticosteroid excretion, low normal serum ACTH (but inappropriately low for cortisol levels) and do not respond to metapyrone stimulation. In some patients cortisol and ACTH increase in response to hypoglycemia or vasopressin. Functional ACTH Deficiency The most common causes of tertiary adrenal insufficiency are relatively abrupt cessation of high-dose glucocorticoid therapy [371–379] and correction of Cushing’s syndrome. • ACTH axis: glucocorticoid-induced ACTH deficiency is the most common cause of secondary adrenocortical failure. Cortisol or any of its glucocorticoid-analogues, if given long enough and in supraphysiologic doses, will suppress hypothalamic CRH production and the pituitary corticotrope response to CRH. As a result, suppression of ACTH secretion occurs with consequent adrenocortical failure. This hypothalamic–pituitary–adrenal (HPA) axis suppression is dependent on the potency and dosage of the particular glucocorticoid used, and the schedule and duration of its administration. Generally speaking, HPA suppression is less likely with small dosage, given as a single morning daily dose, or as alternate day therapy, or for a short duration of time. Any patient who has received a glucocorticoid in doses equivalent to 20–30 mg per day of prednisone for more than 5 days, or lower supraphysiologic doses of more than 1 month, should be suspected of having HPA suppression. Replacement doses of 20–30 mg hydrocortisone, 5–71/2 mg of prednisone or equivalent, do not suppress the axis if given early in the day; however,

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suppression may occur if these replacement doses are given late in the day because of inhibition of ACTH early morning diurnal surge. Patients who receive alternate day glucocorticoid therapy have less suppression of the HPA axis than patients who receive daily therapy [375,376,378]. Basal HPA axis function may be modestly suppressed but response to stress and provocative tests are usually normal. There are only a few well-documented cases of acute adrenocortical insufficiency after prolonged glucocorticoid therapy [377]. This sparsity of reports may be due to the rarity of acute adrenocortical insufficiency in properly managed patients, or due to reluctance of clinicians to report such effects. Secondary adrenal insufficiency may express itself days to months after discontinuation of therapy, usually in a stressful setting associated with acute medical or surgical illness. During recovery from HPA suppression, restoration of pituitary ACTH secretion occurs before that of adrenocortical cortisol secretion. The time course of recovery also depends on the type of glucocorticoid used, its potency, total dose, and duration of use. Generally speaking, recovery from suppression induced by a short course of glucocorticoids occurs within a few days; however, that induced by supraphysiologic doses given for a prolonged period of time may require up to 12 months. Recovery of HPA axis function occurs more rapidly in those patients with mild HPA suppression (normal plasma cortisol and blunted response to ACTH) than in those patients with more severe HPA suppression (low plasma cortisol and absent response to ACTH). Since it is difficult to predict, in a given patient with HPA suppression, the time needed for full recovery of the axis it is prudent to suspect presence of HPA axis suppression for 12 to 18 months after the discontinuation of supraphysiologic glucocorticoid therapy. With regard to exogenous ACTH therapy and the HPA axis, there is no reported evidence of clinically significant HPA suppression in patients who have received ACTH therapy irrespective of dose, schedule of administration, or duration of therapy. The author suspects that this is due to reluctance by physicians to report such events, since it is anticipated that the exogenous ACTH-induced increase in endogenous cortisol production would suppress the hypothalamic pituitary ACTH axis. As stated earlier, during recovery from HPA suppression the function of the hypothalamic pituitary unit recovers earlier than that of the adrenal cortex. Therefore, documentation of recovery of adrenal cortex by assessment of responsiveness to exogenous ACTH (cortrosyn test) is a useful guide to monitor HPA recovery [379]. A normal adrenocortical response, in this setting, implies a recovered axis. In such patients, the maximal response to ACTH corresponds to maximal response observed during induction of general

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anesthesia or surgery. Alternatively, other tests such as metapyrone or insulin-provocative tests can be used to assess the HPA axis. However, they are less convenient, more costly, and may be hazardous. • GH axis [380–385]: glucocorticoid excess, whether from an exogenous or endogenous source, inhibits linear growth and skeletal maturation in children. The mechanisms underlying this defect include direct inhibitory effects of glucocorticoids on bony epiphyses, on GH secretion, and on IGF-1 synthesis and secretion and peripheral resistance to the action of growth hormone. • LH/FSH axis: glucocorticoids inhibit LH-FSH secretion both in the basal state and in response to GnRH and also exert direct inhibitory effects on the gonad. Consequently, there is impairment in both steroid secretion and gametogenesis. Hypogonadism and infertility in adults and delayed sexual maturation in adolescence are common [386–388]. • TSH axis: glucocorticoids blunt the TSH response to TRH and the peripheral conversion of T4 to T3. These effects are usually without clinical significance but may contribute to the suppressed serum TSH levels occasionally seen in the euthyroid sick syndrome. After selective pituitary adenomectomy for Cushing’s disease, the majority of successfully treated patients develop secondary adrenocortical insufficiency and require cortisol replacement therapy. The duration of time required for recovery of normal responsiveness of HPA axis is usually 9 to 12 months but may be prolonged to 2 years [388]. Patients with unilateral adrenal tumors associated with Cushing’s syndrome have hypothalamic–pituitary– corticotroph suppression and atrophy of the contralateral adrenal cortex. Similarly patients with ectopic ACTH syndrome have hypothalamic–pituitary ACTH secretion impairment. After unilateral adrenalectomy for Cushing’s syndrome due to an adrenal adenoma or carcinoma or in those few patients with successful surgical ablation of the ectopic ACTH producing tumor, it may require more than 12 months for recovery of the axis to occur. Megestrol acetate, a progestin with modest glucocorticoid activity, is used to treat patients with metastatic breast cancer and to increase appetite in patients with wasting diseases such as AIDS. Its withdrawal can occasionally cause secondary adrenal insufficiency. Unexpectedly, adrenal insufficiency has also been reported to occur during megestrol therapy. Possible explanations include the inadvertent or unreported patient discontinuation of megestrol; and dual agonist–antagonist properties of the drug, which acts as a weak agonist by binding to the glucocorticoid receptor, but also may act as an antagonist by blocking the binding of the more potent endogenous glucocorticoid, cortisol [389–391].

Clinical Features

The clinical features of ACTH deficiency [327] usually have a gradual onset and a chronic course. The symptoms are nonspecific and consist characteristically of weakness lethargy, fatigue, gastrointestinal symptoms of anorexia, nausea, occasional vomiting, arthralgias, and myalgias. Because of impaired neoglucogenesis, symptomatic hypoglycemia, especially after prolonged fast and/or moderate alcohol ingestion, may occur, and this is occasionally the presenting feature; it may be more prominent than in primary adrenocortical failure due to the associated GH deficiency. Hyponatremia may occur and is usually due to inappropriate ADH secretion and inability to excrete a water load and is reversible with glucocorticoid therapy. It is less pronounced than in primary adrenocortical failure. Congenital ACTH deficiency can present as neonatal jaundice [392–394]. Loss of adrenal androgens in the male is of little consequence, if testicular androgen production is preserved. In the female, however, such loss contributes to decreased libido and is largely responsible for the loss of axillary and pubic hair. The usual presentations of ACTH deficiency are similar to that of primary adrenocortical failure, except for two characteristic features: (i) because of ACTH and related POMC-derived peptide deficiency, the characteristic hyperpigmentation of Addison’s disease is absent and patients in fact have pallor of the skin and diminished tanning after exposure to sunlight; and (ii) because of the primary dependence of aldosterone secretion on the renin-angiotensin systems, the clinical features of mineralocorticoid deficiency are usually absent in ACTH deficiency in the unstressed state [395–397]. Dehydration, volume depletion, and electrolyte abnormalities are usually not seen. Hypotension is less severe except in acute presentations. Frequently, the impairment of ACTH secretion is a partial one. Such affected patients may experience symptoms only during periods of acute medical and surgical illness, and ACTH deficiency may thus remain subclinical and undiagnosed for prolonged periods of time. True Addisonian crisis is infrequent because the renin angiotensin-aldosterone system is largely intact; however, acute decompensation with severe hypotension or shock may occur. This is usually unresponsive to vasopressors until glucocorticoids are replaced. Such an acute presentation in the ACTH deficient patient can occur in the patients who do not increase the glucocorticoid dosage in such circumstances, and in pituitary apoplexy. Except in the isolated form of ACTH deficiency, patients with ACTH deficiency commonly have associated clinical features which suggest the diagnosis. Among these are a history of glucocorticoid therapy, presence of clinical evidence of exogenous Cushing’s syndrome, loss of other pituitary functions, evidence of hypersecretory syndromes caused by functioning pituitary tumors, anatomical presentations of tumors in the hypothalamic pituitary area such as

Chapter 9

headache, visual field defects, and a sellar mass on imaging studies. Because cortisol clearance is decreased in hypothyroidism, ACTH deficiency may not be apparent if hypothyroidism is present concomitantly, If ACTH impairment is only partial, normal serum cortisol may be maintained. Therefore, in patients with pituitary disease who have hypothyroidism, it is critical to establish that ACTH secretion is normal prior to initiating thyroid hormone therapy. Because treatment with thyroid hormone replacement accelerates cortisol metabolism, in such patients it may precipitate adrenocortical crisis. Also, ACTH deficiency may mask the manifestations of diabetes insipidus because cortisol is required for renal free-water clearance. The manifestations of diabetes insipidus may be unmasked after glucocorticoid replacement. Diagnosis

Routine laboratory tests may reveal a mild normochromic normocytic anemia, neutropenia, relative lymphocytosis, and eosinophilia. Hypoglycemia and hyponatremia may be present.

Table 9.10.

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373

The standard endocrine tests utilized in the evaluation of the hypothalamic–pituitary–adrenal axis, their implications, and their clinical utility are outlined in Table 9.10. Provocative tests which are available to assess the axis are outlined in Table 9.11. The diagnostic approach is outlined in Figures 9.8a & b. The predominant effects of ACTH deficiency are a decreased adrenocortical secretion of cortisol and adrenal androgens. In those patients with a chronic, slowly progressive, hypothalamic–pituitary disorder, as exemplified by a pituitary tumor or craniopharyngioma, the impairment of the corticotropes and ACTH secretion evolve gradually. Initially, basal ACTH secretion is maintained, but ACTH responsiveness to provocative stimuli is impaired. In such circumstances, the functional integrity of the zona fasciculata/reticularis and basal cortisol secretion are maintained, but ACTH and cortisol levels do not rise in response to acute illness or such provocative tests which stimulate the whole axis as insulin hypoglycemia or metapyrone. However, cortisol secretion can rise in response to acute stimulation by exogenous ACTH. With disease progression, basal ACTH secretion become impaired with ensuing

Laboratory tests in assessment of TSH–thyroid axis

Tests

Determinants

Hypothyroidism

Total thyroxine (TT4) Normal, 5.0–12.5 mg/dl

Thyroid function; thyroxine-binding globulins; TT4 measures both bound (99.95%) and free (0.05%) T4

Decreased in primary, secondary, and tertiary hypothyroidism. Can be decreased in euthyroid patients with: (a) Low serum-binding proteins (androgen and anabolic steroid therapy, marked hypoproteinemia, genetic TBG absence or deficiency, glucocorticoid excess, chronic liver disease, acromegaly) (b) Inhibitors of serum T4 binding (salicylates, phenytoin) (c) T3 therapy (d) Euthyroid sick syndrome

Free serum thyroxine (FT4) Normal, 0.7–1.8 ng/dl

Thyroid function

Decreased. May be decreased in euthyroid patients with euthyroid sick syndrome

Free thyroxine index Normal (laboratory dependent)

Total thyroxine and an indirect measure of TBG binding (T3 resin uptake, RT3U). It is equivalent to the free serum thyroxine

Decreased. May be decreased also in euthyroid sick patients

Serum triiodothyronine (T3) Normal, 90–230 ng/dl

Thyroid function, thyroid-binding globulin levels, peripheral T4 to T3 conversion. Measures both bound (99.5%) and free (0.5%) T3

Decreased. May also be decreased in euthyroid patients with decreased T4 to T3 conversion. (a) Neonatal and elderly patients (b) Acute or chronic illness (euthyroid sick) (c) No carbohydrate intake and caloric deprivation (malnutrition, anorexia nervosa uncontrolled diabetes mellitus) (d) Drugs (propylthiouracil, propranolol, glucocorticoids, certain iodinated contrast agents, and amiodarone)

Serum TSH Normal, 0.5–6.0 IU/ml

Hypothalamic–pituitary–thyroid axis function

Increased in primary hypothyroidism; normal or low in secondary and tertiary hypothyroidism. Serum TSH may be low or undetectable in euthyroid sick, use of glucocorticoids or dopamine, and in hyperthyroidism

TSH, thyroid-stimulating hormone.

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Table 9.11.

Hypothalamic–Pituitary Dysfunction

TSH provocative test

Provocative test TRH test Measure serum TSH at 0 minutes and 30 and 60 minutes after administration of TRH 500 mg i.v. (in children 10 mg/kg or 200 mg/1.7 m2)

Response

Comments

Serum TSH increases. Normal responses should be standardized by each laboratory. In general, peak values of TSH are at least twice the basal levels

In patients with hypothyroidism, absence of response suggests pituitary disease, whereas a delayed response favors hypothalamic disease. Impaired responses are seen also in patients with thyrotoxicosis, in euthyroid elderly patients, and in those with renal failure

TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

(a)

(b) FIGURE 9.8.

(a) Approach to suspected ACTH deficiency—flow chart 1. (b) Approach to suspected ACTH deficiency—flow chart 2.

atrophy of the adrenocortical zona fasciculata/reticularis. Basal cortisol secretion is decreased. Such an impaired axis cannot increase ACTH secretion during stress, acute illness, or following insulin hypoglycemia or metapyrone administration. In addition, the atrophic adrenal cortex becomes unable to increase cortisol secretion in response to acute stimulation by exogenous ACTH. Derangements due to mineralocorticoid deficiency are usually absent in ACTH deficiency because aldosterone secretion depends primarily on the integrity of the reninangiotensin system and not on optimal ACTH secretion. In the early stages of ACTH deficiency aldosterone secretion is normal, but when ACTH deficiency is long standing, mineralocorticoid deficiency may develop in a minority of patients. Of those patients with such abnormality in aldosterone secretion, some maintain normal basal aldosterone secretion with decreased responsiveness in the face of salt deprivation. With progression, deficient basal and stimulated aldosterone secretion may occur. The mechanism of this mineralocorticoid deficiency is not well understood at this

time. It has been suggested that it is due to a loss of the effects of ACTH or other POMC derived peptides on the zona glomerulosa. In rare patients with ACTH deficiency hypoaldosteronism may be associated with hypo- or normoreninemia and may be corrected by glucocorticoid administration. In patients with suspected ACTH deficiency, one needs to assess basal ACTH-cortisol production and demonstrate whether or not the hypothalamic–pituitary–adrenal axis can respond to stress normally. A low basal serum cortisol concentration in the morning (less than 3 mg/dL [80 nmol/L]) provides presumptive evidence that the patient has adrenal insufficiency and a value below 10 mg/dL (275 nmol/L) strongly suggests the diagnosis. A plasma cortisol level greater than 18 mg/dL (500 nmol/L) excludes adrenocortical insufficiency. A “normal value” between 3–18 mg/dL (80 nmol/L– 500 nmol/L) does not exclude partial insufficiency; in this circumstance, a provocative test is needed to document adrenocortical reserve. It is important to remember that a

Chapter 9

“normal plasma cortisol” in an acutely ill patient (in whom plasma cortisol should be high) points to adrenocortical insufficiency [398]. A short ACTH stimulation test [399] is commonly performed in patients suspected of having adrenal insufficiency. Synthetic ACTH (1–24) (cosyntropin), which has the full biologic potency of native ACTH (1–39) is administered intravenously, and plasma cortisol responses are assessed at 30 and 60 minutes following the administration of ACTH. The response to cosyntropin is the same in the morning and afternoon; the test can therefore be performed at either time. The short ACTH test can be performed utilizing a standard dose (250 mg) or a low dose (1 mg) of cosyntropin. A normal response to the ACTH stimulation test is a serum cortisol concentration at any time during test which is equal to, or exceeds, 18–20 mg/dL (500–550 nmol/L). A subnormal response confirms the diagnosis of adrenal insufficiency. It indicates that the adrenals are unresponsive to ACTH stimulation and can be due to primary adrenocortical failure or to adrenocortical atrophy resulting from hypothalamic–pituitary failure and ACTH deficiency. The differential diagnosis between these two entities is based on measurement of serum ACTH which is high in primary adrenocortical failure and inappropriately low in hypothalamic–pituitary–ACTH deficiency. If serum ACTH measurements are not available or are unreliable, a long ACTH stimulation can be used [417]. Absence of response to prolonged ACTH stimulation indicates primary adrenocortical failure. In secondary adrenocortical insufficiency, there is a progressive stepwise response to ACTH stimulation. A normal response excludes primary adrenal insufficiency, and by inference, implies normal pituitary ACTH secretion and support of adrenal steroidogenesis [401,402,411]. However, the standard ACTH test does not entirely exclude ACTH deficiency if it is of recent onset (e.g., within 1 to 2 weeks after pituitary surgery) or it is of partial severity. In such patients, the adrenal glands have not yet become completely atrophic, and are still capable of responding to ACTH stimulation. Ninety percent of patients with impaired ACTH secretion, as defined by a subnormal response to insulin-induced hypoglycemia, have a diminished response to the short standard-dose ACTH test. The low-dose ACTH test (1 mg or 0.5 mg/1.73 m2 surface area as an iv bolus) is preferred by many centers for the evaluation of patients suspected of secondary or tertiary adrenal insufficiency [404–416]. The results of the low-dose ACTH stimulation test correlates highly with those of the insulin-tolerance test with regard to possible ACTH deficiency. It can detect partial adrenal insufficiency that may be missed by the standard high-dose test, which provides a supraphysiologic stimulus that can stimulate a partially diseased adrenal. Patients with secondary adrenal insufficiency of recent onset have not been studied, but it is unlikely that this test will any more reliably identify these patients than other ACTH stimulation tests.

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375

Insulin-induced hypoglycemia test [400,412] or metyrapone test [418–427] are the tests of choice for the definitive diagnosis of recent or partial ACTH deficiency. A normal response to any of these two provocative tests indicates a normal CRH-ACTH-adrenal axis. A subnormal response indicates a defective axis but cannot differentiate between primary and central adrenocortical failure. The differential diagnosis between these two entities is based on measurement of serum ACTH, which is high in primary adrenocortical failure and inappropriately low in hypothalamic–pituitary–ACTH deficiency. Administration of CRH [428,429] can be used to assess corticotropin reserve and may be useful in distinguishing hypothalamic from pituitary etiology of ACTH deficiency.

Thyrotropin Deficiency Thyrotropin (TSH) deficiency can occur from either decreased production or tissue resistance. Decreased TSH production may result from either a hypothalamic disorder, functional or organic, which results in a decrease in TRH or an increase in somatostatin production, or from intrinsic pituitary disease [430,431]. As is true of most other pituitary hormone deficiencies, TSH deficiency can be congenital or acquired, familial or sporadic, and partial or complete. It may occur as an isolated deficiency or as a part of a more global hypopituitarism. Etiology (Table 9.12)

Congenital Central Hypothyroidism Inactivating mutations in the TRH receptor gene [432–434] are transmitted as an autosomal recessive trait. The clinical findings are those of

Table 9.12.

The etiology of TSH deficiency.

Structural Genetic/familial Mutations in the TRH receptor Pituitary hypoplasia or aplasia Mutations in the Pit-1 gene Mutations in the PROP1 gene Mutations in the TSHb-gene Mutations in the TSH receptor Acquired (see Table 9.2) Traumatic Inflammatory Degenerative Vascular Neoplastic Functional After treatment of the hyperthyroid state After discontinuation of exogenous thyroid hormone therapy During nonthyroidal illness Use of dopamine, glucocorticoids, somatostatin

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central hypothyroidism. Biochemical findings include a normal serum TSH, low serum T4 and T3 concentrations, and absence of serum TSH or prolactin responses to the administration of TRH. • Pituitary aplasia and hypoplasia, usually accompanied by other CNS anomalies (see Etiology). • Mutations of the Pit-1 gene (see Growth Hormone (GH) section). • Mutations of the PROP1 gene (see Growth Hormone (GH) section). Mutations in the gene coding for the TSH-b subunit [437–440] result in isolated central hypothyroidism at birth. In several Japanese families a single nucleotide substitution resulted in an altered TSH-b subunit unable to bind to the alpha-subunit to form intact TSH. In two Greek families, a single nucleotide substitution resulted in a severely truncated TSH-b subunit. Serum TSH levels, and free b-subunit levels are undetectable and do not respond to thyrotropinreleasing hormone, TRH. However, aTSH-subunit concentrations are elevated, and increase significantly in response to TRH. Inactivating mutations in the TSH receptor [441] is an uncommon disorder that is transmitted as an autosomal recessive trait. In most patients, the inactivating mutations occur in the extracellular domain of the TSH receptor. Such mutations lead to TSH-resistance, reduced T4 and T3 synthesis and secretion and a compensatory increase in TSH secretion. Some patients with TSH resistance have no detectable TSH receptor mutations, nor inactivating mutations in Gprotein, and the cause of their TSH resistance is not known. TSH resistance also occurs in patients with type 1a pseudohypoparathyroidism; the TSH receptors are normal but the deficient activity of guanine nucleotide regulatory protein results in reduced adenylyl cyclase responses to TSH. The clinical manifestations of TSH resistance [442–450] include a spectrum of abnormalities which relate to the variable impairment of the function of the TSH receptor. • Complete lack of TSH receptor function results in severe hypothyroidism. • Less severe impairment of receptor function may present as subclinical hypothyroidism. • Partial impairment of the receptor function is associated with a euthyroid state because TSH hypersecretion overcomes the resistance. In the 10 families that have been reported with TSH resistance, the patients had severe hypothyroidism in three families, were euthyroid in five families, had subclinical hypothyroidism in two families. Acquired Central Hypothyroidism Structural Disorders Acquired central hypothyroidism is much less common than primary hypothyroidism and probably accounts for less than 5% of all cases of hypothyroidism.

Pituitary tumors, functioning or nonfunctioning, are the most common cause in the adult. TSH deficiency usually occurs in the setting of macroadenomas and very rarely in microadenomas. It may also result from ablative surgery or radiation therapy. Other causes of organic pituitary disease which may lead to TSH deficiency are as described earlier. TSH deficiency in these circumstances is usually associated with other pituitary hormone deficiencies but may be isolated. Hypothalamic hypothyroidism may result from cranial irradiation or other organic hypothalamic diseases. Affected patients often have diabetes insipidus, mild elevation of serum prolactin, neurologic abnormalities, and other manifestations of hypothalamic disease including disturbance of temperature regulation, sleep cycle, food and water intake, autonomic function, and emotional ability. Reversible hypothalamic hypothyroidism has been reported in children receiving GH therapy, probably because of GH-induced hypersecretion of somatostatin [460]. In rare patients with hypothalamic hypothyroidism, basal serum TSH levels are elevated. The secreted TSH in these patients is immunoreactive but appears to be of reduced biologic potency. Administration of TRH leads to an increase in the biologic activity of TSH. These patients may have either idiopathic or tumor related hypothalamic disease. Functional Disorders Transient isolated TSH deficiency in the postpartum period has been reported, and may be related to lymphocytic hypophysitis or to TSH suppression from clinically silent and resolving painless thyroiditis. Functional suppression of TSH production also occurs in: • Hyperthyroid states caused by primary thyroid disorders, exogenous thyroid hormone administration, or struma ovarii. After treatment of the hyperthyroid state with an antithyroid drug, radioiodine, or surgery, serum TSH concentrations remain low for approximately 3 to 4 weeks. • Thyroid hormone suppressive therapy of benign or malignant thyroid disease. Serum TSH concentrations may remain low for a few weeks after T4 therapy is discontinued in a patient with a nodular goiter. • Pharmacologic suppression of pituitary TSH production by dopamine, glucocorticoids, retinoic acid, GH therapy and somatostatin [461]. Basal serum TSH levels are normal in euthyroid individuals during mild to moderate illness. However, in some severely ill patients, TSH levels may decline and be followed by a decline in serum T4. With recovery, TSH and T4 levels return to normal and point toward reversible impairment of hypothalamic–pituitary thyrotrope function. TSH levels may be transiently elevated in the recovery period. The underlying mechanism(s) of this impaired TSH secretion in severe illness are not fully understood. It is possible that the

Chapter 9

endogenous hypercortisolism consequent on the severe illness and drug therapy with such agents as glucocorticoids and dopamine, which are known inhibitors of TSH secretion, contribute to this impairment [451–455]. At times it may be deemed necessary in certain patients to discontinue thyroid hormone replacement therapy: when adequate documentation of pretreatment hypothyroid state is lacking, or when the hypothyroid state is transient, e.g., resolving silent or subacute thyroiditis, postpartum thyroiditis, etc. Since it is impossible to establish the intrinsic function of the hypothalamic–pituitary–thyroid axis while the patient is on thyroid hormone replacement, such replacement therapy needs to be discontinued and the axis function assessed in 6 to 8 weeks. In the normal individual exogenous thyroid hormone will have suppressed the TSHthyroid axis, and T4 levels will decrease to low levels in 2 to 3 weeks after thyroid replacement therapy is discontinued. T4 levels then gradually increase to the normal range in about 4 to 6 weeks. Serum TSH, initially low, will become normal at the same time. Many patients may have transient symptoms of hypothyroidism in the first few weeks after withdrawal of replacement therapy [455,456]. With regard to drugs and the pituitary thyroid axis, endogenous or exogenous glucocorticoid excess exerts effects at multiple levels of the hypothalamic pituitary thyroid axis [457–459]. These include inhibition of TSH secretion both at the hypothalamic and pituitary levels, inhibition of T4 and T3 release by the thyroid gland, inhibition of peripheral T4 to T3 conversion, and a change in thyroid binding protein levels. The net result of these glucocorticoid effects are a low-normal serum T4, a normal free T4, a low serum T3, a low or normal serum TSH, and blunted TSH response to TRH. A rebound in TSH secretion occurs following discontinuation of glucocorticoid therapy. Dopamine, l-dopa, and such dopamine agonists as bromocriptine inhibit TSH secretion and blunt the thyrotrope responsiveness to TRH. The principal site of action is at the thyrotrope and results in a low basal TSH level. Dopamine receptor blockers, such as metaclopramide, increase serum TSH in euthyroid patients [461].

Anterior Pituitary Failure

The diagnostic approach to hypothyroidism is outlined in Figure 9.9. Typical clinical settings in which central hypothyroidism should be considered include: (i) the patient with known hypothalamic or pituitary disease; and (ii) the patient with clinical syndrome suggestive of hypothyroidism, who has low free T4 concentrations but who has a serum TSH concentration below 10 mU/L. The diagnosis rests on two characteristic laboratory findings: a low serum free thyroxine (FT4), and a low, normal, or modestly elevated serum TSH. Measurement of circulating thyroxine (T4) levels is the most reliable test to exclude hypothyroidism. The tests selected are either free thyroxine (FT4) or the calculated free thyroxine index (FTI). A normal free thyroxine (or free thyroxine index) rules out hypothyroidism, while low values point to hypothyroidism if the euthyroid sick syndrome is excluded. Serum T3 is not useful in the diagnosis of hypothyroidism; it may be normal in hypothyroid patients and low in euthyroid patients when peripheral T4 to T3 conversion is reduced. Serum TSH is critical in the differential diagnosis of hypothyroidism. In primary thyroid failure, serum TSH is high while in hypothyroidism caused by hypothalamic– pituitary disease the serum TSH is low-normal or low and always inappropriately low for the levels of circulating T4. It is important to remember that with use of the serum TSH assay as an initial screening test for thyroid disease, the diagnosis of central hypothyroidism can be missed or delayed because most patients have normal or slightly low serum TSH concentrations. Decreased serum TSH levels can also be seen in thyrotoxicosis, nonthyroidal illness, acute psychiatric illness, and with the use of medications, especially glucocorticoids or dopamine. TRH-stimulated serum TSH levels are now known to have little differential diagnostic value in distinguishing pituitary from hypothalamic disease [462]. Additional diagnostic steps include: (i) an assessment of associated other pituitary hormone functions, since the

Clinical Features

The features of central hypothyroidism are generally indistinguishable from those of primary hypothyroidism and include fatigue, lethargy, cold intolerance, decreased appetite, constipation, facial puffiness, dry skin, bradycardia, delayed relaxation phase of the deep tendon reflexes, anemia, hyperlipidemia, and low HDL-cholesterol. These manifestations may overlap those of associated other pituitary hormone deficiencies. The degree of symptoms and abnormal physical findings usually parallels the degree of thyroxine deficiency; however, some patients with marked TSH deficiency have few or no symptoms. Diagnosis

The laboratory tests which are available to assess the TSH axis and their implications are outlined in Table 9.13.

377

FIGURE 9.9. deficiency.

Approach to suspected thyrotropin (TSH)

Table 9.13.

ACTH provocative tests

Test

Procedure

Comments

Rapid ACTH stimulation test (Cosyntropin)

Can be performed on an outpatient basis any time of the day. Synthetic ACTH (Cosyntropin) is given in the dose of 250 mg intramuscularly or intravenously. Samples for plasma cortisol (± aldosterone) are obtained before and at 30 and 60 minutes following the injection. The normal response is a plasma cortisol increment greater than 7 mg/dl with peak cortisol levels greater than 18 mg/dl; plasma aldosterone increment greater than 4 ng/dl

Subnormal cortisol responses establish the diagnosis of adrenocortical failure but cannot differentiate between primary and secondary failure. A normal cortisol response excludes primary adrenocortical failure but can be seen in partial secondary (ACTH) deficient failure. In an adrenocortical deficient patient, subnormal aldosterone responsiveness points to primary adrenocortical failure, whereas a normal aldosterone response points to secondary adrenocortical failure

Three-day ACTH stimulation tests

A baseline 24-hour urine for 17-OHCS or 17-KGS, plasma cortisol is obtained. Synthetic ACTH 250 mg or bovine ACTH 40 units are administered intravenously in 500-ml saline over 8 hours for 3 consecutive days (alternatively, long-acting ACTH gel, 40 units intramuscularly twice a day for 3 days). A 24-hour urine for steroids and plasma cortisol is obtained daily. In suspected adrenocortical failure, patients can be simultaneously treated with dexamethasone 0.5 twice a day

Useful in the differential diagnosis of primary versus secondary adrenocortical failure. In primary failure, 17-OHCS and plasma cortisol fail to rise even with repeated stimulation. In secondary adrenocortical failure, ACTH stimulates the atrophic adrenals, and a stepwise increase in 17-OHCS values and plasma cortisol to three times the basal level is obtained on the third day

Insulin tolerance test

See Table 9.8

A normal response indicates intact hypothalamic–pituitary adrenal axis and excludes adrenocortical insufficiency. An impaired response indicates adrenocortical failure but does not identify whether it is primary or secondary failure

Standard metyrapone test

Metyrapone is an 11-hydroxylase blocker. It decreases adrenal cortisol production. A normal axis responds by increasing ACTH secretion, steroidogenesis, and levels of 11-deoxycortisol (compound F). Metyrapone is given 500 mg by mouth every 4 hours for 6 doses in the adult (300 mg/m2 body surface area in children). Twentyfour-hour urine for ketogenic or 17-hydroxysteroid, serum cortisol, and serum 11-deoxycortisol on the day before and the day after metyrapone. In the normal, urinary ketogenic or 17-hydroxysteroids increase two to four times above the basal value. Serum 11deoxycortisol rises to >7.5 mg/dl. A drop in serum cortisol testifies to adequate blockade by metyrapone

A normal response indicates normal hypothalamic– pituitary adrenal axis. An impaired response can occur in adrenocortical insufficiency due to either hypothalamic–pituitary or adrenal disease. In suspected ACTH–cortisol lack, metyrapone may cause further decrease in cortisol and may precipitate adrenocortical crisis. Tests should be done in hospital under close medical supervision. Patients on phenytoin may give false negative results (rapid inactivation of metyrapone). The response may be blunted during recovery from suppression of hypothalamic–pituitary adrenal axis by exogenous steroids

Overnight metyrapone test

Metyrapone is given by mouth at midnight as a single dose, 2.0 g if weight is <70 kg, 2.5 g if weight is 70–90 kg, 3 g if weight is >90 kg. Obtain blood sample for serum cortisol and serum 11-deoxycortisol at 8 a.m. the day following metyrapone. Serum 11deoxycortisol rises to >7 mg/dl. Drop in serum cortisol testifies to adequate blockade by metyrapone

As under standard metyrapone test. The test is safe, has no known contraindication, and may be done under close supervision as an outpatient

CRH test

Synthetic ovine CRH is administered in a dose of 100 mg or 1 mg/kg intravenously. Plasma ACTH and cortisol are sampled at 0, 30, 45, and 60 minutes. In normal individuals, ACTH levels increase two- to fourfold and cortisol to a level >20 mg/dl or increase of 10 mg/dl over basal level. The response is inversely related to basal plasma ACTH and cortisol levels. The test assesses the integrity of the ACTH–cortisol axis. In ACTH deficient patients, absent responses are seen in pituitary diseases; normal but delayed responses are seen in hypothalamic diseases. The test is also useful in assessment of ACTH axis after pituitary surgery

Facial flushing and feeling of warmth may occur in about 10% of patients. Avoid larger doses because of risk of hypotension. Some normal individuals may show a minimal response. Blunted responses are seen in depression, anorexia nervosa, and in hypercortisol states with the exception of Cushing’s disease

ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.

Chapter 9

majority of patients with central hypothyroidism have coexisting deficiencies in other pituitary hormones; and (ii) pituitary and hypothalamic imaging with MR or CT imaging is essential for definitive etiologic diagnosis.

Prolactin Deficiency Prolactin (PRL) deficiency is rarely reported in the medical literature. It is apparently overlooked and its true incidence is underestimated because of: (i) being clinically asymptomatic unless it is present in the postpartum state when it causes failure of milk production; and (ii) lack of availability of replacement therapy. Prolactin deficiency is recognized when alactogenesis is experienced by a woman in the postpartum state or when the prolactin axis is assessed by provocative tests during the evaluation of pituitary reserve in various disorders of the hypothalamic–pituitary axis. Etiology

Prolactin deficiency can occur as a monotropic failure or as a part of multitropic or pantropic hypopituitarism. The etiology can be either congenital or acquired. Unlike other pituitary hormones, prolactin deficiency occurs only in intrinsic pituitary disease. Hypothalamic disease is not associated with hypoprolactinemia; because of impairment of the dominant hypothalamic-inhibitory regulation of prolactin, it is often associated with hyperprolactinemia. Congenital Prolactin Deficiency Idiopathic familial prolactin deficiency has been reported in patients with type 1b pseudohypoparathyroidism [463–465] in hereditary hypopituitarism with mutations in the Pit-1 and PROP1 genes (see Growth Hormone (GH) section), and in association with myotonia dystrophica [466,467]. In hereditary hypopituitarism, prolactin deficiency is associated with variable degrees of other pituitary hormone deficiencies. Acquired Prolactin Deficiency Acquired prolactin deficiency can be either “functional” or organic. Functional reversible prolactin deficiency is seen with the administration of dopaminergic agonists such as bromocriptine or l-dopa. Idiopathic prolactin deficiency has been reported in the postpartum state in women who presented with alactogenesis. It may be isolated [467] or occur in association with deficiency of other pituitary hormones [468–470]. Prolactin secretion does not respond to TRH, metoclopramide, or insulin provocative tests. In one reported case, prolactin secretion failed to show the expected rise during a subsequent pregnancy. No clinically identifiable cause was evident, but in one patient pituitary antibodies were present, raising the suspicion of underlying lymphocytic hypophysitis. Idiopathic prolactin deficiency has been reported in association with primary hypothyroidism. Prolactin deficiency has also been reported in some patients with Sheehan’s syndrome [469,470] lymphocytic hypophysitis

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[471], and occasionally in posttraumatic hypopituitarism [472]. Clinical Features

The only clinical expression of prolactin deficiency is failure of lactation in the postpartum state. This is classically associated with Sheehan’s syndrome, but can be seen in other pituitary diseases. Diagnosis and Laboratory Features

A high-normal basal or random serum prolactin excludes prolactin deficiency. Since the secretion of prolactin is episodic and some normals may have prolactin basal values approaching the lower limit of assay sensitivity, the diagnosis of prolactin deficiency cannot be made on the basis of a single low prolactin value. In such circumstances, a provocative test is needed. Chlorpromazine, metoclopramide, and TRH provocative tests are available. The TRH provocative test is regarded as the test of choice, since it allows the simultaneous assessment of pituitary TSH reserve. An impaired or absent prolactin response to provocative tests cannot be regarded as diagnostic of pituitary lactotroph failure. An impaired response may also be noted in such nonpituitary diseases as thyrotoxicosis, renal failure, malnutrition, anorexia nervosa, and with the use of such drugs as dopamine, l-dopa, bromocriptine, thyroid hormones, and glucocorticoids. Treatment of these nonpituitary diseases with a reversal of the disease process or discontinuation of the offending drug results in restoration of normal prolactin responses. DIAGNOSIS OF HYPOPITUITARISM In the diagnostic approach to hypopituitarism, the physician must document the presence of hypopituitarism and delineate its cause. The diagnostic process has been dealt with extensively under the headings of the separate anterior pituitary hormone deficiencies (see above). For trophic hormone deficiencies, the diagnosis rests on the evaluation of the function of the target gland. If target gland failure is present, additional studies are required to distinguish between primary target gland failure and target gland failure secondary to central hypothalamic–pituitary disease. As discussed earlier, in the hypothyroid patient, a high serum TSH or the presence of a goiter point to primary hypothyroidism. An inappropriately low serum TSH and an atrophic thyroid gland confirm the diagnosis of central hypothyroidism. In a hypogonadal patient, high serum LH and FSH point to primary gonadal failure; in hypogonadism secondary to hypothalamic–pituitary disease, the serum LH and FSH levels are inappropriately low. If a hypocortisol state is present, based on low serum cortisol concentrations, and an impaired serum cortisol respon-

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siveness to a provocative test (short standard or low-dose cortrosyn stimulation test, or metapyrone or insulin hypoglycemia test), a diagnosis of primary adrenocortical failure is suggested based on the presence of hyperpigmentation and of mineralocorticoid deficiency and is documented by an elevated serum ACTH concentration. In adrenocortical failure secondary to hypothalamic–pituitary disease, there is pallor, loss of tanning ability, absence of mineralocorticoid deficiency, and an inappropriately low serum ACTH level. For the nontrophic hormones, GH and prolactin, a provocative test is needed to assess hormone reserve. Failure to respond to provocative tests indicate deficiency, if nonpituitary causes of nonresponsiveness (i.e., obesity, glucocorticoid excess, and thyroid dysfunction) can be excluded. Prolactin provocative tests are very rarely used in clinical practice because, apart from in the postpartum state, prolactin deficiency is asymptomatic, and because there is no effective replacement therapy at the present time.

Etiologic Diagnosis In determining the cause of the hypopituitarism, suspected functional causes of hypopituitarism must be identified and corrected; normalization of pituitary function lends support to a diagnosis of functional hypopituitarism. If functional causes are excluded, or if hypopituitarism persists despite the removal or correction of a functional cause, the next step is to evaluate for organic hypothalamic pituitary disease. This evaluation is based on the clinical setting and appropriate laboratory and radiologic studies. The presence of diabetes insipidus or hypothalamic vegetative dysfunction point to suprasellar disease. If an identifiable cause is not found to explain the hypopituitarism, the patient is said to have idiopathic hypopituitarism or “hypopituitarism of indeterminate cause.” These patients may harbor an organic disease that is too small to be delineated by our presently available radiologic tools. A close long-term follow-up is mandatory since the organic lesion may make its appearance known sometime during the follow-up. The reader is referred to the section dealing with Etiology (above) for discussion of the various etiologic disorders and for appropriate references. Here some of the commonly encountered disorders will be considered. The radiologic findings are discussed in detail elsewhere. Functioning and nonfunctioning pituitary tumors are the most common cause of the hypopituitary syndrome in the adult. In patients with pituitary tumors, hypopituitarism may result from: (i) compression and atrophy or infiltration and adenohypophysis by the expanding tumor mass; (ii) hypothalamus-stalk impairment by suprasellar extension of the tumor; (iii) functional suppression of certain pituitary hormonal axes by hypersecretory effects of functioning pituitary tumors, such as hyperprolactinemia-induced hypogonadotropism; and (iv) by surgical or radiation

therapeutic modalities applied to the tumor. Hypopituitarism occurs often with macroadenomas, and is rarely seen with microadenomas. It is usually of gradual onset and slowly evolving course; however, it may be of sudden onset in posthypophysectomy hypopituitarism and culminating in pituitary apoplexy. Commonly the manifestations of hypopituitarism are subtle and overlooked, being dominated by hypersecretory syndromes of functioning pituitary tumors or by neuroophthalmologic expressions of extrasellar tumor extension. The diagnosis of pituitary tumors is supported by the clinical setting, and documentation of a sellar mass on CT or MR imaging. A definitive diagnosis of pituitary tumor can be made only if a pituitary hypersecretory clinical syndrome is present (except for modest hyperprolactinemia which may occur in other functional or organic hypothalamic–pituitary disease). Nonfunctioning pituitary tumors cannot be differentiated from other sellar masses solely on the basis of radiologic mass findings. The diagnosis rests on the findings of tumor markers of gonadotropinoma or is based on exploration and pathologic examination of the excised tissue, or the findings of glycoprotein tumor-markers (a-glycoprotein subunit, FSH, LH or their b-subunits). Pituitary apoplexy [80–83] is expressed clinically in a variety of ways. Most often it presents as an acute neurologic/endocrine catastrophic event which evolves over 24 to 48 hours and which consists of sudden onset of severe headache, meningismus, variably depressed sensorium, visual disturbances, pupillary disturbances and ophthalmoplegia, autonomic dysfunction, and, infrequently, acute adrenocortical insufficiency. The clinical picture may mimic subarachnoid hemorrhage. The etiologic setting has been described earlier. An acute neurologic event in any of these settings should be regarded and managed as pituitary apoplexy until proven otherwise. In those who survive the catastrophic event, variable degrees of hypopituitarism may develop, months or years after the occurrence of the event. The majority of patients will have GH deficiency and hypogonadotropism (75% to 90% of patients) and a significant number will have ACTH or TSH deficiency (40% to 50% of patients). Diabetes insipidus is rare. The prolactin axis has not been studied in pituitary apoplexy, but either hyperprolactinemia or prolactin deficiency may be found. Other sequelae of the apoplectic event may include the ultimate development of secondary empty sella or regression of hyperfunctioning endocrine syndrome after hemorrhage into a hypersecretory pituitary tumor. In some patients the hemorrhagic mass and associated hypopituitarism may be transient and regress in a few months. Clinically-silent hemorrhages in pituitary tumors demonstrated by CT or MR imaging, or as may be found at surgery for pituitary tumors, is not an uncommon occurrence which may affect macroadenomas as well as microadenomas. Diagnosis of pituitary apoplexy depends on radiologic evidence of hemorrhage either by CT or MR imaging or at neurosurgical exploration. Treatment is directed at neurosurgical decom-

Chapter 9

pression, management of hormonal deficit, and symptomatic supportive therapy. The diagnosis of postpartum pituitary necrosis [71,72, 108,109] depends on the clinical history of hemorrhage and vascular collapse during delivery followed by inability to lactate and to re-establish normal menstrual function in the postpartum period. It is important to note that because some cases develop slowly or lead to partial pituitary failure, presence of postpartum lactation, or restoration or resumption of normal menstrual function in the postpartum state and ensuing pregnancy cannot be used to exclude the existence of partial pituitary failure. Rarely there may be recovery of pituitary function. In many patients, there is evidence of subclinical impairment in neurohypophyseal function expressed as impaired AVP response to osmotic stimuli; only a few patients have clinical diabetes insipidus. In others, hyponatremia may develop because of inappropriate AVP secretion. A secondary empty sella may ensue as a result of scarring and atrophy of pituitary tissue. The diagnosis rests on the clinical setting and the exclusion of other causes of hypopituitarism, notably space-occupying lesions in or around the hypothalamic–pituitary area, and, in the early postpartum state, the presence of lymphocytic hypophysitis. Hypopituitarism is the most frequently encountered complication of conventional radiotherapy of pituitary tumors, and occurs commonly in patients irradiated for CNS tumors of the nasopharynx, and retinoblastoma [53–69]. The incidence of endocrine dysfunction can be as high as 100%; such dysfunction being due to both hypothalamic and pituitary radiation damage. Hypopituitarism may develop any time after radiation therapy, and impairment has been found as late as 25 years after radiation. Postradiation hypopituitarism can by monotropic or multitropic, partial or complete, and can be associated with hyperprolactinemia. GH deficiency is the most common postradiation endocrine dysfunction. Patients receiving therapy for the management of pituitary tumors, extrapituitary brain tumors, or head and neck cancers require periodic careful and long-term endocrine assessment for an indefinite period of time. The incidence of hypopituitarism following gamma-knife radiotherapy is, at this time, premature to assess because of the relatively new therapeutic modality; early indications are that, in the short term, it would be less than 5% [69]. Lymphocytic hypophysitis [106–109] occurs predominantly in women of reproductive age. It may present with features of an expanding sellar mass or with varying degrees of pituitary dysfunction, usually during the last trimester of pregnancy or during the early puerperium, in patients in whom delivery was normal and unaccompanied by hemorrhage or shock. Rarely it has occurred in nulliparous or postmenopausal women; only one case has been reported in a middle-aged man. Hypopituitarism occurs in more than 90% of patients at some time during the course of the disease. It may be complete or partial, monotropic or multitropic, and in any combination. It is characteristically more

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than can be suggested by the size of the inflammatory mass. Death may occur from adrenocortical insufficiency and has been reported to occur suddenly during labor. Occurrence of diabetes insipidus is extremely rare except as a sequela of surgical intervention. Prolactin axis function is variable: in some patients prolactin deficiency occurs, while in others hyperprolactinemia and the sellar mass may dramatically mimic a prolactin producing pituitary tumor. Later in the course of the disease regression of the inflammatory mass usually occurs. Recovery of pituitary function may occur but infrequently. A secondary empty sella may result. CT demonstrates an enlarged homogeneously enhancing pituitary gland with or without suprasellar extension not distinguishable from a pituitary adenoma. MR imaging shows an isointense diffusely enlarged gland. Diagnosis depends on the clinical setting and on tissue diagnosis obtained at the time of surgery. Posttraumatic hypopituitarism [23–25] is being increasingly recognized because of increased awareness of its entity, increased incidence of traffic accidents, and improved intensive care management and survival of patients who sustain severe head injuries. In the majority of patients, head trauma is significant enough to cause skull fractures, especially involving the skull base and often the sellar turcica. Except for early posttraumatic diabetes insipidus, there is usually a delay of months to years from injury to presentation of hypopituitarism. The usual presentation is with manifestations of panhypopituitarism; the endocrine findings usually reflect a combined hypothalamic and pituitary etiology. Prolactin is elevated in the majority of patients. Transient or permanent diabetes insipidus occurs in about 50% of the patients, and its presence can lead to the earlier diagnosis of hypopituitarism. Craniopharyngioma [132–135] has a bimodal peak of incidence, occurring predominantly in children between the ages of 5 and 10 years, in whom they account for 5% to 10% of brain tumors. A second smaller peak in incidence occurs in the sixth decade. Craniopharyngiomas present with manifestations of a space-occupying lesion in the hypothalamic–pituitary area; endocrine dysfunction including hypopituitarism, diabetes insipidus, and hyperprolactinemia; manifestations of hypothalamic syndrome including obesity or emaciation, somnolism or hyperkinetic behavior, adypsia or hypodypsia, and temperature disturbances such as poikilothermia and manifestations of obstructive hydrocephalus. Suprasellar or intrasellar calcifications on skull films or CT scans strongly point to the diagnosis. Such calcifications, however, are present in only 75% of children and in 35% of adults with the disease. Although the presence of calcifications may be helpful in the differential diagnosis, it is not specific. MR imaging shows variable findings depending on proportions of solid versus cystic components, in the amount of calcifications, and in the content of the cyst fluid. The solid portions typically appear isointense or hypointense on T1-weighted images and hyperintense on T2-weighted images but can also have a mottled appearance owing to

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calcific regions on MR imaging. Cystic components demonstrate a high signal on T1-weighted images owing to their high protein content or hemorrhagic components. Sarcoidosis of the hypothalamic pituitary area is rare [112–114]. It may present with diabetes insipidus, hyperprolactinemia, hypothalamic syndrome, and optic atrophy. Diabetes insipidus and hyperprolactinemia, due to hypothalamic stalk involvement, are often but not always present. Neuro-ophthalmologic signs may mimic those of tumors of that area. Hypopituitarism is commonly partial and usually results from hypothalamic damage, although intrinsic pituitary destruction by the inflammatory process may contribute to the hormonal deficiencies. Later in the disease a secondary empty sella may result. Regression of the endocrine deficit is unusual. The diagnosis is supported by other evidence of systemic or CNS sarcoid, and by absence of radiologic evidence of bony sellar changes. CT demonstrates an isodense or minimally hyperdense suprasellar mass with homogeneous contrast enhancement. The reader is referred to a few excellent articles on the differential diagnosis of other sellar and parasellar masses [7–9].

Pitfalls The differential diagnosis of primary target gland failure (thyroid, adrenal, or gonad failure, singly or in combination) is based on the clinical and laboratory features described previously. Other associated pituitary function abnormalities, diabetes insipidus, or anatomic clinical and radiologic manifestations of hypothalamic–pituitary disease, further point to hypopituitarism. Several other pitfalls can be encountered in the evaluation of hypopituitarism: (i) failure to determine the extent and the degree of hypopituitarism; (ii) failure to rule out functional causes (these are important because they are common and potentially reversible); (iii) failure to look for organic causes and to follow closely those patients with hypopituitarism in whom such an organic cause is not found (hypopituitarism may precede the clinical appearance of its cause by a long period); and (iv) failure to look for other evidences of multiple endocrine neoplasia type I in those in whom the hypopituitarism is caused by a pituitary tumor. A physician facing the challenge of diagnostic work-up on a patient with suspected hypopituitarism will face a vast array of potential diagnostic tests. Attention should be given to the following practical considerations: (i) the choice of tests should be aimed at the provision of information that will be clinically useful and have an impact on the diagnosis and management; (ii) there should be awareness of the potential endocrine or nonendocrine factors that may interfere with proper interpretation of tests and give falsepositive or false-negative results; and (iii) information regarding the wide range of normal responses of the tests, their side effects, and costs should be available. Rapid sequential

intravenous administration of hypothalamic hormones as a combined anterior pituitary function test is a case in point. Potential sources of error in the interpretation of tests include the presence of specific carrier proteins for hormones of the target glands, the status of liver degradation and renal excretion, alternation in tests induced by drugs or associated disease state, and lastly that one hormone impairment may lead to functional impairment of one or more of the other. THERAPY OF HYPOPITUITARISM Treatment of hypopituitarism is based on recognition and removal or reversal of the cause, if possible, and on substitution of the deficient hormone. There are three potential options to replace a given pituitary hormone deficiency: (i) administration of the hormone of the affected target gland or one of its synthetic analogs (this is the most practical and effective means of hormone replacement in target gland failure because of its cost advantage and ease of administration); (ii) administration of the anterior pituitary hormone (this has been limited to the use of GH to promote linear growth in GH-deficient children or adolescents, and to the use of gonadotropins in hypogonadism to promote fertility); and (iii) administration of the hypothalamic regulatory hormone (at present this is feasible only for GnRH and GHRN in patients with secondary hypopituitarism). In patients with multiple pituitary–hormone deficiencies, cortisol should be replaced first, followed by thyroxine, and sex steroids once the patient’s condition has stabilized. If necessary, growth hormone can be replaced last.

Corticotropin (ACTH) Deficiency ACTH deficiency is potentially a life-threatening deficiency and its treatment takes precedence over that of all other anterior pituitary hormones. The goal of treatment in ACTH deficiency is to restore a eucortisol state. This is achieved by administration of cortisol or one of its glucocorticoid analogues in a dose equivalent to daily normal cortisol production and in a way that attempts to mimic normal diurnal rhythm. In addition, the dose is increased during periods of acute medical or surgical illness to mimic the normal increased production of cortisol in such situations. There is no universal agreement on the choice of glucocorticoid, appropriate doses, timing, and monitoring of glucocorticoid-replacement therapy [473,475,478]. The standard approach to glucocorticoid therapy has been to give either hydrocortisone 20–30 mg per day, cortisone acetate 25–37.5 mg per day, or prednisone 5–7.5 mg per day; with two-thirds of the dose given in the morning and the other third in early or mid-afternoon. However, modifications in this standard approach seem to be necessary. Daily cortisol production rate in normal adults has been reassessed with isotope studies and found to be 5.7 mg/m2,

Chapter 9

rather than 12–15 mg/m2 as previously believed. This lower cortisol production rate translates to about 10–12 mg/m2 (about 20 mg for normal adults) for oral hydrocortisone after allowance for first-pass hepatic metabolism and bioavailability [476]. It is apparent that the standard replacement dose of 30 mg/day of hydrocortisone is supraphysiologic for the majority of patients. In line with this conclusion is the negative relation which was found in patients with primary and secondary adrenal deficiency between the glucocorticoid replacement dose and markers of bone remodelling and bone-mineral density [474,477–480]. Regimens of hydrocortisone three times daily (e.g., 10 mg at 0800 hours, 5 mg at 1200 hours, and 5 mg at 1700 hours) have been advocated and shown to mimic the normal pattern of cortisol secretion more closely than twice-daily administration [473,475,478]. Some studies suggest that hydrocortisone therapeutic dose should be monitored by measurement of serum and urinary concentrations of cortisol and adjusted accordingly [473]. Despite our best intentions regarding cortisol replacement therapy, at present we do not have any way to mimic faithfully the normal 24-hour secretory pattern of cortisol secretion. Patients on glucocorticoid-replacement therapy may complain of morning fatigue and headaches that improve after breakfast and the first hydrocortisone dose, which possibly reflects overnight cortisol deficiency. Despite administration of a total dose of 20 mg hydrocortisone per day, plasma cortisol concentrations in hypopituitary patients remain low between 0400 hours and 0730 hours, during which time cortisol secretion starts to increase in normal people. This low concentration has been related to earlymorning disturbances in intermediary and glucose metabolism, such as lowered fasting serum glucose, and concentrations of free fatty acid and 3-hydroxybutyrate [481,482]. Growth hormone deficiency may also contribute to these abnormalities in intermediary metabolism and insulin sensitivity; replacement of growth hormone in hypopituitarism patients substantially increases fasting glucose concentrations [483]. It is to be noted that cortisone and prednisone are biologically inactive and need to be converted in the liver to the biologically active cortisol and prednisolone respectively. If severe liver disease is present, cortisol is the replacement therapy of choice. High-potency long-acting glucocorticoids such as dexamethasone, given once daily at bedtime, although advocated by some authorities, are not recommended for glucocorticoid replacement. Occasional patients who perform heavy manual labor may require up to 40 mg of hydrocortisone per day or its equivalent. It is critical in children to avoid supraphysiologic glucocorticoid therapy since it leads to decreased responsiveness to GH and to a decrease in linear growth. Response to therapy is quite dramatic and rapid. Many patients recognized only in retrospect the degree of their ill health prior to the institution of therapy. Persistence of chronic symptoms suggestive of adrenocortical insufficiency

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imply either a medication dose error, patient noncompliance, or that the symptoms are related to another cause. Complications are rare with the doses just described. Some patients may have insomnia or irritability after therapy is begun, and for these the dosage should be reduced. Follow-up of the adequacy of therapy consists of assessing the patient’s feeling of well being and examining for evidence of glucocorticoid deficiency or excess. Because of the short serum half-life of replacement glucocorticoids, measurement of serum cortisol is not helpful in this regard. Every patient is informed of the nature of the underlying disorder, that lifelong therapy is required and that discontinuation of therapy or chronic overdosage may endanger life. Instructions are given in the standard steroid stress precautions and in the necessity of seeking prompt medical help in the event of acute medical illness or significant trauma. Under conditions of acute medical or surgical illness [484], the dose should be increased to two to three times the usual daily replacement dose and given in divided doses daily until the acute illness subsides, when the patient can resume the usual daily replacement dose. If it is difficult for the patient to decide about the need for increased glucocorticoid administration during a given period of illness, it is better to err on the side of overreplacement. In the event of vomiting, injectable steroids should be used and medical attention sought promptly. Dexamethasone, 4 mg, intramuscularly or hydrocortisone hemisuccinate, 100 mg, intramuscularly may be taken. Parenteral cortisone acetate should not be used in situations necessitating rapid replacement because absorption and therefore the onset of action is not dependable. Patients should always carry with them an injectable steroid for emergency treatment and they should be instructed in self-injection technique. All patients on replacement glucocorticoid therapy should wear an appropriate medical identification bracelet or necklace explaining glucocorticoid replacement and the need for increased steroid dosage during periods of illness. Special Considerations 1. If ACTH deficiency is partial, the patient may be able to secrete enough cortisol to take care of day-to-day needs and thus may not need daily replacement therapy. The patient with partial ACTH deficiency must be educated to use glucocorticoids during periods of illness and to undergo periodic assessment because of the potential for progression from partial to complete ACTH deficiency. 2. Some patients with hypopituitarism of long duration may exhibit euphoria or psychotic behavior with full replacement doses of glucocorticoids. For these, the minimum replacement dose necessary should be used. 3. In patients with diabetes insipidus, concomitant lack of cortisol may mask polyuria and polydipsia because cortisol is needed for free water clearance.

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In these, glucocorticoid therapy permits the clinical reemergence of diabetes insipidus. 4. Drugs such as phenytoin, barbiturates, and rifampin can accelerate glucocorticoid metabolism by induction of hepatic microsomal enzyme activity and can increase the glucocorticoid replacement dose requirement. If this increased requirement is not met, adrenal crisis may occur. 5. The bioavailability of prednisone is decreased by antacid. It is best to avoid the use of these drugs, if at all possible, or otherwise the replacement dosage should be appropriately increased. 6. Growth hormone-replacement therapy in hypopituitarism adults is associated with an apparent decrease in availability of administered hydrocortisone [553], as measured by urine cortisol metabolites and urinary free cortisol. The changes in cortisol metabolism might be the consequences of a growth-hormone-mediated or IGF-1-mediated modulation of the activity of the enzyme 11 b-hydroxysteroid dehydrogenase. This effect might be of clinical importance only in patients with ACTH deficiency because of suboptimum hydrocortisone replacement [553,554]. Acute ACTH Deficiency

In acute ACTH deficiency such as occurs in pituitary apoplexy, therapy is instituted promptly after the diagnosis is suspected. A blood sample is drawn for serum cortisol and serum ACTH. A parenteral soluble glucocorticoid and supportive care are given simultaneously with the assessment and correction of precipitating factors. Hydrocortisone 100 mg is given intravenously followed by 50–100 mg every 6 hours on the first day, 50 mg every 6 hours on the second day, and 25 mg every 6 hours on the third day, tapering to maintenance dose by the fourth to fifth day. Perioperative Glucocorticoid Therapy

A soluble parenteral steroid is mandatory. As an example, hydrocortisone phosphate or hemisuccinate 100 mg intramuscularly is given on call to the operating room; 50 mg IM or IV in the recovery room; and then 50 mg every 6 hours for the first 24 hours. If the patient’s progress is satisfactory, the dose can be reduced to 25 mg every 6 hours for 24 hours and then gradually tapered to maintenance dose by the third to fifth day. However, if fever, hypotension, or other complications occur, the dose of hydrocortisone is increased to 200–400 mg per day in divided doses every 6 hours followed by gradual tapering to maintenance dose.

Gonadotropin (LH-FSH) Deficiency In patients with gonadotropin deficiency, the possibility of the presence of functional hypothalamic hypogonadism should be considered. If present, this is generally reversible

by simple direct means such as psychiatric and supportive care in anorexia nervosa, correction of nutritional abnormalities in starvation and obesity, thyroid hormone replacement therapy in primary hypothyroidism, or the use of dopaminergic agonists in hyperprolactinemic states. The goal of treatment of gonadotropin deficiency is to restore gonadal function. This is accomplished by: (i) replacing gonadal steroids; and (ii) when desired, the administration of gonadotropins or GnRH to restore fertility. Male

The goals of therapy can be achieved by: (i) restoration of normal serum testosterone concentrations to stimulate and maintain growth and development of the external genitalia and secondary sex characteristics, and to initiate and maintain male sexual behavior and androgenic anabolic actions including bone mineral density; and (ii) restoration of fertility potential by stimulating and maintaining normal seminiferous tubule function and spermatogenesis. The androgenic functions are readily achieved by therapy with testosterone. Stimulation of spermatogenic function can rarely be achieved by testosterone therapy alone and, in most patients, requires restoration of normal gonadotropin concentrations. This can be achieved in one of two ways: (i) gonadotropin therapy in the form of human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG); or (ii) gonadotropin-releasing hormone (GnRH) therapy to stimulate production of endogenous gonadotropins by the gonadotropes. If the pituitary gland is not functional, combined hCG and hMG are required. If the hypogonadotropism is due to hypothalamic disease and the gonadotrope-cell population is functional, GnRH or gonadotropin therapy can be used. Androgen Therapy The principal goal of androgen therapy is to restore to normal the serum concentrations of testosterone and male androgenic functions [500–502]. Native testosterone is absorbed well from the intestinal tract. However, because of rapid metabolism by the liver, it is not effective to maintain normal serum testosterone concentrations. With alkylated testosterone derivatives, the addition of an alkyl group to the 17-alpha position of testosterone retards its hepatic degradation; however, such oral preparations as methyltestosterone or fluoxymesterone are not recommended for treatment of hypogonadism because of their lesser potency, greater cost, variability in absorption, and known association, in a small percentage of patients, with the development of cholangiolitic hepatitis, peliosis hepatitis, or hepatoma [485–489]. Parenteral and transdermal testosterone preparations do not have these drawbacks and are the agents of choice for androgen-replacement therapy. They are effective and safe, and the adequacy of therapy can be assessed by the measurement of serum testosterone concentrations. Measurements of serum LH concentrations cannot be used to assess adequacy of

Chapter 9

therapy in hypogonadotropic men with central hypogonadism, because they are already low or inappropriately “normal” in the pretreatment stage. Esterification of a lipophilic fatty acid to the 17b hydroxyl group of testosterone makes testosterone lipophilic; intramuscular injection of such esters will result in their storage in, and gradual release from, adipose tissue, thereby rendering the compound long-acting. Parenteral testosterone is biologically effective and can be administered as testosterone enanthate or cypionate, 100–300 mg intramuscularly every 1 to 2 weeks (or rarely as testosterone propionate, 25–50 mg intramuscularly two to three times a week). Patients are taught self-injection to reduce cost. Disadvantages of parenteral testosterone injections are the need for deep intramuscular administration of an oily solution, and fluctuations in the serum testosterone concentrations between peak levels, which occur 1 to 3 days after the injection, and nadir levels, which occur one to a few days before the next injection. Such fluctuations are more prominent with increase in the dosing interval, and result, in many patients, in fluctuations in mood, energy level and stamina, and libido. The effectiveness of parenteral therapy can be monitored by the patient’s clinical state and by normalization of plasma concentrations of testosterone which should be measured midway between injections. Testosterone esters rarely lead to infection at the injection site [490]. Administration of testosterone by application of a testosterone-impregnated membrane to the skin was introduced in 1994, and is presently available in two forms. 1. Scrotal patch: testosterone, without chemical enhancement, can be absorbed through the scrotal skin and can normalize the serum testosterone concentration. The patch is applied to the scrotal skin once a day and worn continuously except when bathing; jockey-style undershorts should be worn day and night to support the patch. To ensure adequate absorption of testosterone, the scrotum should be shaved twice a week, and the patch should be warmed with a hair dryer immediately before application. The usual dose is the daily application of the 6 mg patch. If the scrotum is inadequate, a 4 mg patch can be used. Adequacy of therapy is assessed by measurement of serum testosterone concentrations 3 to 5 hours after the application of the patch. The scrotal patch occasionally leads to mild to moderate scrotal itching, which remits spontaneously or after the application of hydrocortisone cream. 2. Nonscrotal patch: reliance is placed on chemical means to enhance the absorption of testosterone through dry, clean nonscrotal skin. Two nonscrotal patches are available: Androderm (2.5 mg or 5 mg patch) and Testoderm TTS (5 mg patch), and can be worn for 24 hours on any area of skin except that of the

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scrotum or that covering bony prominences. Both preparations can deliver approximately 5 mg of testosterone per 24 hours and can normalize serum testosterone concentrations. Adequacy of therapy is assessed by measurement of serum testosterone concentrations 6 to 10 hours after the application of the patch. Androderm often causes skin rashes (17% incidence) which may sometimes be severe enough to discontinue this form of treatment, but which are usually mild and which can be prevented by pretreatment of the skin with a corticosteroid cream. Transdermal testosterone administration maintains relatively stable serum testosterone concentrations, and therefore results in relatively stable mood, energy, stamina and libido. The major disadvantage is the failure to achieve normal testosterone values in some hypogonadal men, particularly those who weigh more than 90 kg [491–495]. Regarding safety considerations, testosterone therapy is contraindicated in patients who have, or have had, the androgen-dependent tumors of prostate or breast. Testosterone therapy may lead to salt and fluid retention, edema, excessive sexual stimulation, priapism, gynecomastia, aggressive behavior, polycythemia, aggravation of sleep apnoea [503] and worsening of benign prostatic hypertrophy in middleaged and elderly males. In long-standing hypogonadism, psychosocial defenses in the patients’ relationships occur that may affect their lifestyle, including marital status, choice of marital partner, and occupation. Testosterone therapy may lead to major problems of adjustment, and these must be carefully considered and discussed with patients before therapy is begun. In hypopituitary children who have hypogonadism and GH deficiency, therapy is initiated with growth hormone until reasonable height is achieved before testosterone therapy is started. Testosterone enanthate or cypionate is started at a dose of 50–75 mg every 3 to 4 weeks; and in 4 to 6 months, the dose can be gradually increased to 100– 150 mg every 3 to 4 weeks. The main concern is not to interfere with the natural height potential of the pubertal child in whom early or excessive androgen replacement will cause premature closure of epiphyses. Measures which may be helpful in assessment of sideeffects of testosterone therapy include: (i) clinical assessment of symptoms of obstructive uropathy and sleep apnea; (ii) an annual digital rectal examination and measurement of serum prostate specific antigen (PSA)—the patient should be referred for prostate biopsy if: (i) a prostate nodule is palpated at any time, or (ii) the serum PSA concentration is above 4.0 ng/mL or if it rises by more than 0.75 ng/mL per year over a 2-year period. An annual measurement of hemoglobin and hematocrit should be taken and when indicated, measurement of the urine flow rate and that of postvoid residual urine by ultrasonography.

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Future Potentialities in Testosterone Therapy First, injection of biodegradable microcapsules of testosterone, which can maintain a normal serum testosterone concentration for 10 to 12 weeks [496]; secondly, injection of a very longacting ester of testosterone, testosterone buciclate, which is administered in an aqueous solution and maintains a lownormal serum testosterone concentration for about 8 weeks [497]; and thirdly, sublingual and implantable preparations [498–500]. Gonadotropin Therapy [504–508] Fertile men who are about to undergo surgical or radiotherapeutic ablative treatment that is potentially destructive to the hypothalamic pituitary unit may wish to consider placing sperm in a sperm bank where it might be kept viable for several years. Exogenous gonadotropin therapy has been used successfully to induce spermatogenesis and fertility. In adult hypogonadism and in patients with partial IHH, some residual but low gonadotropin secretion persists, maintaining some degree of intratesticular testosterone production and spermatogenesis. Restoration of androgen production by hCG often results in sperm production sufficient for conception and makes hCG the initial treatment of choice. FSH preparations are added if hCG fails. It is important to take sufficient time, about 6 months, to allow hCG to prime the seminiferous tubules to respond to FSH. In individuals with infantile testes, i.e., less than 4 ml in volume, combined therapy with hCG and hMG should be initiated at the outset. hCG is given in a dose of 500–2000 IU three times per week subcutaneously or intramuscularly. Higher doses can increase estradiol production by the testis and cause gynecomastia, and suppress endogenous FSH levels and should be avoided. FSH is available commercially as human menopausal gonadotropin (hMG) which contains equal amounts of LH and FSH or as purified FSH with no LH activity. Either preparation can be used to induce spermatogenesis. The required FSH dosage is between 37.5 and 150 IU three times per week. The hCG and FSH are administered together. Restoration of full spermatogenesis may take 12 to 24 months at which time spermatogenesis can be maintained by hCG alone. Impregnation often occurs with total sperm counts below 20 million per ml. After successful conception, the male is switched back to testosterone parenteral therapy. Gonadotropin therapy should be initiated and followed by experienced endocrinologists. Periodic assessments of hormonal levels, testicular volumes, and semen analysis are used to monitor therapy. Gonadotropin therapy to induce fertility is not successful in patients with cryptorchidism. In hypothalamic hypogonadotropism, pulsatile GnRH therapy [509–511] can be used successfully to initiate and maintain spermatogenesis and fertility potential. Using a small programmable portable effusion pump, GnRH may be given in initial doses of 10 to 25 micrograms per kilo of native GnRH subcutaneously on IV at 2-hour intervals. The

dose is increased over several months until testosterone levels are normalized. Sperm appears in the ejaculate in 4 to 36 months. The fertility potential is excellent, and the time required to achieve end points depends primarily upon the initial testicular volume and the dose of GnRH employed. Sperm counts immediately preceding time of conception have varied between 1 to 68 millons per ml, with 75% of pregnancies occurring with sperm counts less than 15 million per ml. Therapy is monitored by serum LH and testosterone, rate of testicular growth, and semen analysis. GnRH treatment is remarkably free of side effects. Subnormal responses occur primarily in the presence of cryptorchid testes but may also occur due to the rare development of anti-GnRH antibody. Female

Sex Steroid Therapy In premenopausal women, estrogen therapy is indicated for maintenance of secondary sexual characteristics, integrity of the genitourinary tract, prevention of osteoporosis and possibly of coronary artery disease, and preservation of a general sense of well being. Consideration should be given to the type of estrogen and the route by which it is to be given, as well as the need for progestin and the most appropriate progestin regimen. In the United States, estrogen may be given orally, transdermally, intravaginally, or in a vaginal ring. In other countries estrogen can also be given in the form of percutaneous gels and subcutaneous implants. Estrogen can be administered systemically either orally or transdermally [512–513]. Increase in hepatic production of thyroxine-binding globulin, corticosteroid-binding globulin, triglycerides, high-density lipoprotein (HDL) cholesterol is seen principally with oral estrogen due to the first-pass effect [514]. Similarly, the saturation of bile with cholesterol is adversely affected by oral, but not by transdermal, estrogen [515]. Therefore, transdermal estrogen is preferred in those women in whom it is important to minimize these effects (e.g., women with a tendency to thrombosis). Although transdermal estrogen is as effective as oral estrogen in preserving bone density and in treating menopausal symptoms, the cardiovascular benefit of estrogen replacement has been clearly demonstrated only for oral therapy. In addition, when compared to oral estrogen, transdermal estrogen may decrease fat mass and increases lean body mass [517]. The author recommends transdermal estrogen only for those women in whom it is desirable to avoid first-pass hepatic effects. Many oral preparations of estrogen are available, and, for practical purposes, are of equal therapeutic efficacy. The most commonly used preparation has been a mixture of sulfoconjugated equine estrogens (Premarin), which is derived from pregnant mares’ urine. Many of the other oral estrogen preparations are derived from plant sources (soy and yams). Premarin is comprised mostly of estrone sulfate, with small amounts of equilin sulfate, dihydroequilin sulfate, and many other estrogens. Cenestin, a brand of conjugated estro-

Chapter 9

gens derived from a plant source, is similar, but not identical to Premarin, as it contains only nine forms of estrogen. Estratab and Menest are brands of esterified estrogens also derived from a plant source that result in serum estradiol and estrone levels that are comparable to those seen with Premarin. Ogen is made from naturally derived but purified estrone sulfate, while Estrace (also available as a generic) is a micronized preparation of estradiol. Ethinyl estradiol is an extremely potent synthetic estrogen that is used in oral contraceptive preparations. There is no evidence that plantderived estrogens have safety and efficacy advantages over those derived from other sources. In general, 0.625 mg of conjugated estrogens, esterified estrogens, or estrone sulfate is considered equivalent to one mg of micronized estradiol, 50 mg of transdermal estradiol, or 5–10 mg of ethinyl estradiol. The transdermal estrogen preparations available in the United States—Estraderm, Climara, Vivelle, FemPatch, and Alora—all contain 17-beta estradiol. The Estraderm and Climara patches deliver 50 or 100 mg/day; the Estraderm patch must be changed every 3 days, and the Climara patch weekly. Vivelle is the newest preparation, and offers additional dosing options such as 33 and 75 mg/day. FemPatch has the lowest estrogen dose (25 mg/day with weekly application); it is aimed at relief of menopausal symptoms. A transdermal dose of 50 mg/day is approximately equivalent to a 0.625 mg daily oral dose of conjugated estrogens. Progestins are now routinely added for the woman who has her uterus intact based on the known increased risk of endometrial cancer with unopposed estrogen. The most commonly prescribed progestin is medroxyprogesterone acetate, available as Provera, Cycrin, or Amen. There are many other progestin preparations, such as norethindrone and norgestrel, used primarily in oral contraceptive preparations; most are testosterone derivatives and therefore have some weak androgenic actions. Therapeutic Regimens For the woman with an intact uterus, a number of regimens are in clinical use. The most commonly used regimen in the past has been conjugated estrogens 0.625–1.25 on days 1 to 25 of the calendar month plus 10 mg of medroxyprogesterone given for 12 to 14 days to maximize the protective effect on the endometrium. More recently, lower doses of medroxyprogesterone have been used to minimize its side effects. Many women are now being treated with 0.625–1.25 mg conjugated estrogens continuously and 5 mg medroxyprogesterone on days 1 to 13 of each month. There are data to show that daily progestin administration, which results in an atrophic endometrium, further decreases or may even protect against endometrial cancer. Unlike cyclic therapy, continous estrogen-progestin therapy induces amenorrhea in most women. The most commonly used continuous regimen in the United States is 0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone daily. Although the goal of continous estrogen-progestin therapy is to induce amenorrhea, the

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main drawback has been irregular bleeding soon after therapy is started, which can persist for many months, even though most women eventually develop amenorrhea [516]. Alternatively, one of the oral contraceptive preparations can be used in cyclic fashion in nonsmoking women below 50 years of age, and in women who smoke below 35 years of age. Natural oral micronized progesterone (Prometrium) has recently been approved by the FDA, and appears to protect the endometrium with the advantage of little impact upon serum lipids. The usual dose is 200–400 mg/day cyclically or 100–200 mg/day continuously. Replacement therapy is initiated after careful consideration of the appropriate contraindications for and precautions related to estrogen therapy. Decreased libido often results from absence of adrenal androgens and may not be corrected by estrogen-progesterone replacement. Restoration of libido can be accomplished by the administration of a small amount of methyltestosterone (2.5 mg/day). The lowest effective dose should be used to avoid development of hirsutism, acne, and other evidences of hyperandrogenesity. In prepubertal girls, estrogen should be started only after consideration of psychosocial development, height, and the need for growth hormone therapy. Since estrogen can cause premature epiphyseal closure, therapy should be withheld as long as practical to allow for optimal linear growth. Therapy can be initiated with 0.3 mg of conjugated estrogen daily. If no breast development is apparent after 3 months, the dose is increased to 0.625 mg per day. This daily dose is maintained for 12 to 18 months or until breakthrough vaginal bleeding occurs. A progestational agent is then added to induce cyclic menses. After 1 to 2 years on this regimen, the dose of conjugated estrogen should be increased to 1.25 mg per day to complete feminization. Occasionally, a larger dose of estrogen, 2.5 mg of conjugated estrogen, may be needed to complete female development. After several months, the patient is then placed and maintained on one of the oral contraceptives in standard cyclic fashion. Gonadotropin Therapy With gonadotropin deficiency, infertility can be due to an inadequate luteal phase or to anovulation. Hyperprolactinemic luteal insufficiency or anovulation can be reversed by suppression of hyperprolactinemia by dopamine-agonists. If euprolactinemic anovulation is present and the patient has withdrawal bleeding in response to progesterone, stimulation of gonadotropin secretion by clomiphene will result in ovulation. Clomiphene is binding to estrogen receptors in the hypothalamus. In response to clomiphene, the secretion of FSH and LH is increased, resulting in stimulation of follicular development and ovulation. It is usually started with a dose of 50 mg by mouth daily for 5 days commencing on the fifth day of spontaneous or progestin-induced menstrual bleeding. If ovulation does not occur with this dose, it can

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be increased in a step-wise fashion to a maximal dose of 200 mg per day for a 5-day cycle. Three to four cycles are required before this therapy can be regarded as a failure. In patients with primary pituitary disease, gonadotropin therapy [518,519] consisting of human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) can be used to induce ovulation. Gonadotropin therapy is expensive and hazardous and may lead to hyperstimulation syndromes or to multiple births. Therefore, it should be undertaken only under the direction of reproductive endocrinologists. Alternatively, in hypothalamic hypogonadism, pulsatile GnRH therapy [519] can be used. GnRH stimulates gonadotropin secretion follicular maturation and ovulation and can be monitored by plasma estradiol levels and ultrasound of the ovaries. Specific details of gonadotropin and GnRH therapy in the female, because of their complexity, are beyond the scope of this chapter.

Thyrotropin (TSH) Deficiency The goal of treatment is to restore the euthyroid state and it is achieved by the administration of thyroid hormones. For most patients this translates into a life-long need for replacement. Two general types of thyroid hormone preparations are available: (i) thyroproteins derived from animal thyroids (thyroid extract, USP); and (ii) synthetic hormones which include l-Thyroxine (T4), l-Triiodothyronine (T3), or a combination of the two. Synthetic preparations are preferred because of their uniform potency. T4 is the agent of choice because it does not lead to abrupt increases in serum T3 concentrations which could be hazardous in older patients or those with ischemic heart disease. T4 therapy is associated with a stable T3 concentration because of the constant generation of T3 by the peripheral tissues from the administered T4. Other thyroid hormone preparations can be used but are not recommended; they do not have any advantage over T4, serum T3 concentrations can fluctuate widely, and serum T4 levels remain low prompting an underestimation of effective dosage and often leading to supraphysiologic thyroid hormone replacement. It is important to remember that there may be small variations in potency or bioavailability among the different T4 preparations [550]. The usual replacement dose of l-Thyroxine is between 0.1 and 0.15 mg per day [549]. Endogenous T4 production is decreased in the elderly; therefore, a reduction of 20% to 40% in replacement dose is often required in elderly patients to avoid subtle manifestations of overdosage. To establish the adequacy of therapy, reliance is placed on clinical assessment accompanied by serum free T4 determinations [550]. Since in central hypothyroidism serum TSH concentrations are either minimally increased, “normal” or low, serum TSH cannot be used as indicator of attainment of an euthyroid state. Periodic follow-up is indicated to evaluate response to therapy and to monitor compliance. This is particularly true

in hypopituitarism, where the patient may be on multiple hormone replacement preparations. Larger replacement doses may be required in patients with various biliary and intestinal disorders, which may cause reduction in T4 absorption, or with concurrent use of drugs such as rifampin or phenytoin which augment T4 and T3 catabolism. Cholestyromine and other binding resins may decrease absorption of thyroid hormones;T4 should be given one hour before, or four hours after, the binding resin dose. Thyroid hormone replacement therapy can be initiated at the replacement dose in an otherwise healthy young patient with hypopituitarism or in hypopituitarism of recent onset. If however, the hypopituitarism is severe or longstanding, or if there is coexistent ischemic heart disease, a sudden increase in metabolic demands may tax cardiac reserve. In these patients therapy is initiated with 0.025 mg of T4 per day and the daily dose is increased slowly by 0.025 mg of T4 every 3 to 4 weeks until the optimal replacement dose is achieved. If anginal symptoms develop before the full replacement dose is achieved, the dose of T4 is reduced and the final replacement dose must be balanced between that which does the most to relieve symptoms of hypothyroidism and that which does not produce angina. A recent report suggests that adding T3 to T4 replacement regimen may improve cognitive performance, mood, and physical performance. These findings need confirmation of efficacy and safety [551]. The restoration of a euthyroid state can affect the handling or the requirement of a variety of drugs; dosage of anticoagulants may need to be decreased while dosages of insulin, oral antidiabetic agents, digitalis, propranalol, and opiates may have to be increased. Administration of thyroid hormone to treat TSH deficiency in a patient with unrecognized ACTH deficiency may precipitate an Addisonian crisis because thyroid hormone accelerates cortisol metabolism and increases the requirement for glucocorticoids. It is therefore critical that the ACTH-cortisol axis be evaluated in any patient with TSH deficiency. If ACTH deficiency is found, glucocorticoid replacement should be instituted before or concurrently with T4 therapy. In childhood and juvenile hypothyroidism, full replacement therapy is started promptly after the diagnosis of central hypothyroidism is made, to optimize normal intellectual development and physical growth. It is important to avoid supraphysiologic thyroid hormone replacement because this accelerates bone age and ultimately reduces growth hormone responsiveness. In infants and neonates the initial dose is 25 mg T4 daily with increments of 12.5 mg T4 at the age of 6 months and another 12.5 mg at the age of 1 year. In children 2 to 10 years old, the initial dose is 50 mg T4 daily with an increment of 12.5–25 mg every 4 to 8 weeks to a maintenance dose of 150–200 mg T4. If hypothyroid coma or precoma is present, there is urgency in thyroid hormone replacement and the situation

Chapter 9

is approached in a fashion similar to that for myxedema coma. This is optimally done in an intensive care unit with continuous ECG monitoring. A dose of 400 mg of lthyroxine is given parenterally followed by a daily dose of 50 mg. The danger from this abrupt increase in circulating thyroid hormone levels is the precipitation of myocardial ischemia and ventricular arrhythmia. This disadvantage is outweighed by the very poor survival rate in these patients if replacement is accomplished by small gradual increases in thyroid hormone dosage.

Growth-Hormone (GH) Deficiency Adults [290,520–522,542,545]

It is important, if possible, to treat/remove the cause of GHD because effective management of the cause may result in recovery of normal GH secretion. As implied earlier, other pituitary hormone deficiencies will need to be replaced optimally, and the absolute contraindications to GH therapy excluded, before consideration is given to GH therapy. Contraindications Absolute contraindications to GH therapy include active malignancy, benign intracranial hypertension, and proliferative or preproliferative diabetic retinopathy. Early pregnancy is not a contraindication, although GH should be discontinued in the second trimester as GH is produced by the placenta. Effects of GH Therapy GH therapy in adults with GHdeficiency has been shown to: (i) increase lean body mass, decrease adipose body mass, change the distribution of fat from abdominal to even distribution, decrease waist/hip ratio [523,524,526], increase muscle strength and stamina [523,524,526], increase exercise performance [525]; (ii) increase bone mineral density [524,526–529]—long-term studies show significant increase in bone density in spine and hip; (iii) decrease total cholesterol and LDL-cholestrol and beneficial effects on fibrinolysis, however, GH therapy may increase Lp(a) serum concentrations and has no effect on serum triglycerides or HDL-cholesterol concentrations [529–535,537,539]; (iv) correct the abnormalities in cardiac structure and function and increase cardiac performance [537,539,538]; (v) reverse the increased intima and media thickness of carotid artery [536]; and (vi) lead to improvement in mood and sense of well being [540]. For continued improvement, GH needs to be administered on a continuous basis; dscontinuation of GH Rx results in reversal of all the benefits of therapy. Patients with hypopituitarism who are replaced with thyroxine glucocorticoids and usually gonadal steroids [313]. It has not been demonstrated that treatment with GH restores mortality rates to normal. Administration and Dosage [520–522,541] Several recombinant human growth hormone preparations (Huma-

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trope®, Nutropin®, Serostim®, and Genotropin®) have been approved in many countries for treating adults with growth hormone deficiency. GH replacement therapy should be initiated with low doses of GH of 0.15– 0.30 mg/day (0.45–0.90 IU/day). A dose of 0.1 mg/day (0.3 IU/day) should not be exceeded in patients over 60 years of age. The dose is increased slowly and gradually, and on the basis of clinical and biochemical responses, with at least 1 month between dose adjustments. The maintenance dose will vary from one person to the other, but will not usually exceed 1.0 mg/day (3 IU/day). It is to be noted that: (i) elderly patients require less GH compared with younger patients [327–329,520–522,543]; (ii) obese patients with GHD appear to be more sensitive to GH treatment and experience more side effects of GH treatment, perhaps because dosage is usually based on weight [268,330,520–522] (do not exceed dose of 1.0 mg/day, even when indicated based on weight); (iii) women may require higher doses than men (they have higher daily GH production); (iv) older women receiving ERT have a diminished response to GH and require higher GH dose to normalize IGF-I; and (v) adults are more sensitive to GH, and therefore are more prone to develop side effects than children with GHD. GH is administered once daily, subcutaneously in the abdomen or thigh areas, in the evening. This is believed to mimic the natural circadian rhythm, improve hormone bioavailability, and improve some indices of GH action. Monitoring of Therapy [544] Monitoring is based on the clinical assessment of patient’s response to therapy and on the appropriate use of biochemical and radiologic parameters. Serum IGF-I, IGFBP-III Concentrations The concentrations of these markers generally show a dose-dependent increase during GH therapy. The dose of GH required to achieve normalization of these parameters varies widely between patients. IGF-I is believed to be the best indicator of adequacy of therapy, because it is more sensitive than other parameters to detect GH excess. Serum IGF-I concentrations are, unfortunately, not useful as a monitoring tool in patients who have normal pretreatment baseline concentrations of IGF-I. Serum lipid concentrations, fasting plasma glucose and bone mineral density need to be followed on a regular basis. There are several outstanding questions about general acceptance of growth hormone replacement therapy as routine: its possible role in tumor formation (in the prostate, breast, and colon) and possible recurrences of preexisting pituitary adenomas and craniopharyngeomas. Good clinical practice requires regular imaging of residual pituitary tumor or other mass lesions; however, GH replacement does not impose a need for intensifying this follow-up. Current recommendations for cancer prevention and early detection in the general population should be implemented.

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Dosages of Other Hormones and Medications Because GH influences the metabolism of many substances, including other hormones and medications, alterations in the dose requirements of such compounds should be anticipated. Thyroxine Therapy Growth hormone-replacement therapy directly, or indirectly via IGF-I, stimulates the conversion of thyroxine to tri-iodothyronine. A slight decrease in free T4 concentrations and a simultaneous increase in free T3 concentrations commonly occur after the start of growth hormone treatment. These changes are transient, do not affect the normal thyroid function, and generally do not require adjustment of the thyroxine replacement dose in the hypothyroid patient [552]. Hydrocortisone Therapy Growth hormone-replacement therapy in hypopituitary adults is associated with an apparent decrease in availability of administered hydrocortisone, as measured by urine cortisol metabolites and urinary free cortisol. The changes in cortisol metabolism might be the consequences of a growth hormone-mediated or IGFI-mediated modulation of the activity of the enzyme 11 b-hydroxysteroid dehydrogenase. This effect might be of clinical importance only in patients with ACTH deficiency because of suboptimum hydrocortisone replacement. Estrogen Therapy Oral oestrogen-replacement therapy results in a significant fall in serum IGF-I concentrations, whereas transdermally administered estradiol, which circumvents the liver, does not cause such decreases. Whether these changes have therapeutic consequences for the optimum route of oestrogen administration in hypopituitary patients has not yet been determined. Gonadotropin Therapy Hypogonadotropic women with GHD may require doses of gonadotropins that are higher than normal for successful induction of ovulation, and may therefore benefit from adjuvant therapy with growth hormone. Such an approach to treatment might also apply to hypogonadal male patients for spermatogenesis. Intermediary Metabolism In many hypopituitary patients, intermediary and glucose metabolism is not controlled to the optimum during routine hydrocortisone, thyroxine, and sex-steroid replacement. The addition of growth hormonereplacement therapy increases glucose concentrations and commonly corrects the metabolic disturbance. Whether this effect contributes to a further improvement in symptoms and in the subjective well-being of these patients has to be studied. Side Effects [326,546] Initial studies which utilized higher doses of GH and therefore were associated with supraphysiologic levels of IGF-I, were associated with increased incidence of side effects. However, in the more recent studies, with more physiologic replacement, the incidence of

side effects has been significantly reduced. The commonest side effects included edema (37.4%), arthralgia (19.1%), myalgia (15.7%), and parasthesias (7.8%). Most of these adverse effects are related to the GH-induced sodium retention and increased extracellular fluid volume. These side effects appear early, within days or weeks of initiating therapy; are dose-related and usually disappear spontaneously with dose reduction. They are seen more commonly in the elderly patient; in patients with higher IGF-I values at baseline, and in the obese. Benign intracranial hypertension (pseudotumor cerebri) [547] has also been reported, mostly in children, and macular edema or proliferative retinopathy in the absence of diabetes mellitus also have been described [548]. Long-term Care Although insufficient information is available at present, GH replacement (as with other hormones) is most likely for life. It is possible that the dose requirement may decrease over time. Replacement therapy in the elderly should be monitored particularly carefully as the patient ages, with special emphasis on dosage adjustment and assessment of perceived benefit and the desirability of continuing the GH therapy. If a patient does not perceive benefit from growth hormone-replacement therapy after about 6 months, withdrawal of therapy should be considered. Children [556]

Full details of GH therapy in childhood and adolescence is beyond the scope of this book, and readers are encouraged to consult appropriate pediatric texts. Until 1985 human “cadaveric” pituitary derived GH was the only therapeutic GH available for GH-deficient children. Given in the usual dose of one to two units intramuscularly three times per week, it was effective and thought to be reasonably safe. Its limited supply, however, eliminated many GH-deficient children from consideration for therapy, and detailed studies to determine optimal dose could not be performed. In 1985, concerns over transmission of Creutzfeldt-Jakob disease by human pituitary derived GH lead to its withdrawal from the market by the FDA. Fortunately, recombinant DNAproduced GH has become available and found to be as potent as native hormone. Both forms of GH therapy have been effective and to date safe. Several dose regimens have been reported. The usual dose is 0.05 mgm (0.1 unit) of GH per kg three times per week given either subcutaneously or intramuscularly. Recent reports suggest that a higher dose per kg or increasing frequency of GH administration to six times per week may be more beneficial in increasing growth velocity. In response to GH therapy, growth velocity increases two- to threefold in the first year but tends to fall off in the second and third years. Increasing the dose of GH at that time to 0.15 mg per kilo three times per week may restore growth velocity. A safe upper limit for GH dosage has not been defined as yet.

Chapter 9

Studies of the final height achieved by GH therapy in GH-deficient children have revealed that less than 50% of treated children achieve a final height within 2 SD deviations of their midparental height. Since lost growth cannot be restituted by GH therapy, it is crucial that the diagnosis of GH deficiency be made and GH therapy initiated as early as possible and before a significant growth potential has been lost. The treatment of associated hormonal deficiencies in the GH-deficient child deserves special mention. Physiologic thyroid hormone and cortisol replacement are essential for optimal response to GH therapy. However, caution must be used in the choice of the appropriate dose of thyroxine and of hydrocortisone, as supraphysiologic doses of thyroxine can unduly accelerate bone age and that of hydrocortisone can blunt GH response. The recommended dosage of l-thyroxin is 2–5 mg per kilo per day to a maximum of 150 mg in a single daily dose, and for hydrocortisone is not more than 10 mg per meter square per day in two or three divided doses. The treatment of micropenis with three to six injections of 25 mg of Depo-Testosterone is useful and gives its best results when therapy is given to infants aged 6 to 18 months. GH therapy should continue concurrently, with sex-steroid therapy given for the induction of puberty in the GH-deficient adolescent and should only be stopped when pubertal development is completed. Psychological support of GH-deficient children is extremely important. Preliminary studies of psychosocial outcome of GH-treated patients have revealed suboptimal education achievements, job placement, and marital success. The cost of GH treatment is on average $10,000 to $15,000 per year. Since most patients will need this therapy for greater than 10 years, such treatment imposes a heavy financial burden for the family and health economy. Recombinant GH has been shown not to have significant side effects in treated children. In a significant number of children, anti-GH antibodies appear in low titers in the first 3 to 6 months of therapy. Except in a few instances, these antibodies do not affect the growth response, but the long-term effects are unknown. Hypothyroidism may develop during hGH therapy, its pathogenesis is not clear but is believed to be due to increase in somatostatin secretion caused by GH therapy. Thyroid function should be monitored at 6 to 12 month intervals during GH therapy. Hypothyroidism encountered during GH therapy is transient and reversible. Other potential adverse effects of GH therapy include insulin resistance, glucose intolerance, and slipped femoral epiphysis. A possible link between GH therapy and leukemia has also been reported but has not been confirmed.

Prolactin (PRL) Deficiency Prolactin is not available for substitution therapy. No satisfactory form of therapy is available for the management of a lack of postpartum lactation.

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265 Reutens AT, Veldhuis JD, Hoffman DM et al. A highly sensitive growth hormone (GH) ELISA uncovers increased contribution of a tonicode of GH secretion in adults with organic GH deficiency. J Clin Endocrinol Metab 1996;81:1591. 266 Jansson C, Boguszewski C, Rosberg S et al. Growth hormone (GH) assays: influence of standard preparations, GH isoforms, assay characteristics, and GH-binding protein. Clin Chem 1997;43:950. 267 Celnicker AC, Chen AB, Wert RM et al. Variability in the quantitation of circulating growth hormone using commercial assays. J Clin Endocrinol Metab 1989;68:68–71. 268 Juul A, Kastrup KW, Pederson SA et al. Growth hormone provocative retesting of 108 young adults with childhood-onset growth hormone deficiency and the diagnostic value of insulin-like growth factor (IGF-1) and IGF-binding protein-3. J Clin Endocrinol Metab 1997;82:1195–1201. 269 Hoffman DM, O’Sullivan AJ, Baxter RC et al. Diagnosis of growth-hormone deficiency in adults. Lancet 1994;343:1064. 270 Hilding A, Hall K, Wivall-Helleryd I-L et al. Serum levels of insulin-like growth factor 1 in 152 patients with growth hormone deficiency, aged 19–82 years, in relation to those in healthy subjects. J Clin Endocrinol Metab 1999;84:2013. 271 Svensson J, Johannsson G, Bengtsson BÅ. Insulin-like growth factor-1 in growth hormone-deficient adults: relationship to population-based normal values, body composition and insulin tolerance test. Clin Endocrinol (Oxf.) 1997;46:579. 272 Underwood LE. Clinical uses of IGF-1 and IGF binding protein assays. In: Rosenfeld RG, Roberts CT eds. The IGF system: molecular biology, physiology, and clinical applications. Totowa, NJ: Human Press Inc, 1999:617. 273 Hasegawa Y, Hasegawa T, Aso T et al. Comparison between insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) measurement in the diahnosis of growth hormone deficiency. Endcr J 1996;40:185. 274 Nunez SB, Municchi G, Barnes KM et al. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) concentrations compared to stimulated and night growth hormone in the evaluation of short children: a clinical research study center. J Clin Endocrinol Metab 1996;81:1927. 275 Blum WF, Albertson-Wikland K, Rosberg S et al. Serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab 1993;76:1610–1616. 276 Ghigo E, Bellone J, Aimaretti G et al. Reliabilty of provocative tests to assess growth hormone secretory state. Study in 472 normally growing children. J Clin Endocrinol Metab 1996;81:3323–3327. 277 Aimaretti G, Corneli P, Razzore P et al. Comparison between insulin-induced hypoglycemia and growth hormone-releasing hormone + arginine as proactive tests for the diagnosis of growth hormone-deficiency in adults. J Clin Endocrinol Metab 1998;83:1615–1618. 278 Eddy RL, Gilliland PF, Ibarra JE Jr. Human growth hormone release. Comparison of provocative test procedures. Am J Med 1974;56:179. 279 Landon J, Greenwood FC, Stamp TCB et al. The plasma sugar, free fatty acid, cortisol and growth hormone response to insulin, and comparison of this procedure with other tests of pituitary and adrenal function. II. In patients with hypothalamic or pituitary dysfunction or anorexia nervosa. J Clin Invest 1966;45:437. 280 Root AW, Rosenfeld RL, Bongiovanni AM et al. The plasma growth hormone response to insulin-induced hypoglycemia in children with retardation of growth. Pediatrics 1967;39:844. 281 Merimee TJ, Rabinowitz D, Riggs L. Plasma growth hormone after arginine infusion. Clinical experiences. N Engl J Med 1967;276:434. 282 Aimaretti G, Corneli G, Razzore P et al. Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults. J Clin Endocrinol Metab 1998;83:1615. 283 Boyd AE III, Lebovitz HE, Pfeiffer JB. Stimulation of human-growthhormone secretion by L-dopa. N Engl J Med 1970;283:1425. 284 Milner RDG, Barnes ND, Betts PR et al. Comparison of the intravenous insulin and oral clonidine tolerance tests for growth hormone secretion. Arch Dis Child 1981;56:852. 285 Mitchell ML, Byrne MJ, Sanchez Y et al. Detection of growth-hormone deficiency: the glucagon stimulation test. N Engl J Med 1970;282:539. 286 Orme SM, Price A, Weetman AP et al. Comparison of the diagnostic utility of the simplified and standard i.m. glucagon stimulation test (IMGST). Clin Endocrinol (Oxf.) 1998;49:773. 287 Parks JS, Amrhein JA, Vaidya V et al. Growth hormone responses to propranolol-glucagon stimulation: a comparison with other tests of growth hormone reserve. J Clin Endocrinol Metab 1973;37:85.

288 De Boer H, Blok GJ, Van der Veen EA. Clinical aspects of growth hormone deficiency in adults. Endocr Rev 1995;16:63. 289 Carroll PV, Christ ER, Bengtsson BA et al. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 1998;83:382. 290 AACE Clinical practice guidelines for growth hormone use in adults and children. American Association of Clinical Endocrinologists, 1998. 291 Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workship on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998;83:379. 292 De Boer H, Blok GJ, Voerman HJ et al. Body composition in adult growth hormone-deficient men, assessed by anthropometry and bioimpedence analysis. J Clin Endocrinol Metab 1992;75:833. 293 Binnerts A, Deurenberg P, Swart GR et al. Body composition in growth hormone deficient adults. Am J Clin Nutr 1992;55:918. 294 Rosén T, Bosaeus I, Tölli J et al. Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency. Clin Endocrinol (Oxf.) 1993;38:63. 295 Cuneo RC, Salomon F, Wiles CM et al. Skeletal muscle performance in adults with growth hormone deficiency. Horm Res 1990;33(Suppl 4):55. 296 Baum HBA, Biller BMK, Finkelstein JS et al. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency: a randomized, placebo-controlled trial. Ann Intern Med 1996;125:883. 297 Bengtsson BA, Eden S, Lonn L et al. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 1993;76:309. 298 Juul A, Main K, Nielsen B et al. Decreased sweating in growth hormonedeficiency: does it play a role in thermoregulation? J Pediatr Endocrinol 1993;6:39–44. 299 DeBoer H, Blok GJ, Voerman HJ et al. Serum lipid levels in growth hormone deficient men. Metabolism 1994;43:199. 300 Beshyah SA, Henderson A, Niththyananthan R et al. The effects of short and long-term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance. J Clin Endocrinol Metab 1995;80:356. 301 Weaver JU, Monson JP, Noonan K et al. The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults. J Clin Endocrinol Metab 1995;80:153. 302 O’Halloran DJ, Wieringa G, Tsatsoulis A et al. Increased serum lipoprotein(a) concentrations after growth hormone (GH) treatment in patients with isolated GH deficiency. Ann Clin Biochem 1996;33:330. 303 Leese GP, Wallymahmed M, VanHeyningen C et al. HDL-cholesterol reductions associated with adult growth hormone replacement. Clin Endocrinol (Oxf.) 1988;49:673. 304 Rosén T, Bengtsson BA. Premature mortality due cardiovascular disease in hypopituitarism. Lancet 1990;336:285. 305 Borson-Chazot F, Serusclat A, Kalfallah Y et al. Decrease in carotid intimamedia thickness after one year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab 1999;84:1329. 306 Holmes SJ, Economou G, Whitehouse RW et al. Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab 1994;78:669. 307 Johansson AG, Burman P, Westermark K et al. The bone mineral density in acquired growth hormone deficiency correlates with circulating levels of insulin-like growth factor I. J Intern Med 1992;232:447. 308 Colao A, Di Somma C, Pivonello R et al. Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab 1999;84:1919. 309 Rosén T, Hansson T, Granhed H et al. Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh.) 1993;129:201. 310 McGauley GA. Quality of life assessment before and after growth hormone treatment in adults with growth hormone deficiency. Acta Paediatr Scand 1989;356(Suppl):70. 311 Björk S, Jönsson B, Westphal O et al. Quality of life of adults with growth hormone deficiency: A controlled study. Acta Paediatr Scan 1989;356(Suppl):55. 312 Rosén T, Wiren L, Wilhelmsen L et al. Decreased psychological well-being in adult patients with growth hormone deficiency. Clin Endocrinol 1994;40:111. 313 Bates AS, Van’t Hoff W, Jones PJ et al. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 1996;81:1169.

Chapter 9 314 Mereola B, Cittadini A, Colao A et al. Cardiac structural and functional abnormalities in adult patients with growth hormone-deficiency. J Clin Endocrinol Metab 1993;77:1658–1661. 315 Amato G, Carella C, Fazio S et al. Body composition, bone metabolism, and heart structure and function in growth hormone-deficient adults before and after Gh replacement therapy at low doses. J Clin Endocrinol Metab 1993;77:1671–1676. 316 Rosén T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285. 317 Cuneo RC, Salomon F, Watts GF et al. Growth hormone treatment improves serum lipids and lipoproteins in adults with growth hormone deficiency. Metabolism 1993;42:1519–1523. 318 Johansson J-O, Landin K, Tengborn L et al. High fibrinogen and plasminogen inhibitor activity in growth hormone-deficient adults. Arterioscler Thromb 1994;14:434–437. 319 Johansson J-O, Fowelin J, Landin K et al. Growth-hormone deficient adults are insulin-resistant. Metabolism 1995;44:1126–1129. 320 Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 1998;19:717. 321 Thorner MO, Vance ML. Growth hormone. J Clin Invest 1988;82:745. 322 Maghnie M, Strigazzi C, Tinelli C et al. Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab 1999;84:1324. 323 Muggeo M, Fedele D, Tiengo A et al. Human growth hormone and cortisol response to insulin stimulation in aging. J Gerontol 1975;30:546–551. 324 Lang T, Schernthaner G, Pietschmann P et al. Effects of sex and age on growth hormone response to growth hormone-releasing hormone in healthy individuals. J Clin Endocrinol Metab 1987;65:535–540. 325 Toogod AA, Shalet SM. Growth hormone replacement therapy in the elderly with hypothalamic-pituitary disease: a dose-finding study. J Clin Endocrinol Metab 1999;84:131–136. 326 Holmes SJ, Shalet SM. Which adults develop side-effects of growth hormone replacement? Clin Endocrinol (Oxf.) 1995;43:143–149. 327 Oelkers, W. Adrenal insufficiency [see comments]. N Engl J Med 1996; 335:1206. 328 Woods KA, Weber A, Clark AJL. The molecular pathology of pituitary hormone deficiency and resistance. Baillière’s Clin Endocrinol Metabolism 1995;9:453–487. 329 Krude H, Biebermann H, Luck W et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998;19:155. 330 Hinney A, Becker I, Heibült O et al. Systematic mutation screeing of the pro-opiomelanocortin gene: identification of several genetic variants including three different insertions, one nonsense and two missense point mutations in probands of different weight extremes. J Clin Endocrinol Metab 1998;83:3737. 331 Nussey SS, Soo SC, Gibson S et al. Isolated congenital ACTH deficiency: a cleavage enzyme defect? Clin Endocrinol 1993;39:381. 332 Parks JS, Brown MR, Hurley DL et al. Heritable disorders of pituitary development. J Clin Endocrinol Metab 1999;84:4262–4370. 333 Clark AJL, McLoughlin A, Grossman A. Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet 1993;341:461–462. 334 Tsigos C, Arai K, Hung W et al. Hereditary isolated glucocorticoid deficiency associated with abnormalities of the adrenocorticotropin receptor gene. J Clin Invest 1993;92:2458–2461. 335 Weber A, Clark AJL. Mutations in the ACTH receptor gene are only one cause of familial glucocorticoid deficiency. Hum Mol Genet 1994;3: 585–588. 336 Geffner ME, Lippe BM, Solomon AK et al. Selective ACTH insensitivity, achalasia and alacrima: a multisystem disorder presenting in childhood. Pediatr Res 1983;17:532. 337 Moshang T Jr, Rosenfield RI, Bongiovanni AM et al. Familial glucocorticoid insufficiency. J Pediatr 1973;82:821. 338 Naville D, Chatelain P, Brunelli V et al. A study of the ACTH receptor gene in five different families with ACTH insensitivities. Abstract of the 75th Annual Meeting of the Endocrine Society 1993;747:237. 339 Takanayagi R, Sugai Y, Nawata HL et al. Adrenocorticotrophin receptor in familial glucocorticoid deficiency. Jap J of Clin Med 1993;51:2643–2648. 340 Allgrove J, Clayden GS, Grant DB et al. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1978;i:1284–1286.

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341 Lanes R, Plotnick L, Bynum TE et al. Glucocorticoid and partial mineralocorticoid deficiency associated with achalasia. J Clin Endocrinol Metab 1980;50:268–270. 342 Moore PSJ, Couch RM, Perry YS et al. Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima. Clin Endocrinol 1991;34:107–114. 343 Sperling MA, Wolfsen AR, Fisher DA. Congenitial adrenal hypoplasia: an isolated defect of organogenesis. J Pediatr 1973;82:444. 344 Kruse K, Sippell WG, Schnakenberg KV. Hypogonadism in congenital adrenal hypoplasia: evidence for a hypothalamic origin. J Clin Endocrinol Metab 1984;58:12. 345 Nishihara E, Kimura H, Ishimaru T et al. A case of adrenal insufficiency due to acquired hypothalamic CRH deficiency. Endocr J 1997;44:121. 346 Stacpoole PW, Interlandi JW, Nicholson WE, Rabin D. Isolated ACTH deficiency: A heterogeneous disorder. Critical review and report of four new cases. Medicine 1982;61:13. 347 Perkoff GT, Eik-Nes K, Carnes WH et al. Selective hypopituitarism with deficiency of anterior pituitary basophils: a case report. J Clin Endocrinol Metab 1960;20:1269. 348 Nichols ML, Brown RD, Granville GE et al. Isolated deficiency of adrenocorticotropin (ACTH) and lipotropins (LPHs). J Clin Endocrinol Metab 1978;47:84. 349 Yoshida T, Arai T, Sugano J et al. Isolated ACTH deficiency accompanied by “primary hypothyroidism” and hyperprolactinaemia. Acta Endocrinol (Copenh.) 1983;104:397. 350 Koide Y, Kimura S, Inoue S et al. Responsiveness of hypophyseal– adrenocortical axis to repetitive administration of synthetic ovine corticotropin-releasing hormone in patients with isolated adrenocorticotropin deficiency. J Clin Endocrinol Metab 1986;63:329. 351 Cantalamessa L, Catania A, Baldini M et al. CRH and lysine-vasopressin stimulation tests in the diagnosis of hypoadrenalism secondary to hypothalamic or pituitary disorders. Horm Metab Res 1990;22:389. 352 Kanemaru Y, Noguchi T, Onaya T. Isolated ACTH deficiency associated with transient thyrotoxicosis and hyperprolactinemia. Endocrinol Jpn 1989;36:459. 353 Shigemasa C, Kouchi T, Ueta Y et al. Evaluation of thyroid function in patients with isolated adrenocorticotropin deficiency. Am J Med Sci 1992;304:279. 354 Shigemasa C, Kouchi T, Ueta Y et al. Evaluation of thyroid function in patients with isolated adrenocorticotropin deficiency. Am J Med Sci 1992; 304:279. 355 Jensen MD, Handwerger BS, Scheithauer BW et al. Lymphocytic hypophysitis with isolated corticotropin deficiency. Ann Intern Med 1986;105:200. 356 Sugiura M, Hashimoto A, Shizawa M et al. Heterogeneity of anterior pituitary cell antibodies detected in insulin-dependent diabetes mellitus and adrenocorticotropic hormone deficiency. Diabetes Res 1986;3:111. 357 Sauter NP, Toni R, MaLaughlin CD et al. Isolated adrenocorticotropin deficiency associated with an autoantibody to a corticotroph antigen that is not adrenocorticotropin or other proopiomelanocortin-derived peptides. J Clin Endocrinol Metab 1990;70:1391. 358 Tillil H, Kobberling J. Isolated ACTH deficiency and type 1 diabetes mellitus [letter]. J Endocrinol Invest 1988;11:815. 359 Guistina A, Candrina R, Cimino A, Romanelli G. Development of isolated ACTH deficiency in a man with type I diabetes mellitus. J Endocrinol Invest 1988;11:375–377. 360 Wieland RG, Wieland JM. Isolated adrenocorticotropic hormone deficiency with antepartum pituitary infarction in type I diabetic. Obstet Gynecol 1985;65:58S–59S. 361 Dewailly D, Bourdelle Hego MF, Pouplard Barthelaix A, Fossati P. Recovery of ovulatory menstrual cycles under hydrocortisone in two amenorrheic women with isolated corticotropin deficiency. Horm Res 1988;29:14–16. 362 Stephens WP, Goddard KJ, Laing I, Adams JE. Isolated adrenocorticotrophin deficiency and empty sella associated with hypothyroidism. Clin Endocrinol (Oxf.) 1985;22:771–776. 363 Fang VS, Jaspan JB. Delirium and neuromuscular symptoms in an elderly man with isolated corticotroph-deficiency syndrome completely reversed with glucocorticoid replacement. J Clin Endocrinol Metab 1989;69:1073–1077. 364 Jialal I, Desai RK, Maharaj IC et al. Isolated adrenocorticotrophic hormone (ACTH) deficiency associated with acute adrenal crisis. Postgrad Med J 1985;61:423–425. 365 Carroll PB, McHenry L, Verbalis JG. Isolated adrenocorticotrophic hormone deficiency presenting as chronic hyponatremia. NY State J Med 1990;90:210–213. 366 Major P, Kuchel O, Boucher R et al. Selective hypopituitarism with severe hyponatremia and secondary hyporeninism. J Clin Endocrinol Metab 1978;46:15.

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367 Shimatsu A, Suzuki Y, Tanaka S. Gynecomastia associated with isolated ACTH deficiency. J Endocrinol Invest 1987;10:127–129. 368 Schmidli RS, Donald RA, Espiner EA. ACTH deficiency: problems in recognition and diagnosis. N Z Med J 1989;102:255–257. 369 Nowakowski KJ, Tucci JR. Idiopathic isolated ACTH deficiency and the response to CRF. J Endocrinol Invest 1989;12:253–255. 370 Tsatsoulis A, Shalet SM, Harrison J et al. Adrenocorticotrophin (ACTH) deficiency undetected by standard dynamic tests of the hypothalamic–pituitary–adrenal axis. Clin Endocrinol (Oxf.) 1988;28:225–232. 371 Axelrod L. Glucocorticoid therapy. Medicine 1976;55:39. 372 Streck WF, Lockwood DH. Pituitary adrenal recovery following short-term suppression with corticosteroids. Am J Med 1979;66:910. 373 Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999;159:941. 374 Allen DB, Julius JR, Breen TJ, Attie KM. Treatment of glucocorticoid-induced growth suppression with growth hormone. J Clin Endocrinol Metab 1998;83:2824. 375 Harter JG, Reddy WJ, Thorn GW. Studies on an intermittent corticosteroid dosage regimen. N Engl J Med 1963;269:591. 376 Fauci AS. Alternate-day corticosteroid therapy. Am J Med 1978;64:729. 377 Sampson PA, Brooke BN, Winstone NE. Biochemical confirmation of collapse due to adrenal failure. Lancet 1961;1:1377. 378 Ackerman GL, Nolan CM. Adrenocortical responsiveness after alternate-day corticosteroid therapy. N Engl J Med 1968;278:405. 379 Kehlet H, Binder C. Value of an ACTH test in assessing hypothalamic pituitary adrenocortical functions in glucocorticoid treated patients. Br Med J 1973;2:147–149. 380 Bennett A, Chen T, Feledman D, Hintz RL. Characterization of insulin-like growth factor I receptors on cultured rat bone cells: regulation of receptor concentration by glucocorticoids. Endocrinology 1984;116:1577. 381 Daughaday WJ, Herrington AC, Phillips LS. The regulation of growth by endocrines. Annu Rev Physiol 1975;37:211. 382 Brouhard BH, Travis LB, Cunningham RJ et al. Inhibition of linear growth using alternate-day steroids. J Pediatr 1977;90:343. 383 Allen DB. Growth suppression by glucocorticoid therapy. Endocrinol Metab Clin North Am 1996;25:699. 384 Wolthers OD, Pedersen S. Growth of asthmatic children during treatment with budesonide: a double blind trial. BMJ 1991;303:163. 385 Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999;159:941. 386 MacAdams MR, White RH, Chipps BE. Reduction of serum testosterone levels during chronic glucocorticoid therapy. Ann Intern Med 1986;104:648. 387 Crilly R, Cawood M, Marshall DH, Nordin BEC. Hormonal status in normal, osteoporotic and corticosteroid-treated postmenopausal women. J R Soc Med 1978;71:733. 388 Fitzgerald PA, Aron DC, Findling JW et al. Cushing’s disease: transient secondary adrenal insufficiency after selective removal of pituitary tumors. Evidence for a pituitary origin. J Clin Endocrinol Metab 1982;54:413. 389 Mann M, Koller E, Murgo A et al. Glucocorticoid-like activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature. Arch Intern Med 1997;157:1651. 390 Leinung MC, Liporace R, Miller CH. Induction of adrenal suppression by megestrol acetate in patients with AIDS. Ann Intern Med 1995;122:843. 391 Subramanian S, Goker H, Kanji A et al. Clinical adrenal insufficiency in patients receiving megestrol therapy. Arch Intern Med 1997;157:1008. 392 Copeland KC, Franks RC, Ramamurthy R. Neonatal hyperbilirubinemia and hypoglycemia in congenital hypopituitarism. Clin Pediatr 1981;30: 523–526. 393 Burton EM, Babcock DS, Heubi JE, Gelfand MJ. Neonatal jaundice: clinical and ultrasonographic findings. South Med J 1990;83:294–302. 394 Lanes R, Blanchette V, Edwin C et al. Congenital hypopituitarism and conjugated hyperbilirubinemia in two infants. Am J Dis Child 1978;132:926. 395 Bakiri F, Benmiloud M, Vallotton MB. The renin-angiotensin system in panhypopituitarism: dynamic studies and therapeutic effects in Sheehan’s syndrome. J Clin Endocrinol Metab 1983;56:1042. 396 Birkhauser M, Riondel AM, Gaillard R et al. Plasma aldosterone response to acute stimulation in panhypopituitarism. Acta Endocrinol 1981;97:514–521. 397 Lieberman AH, Luescher JA. Some effects of abnormalities of pituitary, adrenal, or thyroid function on excretion of aldosterone and the response to corticotropin or sodium deprivation. J Clin Endocrinol Metab 1960;20:1004. 398 Hagg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clin Endocrinol 1987;26:221. 399 Jenkins D, Forsham PH, Laidlaw JC et al. Use of ACTH in the diagnosis of adrenal cortical insufficiency. Am J Med 1955;18:3.

400 Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of the hypothalamic–pituitary–adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab 1998;83:2350. 401 Watts NB, Tindall GT. Rapid assessment of corticotropin reserve after pituitary surgery. JAMA 1988;259:708. 402 Streeten DHP, Anderson GH Jr, Bonaventura MM. The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test. J Clin Endocrinol Metab 1996;81:285. 403 Dickstein G, Shechner C, Nicholson WE et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773. 404 Crowley S, Hindmarsh PC, Honour JW, Brook CG. Reproducibility of the cortisol response to stimulation with a low dose of ACTH (1–24): the effect of basal cortisol levels and comparison of low-dose with high-dose secretory dynamics. J Endocrinol 1993;136:167. 405 May ME, Carey RM. Rapid adrenocorticotropic hormone test in practice. Am J Med 1985;79:679. 406 Thaler LM, Blevins LS Jr. The low dose (1-mg) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998;83:2726. 407 Oelkers W, Diederich S, Bahr V. Diagnosis and therapy surveillance in Addison’s disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone. J Clin Endocrinol Metab 1992;75:259. 408 Rasmuson S, Olsson T, Hagg E. A low dose ACTH test to assess the function of the hypothalamic–pituitary–adrenal axis. Clin Endocrinol 1996;44:151. 409 Cunningham SK, Moore A, McKenna TJ. Normal cortisol response to corticotropin in patients with secondary adrenal failure. Arch Intern Med 1983;143:2276. 410 Lindholm J, Kehlet H. Re-evaluation of the clinical value of the 30 min ACTH test in assessing the hypothalamic–pituitary–adrenocortical function. Clin Endocrinol 1987;26:53. 411 Streeten DHP, Anderson GH Jr, Bonaventura MM. The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test. J Clin Endocrinol Metab 1996;81:285. 412 Hurel SJ, Thompson CJ, Watson MJ et al. The short Synacthen and insulin stress tests in the assessment of the hypothalamic–pituitary–adrenal axis. Clin Endocrinol 1996;44:141. 413 Broide J, Soferman R, Kivity S et al. Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab 1995;80:1243. 414 Thaler LM, Blevins LS Jr. The low dose (1-mg) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998;83:2726. 415 Mayenknecht J, Diederich S, Bahr V et al. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998;83:1558. 416 Streeten DH. What test for hypothalamic–pituitary–adrenal insufficiency. Lancet 1999;354:179. 417 Rose LI, Williams GH, Jagger PI, Lauler DP. The 48-hour adrenocorticotropin infusion test for adrenocortical insufficiency. Ann Intern Med 1970;73:49. 418 Jubiz W, Matsukura S, Meikle AW et al. Plasma metyrapone, adrenocorticotropic hormone, cortisol, and deoxycortisol levels. Sequential changes during oral and intravenous metyrapone administration. Arch Intern Med 1970;125:468. 419 Jubiz W, Meikle AW, West CD, Tyler FH. Single-dose metyrapone test. Arch Intern Med 1970;125:472. 420 Liddle GW, Estep HL, Kendall Jr, JW et al. Clinical application of a new test of pituitary reserve. J Clin Endocrinol Metab 1959;19:875. 421 Feek CM, Bevan JS, Ratcliffe JG et al. The short metyrapone test: comparison of the plasma ACTH response to metyrapone with the cortisol response to insulin-induced hypoglycaemia in patients with pituitary disease. Clin Endocrinol 1981;15:75. 422 Dolman LI, Nolan G, Jubiz W. Metyrapone test with adrenocorticotrophic levels. Separating primary from secondary adrenal insufficiency. JAMA 1979;241:1251. 423 Mahajan DK, Wahlen JD, Tyler FH, West CD. Plasma 11-deoxycortisol radioimmunoassay for metyrapone tests. Steroids 1972;20:609. 424 Spiger M, Jubiz W, Meikle AW et al. Single-dose metyrapone test: Review of a four-year experience. Arch Intern Med 1975;135:698. 425 Feek CM, Bevan JS, Ratcliffe JG et al. The short metyrapone test: Comparison of the plasma ACTH response to metyrapone with the cortisol response to insulin-induced hypoglycaemia in patients with pituitary disease. Clin Endocrinol 1981;15:75.

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453 Stockigt JR. Guidelines for diagnosis and monitoring of thyroid disease: nonthyroidal illness. Clin Chem 1996;42:188. 454 Attia J, Margetts P, Guyatt G. Diagnosis of thyroid disease in hospitalized patients: a systematic review. Arch Intern Med 1999;159:658. 455 Uy HL, Reasner CA, Samuels MH. Pattern of recovery of the hypothalamic–pituitary–thyroid axis following radioactive iodine therapy in patients with Graves’ disease. Am J Med 1995;99:173. 456 Vagenakis AG, Braverman LE, Azizi F et al. Recovery of pituitary thyrotropic function after withdrawal of prolonged thyroid-suppression therapy. N Engl J Med 1975;293:681. 457 Otsuki M, Dakoda M, Baba S. Influence of glucocorticoids on TRF-induced TSH response in man. J Clin Endocrinol Metabolism 1973;36:95. 458 Re RN, Kourides IA, Ridgway EC et al. The effect of glucocorticoid administration on human pituitary secretion of thyrotropin and prolactin. J Clin Endocrinol Metab 1976;43:338. 459 Peters JR, Foord SM, Dieguez C, Scanlon MF. TSH neuro-regulation and alterations in disease states. Clin Endocrinol Metabolism 1983;12:669. 460 Lippe BM, Van Herle AJ, LaFranchi SH et al. Reversible hypothyroidism in growth hormone-deficient children treated with human growth hormone. J Clin Endocrinol Metab 1975;40:612. 461 Morley JE. Neuroendocrine control of thyrotropin secretion. Endocr Rev 1981;2:396. 462 Snyder PJ, Jacobs LS, Rabello MM et al. Diagnostic value of thyrotropinreleasing hormone in pituitary and hypothalamic disease. An Intern Med 1974;81:751–757. 463 Carlson HE, Brickman AS, Bottazo GF. Prolactin deficiency in pseudohypoparathyroidism. N Engl J Med 1977;296:140–144. 464 Kruse A, Gutekunst B, Kracht U. Deficient prolactin response to parathyroid hormone in hypocalcemic and normocalcemic pseudohypoparathyroidism. J Clin Endocrinol Metab 1981;52:1099. 465 Spiegel AM. Pseudohypoparathyroidism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. New York: McGraw Hill 1989:2013–2027. 466 May PB, Renny A, Bastek J et al. Diminished prolactin reserve with myotonic dystrophy. J Endocrinol Invest 1980;3:415–418. 467 Kauppila A, Chatelain P, Kirkinen P et al. Isolated prolactin deficiency in a woman with puerperal alactogenesis. J Clin Endocrinol Metab 1987;64:309–312. 468 Puig ML, Webb SM, del Pozo C et al. ACTH and prolactin deficiency. Acta Endocrinol (Copenh.) 1986;111:296–299. 469 Jialal I, Desai R, Rajput MC et al. Prolactin secretion in Sheehan’s syndrome. Responses to thyrotropin-releasing hormone and metoclopramide. J Reprod Med 1986;31:487–490. 470 Jialal I, Naidoo C, Norman RJ et al. Pituitary function in Sheehan’s syndrome. Obstet Gyencol 1984;63:15–19. 471 Cosman F, Post KD, Holub DA, Wardlaw SL. Lymphocytic hypophysitis. Report of 3 new cases and review of the literature. Medicine (Baltimore) 1989;68:240–256. 472 Edwards OM, Clark JD. Post-traumatic hypopituitarism. Six cases and a review of the literature. Medicine (Baltimore) 1986;65:281–290. 473 Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol 1997;46:263–268. 474 DeVile CJ, Stanhope R. Hydrocortisone replacement therapy in children and adolescents with hypopituitarism. Clin Endocrinol (Oxf.) 1997;47:37–41. 475 Monson JP. The assessment of glucorticoid therapy. Clin Endocrinol (Oxf.) 1997;46:269–270. 476 Esteban NV, Loughlin T, Yergey AL et al. Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab 1991;71:39–45. 477 Peacey SR, Guo CY, Robinson AM et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol 1997;46:255–261. 478 Peacey SR, Yuan Guo C, Eastell R et al. Optimization of glucocorticoid replacement therapy: the long-term effect on bone mineral density. Clin Endocrinol (Oxf.) 1999;50:815–817. 479 Zelissen PM, Croughs RJ, van Rijk PP, Raymakers JA. Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Ann Intern Med 1994;120:207–210. 480 Wichers M, Springer W, Bidlingmaeir F et al. The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolinism. Clin Endocrinol (Oxf.) 1999;50:759–765. 481 Al-Shoumer KAS, Beshyah SA, Niththyananthan R, Johnston DG. Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypoituitary adults. Clin Endocrinol 1995;42:85–90.

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482 Al-Shoumer KAS, Ali K, Anyaoku V et al. Overnight metabolic fuel deficiency in patients treated conventionally for hypopituitarism. Clin Endocrinol 1996;45:171–178. 483 Fowlen J, Attvall S, Lager I, Bengtsson BA. Effects of treatment with recombinant growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism 1993;42:1443-1447. 484 Lamberts SWJ, Bruining HA, de Jong FA. Corticosteroid therapy in severe illness. N Engl J Med 1997;337:1285–1292. 485 Bernstein MS, Hunter RL, Yachnin S. Hepatoma and peliosis developing in a patient with Fanconi’s anemia. N Engl J Med 1971;284:1135. 486 Johnson FL, Lerner KG, Siegel M. Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 1972;2:1273. 487 Henderson JT, Sumerling MD. Androgenic-anabolic steroid therapy and hepatocellular carcinoma. Lancet 1973;1:934. 488 Westaby D, Paradinas Ogle SJ et al. Liver damage from long-term methyltestosterone. Lancet 1977;2:261. 489 Overly WL, Dankoff JA, Wang BK et al. Androgens and hepatocellular carcinoma in the athlete. Ann Intern Med 1984;100:58. 490 Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab 1980;51:1335. 491 Korenman SG, Viosca S, Guralnick M et al. Androgen therapy of hypogonadal men with transscrotal testosterone systems. Am J Med 1987;83:471. 492 Findlay JC, Place VA, Snyder PJ. Treatment of primary hypogonadism in men by the transdermal delivery of testosterone. J Clin Endocrinol Metab 1989;68:369. 493 Meikle AW, Mazer NA, Moellmer JF et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab 1992;74:623. 494 Meikle AW, Arver S, Dobs AS et al. Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: influence of application site—a clinical research center study. J Clin Endocrinol Metab 1996;81:1832. 495 Bocks DR, Meikle AW, Boike SC et al. Pharmacokinetics of testosterone in hypogonadal men after transdermal delivery: influence of dose. J Clin Pharmacol 1996;36:732. 496 Bhasin S, Swerdloff RS, Steiner B. A biodegradable testosterone microcapsule formulation provides uniform eugonadal levels of testosterone for 10–11 weeks in hypogonadal men. J Clin Endocrinol Metab 1992;74:75. 497 Behre HM, Nieschlag E. Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and pharmacodynamics of the new long-acting androgen ester. J Clin Endocrinol Metab 1992;75:1204. 498 Salehian B, Wang C, Alexander G et al. Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate—a clinical research center study. J Clin Endocrinol Metab 1995;80:3567. 499 Jockenhövel F, Vogel E, Kreutzer M et al. Pharmacokinetics and pharmacodynamics of subcutaneous testosterone implants in hypogonadal men. Clin Endocrinol 1996;45:61. 500 Handelsman DJ, Mackey MA, Howe C et al. An analysis of testosterone implants for androgen replacement therapy. Clin Endocrinol 1997;47:311. 501 Bhasin S, Storer TW, Berman N et al. Testosterone replacement increases fatfree mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 1997;82:407. 502 Behre HM, Kliesch S, Leifke E et al. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab 1997;82:2386. 503 Matsumoto AM, Sandblom RE, Schoene RB. Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep. Clin Endocrinol 1985;22:713. 504 Burris AS, Rodbard HW, Winters SJ et al. Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metabolism 1988;66:1144. 505 Kliesch S, Behre HM, Nieschlag E. Recombinant human follicle-stimulating hormone and human chorionic gonadotropin for induction of spermatogenesis in a hypogonadotropic male. Fertil Steril 1995;63:1326. 506 Abboud CF. Laboratory diagnosis of hypopituitarism. Mayo Clin Proc 1986;61:35. 507 Mannaerts B, Fauser B, Lahlou N et al. Serum hormone concentrations during treatment with multiple rising doses of recombinant follicle stimulating hormone (Puregon) in men with hypogonadotropic hypogonadism. Fertil Steril 1996;65:406.

508 Saal W, Happ J, Cordes U et al. Subcutaneous gonadotropin therapy in male patients with hypogonadotropic hypogonadism. Fertil Steril 1991;56:319. 509 Spratt DI, Crowley WF Jr, Butler JP et al. Pituitary luteinizing hormone responses to intravenous and subcutaneous administration of gonadotropinreleasing hormone in men. J Clin Endocrinol Metabolism 1985;61:890. 510 Schopohl J, Eversmann T, Mehltretter G et al. Comparison of gonadotropinreleasing hormone and gonadotropin therapy in male patients with idiopathic hypothalamic hypogonadism. Fertil Steril 1991;56:1143. 511 Berezin M, Weissenberg R, Rabinovitch O et al. Successful GnRH treatment in a patient with Kallmann’s syndrome, who previously failed hMG/hCG therapy. Andrologia 1988;20:285. 512 Baker VL. Alternatives to oral estrogen replacement: transdermal patches, percutaneous gels, vaginal creams and rings, implants, and other methods of delivery. Obstet Gynecol Clin North Am 1994;21:271. 513 Chetkowski RJ, Meldrum DR, Steingold KA et al. Biologic effects of transdermal estradiol. N Engl J Med 1986;314:1615. 514 Walsh BW, Schiff I, Rosner B et al. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991;325:1196. 515 van Erpecum KJ, van Berge Henegouwen GP. Verschoor L et al. Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women. Gastroenterology 1991;100:482. 516 Clisham PR, Cedars MI, Greendale G et al. Long-term transdermal estradiol therapy: effects on endometrial histology and bleeding patterns. Obstet Gynecol 1992;79:196. 517 Stevenson JC, Cust MP, Gangar KF et al. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet 1990;335:265. 518 Martin K Santoro N, Hall J et al. Management of ovulatory disorders with pulsatile gonadotropin-releasing hormone. J Clin Endocrinol Metabolism 1990;71:1081A. 519 Martin KA, Hall JE, Adams JM et al. Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metabolism 1993;77:125. 520 Carroll PV, Christ ER, Bengtsson BA et al. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 1998;83:382. 521 Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on adult growth hormone deficiency. J Clin Endocrinol Metab 1998;83:379. 522 Cuneo RC, Salomon F, Watts GF et al. The Australian multicenter trial of growth hormone treatment in growth hormone-deficient adults. J Clin Endocrinol Metab 1998;83:107–116. 523 de Boer H, Blok G-J, Voerman B et al. Changes in subcutaneous and visceral fat mass during growth hormone replacement therapy in adult men. Int J Obes Relat Metab Disord 1996;20:580–587. 524 Baum HBA, Biller BMK, Finkelstein JS et al. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency: a randomized, placebo-controlled trial. Ann Intern Med 1996;125:883. 525 Cuneo RC, Salomon F, Wiles CM et al. Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance. J Appl Physiol 1991;70:695–700. 526 Baum HB, Biller BM, Finkelstein JS et al. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebo-controlled trial. Ann Intern Med 1996;125:883–890. 527 Ohlsson C, Bengtsson BA, Isaksson OG et al. Growth hormone and bone. Endocr Rev 1998;19:55–79. 528 Kann P, Piepkorn B, Schehler B et al. Effect of long-term treatment with growth hormone on bone metabolism, bone mineral density and bone elasticity in growth hormone deficient adults. Clin Endocrinol (Oxf.) 1998;48:561–568. 529 Johansson G, Rosen T, Lindstedt G et al. Effect of 2 years of growth hormone treatment on body composition and cardiovascular risk factors in adults with growth hormone deficiency. Endocrinol Metab 1996;3(suppl A):3–12. 530 Russell-Jones DL, Watts GF, Weissberger A et al. The effect of growth hormone replacement on serum lipids, lipoproteins, apolipoproteins and cholesterol precursors in adult growth hormone-deficient patients. Clin Endocrinol (Oxf.) 1994;41:345–350. 531 Rosen T, Johansson G, Johansson J-O et al. Longterm effects of growth

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hormone replacement on cardiovascular risk factors. Endocrinol Metab 1996;3(suppl A):13–17. Beshyah SA, Henderson A, Niththyananthan R et al. The effects of short and long-term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance. J Clin Endocrinol Metab 1995;80:356. Weaver JU, Monson JP, Noonan K et al. The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity. and cardiovascular risk factors in hypopituitary adults. J Clin Endocrinol Metab 1995;80:153. O’Halloran DJ, Wieringa G, Tsatsoulis A et al. Increased serum lipoprotein(a) concentrations after growth hormone (GH) treatment in patients with isolated GH deficiency. Ann Clin Biochem 1996;33:330. Leese GP, Wallymahmed M, VanHeyningen C et al. HDL-cholesterol reductions associated with adult growth hormone replacement. Clin Endocrinol (Oxf.) 1998;49:673. Borson-Chazot F, Serusclat A, Kalfallah Y et al. Decrease in carotid intimamedia thickness after one year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab 1999;84:1329. Cuneo RC, Salomon F, Watts GF et al. Growth hormone treatment improves serum lipids and lipoproteins in adults with growth hormone deficiency. Metabolism 1993;42:1519–1523. Cuneo RC, Wilmhurst P, Lowy C et al. Cardiac failure responding to growth hormone. Lancet 1989;1:838–839. Thuesen L, Jorgenson JO, Muller JR et al. Short and longterm cardiovascular effects of growth hormone therapy in growth hormone deficient adults. Clin Endocrinol (Oxf.) 1994;41:615–620. Wiren L, Bengtsson B-A, Johannson G. Beneficial effects of long-term growth hormone replacement on quality of life in adults with growth hormone deficiency. Clin Endocrinol (Oxf.) 1998;48:613–620. Drake WM, Coyte D, Camacho-Hubner C et al. Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults. J Clin Endocrinol Metab 1998;83:3913–3919. Bengtsson B, Abs R, Bennmarker H et al. The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults. J Clin Endocrinol Metab 1999;84:3929–3935.

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543 Lieberman SA, Mitchell AM, Marcus R et al. The insulin-like growth factor 1 generation resistance to growth hormone with aging and estrogen replacement therapy. Horm Metab Res 1994;26:229–236. 544 de Boer H, Blok J, Popp-Snijders C et al. Monitoring of growth hormone replacement therapy in adults, based on measurements of serum markers. J Clin Endocrinol Metab 1996;81:1371–1377. 545 Ter Maaten JC, de Boer H, Kamp O et al. Long-term effects of growth hormone (GH) replacement in men with childhood-onset GH deficiency. J Clin Endocrinol Metab 1999;84:2373–2380. 546 Holmes SJ, Shalet SM. Which adults develop side-effects of growth hormone replacement? Clin Endocrinol (Oxf.) 1995;43:143. 547 Malozowski S, Tanner LA, Wysowski D et al. Growth hormone, insulin-like growth factor I, and benign intracranial hypertension. N Engl J Med 1993;329:665. 548 Koller EA, Green L, Gertner JM et al. Retinal changes mimicking diabetic retinopathy in two nondiabetic, growth hormone-treated patients. J Clin Endocrinol Metab 1998;83:2380. 549 Fish LH, Schwartz HL, Cavanaugh J et al. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med 1987;316:764. 550 Ferretti E, Persani L, Jaffrain-Rea ML et al. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999;84:924. 551 Bunevicius R, Kazanavicius G, Zalinkevicius R et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340:424–429. 552 Wyatt DT, Gesundheit N, Sherman B. Changes in thyroid hormone levels during growth hormone therapy in initially euthyroid patients: lack of need for thyroxine supplementation. J Clin Endocrinol Metab 1998;83:3493–3497. 553 Rodriguez-Arnao J, Perry L, Besser GM, Ross RJM. Growth hormone treatment in hypopituitary GH deficient adults reduces circulating cortisol levels during hydrocortisone replacement therapy. Clin Endocrinol 1996;45:33–37. 554 Weaver JU, Thaventhiran L, Noonan K et al. The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults. Clin Endocrinol 1994;41:639–648.

S e c t i o n 3

Pituitary Tumors

C h a p t e r

10 Pituitary Surgery R. F M. Buchfelder P. Nomikos

The goal of pituitary surgery changed during the twentieth century – in 1889, the first pituitary surgeons tried to find an approach to the sellar region and decompress the optic nerves, preserving thus patient’s life. When mortality statistics became better, the goal was to remove as much tumor as possible in order to prevent recurrences. Low morbidity, better cosmetic results and quality of life played an important role much later. It is only in recent years that complete tumor removal and restoration of visual disturbances under preservation or even recovery of pituitary function were to become the goal to reach. A brief review of the amazing evolution of pituitary surgery, surgical anatomy, diagnostic evaluation, modern surgical techniques and the surgical results in the consecutive series of patients treated in the Neurosurgical Department of Erlangen-Nürnberg follow. The future of pituitary surgery is then discussed. HISTORICAL OVERVIEW Pituitary tumors may compose about 15% of intracranial neoplasms. Due to their frequency, the management of these neoplasms presents a common problem in general neurosurgical practice. This is why the first surgical interventions were performed early but with great doubt that they could be successful. The first surgeon to operate on a pituitary tumor was Sir Victor Horsley in 1889, however, he did not report this new innovative operative technique until 1906 [1]. He first used a frontal and later a temporal craniotomy to avoid vascular complications, dealing with frontal veins in a total of 10 patients with two deaths. By then, several other surgeons have developed approaches to the sellar region. A right frontal osteoplastic approach was developed by Fedor Victor Krause (Berlin), who removed a bullet located in the region of the right optic foramen in a 20-year-old patient in 1900 [2]. He quickly realized the approach could also be

used to access pituitary tumors and operated on several cases. In 1913, Charles Frazer (Philadelphia) reported his experience with a frontal extradural approach, which was later modified to an intradural one with removal of the supraorbital ridge and parts of the orbital roof [3,4]. In 1918, George Heuer and Walter E. Dandy (Baltimore) presented 24 patients operated by a frontal intradural approach using a larger exposure of the brain than Frazer [5]. This approach was later modified by Dandy, who performed a smaller craniotomy in order to avoid extended brain trauma and to lower the risk of postoperative epidural hematoma from the large bone flap. In 1934, he mentioned in his report that “the nasal route was impractical and can never be otherwise” [6]. Even Harvey Cushing, who established the transsphenoidal operation we know today, favored the transcranial route. A few surgeons continued to prefer the transnasal route, which later became the most frequently used approach due to further technical refinements dealing with sellar lesions. The first transnasal operation to remove a pituitary tumor was performed by Herman Schloffer in Austria in 1907. The incision was performed around the left side of the nose, which was then completely dislocated and turned to the right side [7]. In the same year, Anton von Eiselsberg (Vienna) modified the approach, dislocating the nose downwards, and reported on six cases in 1910 [8,9]. An otolaryngologist, Oscar Hirsch, developed the first approach that did not require complete dislocation of the nose in 1910 [10]. Some months later, he performed a submucous paraseptal approach using a nasal speculum for the first time [11]. Some otolaryngologists preferred the extra-axial superior transethmoidal approach of Chiari, others the extra-axial inferior transmaxillar approach of Denker and Hamberger. Both methods have only been used sporadically and never gained wide acceptance. 405

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Harvey Cushing performed his first transsphenoidal approach on March 26, 1909 [12]. He refined his technique, combining methods of several other surgeons, for example the sublabial incision, the submucous paraseptal preparation to the sphenoid sinus, the use of nasal specula, and the use of an electric forehead lamp. The procedure has become known as the “Cushing’s approach” to sellar lesions. Cushing later abandoned this procedure, preferring the transcranial approach, mainly because of a better normalization rate of impaired vision and lower risk of repeat surgery [13]. This prompted neurosurgeons to abandon the transsphenoidal approach. Sporadic reports of various modifications came from otorynolaryngologist like Hirsch, who in the meantime had emigrated to Boston, James to London, and Hamberger to Stockholm. The reintroduction of the so-called “Cushing’s procedure” was performed by Norman Dott, the only pupil of Cushing’s who did not abandon his method. Dott operated in Edinburgh on more than 100 pituitary adenomas without mortality and without recurrences, due to postoperative radiotherapy. It is not clear why he never published his results. In 1956, Dott introduced Gerard Guiot to his method. It was Guiot who refined the technique, using image intensification and introducing the semisitting position [14,15]. Jules Hardy, a pupil of Guiot, introduced the operative microscope, operated on several thousand patients in Canada and published several reports concerning transsphenoidal surgery. Even after the introduction of medical treatment with antisecretory drugs and further refinement of the techniques of radiotherapy, surgery still plays the most important role in the management of pituitary tumors. DIAGNOSTIC EVALUATION An overview of the interdisciplinary diagnostic procedures available is presented in Figure 10.1. Currently the most frequently used and most helpful diagnostic imaging procedure in the neuroradiological work-up of patients harboring pituitary tumors is magnetic resonance imaging (MRI) [16]. MRI not only directly depicts tumor size, extension and characteristics such as hemorrhagic and cystic changes (T2weighted images), but also helps to delineate the tumor from the surrounding anatomical structures (T1-weighted images pre- and post-Gadolinium). This is important primarily in parasellar invasive tumors, where encroachment of the tumor tissue along the basal dura and localized or generalized invasion into the cavernous sinus need to be differentiated from displacement without invasion. Multinodular development is usually considered to be very suspicious of invasive tumor growth, just as marked suprasellar extension without adequate visual compromise. The course of the major intracranial vessels may be visualized by MRangiography and may add information on the exact localization of the branches of the carotid artery, mostly replacing the need for conventional carotid angiography.

Neuroradiology • MRI • MR-angiography • (CT)

Ophthalmology OC

CA

Endocrinology • Pituitary deficiency • Hormone excess

FIGURE 10.1. sellar tumors.

Interdisciplinary diagnostic evaluation of

The value of plain skull X-rays and computerized tomography (CT) in the diagnostic evaluation of pituitary tumors has decreased. In plain skull X-rays, ballooning or even some destruction of the sella floor may be visible. However, a thin sellar floor, which is preserved in its continuity, may mimic destruction. Therefore, this finding is not conclusive of an invasive tumor. On the other hand, circumscribed penetration of the sella floor by a truly invasive tumor may not be visible in X-ray films of the sella. For planning the operative approach, a possible deviation of the osseous nasal septum and also the pneumatization of the sphenoid sinus are of some significance. Thin collimation CT with reconstruction of the sella may directly depict the tumor as well as the bony structures so that infiltration of the sellar floor and penetration in the sphenoid sinus may be easily detected [17]. Invasion of the cavernous sinus by a parasellar tumor is hardly recognizable by CT since the cavernous sinus exhibits similar contrast enhancement, thus hindering the differentiation between normal and pathological structures laterally to the sella. Visual compromise develops only in tumors with a suprasellar extension of more than 10–15 mm above the plane of the diaphragma sellae. Assessment of visual fields and visual acuity is then necessary. Parasellar tumor extension sometimes leads to palsies of the cranial nerves III, IV, and VI. The trigeminal nerve is rarely involved in parasellar tumors. However, many patients with infiltration or invasion of the cavernous sinus complain about periorbital pain, which in the majority of the cases disappears after tumor removal. A specific situation exists in pituitary apoplexy which may either be caused by acute hemorrhage or by infarction of a pituitary adenoma. Frequently, the oculomotor nerve is involved. Endocrine evaluation is mandatory as soon as the pituitary fossa or gland is involved in the pathological process. Anterior pituitary function and a possible hormonal activ-

Chapter 10

ity of pituitary adenomas are assessed by dynamic endocrine pituitary tests, such as ACTH-, TRH-, LHRH-, CRH-, GRH-stimulation, oral glucose load, insulin tolerance testing and dexamethason-suppression. In particular, the exact knowledge of the serum prolactin level is mandatory. In case of a prolactinoma (prolactin levels >six to 10-fold elevated) medical treatment with dopamine agonists has generally to be taken into consideration as a therapy option. In invasive growth hormone producing adenomas, preoperative treatment with somatostatin analogs may be utilized to shrink the tumor within the cavernous sinus, soften its consistency and thus allow easier surgical removal. SURGICAL AND FUNCTIONAL ANATOMY Understanding the anatomical relationships between the hypothalamus, the pituitary gland, the carotid artery, the optic nerve and the bony structures around them is paramount for every surgical approach to the sellar area. The hypothalamus is located behind the optic chiasm, between the optic tracts and anterior to the mammilary bodies and can be divided into four regions: (i) preoptic; (ii) supraoptic; (iii) tuberal; and (iv) posterior [18,19]. The numerous hypothalamic nuclei have connections to optic and olfactory centers and regulate body temperature, food and water intake, sleep, reproduction, the physiologic circadian rhythms and behavioral responses by producing and releasing neurally active substances. Stimulatory and inhibiting hormones travel into the capillaries of the portal venous plexus to reach the anterior lobe of the pituitary gland. Vasopressin and oxytocin are transported to the posterior lobe by axoplasmatic flow along the hypothalamo–hypophyseal tract. The pituitary gland or hypophysis cerebri (from the Greek upo- [below], and jue´sqai [to grow]) consists of the adeno- and the neurohypophysis. The adenohypophysis is divided into three regions: (i) the pars distalis or anterior lobe; (ii) the pars intermedia; and (iii) the pars tuberalis, which is applied to the infundibular stem. Five distinct cell types produce different hormones: (i) somatotrophs (growth hormone); (ii) lactotrophs (prolactin); (iii) corticotrophs (adrenocorticotropin hormone); (iv) thyrotrophs (thyroidstimulating hormone); and (v) gonadotrophs (luteinizing and follicle-stimulating hormone). The neurohypophysis consists of a portion of the base of the hypothalamus, the pituitary stalk and the posterior lobe of the pituitary gland, where oxytocin and vasopressin are stored. The cavernous sinus extends from the superior orbital fissure anteriorly to the petrous apex posteriorly and is conically shaped. The dura of the superior wall of the cavernous sinus forms medially the diaphragm sellae. The third, fourth, fifth and sixth nerves traverse the cavernous sinus during their course. The carotid artery traverses the petrous apex region underneath the Gasserian ganglion and enters the cavernous sinus. The carotid artery exits the cavernous sinus medial to the anterior clinoid process, beneath and lateral to the optic nerves, which form the optic chiasm in their further course,

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that only lies some 10 mm above the diaphragm and exhibits many anatomical variations: it can be prefixed, just above the tuberculum, or postfixed, above the dorsum sellae. All suprasellar arteries give origin to multiple perforating branches. The thalamoperforate and the medial posterior choroid arteries are the largest of these “perforators” that arise from the posterior parts of the circle of Willis [20]. SURGICAL TECHNIQUES The general principles of the various approaches (Fig. 10.2) are similar in different centers, despite technical variations. The most common approaches—the transsphenoidal and the transcranial pterional (frontolateral)—described here in detail are those in use in the Neurosurgical Department of the University of Erlangen-Nürnberg in Germany. Depending on the localization and extension of the tumors, a combination of two or three different approaches may be necessary. Transcallosal approach Transventricular approach

Corpus callosum

Foramen monroi Tumor

Right

Left

Bifrontal approach

Pterional approach

Frontal lobe

Optic chiasm

Tumor Temporal lobe

A. Carotis Clivus

FIGURE 10.2. suprasellar region.

Different transcranial approaches to the

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Transsphenoidal Approach

Transcranial Pterional Approach

The original Cushing’s method is used: the patient is positioned supine with the head tilted downwards about 10 degrees and the surgeon standing behind the patient. A unilateral paraseptal approach is used. Depending on the nasal anatomy and the extent of the lesion, the mucosal incision is usually made in the vestibulum nasii along the cartilaginous nasal septum. Alternatively, a sublabial incision may be used. Under careful dissection with a rasp, the plane between cartilage and perichondrium is exposed. A mucosal tunnel is made without leaving this plane in order to prevent mucosal tearing. Resection of the anterior spine of the maxilla gives better visualization of the tunnel. The basal cartilaginous septum is then mobilized and a Cushing-type speculum is inserted. Using the operating microscope, the tunnel is enlarged exposing the bony nasal septum, which has to be removed in order to the reach the sphenoid sinus. The floor of the sphenoid sinus is then opened using a diamond drill and a larger self-retaining speculum is inserted. The sphenoid sinus is opened wide. The mucosa and all septums have to be removed, exposing the whole sella turcica from the sphenoidal plane to the clivus. In case of incomplete pneumatization of the sphenoid sinus, the use of a drill is necessary in order to achieve such a wide exposure. The sellar floor is then opened and is completely resected to the medial wall of the cavernous sinus. The basal dura is then opened and a small biopsy is taken to rule out tumor invasion histologically. The tumor is then removed using various curettes. During tumor removal, the diaphragm is usually descending in the pituitary fossa. If this does not occur spontaneously, it can be usually accomplished by an increase of the intracranial pressure using positive endexpiratory pressure ventilation or compression of the jugular veins. In case of CSF-leak, the surgical opening is sealed by two pieces of fascia lata fixed by fibrin glue (Fig. 10.3). A lumbar drainage is then placed for CSF-drainage until the third postoperative day. The mucosal incision is then closed and both nostrils are tamponated for 24 hours. Technical variations such as the use of the endoscope or the direct approach through the nasal cavity will be discussed later in this chapter.

A small standard pterional craniotomy is used, but unusual extensions of large tumors require a correspondingly designed approach, such as the bifrontal craniotomy with a subfrontal-translaminar tumor approach for tumors extending into the supra- and retrosellar region, and the transventricular approach for tumors involving the third ventricle and causing (partial) blockage of the foramen of Monro with enlarged ventricles. Following the elevation of the bone flap, the opening is expanded towards the floor of the middle fossa. The dura around the sphenoid wing is separated and the spine of the wing is removed by a rongeur. It is of great importance to completely flatten the posterior ridge of the greater wing in order to free the plane of vision to the suprasellar area without the need for marked retention of the frontal lobe and to gain space for manipulations after the opening of the dura. Once the suprasellar cisterns are visible, CSF should be gained providing an easier access. Due to the lesion, the circle of Willis and the optic apparatus are stretched. It is paramount to prevent further damage to this structure as well as to the hypothalamus. Many suprasellar tumors contact the hypothalamic area and grow adherent to it. Surgical manipulations to separate the tumor from the hypothalamus may lead to severe hypothalamic dysfunction. The tumor is usually resected piecemeal by incising the tumor capsula and performing an intracapsullar evacuation of tumor tissue. The capsula is then mobilized, preserving the perforating arteries to the hypothalamic region and to the optic nerves. The stalk of the pituitary is not always easily identified; sometimes it is stretched, displaced or even infiltrated by tumor. In some cases, complete resection of the lesion means sacrificing of parts or even complete resection of the pituitary stalk. With respect to tumors invading the cavernous sinus, the possibility of increasing the total resectable tumor mass is accompanied by a higher morbidity, particularly of optomotoric nerve dysfunction. Despite these extensive manipulations, total tumor resection and normalization of hormonal hypersecretion can not usually be achieved by surgery alone in these cases. Authors with special anatomic experience describe extensive resection of tumors within the cavernous

DS FL CSF

FIGURE 10.3. CSF-leak during transsphenoidal surgery and repair of the sellar floor with two layers of fascia lata.

Chapter 10

sinus [21]. Regarding the biologic course in case of pituitary adenomas, given the possibility of additional medical treatment in pituitary adenomas secreting prolactin and growth hormone as well as the efficiency of focused and conventional radiotherapy, the authors believe that this kind of surgery should be reserved for specific cases. COMPLICATIONS Mortality and morbidity have decreased tremendously in the microsurgical era. After transsphenoidal surgery, meningitis and CSF-leak occur in less than 1% of the cases [22]. Rebleeding is rare and must be suspected if a severe headache associated with deterioration of vision occurs postoperatively. This situation requires evacuation of the hematoma and is prevented by careful hemostasis. Ocular nerve palsies, occurring especially after transsphenoidal resection of parasellar pituitary tumors have, in our experience, been rare and always transient. Deterioration of the anterior and posterior pituitary lobe may occur and in individual cases necessitate permanent replacement therapy. FURTHER TREATMENT

Radiotherapy Surgical invasion as recognized during surgery is generally considered an indication for postoperative radiotherapy unless only localized invasion, which could be sufficiently treated by surgery, was encountered. In the case of invasive secreting adenomas, irradiation is not mandatory if dynamic endocrine testing postoperatively indicates a normalization of the previously excessive hormone secretion. External megavoltage radiotherapy is mostly used and a total dose ranging from 45 to 50 Gy applied in daily fractions of 1.8–2.0 Gy is recommended [23]. In cases with a distinct and small tumor remnant, focused radiation treatment with the gamma-knife or the LINAC-system should be considered [24]. Severe soft tissue reactions and visual deterioration are rare, and induction of malignancies and cerebral radionecrosis are extremely rare adverse effects of radiotherapy [25]. Primary radiotherapy is used only for some patients in poor general condition and those showing signs of hypothalamic dysregulation. All other tumors should be surgically debulked before being irradiated.

Recurrences Diagnosis of recurrent pituitary tumor depends on the surgeon’s impression of complete tumor resection, normalization of hormonal hypersecretion and the absence of residual tumor in postoperative sophisticated imaging (MRI) [26]. In our experience the CT is much less reliable. However, even today it is not easy to differentiate between tissue suspicious of tumor recurrence and normal sellar structures, for example re-expansion of a compressed cav-

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ernous sinus. This fact, as well as the unequal duration of follow-up intervals, explains why the percentage of recurrences reported in the literature varies considerably. Recurrences can be prevented by more radical resections, for example, surgery in two stages as well as with improved visualization: endoscopy and intraoperative resection control by MRI. Recurrences can also be prevented by postoperative radiotherapy. Histologic proof of invasion and the determination of the cell proliferation (DNA-polymerase activity, Ki-67, immunohistochemistry with proliferation associated antibodies and DNA-flow-cytometry) may also help to predict tumor recurrence [27].

Medical treatment In general, medical treatment supplements surgery. Defective anterior pituitary function and diabetes insipidus require compensation by adequate substitution therapy. Long-term control of tumor growth with medical treatment of pituitary tumors is possible in prolactinomas. Dopamine agonists have been shown to lower prolactin, reduce the size of the adenoma, and to improve disturbed visual function in cases of visual compromise by displacement of the optic nerves or chiasm. Surgery is reserved for cases with intolerance to medical treatment due to side effects (orthostatic dysregulation, gastrointestinal discomfort), for nonresponders and for patients preferring operative treatment. One has to consider that in invasive prolactinomas, normoprolactinaemia is very unlikely to be achieved postoperatively, so that long-term continuation of low dose dopamine agonistic treatment is necessary in nearly all cases of large prolactinomas with and without surgery. Medical treatment with dopamine agonists and somatostatin analogs can be used in cases of invasive growth hormone producing adenomas if surgical therapy fails to restore normal growth hormone dynamics. Ketoconazole, an imidazole derivate that inhibits the synthesis of ergosterol and metyrapone, an inhibitor of the adrenocortical steroid 11-beta-hydroxylation, contributes to an amelioration of clinical symptoms in cases of Cushing’s disease and is used preoperatively in severely ill patients in order to reduce the operative risk or adjunct to external radiation. PITUITARY TUMORS Dealing with sellar lesions, one should distinguish between primary, metastatic and inflammatory pituitary tumors, which may mimic each other in their radiologic and clinical appearance. The relative frequency of various pituitary tumors treated in the Department of Neurosurgery of the University of Erlangen-Nürnberg during the past 16.5 years, is presented in Table 10.1. This classification may be used as one of the clues to the differential diagnosis of these lesions. Beginning with a comprehensive review of the surgical anatomy and continuing with the various tumor types, emphasizing the typical findings in their diagnostic

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Table 10.1. Classification and incidence of pituitary tumors surgically treated in the Department of Neurosurgery of the University of Erlangen–Nürnberg from 1 December 1982–30 June 1999 (n = 3305) I. Common tumors of the sella turcica

n = 3138

Pituitary adenomas Nonfunctioning adenomas GH-omas Prolactinomas ACTH-producing adenomas TSH-omas Craniopharyngiomas Supra- and parasellar meningiomas Miscellaneous cystic lesions Rathke’s cleft cysts Intrasellar colloid cysts Arachnoid cysts

n = 2640 n = 1093 n = 624 n = 519 n = 382 n = 22 n = 202 n = 126 n = 85 n = 39 n = 30 n = 16

II. Rare tumors of the sella turcica

n = 167

Optico-hypothalamic gliomas Metastases Chordomas Inflammatory lesions Germinomas Hypothalamic hamartomas Chondromas Epidermoids

n = 42 n = 27 n = 23 n = 24 n = 15 n=5 n=5 n=5

Miscellaneous pituitary tumors Granular cell tumor, paragangliomas, Pituitary carcinomas, mucocele, chiasmatic cavernoma, hypothalamic lipoma, sarcoidosis

n = 21

endocrinological and radiological evaluation, the management of sellar and parasellar neoplasms is reviewed.

Pituitary Adenomas The incidence of pituitary adenomas in unselected autopsy series is almost 25%, but they account for only 15% of the intracranial tumors in neurosurgical practice [28,29]. In many cases these lesions remain undiagnosed since they do not cause clinical symptoms. Depending on the capability to produce different hormones which can be detected with routine hormone-assays and histological staining methods, pituitary adenomas are classified with the most frequent being prolactinomas and null cell adenomas followed by growth hormone, ACTH and TSH producing adenomas. Some adenomas secrete more than one hormone. The most common combination is the prolactin and growth hormone producing adenoma. Earlier classifications on the basis of cytoplasmatic staining affinities in acidophilic, basophilic and chromophob adenomas are obsolete due to the poor correlation with the secretory activity of the tumors [30]. In cases of hormonal hypersecretion, patients present with well-

defined clinical syndromes. Other patients present with clinical symptoms of impaired pituitary function resulting from compression of the pituitary gland. In such cases, somatotrophs belong to the most vulnerable cell type causing GH-deficiency, followed by gonadotrophs causing hypogonadism, thyrotrophs causing hypothyroidism, and corticotrophs causing secondary adrenocortical failure. Patients may also present with various neurologic symptoms. Tumors with marked suprasellar extension may cause impairment of visual acuity, lead to the pathognomonic (bi-) temporal visual field loss, and may even result in obstruction hydrocephalus due to compression or obstruction of the foramen of Monro. Lesions extending into the parasellar region compress the cavernous sinus and may affect the cranial nerves traversing the sinus, thus causing periorbital pain, facial hypaesthesia and diplopia. Huge invasive tumors extending into the skull base may present with obstruction of nasal air pathways or cerebrospinal fluid leak. In almost every type of pituitary adenomas except prolactinomas, surgery is the primary treatment of choice. Transsphenoidal surgery is the most commonly used approach. It may be applied in almost 90% of these lesions. For the remaining, a transcranial, usually pterional, approach or a combined transsphenoidal and transcranial approach is needed. Nonfunctioning Pituitary Adenomas

Clinically nonfunctioning pituitary adenomas are also called endocrine inactive or nonsecreting adenomas, because they do not cause specific clinical syndromes of hormonal oversecretion, which can be clinically recognized or determined from tumor markers in the patient’s serum. However, the majority of these tumors obviously are endocrinologically active [31]. This can be concluded from the results of cell explant culture studies and immunohistochemical examinations. However, their endocrine activity has no clinical significance until now: it neither offers a basis for an efficient medical treatment (GnRH analogs, somatostatin analogs) nor provides tumor markers which would indicate complete tumor removal, tumor remnants or recurrences [32]. In cell explant cultures, most frequently the expression of gonadotropins can be determined in older patients. Immunohistochemical examinations demonstrate gonadotropins (including alpha- and beta-subunits) in about 80% of the tumors. Some 14% are positive for hormones other than gonadotropins, e.g. the so-called “silent” somatotroph, corticotroph adenomas and gonadotroph adenomas. Only 6% are completely negative for all pituitary hormones—pure or oncocytic null cell adenomas. Lacking clinical significance, the only difference between the two types is that in oncocytomas, there is a marked mitochondrial accumulation. Patients harboring clinically nonfunctioning pituitary adenomas present with tumors large enough to cause mass effects such as visual compromise and various degrees of hypopituitarism. In many cases the lesion is discovered incidentally when radiologic evaluation is performed for an unrelated reason, such as a head trauma.

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Table 10.2 Overview of indications for surgerical treatment in a recent consecutive series of 60 patients being surgically treated between 1997 and 1998 Prolactinomas 1997–1998: indications for surgery Non-responder Dopamine agonists not tolerated Only discrete elevation of prolactin levels Patient’s wish Giant adenoma with apoplexy

FIGURE 10.4. Large intra- and suprasellar nonfunctioning pituitary adenoma surgically treated by a transsphenoidal approach.

Patients with incidental tumors may remain in close observation, particularly if the tumors are small in size. However, impairment of endocrinological and ophthalmological function would add to the indication for surgical treatment. The rate of recurrence-free survival after total removal is approximately 85% after a follow-up period of 10 years (Fig. 10.4). Prolactinomas

Prolactinomas constitute the largest group of pituitary adenomas in autopsy series. However, their relative incidence in recent surgical series is dramatically reduced because medical treatment with dopamine agonists is effective since it leads in many cases to tumor shrinkage and normalization of prolactin levels. Patients present with the clinical symptoms of hyperprolactinemia: menstrual dysfunction and galactorrhea in women and loss of libido and potency in men. Prolactinomas may also cause various clinical symptoms due to their size, compressing surrounding structures like the pituitary gland, cavernous sinus and optic nerves. In men they tend to be diagnosed later than in women [33]; their tumors are larger and more frequently show an inva-

n = 60 22 14 11 9 4

sive pattern. The standard treatment is medical. Disadvantages of medical therapy are side effects, like orthostatic hypotension, nausea and vomiting. However, the changes induced by dopamine agonists are not tumoricidal. The therapeutic effect is only maintained as long as the drug is administered. After withdrawal of the drugs, the prolactin level is expected to rise again and the tumor enlarges. Thus, in most cases, the treatment has to be continued life-long with a few casuistical exceptions, in whom normoprolactinemia is maintained after discontinuation of dopamine agonists. The most commonly used drug is bromocriptine, but several others may be used including lisuride, pergolide, and the newer generation drugs quinagolide and cabergoline. The latter two gained considerable attention because of their extended plasma half-life allowing longer application intervals [34–36]. Surgery is reserved mostly for patients with intolerance to the medication, those not responding to dopamine agonists (which constitute less than 10% of the cases) and those who for personal reasons reject medical treatment. A brief overview of indications of surgery in a recent series of 60 patients treated in 1997 and 1998 is presented in Table 10.2. Remission rates in large series of surgically treated prolactinomas vary between 54% and 86% [37–40]. In our consecutive series of 519 surgically treated prolactinomas, the normalization rate after transsphenoidal surgery depends on the preoperative prolactin levels, the tumor size and extension (Table 10.3). The remission rate of 80% in microprolactinomas with initial prolactin levels <4000 mU/ml still makes surgical treatment an interesting alternative to long-term medical treatment. Growth Hormone-producing Pituitary Adenomas

GH-producing pituitary adenomas are the cause of almost all cases of acromegaly and gigantism. An ectopic GH-producing adenoma or a hypothalamic GHRH-producing tumor is an extreme rarity [41]. Hypersecretion of growth hormone results in acral enlargement of the acres (hands and feet), soft tissue swelling, hyperhidrosis, macroglossia, prognathism, retroorbital pain, carpal tunnel syndrome and in metabolic disturbances. Growth hormone acts anabolic, diabetogenic and lipolytic. Acromegalic patients develop cardiac and respiratory dysfunction and have a significantly decreased life expectancy [42]. The therapy of choice is

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Table 10.3. Normalization of PRL secretion in patients with surgically treated prolactinomas in relation to the tumor extension and preoperative PRL levels after primary surgery (micro: <10 mm; macro: 10–40 mm; giant: >40 mm; is: intrasphenoidal; ps: parasellar; sphe: sphenoidal; S1: suprasellar with no compression of the optic chiasm; S2: suprasellar with compression of the optic chiasm) Tumor extension

Micro

PRL < 500 mU/ml

<4000mU/ml 80%

Macro >4000mU/ml 49%

is 50%

ps/sphe 52%

S1 13%

S2 17%

Giant

S

0%

42%

Table 10.4. Normalization of GH secretion in patients with acromegaly in relation to the tumor extension and preoperative GH levels after primary surgery Giant

S

S2 48%

20%

73%

50–100

100–200

> 200

S

46%

35%

25%

73%

Tumor extension

Micro

Macro

GH (OGT) < 2 ng/ml

83%

is 87%

ps/sphe 67%

S1 70%

Preoperative GH level ng/ml GH (OGT) < 2 ng/ml

< 10

10–30

30–50

73%

57%

51%

surgical treatment. Primary radiation therapy to control tumor growth and/or long-term medical treatment with octreotide is preserved for patients with severe risk factors. Octreotide and lancreotide are both somatostatin analogues, which reduce GH levels and shrink the adenomas [43,44]. The most relevant side effects are gastrointestinal discomfort during short-term and gallstone formation during longterm treatment. Like dopamine agonists for prolactinomas, the effect is reversible concerning tumor extension and GH levels. Dopamine agonists may also be given to acromegalic patients but reduction of GH or IGF-1 to normal levels can be achieved in less than 20% of the cases [45]. In our consecutive series of 624 GH producing adenomas, the normalization rate after transsphenoidal surgery also depends on the preoperative GH levels and the tumor size (Table 10.4). The most favourable remission rate is achieved in the group harboring adenomas <10 mm with an initial serum GH level of <10 ng/ml. Normalization of growth hormone secretion in cases with an initial GH level higher than 50 ng/ml is only exceptionally achieved. The remission criteria were basal GH-levels <5 ng/ml and GH <2 ng/ml during OGTT. Remisson rates in other large published series depend on the remission criteria used and vary between 52% and 85% [46–50]. Cushing’s Disease

ACTH producing adenomas accounted for some 15% of the surgically treated pituitary adenomas in our consecutive surgical series. Cushing’s disease is more common in women (8 : 1) [51]. The patients present with typical clinical symptoms due to hypercortisolism: weight gain, centripetal obesity with moon face and buffalo hump, acne, purple

striae, ecchymoses, hirsutism, menstrual disturbances, loss of libido, osteoporosis with pathologic fractures, glucose intolerance and arterial hypertension [52]. In about 80% of the patients the endogenous Cushing’s syndrome is ACTH dependent (pituitary adenomas 85%, ectopic ACTH-syndrome 15%, ectopic CRH-syndrome <1%). An ACTH independent Cushing’s syndrome caused by adrenal adenomas or carcinomas is present in 20% of the cases [53]. Therefore, sophisticated endocrinological testing is necessary to diagnose the condition and to identify the cause. Circadian rhythm studies of serum and urine cortisol and the low-dose dexamethasone suppression test confirm the diagnosis of Cushing’s syndrome. High-dose dexamethasone and ACTH-stimulation after administration of CRH lead to the diagnosis of pituitary-dependent Cushing’s syndrome (Cushing’s disease). In the vast majority of the cases, the cause is a pituitary microadenoma. If thin collimation MRI fails to demonstrate the lesion (<2–3 mm), then bilateral blood sampling of the inferior petrosal sinuses should be performed. A gradient between central and peripheral ACTH levels confirms the diagnosis. A gradient between right and left petrosal sinus helps to identify the site of the lesion intraoperatively and offer the option of an hemihypophysectomy if no adenoma is found. In most large series, a remission of hypercortisolism can be induced in between 70% and 86% of patients [54–59]. The summary of the results of our series of 382 surgically treated patients is demonstrated in Table 10.5. Because of the severeness of the disease, patients are almost always in reduced general condition and need specific expert intra- and postoperative care. After endocrinological remission, the high recurrence rate of 16% in 10 years makes long-term postoperative

Chapter 10 Table 10.5. Normalization of ACTH secretion in patients with Cushing’s disease after primary surgery Primary surgery for Cushing’s disease n = 347 Selective adenomectomy (295/347) No tumor found 15% (52/347) Partial hypophysectomy n = 31 Remission (217/295) Persistence (78/295) Remission (10/31) Persistence (21/31)

85%

73.5% 26.5% 30.2% 67.7%

endocrinological testing necessary. In case of persistence or recurrence of the disease the treatment options include second-look surgery, bilateral adrenalectomy, medical treatment and radiotherapy. Rare Pituitary Adenomas

Nelson’s Syndrome First reported by Nelson, the syndrome was originally characterized by the classic trias of cutaneous hyperpigmentation, considerably elevated ACTHlevels and enlarged sella turcica when Cushing’s disease was treated by bilateral adrenalectomy [60]. This is the condition of increasing hyperpigmentation in patients with an enlarging ACTH producing adenoma when Cushing’s disease was treated by bilateral adrenalectomy, first described by Nelson. These tumors are usually invasive macroadenomas and the patients develop extremely high ACTH levels. In our series the incidence of this syndrome was 1.3%. The patients should eventually be treated surgically. Radiation therapy should be routinely utilized in these tumors since ACTH levels remain elevated postoperatively and in respect of the aggressive biologic behavior of these lesions [61]. TSH Producing Adenomas The first case with proven TSH secretion by radioimmunoassay was reported in 1970 [62]. Since then only some 300 cases of TSH producing adenomas have been reported in the medical literature—22 such patients underwent surgery in our department and remission was achieved in 14 of the patients. The patients usually present with signs and symptoms of hyperthyroidism in the presence of elevated TSH levels. Almost all patients have a history of surgically treated goitre. The pituitary tumors are mostly invasive macroadenomas and respond well to octreotide, which has been used successfully before surgery to suppress TSH, normalize the peripheral thyroid hormones and shrink the tumor [63]. In cases of residual tumor and persistence of elevated TSH levels medical treatment with octreotide and radiation therapy are utilized. Previous therapies sometimes make the clinical problems very complex. Gonadotropin Producing Adenomas These are uncommon and mostly remain undetected because of the lack of severe symptoms. These lesions have to be differen-

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tiated from nonfunctioning pituitary adenomas with only immunohistochemical evidence of FSH and LH (“silent” gonadotroph pituitary adenomas). Patients usually present with visual compromise and only sporadically an elevation of FSH in the serum may be diagnosed. Gonadotropin and TSH producing adenomas may additionally produce the aand b-subunits, which does not imply therapeutical significance [64].

Craniopharyngiomas Craniopharyngiomas arise from remnants of the Rathke’s pouch and account for 3% of all intracranial tumors. They can be differentiated into adamantinomatous and papillary craniopharyngiomas. The adamantinous type is more frequent and usually presents as a cystic, partially calcified lesion containing cholesterol crystals. Only 10% of the craniopharyngiomas are of the papillary type [65]. They occur only in adults and frequently involve the third ventricle. Both types develop in the intra- and suprasellar region, thus causing visual compromise and endocrine deficiencies (Fig. 10.5). They may cause hydrocephalus by obstruction of the cerebrospinal fluid circulation in cases in which the third ventricle is involved. They may extend into the hypothalamic area and may cause vegetative dysregulation as well as endocrine hypothalamic syndromes, like Fröhlich syndrome (hypothalamic/hypogonadal adipositas). As much as one-half of the newly diagnosed craniopharyngiomas are predominantly cystic. In about 60% of the tumors, different degrees of calcification are encountered. The patients age distribution shows peak incidences between 15 and 20 years, and between 50 and 55 years [66]. Approximately 40% of the patients are children aged less than 16 years at the time of surgery. The vast majority of patients harboring such a lesion present with impairment of anterior pituitary function, hypogonadism being the most frequent deficiency, followed by failure of the corticotrope and thyrotrope axis. Many patients present with diabetes insipidus [67]. Surgical treatment still remains a technical challenge and a subject of controversy. In many early reports, radical surgery led to an unacceptably high mortality and morbidity because of the involvement of both the hypothalamus and the pituitary gland. For this reason, other authors favored the therapeutic concept of conservative incomplete surgery followed by radiotherapy [68,69]. Concerning the many improvements which have been made in recent years, the goal of therapy should be selective removal of the tumor with preservation of the hypothalamus, midbrain, perforating vessels of the circle of Willis, optic pathways, pituitary stalk and pituitary gland. Depending on the tumor location, all available surgical approaches to the sellar region may be used. In many instances, combined approaches are necessary. The cases in which the transsphenoidal approach is suitable have the advantage of a favorably low morbidity and mortality. The rate of recurrence-free survival after total removal of the tumors may attain 80% after a follow-up interval of 10 years.

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FIGURE 10.5. Suprasellar craniopharyngioma. Intraoperative MRI reveals re-expansion of the third ventricle after total removal of the lesion (A: preoperative MRI, 0.2 T, Magnetom Open, Siemens; B: intraoperative MRI, 30 minutes after tumor resection; C: postoperative MRI, day 7).

Supra- and Parasellar Meningiomas Meningiomas originate from arachnoidal cap cells and are surgically classified by their site of origin. They account for about 15% of all intracranial tumors. Some 10% of meningiomas involve sellar and parasellar structures [70]. The tuberculum sellae meningioma is the classic suprasellar meningioma, causing slowly progressive loss of vision and headache. These tumors may invade the bony skull base, causing hyperostosis of the sphenoidal plane, may extend into the optic canal, and displace the carotid and the anterior cerebral arteries and the pituitary stalk causing hyperprolactinaemia, which is the only endocrine disturbance that can be usually detected. Meningiomas of the cavernous sinus usually cause the so-called cavernous sinus syndrome: diplopia and proptosis due to palsy of the sixth and third and periorbital pain and numbness due to compression of the fifth cranial nerves [71]. Patients with optic sheath meningiomas present with progressive and painless loss of vision but orbital pain, exophthalmus and ophthalmoplegia may also occur. Meningiomas of the clinoid however, process into the suprasellar cistern, the optic canal and invade the cavernous sinus. Diaphragma sellae and intrasellar meningiomas are rarely found. Various histologic types including the rare hemangiopericytoma and malignant meningioma can be found. Surgery is the treatment of choice in sellar and parasellar meningiomas. Depending on several factors, like the site of origin, extension, consistency, vascularization but also dura, bone and soft tissue infiltration, several meningiomas can be totally removed; others cannot, at least not without morbidity. The best results are obtained in suprasellar meningiomas, in which the tumor can be completely resected under preservation of the optic and oculomotor nerves. Treatment of meningiomas of the cavernous sinus is handled controversially among neurosurgeons [72]. Complete removal may lead to significant new neurological deficits and ischemia. The authors thus frequently prefer to perform a “slice technique;” trans-

sphenoidal decompression of the cavernous sinus and the pituitary gland in tumors with intra- and parasellar extension. In cases with progressive neurological deficit, transcranial decompression by resection of the lateral portions of the cavernous sinus meningioma is performed followed by radiotherapy. Medical treatment with hydroxyurea for tumor shrinkage, as advocated by Schrell, may be useful in many instances [73,74].

Miscellaneous Cystic Lesions Rathke’s Cleft Cysts

These are found in up to 20% of the specimens as tiny intrasellar lesions in large autopsy series, but it is unusual for them to enlarge and become symptomatic due to compression of the pituitary gland, the optic system and the hypothalamus [75]. Rathke’s cleft cysts are lined by epithelial cells that consist of a single layer of cuboidal and columnar epithelium on a basal membrane. In their radiologic appearance they may mimic craniopharyngiomas. Surgical treatment is suggested, when they become symptomatic. Depending on their location some 90% of these lesions can be removed by the transsphenoidal approach. Only exceptionally a recurrence occurs [76]. Intra- and Suprasellar Colloid Cysts

Also termed pars intermedia cysts, they consist of a circumscribed collection of colloid material within the pituitary gland that lacks a cyst wall [77]. Some of these patients harbor a concomitant pituitary adenoma. The most frequent presenting symptoms are oligomenorrhea, galactorrhea and headaches but panhypopituitarism may also occur. Postoperatively, a normalization of the pituitary function is observed in more than 80% of the cases. Again transsphenoidal surgery is indicated when the lesion becomes symptomatic.

Chapter 10 Arachnoid Cysts

These only sporadically involve the sellar region. Then, they are usually located in the suprasellar area. These patients present with headache, visual disturbances and hypopituitarism. Frequently the radiologic diagnosis is difficult, because in the MRI they appear as isointense lesions which in their signal are identical to CSF. Empty sella is the most probable differential diagnosis. In such a case, only metrizamide cisternography provides reliable preoperative diagnosis. Transsphenoidal or transcranial approaches are used in symptomatic arachnoid cysts for drainage, partial removal of the cyst wall and fenestration to the suprasellar cisterns [78].

Rare Pituitary Tumors Optico-hypothalamic Gliomas

Optico-hypothalamic gliomas are mostly pilocytic astrocytomas arising from the optic nerves, the chiasm, the walls of the third ventricle or the tuber cinereum. The patients present with visual disturbances (loss of vision, papilledema, optic atrophy, visual field defects). Frequently, hypothalamo–pituitary function remains unaffected despite the considerable size of the lesion. However, various endocrine disturbances including hypopituitarism, diabetes insipidus or even Russell syndrome (hypothalamic cachexia) and precocious puberty may occur. In some cases hydrocephalus is present due to obstruction of the foramen of Monro. Neurofibromatosis type 1 is not uncommon among patient harboring optico-hypothalamic gliomas [79,80]. The treatment is handled controversially and depends on the location and clinical symptoms. Treatment options include surgical total removal (intraorbital gliomas), removal of exophytic tumor parts (chiasmatic gliomas), chemotherapy (usually vincristine and carboplastin) or radiation therapy, which is reserved for older patients. In cases without progressive neurologic deficit, observation is recommended since many tumors do not enlarge during a long-term follow-up interval.

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Chordomas

Chordomas are histologically benign tumors that are derived from notochondral remnants and almost always involve the clival area. Their biologic character is extremely aggressive which is expressed by bone destruction, infiltration of the cavernous sinus and basal dura and extension into all cranial fossae [85]. Depending on the location of the chordomas, patients may present with visual compromise, pituitary deficiencies and ophthalmoplegia. Because of the invasive growth pattern total removal is not possible without high mortality and morbidity. Even after radiotherapy, the recurrence rate in our series is found to be 80% in 5 years. The survival rate after a follow-up period of 10 years is lower than 30%, but in individual patients, no tumor progression is observed even after 15 years. Inflammatory Lesions

Hypophysitis Lymphocytic hypophysitis is histologically characterized by infiltration of the pituitary gland by lymphocytes and plasma cells and by fibrosis. An autoimmune background and a relation to pregnancy have been suggested [86,87]. The granulomatous hypophysitis is characterized by granulomas with histiocytes and multinucleated giant cells but also shows a collection of lymphocytes. The most frequent presenting syndrome is a headache occurring in a fluctuating course due to recurrent aseptic meningitis, followed by diabetes insipidus, menstrual irregularities and visual compromise. Radiologically a dumb-bell shape lesion with a tongue-like supra- and retrosellar extension in the MRI is a characteristic finding that is to be seen in more than 60% of the cases (Fig. 10.6). After surgical treatment, recurrence occurs in some 10% of the patients [88]. Repeat surgery, medical treatment with corticosteroids and radiation therapy are additional treatment options.

Metastatic Tumors

Symptomatic metastatic tumors to the sellar area are rare lesions, but in autopsy series of patients with various types of cancer the incidence is reported to be as high as 27% [81]. The most common cancers that metastasize to the pituitary region are lung, prostate and stomach cancer in men and breast, lung and stomach cancer in women [82]. Sellar metastases are usually invasive tumors involving osseous structures as well as the pituitary gland. Patients present with diabetes insipidus and ophthalmological symptoms. Surgery is indicated to decompress surrounding tissue followed by radiotherapy. Involvement of the sellar region in metastasis of hematopoietic neoplasms is rarely observed [83]. However, lymphomas, which involve the hypothalamic area and plasmocytomas, both occur and are associated with poor prognosis whatever treatment is chosen [84].

FIGURE 10.6. Lymphocytic hypophysitis. Characteristic finding on MRI is the tongue-like suprasellar extension along the pituitary stalk.

416

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Pituitary Abscess Pituitary abscesses may be a rare manifestation of an acute bacterial infection that develops per continuitatem in cases with perisellar infections like sinusitis and mastoiditis [89]. However, this entity is not clearly defined and thus a significant confusion exists. A preexisting tumor seems to be evident in many cases. The diagnosis is made intraoperatively and histologically because the pituitary abscess mimics nonfunctional pituitary tumors in radiological and endocrinological evaluation [90]. After surgical removal the patient should receive antibiotics. Staphylococcus aureus is the most relevant microorganism and can be isolated from bacterial cultures, but in many cases these cultures remain sterile. Hypothalamic Hamartomas

Hamartomas are neuronal lesions consisting of neurons within a stroma of axons and astroglial elements. In the few known cases the lesions led to precocious puberty in young males as a result of hypothalamic compression [91]. They may also cause epilepsy with gelastic and complex partial seizures. In some cases gonadotropin-releasing hormone could be detected immunohistochemically. Rarely growth hormone-releasing hormones are secreted, causing acromegaly either to pituitary hyperplasia or to pituitary adenoma [92]. Effective medical treatment with gonadotropin-releasing hormone analogs for precocious puberty and anticonvulsives for gelastic seizures mean that surgery is no longer the preferred initial management for these lesions [93,94]. Germ Cell Tumors

Germ cell tumors develop in the midline and affect the pineal, the suprasellar or both regions simultaneously [95]. 70% of the lesions are germinomas, 30% nongerminomatous lesions including teratomas, embryonal carcinomas, endodermal sinus tumors and choriocarcinomas. Germinomas show an invasive growth pattern and infiltrate the surrounding tissue causing typical clinical symptoms like visual disturbances, diabetes insipidus, hypopituitarism and hydrocephalus [96]. Occasionally biochemical tumor markers like alpha-fetoprotein, human chorionic gonadotropin and placenta alkaline phosphatase may be detected in serum and CSF [97]. In these patients, a biopsy is usually necessary to confirm the diagnosis. These lesions are extremely radiosensitive. Long-term control of tumor growth is achieved in cases with primary radiation therapy. After a few fractions, the MRI should confirm tumor shrinkage. Radiotherapy of the whole neuroaxis should be performed due to the possibility of metastatic dissemination in CSF pathways. Nongerminomatous germ cell tumors are rare lesions with high malignancy, excluding the hypothalamic hamartoma, which is a distinct noninfiltrative lesion containing hair, bone or even teeth. Epidermoid Cysts

Epidermoid cysts are uncommon lesions of the sellar area [98]. They grow slowly and become manifest in the fourth

and fifth decade of life causing visual compromise, hypopituitarism and episodes of aseptic meningitis due to leakage of the cyst content fluid. The treatment is surgical. Recurrence in case of incomplete removal is probable thus necessitating repeat surgery.

Future Avenues Today, even though many treatment options are available, surgical treatment is still the dominating indication for most pituitary lesions. The medical treatment for hormone secreting tumors, such as dopamine agonists for prolactinomas and somatostatin analoga for growth hormone producing tumors, can usually suppress hormone levels but only exceptionally cure the disease. Radiotherapy is also available, but due to the side effects is reserved for surgically incurable cases. Recent developments used in pituitary surgery are the application of neuronavigation, the intraoperative MRI and endoscopy [99,100]. Neuronavigation is helpful for the localization of anatomic structures intraoperatively. This can be achieved by segmentation and 3D-reconstruction of the tumor and its adjacent structures, like the carotid artery. Even in experienced hands, neuronavigation is very helpful in re-operations and in cases with carotid arteries kinking into the midline, large invasive tumors or suprasellar hypothalamic tumors. Intraoperative MRI, until recently available in few centers, provides real-time image guidance. This helps in identifying the border of the lesions and allowing an intraoperative resection control. In cases of large tumors, remnants can be resected completely by a second look in up to one-third of the patients. The use of endoscopy is well established for transsphenoidal pituitary surgery. The main advantage is the superb, panoramic visualization of the anatomic structures due to the wide angle of view and the powerful light devices. This offers advantages in identifying displacement and invasion of the medial wall of the cavernous sinus and control during tumor removal. Many surgeons use endoscopy as a supplementary visualizing tool, some operate only under the endoscope. In both applications, the advantage over the classic sublabial or pernasal approach is the avoidance of the paraseptal preparation of the nasal mucosa and the direct opening of the wall of the sphenoid sinus, making postoperative tamponade of the nasal cavity unnecessary. Free nasal ventilation improves the condition of the patient. Patients feel strong enough to leave the hospital the day after surgery. This can only be done in cases in which close postoperative follow-up for early detection of water and electrolyte disturbances is available and if the patient does not require hospitalization due to preexisting risks like hypertension and diabetes mellitus in acromegaly and in Cushing’s disease. The economic aspect is gaining more and more importance. Treatment should not only be efficient, but also as inexpensive as possible. Thus, it is specifically interesting to compare the long-term results of various treatments. Further

Chapter 10

variations of the approaches may reduce the patient’s stay in the hospital. Whatever approach is used, the authors believe that more favorable economic results can be achieved by treating the patients and training the neurosurgeons in specialized centers with extensive experience in this field, where adequate endocrinologic evaluation and radiotherapy are also available. This will lead to lower mortality and morbidity, as well as higher normalization rates in cases of hormonal oversecretion, and thus a better overall long-term outcome. REFERENCES 1 Horsley V. On operative technique of operations on the central nervous system. BMJ 1906;2:411– 423. 2 Kiliani OGT. Some remarks on tumors of the chiasm, with a proposal on how to reach the same by operation. Ann Surg 1904;40:35–43. 3 Frazier CH. Choice of method in operations upon the pituitary body. Surg Gynecol Obstet 1919;29:9–16. 4 Frazier CH. Lesions of the hypophysis from the viewpoint of a surgeon. Surg Gynecol Obstet 1913;17:724–736. 5 Dandy WE. A new hypophysis operation. Bull Johns Hopkins Hosp 1918; 29:154–155. 6 Dandy WE. The brain. In: Lewis D, ed. Practice of surgery. Hagerstown, MD: WF Prior, 1934:556–605. 7 Schloffer H. Erfolgreiche Operation eines Hypophysentumors auf nasalem Wege. Wien Klin Wochenschr 1907;20:621– 624. 8 von Eiselsberg AF. Über den Endausgang und Obduktion meines ersten operierten Falles von Hypophysentumor. Beitr Pathol Anat 1922;71:619–624. 9 von Eiselsberg AF. My experience about operation upon the hypophysis. Ann Surg 1910;52:1–14. 10 Hirsch O. Endonasal method of removal of hypophyseal tumors: with report of two cases. JAMA 1910;55:772–774. 11 Hirsch O. Über Methoden der Behandlung von Hypophysistumoren auf endonasalem Wege. Arch Laryngol Rhinol 1911;24:129–177. 12 Cushing H. Partial hypophysectomy for acromegaly: with remarks on the functions of the hypophysis. Ann Surg 1909;50:1002–1017. 13 Cushing H. Intracranial tumours. Notes upon a series of two thousand verified cases with surgical-mortality percentages pertaining thereto. Springfield: Ch. C Thomas, 1932:69–79. 14 Guiot G, Arfel G, Brion S et al. Adénomes hypophysaires. Paris: Masson, 1958:1–276. 15 Guiot G. Considerations on the surgical treatment of pituitary adenomas. In: Fahlbusch R, von Werder K, eds. Treatment of pituitary adenomas. Stuttgart: Thieme, 1978:202–218. 16 Knosp E, Steiner E, Kitz K, Matula C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings [see comments]. Neurosurgery 1993;33(4):610–617. 17 Buchfelder M, Fahlbusch R, Nomikos P et al. Recent advances in CT and MRI in the diagnosis and follow-up of hypothalamo–pituitary disease. In: Werder von K, Fahlbusch R, eds. Pituitary adenomas. Amsterdam: Excerpta Medica Elsevier, 1996:132–145. 18 Rhoton-AL J, Hardy DG, Chambers SM. Microsurgical anatomy and dissection of the sphenoid bone, cavernous sinus and sellar region. Surg Neurol 1979;12(1):63–104. 19 Clemente CD. Gross anatomy of the central nervous system. In: Clement CD, ed. Gray’s anatomy. 30th American ed. Philadelphia: Lea & Fiebinger, 1985:1029–1035. 20 Rhoton-AL J, Harris FS, Renn WH. Microsurgical anatomy of the sellar region and cavernous sinus. Clin Neurosurg 1977;24:54 –85. 21 Dolenc VV. Transcranial epidural approach to pituitary tumors extending beyond the sella. Neurosurgery 1997;41(3):542–550. 22 Fahlbusch R, Buchfelder M. Surgical complications. In: Landolt AM, Vance ML, Reilly RL, eds. Pituitary adenoma. New York: Churchill Livingstone, 1996:395–408. 23 Tsang RW, Brierley JD, Panzarella T et al. Role of radiation therapy in clinical hormonally-active pituitary adenomas. Radiother Oncol 1996; 41(1):45–53.

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51 Aron DC, Findling JW, Tyrrell JB. Cushing’s disease. Endocrinol Metab Clin North Am 1987;16(3):705–730. 52 Danese RD, Aron DC. Principles of clinical endocrinology and their applications to the diagnosis of Cushing’s syndrome: Rev. Bayes meets Dr. Cushing. The Endocrinologist 1994;4:339–346. 53 Orth DN. Cushing’s syndrome. N Engl J Med 1995;332:791–803. 54 Fahlbusch R, Buchfelder M, Muller OA. Transsphenoidal surgery for Cushing’s disease. J R Soc Med 1986;79(5):262–269. 55 Chandler WF, Schteingart DE, Lloyd RV et al. Surgical treatment of Cushing’s disease. J Neurosurg 1987;66(2):204–212. 56 Mampalam TJ, Tyrrell JB, Wilson CB. Transsphenoidal microsurgery for Cushing’s disease. A report of 216 cases. Ann Intern Med 1988;109(6):487–493. 57 Carpenter PC. Cushing’s syndrome: update of diagnosis and management. Mayo Clin Proc 1986;61(1):49–58. 58 Guilhaume B, Bertagna X, Thomsen M et al. Transsphenoidal pituitary surgery for the treatment of Cushing’s disease: results in 64 patients and long term follow-up studies. J Clin Endocrinol Metab 1988;66(5):1056–1064. 59 Tindall GT, Herring CJ, Clark RV et al. Cushing’s disease: results of transsphenoidal microsurgery with emphasis on surgical failures. J Neurosurg 1990;72(3):363–369. 60 Nelson DH, Meakin JW, Dealy JB et al. ACTH-producing pituitary tumor of the pituitary gland. Ann Intern Med 1958;52:560–569. 61 Buchfelder M, Fahlbusch R, Thierauf P, Muller OA. Observations on the pathophysiology of Nelson’s syndrome: a report of three cases. Neurosurgery 1990;27(6):961–968. 62 Hamilton C, Adams LC, Maloof F. Hyperthyroidism due to thyrotropinproducing pituitary chromophobe pituitary adenoma. N Engl J Med 1970;283:1077–1080. 63 Comi RJ, Gesundheit N, Murray L et al. Response of thyrotropin-secreting pituitary adenomas to a long-acting somatostatin analogue. N Engl J Med 1987;317(1):12–17. 64 Molitch ME. Gonadotroph-cell pituitary adenomas [editorial; comment]. N Engl J Med 1991;324(9):626–627. 65 Thapar K, Kovacs K, Scheithauer BW et al. Classification and pathology of sellar and parasellar tumors. In: Tindall G, Cooper P, Barrow D, eds. The practice of neurosurgery. Baltimore: Williams & Willkins, 1996:1021–1070. 66 Fahlbusch R, Honegger J, Paulus W et al. Surgical treatment of craniopharyngiomas: experience with 168 patients. J Neurosurg 1999; 90(2):237–250. 67 Honegger J, Buchfelder M, Fahlbusch R. Surgical treatment of craniopharyngiomas: endocrinological results. J Neurosurg 1999;90(2):251–257. 68 Fischer EG, Welch K, Shillito J et al. Craniopharyngiomas in children. Longterm effects of conservative surgical procedures combined with radiation therapy [see comments]. J Neurosurg 1990;73(4):534–540. 69 Raimondi AJ. Craniopharyngioma: complications and treatment failures weaken case for aggressive surgery. Crit Rev Neurosurg 1993;3:7–24. 70 Cushing H, Eisenhardt L. Meningiomas. Their classifications, regional behaviour, life history and surgical end results. Springfield IL: Charles C. Thomas, 1938:298–319. 71 Sekhar LN, Sen CN, Jho HD, Janecka IP. Surgical treatment of intracavernous neoplasms: a four-year experience. Neurosurgery 1989;24(1):18–30. 72 Honegger J, Fahlbusch R, Buchfelder M et al. The role of transsphenoidal microsurgery in the management of sellar and parasellar meningioma. Surg Neurol 1993;39(1):18–24. 73 Schrell UM, Rittig MG, Anders M et al. Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea [see comments]. J Neurosurg 1997;86(5):840–844. 74 Schrell UM, Rittig MG, Anders M et al. Hydroxyurea for treatment of unresectable and recurrent meningiomas. I. Inhibition of primary human meningioma cells in culture and in meningioma transplants by induction of the apoptotic pathway. J Neurosurg 1997;86(5):845–852.

75 McGrath P. Cysts of sellar and pharyngeal hypophyses. Pathology 1971;3(2):123–131. 76 Voelker JL, Campbell RL, Muller J. Clinical, radiographic, and pathological features of symptomatic Rathke’s cleft cysts. J Neurosurg 1991;74(4): 535–544. 77 Nomikos P, Buchfelder M, Fahlbusch R. Intra- and suprasellar colloid cysts. Pituitary 1999;2:123–125. 78 Baskin DS, Wilson CB. Transsphenoidal treatment of non-neoplastic intrasellar cysts. A report of 38 cases. J Neurosurg 1984;60(1):8–13. 79 Jafar J, Crowell R. Parasellar and optic nerve lesions: the neurosurgeon’s perspective. Radiol Clin North Am 1987;25:877–885. 80 Rutka J, Hoffman H, Drake J. Suprasellar and sellar tumors in childhood and adolescence. Neurosurg Clin N Am 1992;3:103–115. 81 Roessmann U, Kaufman B, Friede RL. Metastatic lesions in the sella turcica and pituitary gland. Cancer 1970;25(2):478–480. 82 Teears RJ, Silverman EM. Clinicopathologic review of 88 cases of carcinoma metastatic to the putuitary gland. Cancer 1975;36(1):216–220. 83 Maiuri F. Primary cerebral lymphoma presenting as steroid-responsive chiasmal syndrome. Br J Neurosurg 1987;1(4):499–502. 84 Dhanani A-NN, Bilbao JM, Kovacs K. Multiple myeloma presenting as a sellar plasmocytoma and mimicking a pituitary tumor: report of a case and review of the literature. Endocr Pathol 1990;1:245–248. 85 Wold LE, Laws-ER J. Cranial chordomas in children and young adults. J Neurosurg 1983;59(6):1043–1047. 86 Cosman F, Post KD, Holub DA, Wardlaw SL. Lymphocytic hypophysitis. Report of 3 new cases and review of the literature. Medicine Baltimore 1989;68(4):240–256. 87 Asa SL, Bilbao JM, Kovacs K et al. Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism. Ann Intern Med 1981;95:166–171. 88 Honegger J, Fahlbusch R, Bornemann A et al. Lymphocytic and granulomatous hypophysitis: experience with nine cases. Neurosurgery 1997;40(4):713–722. 89 Berger SA, Edberg SC, David G. Infectious disease in the sella turcica. Rev Infect Dis 1986;8(5):747–755. 90 Bebzel EC, Shockley W, Giyanani VL, Husbands HS. Infectious disease in the sella turcica. Rev Infect Dis 1986;8:747–755. 91 Albright AL, Lee PA. Neurosurgical treatment of hypothalamic hamartomas causing precocious puberty. J Neurosurg 1993;78(1):77–82. 92 Asa SL, Scheithauer BW, Bilbao JM et al. A case for hypothalamic acromegaly: a clinicopathological study of six patients with hypothalamic gangliocytomas producing growth hormone-releasing factor. J Clin Endocrinol Metab 1984; 58(5):796–803. 93 Georgakoulias N, Vize C, Jenkins A, Singounas E. Hypothalamic hamartomas causing gelastic epilepsy: two cases and a review of the literature. Seizure 1998;7(2):167–171. 94 Stewart L, Steinbok P, Daaboul J. Role of surgical resection in the treatment of hypothalamic hamartomas causing precocious puberty. Report of six cases [see comments]. J Neurosurg 1998;88(2):340–345. 95 Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985;63(2):155–167. 96 Buchfelder M, Fahlbusch R, Walther M, Mann K. Endocrine disturbances in suprasellar germinomas. Acta Endocrinol (Copenh.) 1989;120(3):337–342. 97 Baumgartner JE, Edwards MS. Pineal tumors. Neurosurg Clin N Am 1992; 3(4):853–862. 98 Boggan JE, Davis RL, Zorman G, Wilson CB. Intrasellar epidermoid cyst. Case report. J Neurosurg 1983;58(3):411–415. 99 Jho HD, Carrau RL. Endoscopic endonasal transsphenoidal surgery. J Neurosurg 1997;87:44–51. 100 Black PB, Moriarty T, Alexander EAI. Development and implementation of intraoperative MRI and its neurosurgical applications. Neurosurgery 1997; 41:832–845.

C h a p t e r

11 Acromegaly Shlomo Melmed

INTRODUCTION Acromegaly, a spectacular clinical syndrome of disordered somatic growth and proportion, has intrigued physicians since earliest recorded history. It was, however, only in 1886 that Pierre Marie published the first clinical description of the disorder based on observing two of his patients, and his recognition of five other cases previously described by others [1]. He described the features distinguishing the disorder from myxedema and osteodystrophy and proposed the name “acromegaly.” Marie did not recognize the relation of a pituitary tumor to this syndrome until 5 years later when an adenohypophyseal tumor was observed in a patient with acromegaly. In 1900, Benda recognized that pituitary adenomas in patients with acromegaly consisted mainly of adenohypophyseal eosinophilic cells, which he proposed to be hyperfunctioning [2]. Subsequent careful clinicopathologic studies by Cushing, Davidoff, and Bailey were supplemented by demonstrating clinical remission of soft tissue signs of acromegaly after surgical resection of the eosinophilic pituitary adenomas [3–6]. The experiments of Evans and Long demonstrating features of gigantism in rats injected with anterior pituitary extracts confirmed the association of a pituitary factor with somatic growth [7]. Establishment of the unequivocal link between hyperfunctioning adenoma and acromegaly was the earliest example of a pituitary disorder to be clinically and pathologically recognized and appropriately managed.

Incidence of Acromegaly Several studies have undertaken a comprehensive ascertainment of acromegaly in the community. In a retrospective survey of the Newcastle region, the prevalence of

acromegaly was 38 cases/million, while the annual incidence of new patients was almost 3 cases/million [8]. Based on following 166 Swedish acromegalics from 1955 to 1984, the annual incidence of new cases was reported at 3.3/million people with a prevalence of 69 cases/million people [9]. In Northern Ireland, the prevalence of acromegaly in 1984 was 63 cases/million, while the annual incidence of newlydiagnosed acromegaly was 4 cases/million during the preceding 25 years [10]. Because of its geographical isolation and relatively centralized patient referral practices, the ascertainment in Northern Ireland is probably an accurate reflection of the true incidence of acromegaly in the population. Based upon these figures, it is apparent that over 1000 new cases of acromegaly are diagnosed annually in the USA.

Animal Models of Hypersomatotrophism Although the extrapolation of animal data to human acromegaly should be tempered with caution, several animal models of hypersomatotrophism have been developed. Rats bearing transplantable growth hormone (GH)-secreting tumors implanted subcutaneously exhibit accelerated somatic growth, and increased GH and insulin-like growth factor-I (IGF-I) levels [11]. These animals also are mildly hyperinsulinemic but do not develop hyperglycemia. The development of transgenic mouse strains bearing either a growth hormone-releasing hormone (GHRH), GH, or IGF-I trans gene has allowed further elucidation of the respective roles for these three hormones in the development of hypersomatotrophism [12–14]. Expression of a human GHRH trans gene in mice results in increased somatic growth [14], mammosomatotroph hyperplasia [15] and GH-cell adenomas [16]. These mice also express human GHRH messenger RNA (mRNA) in multiple tissues, with highest levels actually found in the pituitary gland [14]. The strong pituitary expression of 419

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GHRH in these mice may reflect pituitary-specific localization of posttranslational processing enzymes for GHRH, in addition to the tissue specificity of the fusion gene employed. These observations imply that GHRH may also act as a paracrine factor in stimulating GH secretion [17,18]. In mice bearing a GH-trans gene, heterologous GH mRNA is detectable from day 13 of gestation, while marked growth acceleration is not evident until about 3 weeks of age [12]. All body organs, except the brain, exhibit increased growth. The liver and spleen of these transgenic mice, however, undergo disproportionate allometric growth [12]. Therefore, although both GH and IGF-I levels are elevated in these animals, overall body growth and growth of individual organs respond in different relative proportions. These observations imply that the pattern of body and organ growth is dependent on at least two variables: external growth factors (e.g., GH and IGF-I) which stimulate cell division, organ and body weight, while each organ appears to possess an intrinsic growth potential that responds to the hormonal environment in achieving final size outcome. In contrast, transgenic mice bearing coding sequences of the human IGF-I gene exhibit selective organomegaly without a profound increase in skeletal growth [13]. As these mice had suppressed endogenous GH levels, GH and IGFI therefore appear to act both independently and synergistically in inducing clinical hypersomatotrophism. Both GH and GHRH transgenic mice also display renal glomerulosclerosis, which is not observed in animals bearing the

IGF-I transgene. This suggests that GH acts directly to cause mesangial changes in the kidney. Interestingly, IGF-I, when administered to hypophysectomized rats, does in fact mimic most of the somatic effects of GH by restoring growth [19]. These observations suggest that both GH and IGF-I may independently contribute to the pathologic findings of hypersomatotrophism [20]. PATHOGENESIS Acromegaly may be caused by pituitary tumors or by extrapituitary disorders [21] (Fig. 11.1 and Table 11.1). Regardless of the etiology of the disorder, the disease is characterized by elevated levels of GH and IGF-I with resultant signs and symptoms of hypersomatotrophism [22].

Pituitary Acromegaly Over 95% of patients with acromegaly harbor a pituitary adenoma. Different pituitary tumor types may be responsible for unrestrained GH secretion and are classified according to their hormone gene expression, ultrastructural features and cytogenesis [21]. Pure GH-cell Adenomas

These tumors contain either densely or sparsely staining cytoplasmic GH granules and account for 60% of pituitary tumors causing acromegaly. These two variants of a pure

FIGURE 11.1. Pathogenesis of acromegaly. Insulin-like growth factor-1 (IGF-I) is produced in both hepatic and extrahepatic tissues and is also locally bioactive in multiple extrahepatic tissues. +, stimulated secretion; -, suppressed secretion. GHRH, growth hormone-releasing hormone; SRIF, somatostatin. Adapted from Melmed [249].

Chapter 11 Table 11.1.

Etiology of hypersomatotrophism*

Excess GH secretion Pituitary Densely or sparsely granulated GH cell adenoma Mixed GH-cell and PRL-cell adenoma Mammosomatotroph cell adenoma Acidophil stem cell adenoma Plurihormonal adenoma GH-cell carcinoma Empty sella Ectopic pituitary tumors Sphenoid or parapharyngeal sinus Extrapituitary tumor Pancreas, carcinoid, lung, ovary, breast Excess GHRH secretion Central Hypothalamic hamartoma Peripheral Carcinoid tumor, pancreatic cell tumor, small-cell lung cancer, adrenal adenoma, pheochromocytoma Excess growth factor secretion or action Acromegaloidism Miscellaneous McCune–Albright syndrome Multiple endocrine neoplasia * From Melmed [22]. GH, growth hormone; GHRH, growth hormone-releasing hormone; PRL, prolactin.

somatotropinoma are either slow (densely granulated) or rapidly growing (sparsely granulated) [23,24]. Mixed GH-cell and prolactin (PRL)-cell adenomas are composed of two distinct cell types, somatotrophs expressing GH and lactotrophs expressing PRL [25,26]. These bimorphous tumors cause acromegaly with moderately elevated serum PRL levels. Acidophil stem cell adenomas are monomorphous tumors arising from the common GH and PRL stem cell and expressing both hormones [27]. In addition to specific hormone granules, these adenomas often contain giant mitochondria and misplaced exocytosis of GH granules. They are often rapidly growing and invasive, and hyperprolactinemia rather than acromegaly may be the predominant presenting feature. In contrast, monomorphous mammosomatotroph cell adenomas consist of a single mature cell expressing both GH and PRL. Serum PRL levels are usually normal or moderately elevated. Plurihormonal tumors, which are either monomorphous or plurimorphous, may express GH with any combination of PRL, thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), or a-subunit [28–30]. Often, little correlation exists between specific hormone staining of the tumor and peripheral hormone levels. These patients may present with clinical features of acromegaly as well as the effects of the respective elevation of other pituitary trophic hormones.

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GH cell carcinomas with well-documented distant metastases are exceedingly rare [31–33]. Even when exhibiting hypercellularity, necrosis, nuclear pleomorphism and mitotic figures, these endocrine adenomas still usually exhibit benign biologic behavior in that they very rarely metastasize. Although locally invasive somatotropinomas are occasionally aggressive and rapidly growing, they should not be classed as malignant unless definitive proof of distant metastases is present. GH cell hyperplasia is difficult to distinguish histologically from a GH cell adenoma [34]. Hyperplasias usually consist of more than one cell type and silver staining reveals the presence of a well-preserved reticulin network without a surrounding pseudocapsule. The rigid morphologic diagnosis of GH cell hyperplasia has usually been associated with extrapituitary stimulation by GHRH from an extrapituitary tumor causing acromegaly. Silent Somatotroph Adenomas

These tumors [35], while staining positively for the presence of GH, are apparently clinically nonfunctional. Features of acromegaly are absent, although GH and/or PRL levels may in fact be elevated in over half these patients. Although a putative defect in the peripheral GH receptor has been postulated to explain the observed absence of hypersomatotrophic signs, no such mutation has been associated with these tumors. Pathogenesis of Somatotroph Cell Adenomas

Both the hypothalamus and the pituitary may contribute to the development of acromegaly [36]. Disordered secretion of GHRH or SRIF has been implicated in the etiology of pituitary acromegaly. Alternatively, an intrinsic pituitary cellular defect may result in adenoma formation. Recent basic and clinical advances in the understanding of neuroendocrine control may, however, provide the basis for a hypothesis that integrates both pituitary as well as hypothalamic influences on pituitary tumor pathogenesis [36,37]. Disordered GHRH Secretion or Action GHRH directly stimulates GH gene expression and also induces somatotroph DNA synthesis, cell replication, and c-fos expression, a growth signal-transducing oncogene [38,39]. These growth-promoting actions of GHRH are prevented by SRIF. Somatotroph GHRH action is mediated by activation of adenylate cyclase and increased cyclic adenosine monophosphate (cAMP) levels. Several observations in transgenic animals imply a role for increased cAMP in stimulating GH secretion and adenoma formation. Somatotroph hyperplasia, increased GH secretion, and gigantism were observed in mice expressing an intracellular cholera toxin trans gene. By irreversibly activating intracellular cAMP, this pituitary-directed trans gene was associated with the development of GH hypersecretion [40]. In contrast, mice expressing a trans gene which inactivated the cAMP response developed dwarfism and low GH secretion [41]. Transgenic mice expressing GHRH develop pituitary

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hyperplasia due to a selective stimulation of somatotroph cells, implying that GHRH may be a direct trophic factor for the somatotroph cell [14]. Eventually, these transgenic animals also develop discrete somatotroph adenomas [16]. Excess production of GHRH by functional hypothalamic tumors or by abdominal or chest neuroendocrine tumors causes somatotroph hyperplasia and occasionally adenoma with resultant unrestrained GH secretion [42]. This clinical observation implies hypothalamic hormone involvement in the pathogenesis of GH-cell adenomas and acromegaly. Nevertheless, excessive stimulation of the somatotroph by GHRH would be expected to result in generalized somatotroph hyperplasia. In fact, pituitary histology of most GH-cell adenoma tissue specimens does not reveal hyperplastic somatotroph tissue surrounding the adenoma [43], implying no exogenous hypothalamic overstimulation of the pituitary. GHRH production by extrapituitary tumors causing acromegaly usually is associated with somatotroph cell hyperplasia and elevated GH levels, and paradoxical responses of GH to glucose, thyrotropin releasing hormone (TRH) and dopamine [44]. These biochemical perturbations revert to normal when the ectopic source of GHRH is removed, suggesting that exposure to high levels of GHRH alters the somatotroph response to other factors regulating GH secretion. The presence of GHRH receptor sites on adenoma tissue, and the failure of downregulation of GH secretion during prolonged GHRH stimulation, also points to a possible role for GHRH in maintaining persistent GH hypersecretion. The expression of intrapituitary and adenomaderived GHRH has been correlated with tumor size and activity, implying a paracrine role for GHRH in mediating adenoma pathogenesis [45]. GHRH also modestly stimulates PRL secretion in most acromegalic patients [44]. These observations, coupled with the fact that up to 40% of acromegalic patients also have hyperprolactinemia, imply a role for GHRH in the pathogenesis of acromegaly. Although SRIF secretion may theoretically be attenuated, thus giving rise to unrestrained GH secretion, TSH responses to TRH in acromegaly are either normal or in fact blunted, suggesting intact SRIF secretion [46]. Alternatively, high GH levels in these patients may abnormally autoregulate the somatotroph. In pituitary acromegaly, the heterogenous GH response to GHRH stimulation persists despite the continuous presence of GHRH, suggesting impaired desensitization of the abnormal somatotroph to GHRH stimulation [47]. Surgical Responses Postoperative GH testing often remains disordered after initial successful surgical resection of the pituitary tumor, suggesting that the hypothalamus is primarily responsible for the altered GH secretion and tumor development [48]. Surgical resection of well-defined GH secreting tumors (<5 mm) results in a definitive cure of excess hormone secretion in most patients [49]. Low postoperative tumor recurrence rates in these patients, together with restoration of most normal dynamic GH responses

after surgery, however, is strongly suggestive of intact hypothalamic function in these patients [50]. GH Secretory Patterns Although basal GH levels are usually high in acromegaly, the episodic pulsatile pattern of GH release is present, and the nocturnal surge of GH is usually preserved [51,52]. Patients receiving long-acting somatostatin analogs also retain GH pulsatility, suggesting persistent GHRH secretion [53]. GH pulse amplitude and sensitivity to GHRH also appear intact, suggesting enhanced GHRH pulsatility. Paradoxical GH responses to glucose, dopamine, and TRH, and loss of pituitary desensitization to hypothalamic GHRH, however, point to an intrinsic somatotroph abnormality. Disordered Somatotroph Cell Function In vitro responses of somatotroph tumor cell cultures exposed to physiologic levels of GHRH, SRIF, and IGF-1, are similar to those observed in the limited number of similar studies in normal cultured human pituitary tissue [54]. GH gene expression is stimulated in vitro by GHRH and inhibited by IGF-1, as evidenced by changes in adenoma cells GH mRNA content [55]. Adenoma tissue also expresses receptors for GHRH, GHRELIN [56] and SRIF [57] and no activating mutations of either the GHRH or SRIF receptor have been discerned. The recently isolated GHRELIN binds to the somatotroph GRS receptor, and the structure of this receptor has not been reported in acromegaly. These apparently physiologic responses imply intact control of GH gene expression in tumor cells and favor disordered hypothalamic etiology for clinically abnormal GH secretion. The initiation or progression of GH-cell transformation may be due to a polyclonal hyperplastic response of somatotroph cells to hypothalamic dysregulation. However, a preexisting somatotroph cell mutation may be a prerequisite for the abnormal growth response to disordered GHRH secretion or action. Most human neoplasms appear to be associated with clonal expansion of genomically altered cells which harbor a mutated tumor oncogene. The clonal origin of somatotroph adenomas as determined by X-chromosome inactivation analysis of somatotroph tumor DNA is in fact monoclonal [58]. These findings suggest that a somatic cell mutation of the somatotroph gives rise to clonal expansion and tumor formation. An altered Gs (a) protein has been identified in a subset of GH-secreting pituitary adenomas characterized by high levels of intracellular cAMP and GH hypersecretion [58]. Point mutations in two critical sites, Arg201, the site for ADPribosylafion, and Gly227, the GTP-binding domain of Gs (a) proteins, prevent GTPase activity and result in constitutive activation of adenylyl cyclase. The tumor contains a dominant mutant Gs (a), termed gsp, which mimics the effect of GHRH and results in elevated cAMP levels [59]. These activating gsp mutations are present in about 30% of GHsecreting tumors and patients harboring the gsp mutation in

Chapter 11

their adenoma DNA have enhanced tumor adenylyl cyclase activity, smaller tumors, and lower GH levels than the nonmutant-bearing tumors. Interestingly, clinical glucose suppressibility of GH is maintained in the gsp-containing tumors [60]. Pure GH-cell adenomas commonly express both GH and PRL mRNA in the same cells, despite the apparent absence of PRL MRNA translation [25]. Neoplastic mutation may therefore occur preferentially in stem cells committed to express both GH and PRL [63]. Alternatively, the cell mutation may be associated with differentiation into an early progenitor cell type expressing both GH and PRL or other plurihormonal combinations including GH with TSH, asubunit, or ACTH. Alternatively, these tumors may originate from an altered primitive totipotential cell. Recently, two major classes of pituitary genetic defects have emerged as molecular mechanisms underlying the pathogenesis of acromegaly. Loss of heterozygosity (LOH) has been observed for chromosomes 11, 13 and 9 [61–64], especially in larger more invasive macroadenomas. No distinct tumor suppressor gene has yet been isolated for these sporadic nonfamilial tumors. An activating gene, PTTG, has been isolated from pituitary tumors [67–68]. This transforming gene is overexpressed in GH-secreting and other functional pituitary tumors, and its abundance correlates with tumor size and invasiveness [67]. PTTG is homologous to a securin protein, regulating sister chromatid separation during the cell cycle [68], and its overexpression may lead to aneuploidy in pituitary and other tumors. Although the somatotroph is clearly transformed in GHsecreting pituitary adenomas, the sequence of events leading to their clonal expansions appears multifactorial. The presence of an activated oncogene in GH-cell adenomas may be required for initiating tumorigenesis, while promotion of tumor growth may require GHRH and other growth factor (e.g. bFGF) stimulation. The cellular mutation may not itself be sufficient to provide growth advantage for a GHsecreting adenoma without disordered hypothalamic or paracrine growth factor input [63]. EXTRAPITUITARY ACROMEGALY The source of the excessive GH secretion in acromegaly may not necessarily be pituitary in origin [69]. Patients with extrapituitary acromegaly include those with excess ectopic GHRH or GH secretion, and very rarely a putative growth factor disorder termed acromegaloidism. These patients have clinical features of acromegaly indistinguishable from pituitary acromegaly, but no demonstrable tumor or biochemical defect.

Criteria for Diagnosis of Ectopic Acromegaly Because ectopic acromegaly requires a different management approach than that recommended for classic pituitary GH

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hypersecretion, stringent clinical and biochemical criteria should be fulfilled to confirm this diagnosis [70]. These include the demonstration of elevated circulating GHRH or GH levels in the absence of a primary lesion of the pituitary gland. A significant arteriovenous gradient in hormone concentrations across the ectopic tumor source should also preferably be present (Fig. 11.2). Removal or functional ablation of the ectopic hormone-producing tumor should ideally result in a biochemical and clinical cure of acromegaly, as well as normalization of the endogeneous GHRH-GH-IGFI axis. Tumor tissue should be shown to express the GHRH or GH gene product by demonstrating specific mRNA expression, hormone biosynthesis and specific polypeptide immunoreactivity. These criteria should be fulfilled to establish the diagnosis of extrapituitary acromegaly. Patients with nonconventional or nonclassical biochemical, radiologic, and clinical features of pituitary acromegaly may inadvertently be diagnosed as harboring a nonpituitary source of excess GH secretion, and be inappropriately treated. A definitive diagnosis of the etiology of hypersomatotrophism should therefore be made prior to instituting therapy. GHRH Hypersecretion

Hypothalamic Hypothalamic GHRH is secreted into the portal system, impinges upon the somatotroph cells, binds to specific surface receptors and elicits intracellular signals that modulate pituitary GH synthesis and or secretion [71]. GHRH-producing neurons have been well characterized in the hypothalamus by immunostaining techniques. Hypothalamic tumors, including hamartomas, choristomas, gliomas, and gangliocytomas may produce excessive GHRH with subsequent GH hypersecretion and resultant acromegaly [43]. These patients may harbor somatotroph hyperplasia, or even a pituitary GH-cell adenoma, supporting the notion that excess hypothalamic GHRH leads to pituitary hyperplasia and subsequent adenoma formation. As patients reported with hypothalamic acromegaly have all undergone resection of the adenomatous or hyperplastic pituitary, proof of a primary hypothalamic tumor causing acromegaly in these patients is not definitive. Pituitary mammosomatotroph hyperplasia with no evidence for pituitary adenoma or an extrapituitary tumor source of GHRH has been described in a young child with gigantism [72]. Excess hypothalamic GHRH secretion or enhanced GHRH sensitivity may explain the potent induction of pituitary hyperplasia and GH secretion. Peripheral GHRH is synthesized and expressed in multiple extrapituitary tissues [73–75]. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation and increased GH secretion. The structure of hypothalamic GHRH was in fact elucidated from material extracted from pancreatic GHRH-secreting tumors in two patients with acromegaly [34,76]. Immunoreactive GHRH is present in

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FIGURE 11.2. SSTR receptor scan for diagnosis of ectopic acromegaly. Radiolabeled octreoscan reveals metastatic neck GH-secreting carcinoma which expresses SSTR2, SSTR3, and SSTR5 receptors. Mass resection normalizes GH levels within 3 hours. From Greenman et al. [113].

several tumors, including carcinoid tumors, pancreatic cell tumors, small cell lung cancers, adrenal adenomas, and pheochromocytomas which have been reported to secrete GHRH. Acromegaly in these patients, however, is uncommon. In a retrospective survey of 177 acromegalic patients only a single patient was identified with elevated plasma GHRH levels [77]. The association of acromegaly with carcinoid tumors had been widely recognized in several patients prior to the characterization of hypothalamic GHRH [78–84]. Carcinoid tumors comprise most of the tumors associated with ectopic GHRH secretion, the majority bronchial in origin [87–98]. Pancreatic cell tumors, small cell lung cancers, adrenal adenoma, pheochromocytoma, medullary thyroid, endometrial, and breast cancer have also rarely been described to express GHRH and cause acromegaly [34,69,94–101]. Although most patients with carcinoid do not exhibit clinical features of acromegaly, many of these tumors do in fact express immunoreactive GHRH [100] and manifest abnormal GH secretary dynamics [101]. The observed high incidence of GHRH expression and low incidence of true acromegaly in these patients may be due to disordered tissue processing of GHRH by some tumors, or to impaired bioactivity of circulating

GHRH. Posttranslational processing and proteolytic degradation of GHRH is tissue- and tumor-specific and peptidase activity in some tumors is similar to hypothalamic activity, while in others, different proteolytic profiles are present [102]. Most carcinoid tumors are slow growing, with insidious development of acromegaly. These patients present with features of classical acromegaly, accompanied by elevated circulating GH and IGF-I levels. Patients also often experience systemic effects, obvious metastatic disease, or other humoral effects of the carcinoid syndrome [96]. Following surgical removal, GH levels fall and soft tissue signs of acromegaly regress. The pituitary often shows evidence of somatotroph hyperplasia with preserved reticulin network. A true GHcell adenoma with distorted reticulin network may also occassionally be present. Treatment Surgical resection of the tumor secreting ectopic GHRH should reverse the GH hypersecretion, and pituitary surgery should not be required in these patients. Nonresectable, disseminated or recurrent carcinoid syndrome with ectopic GHRH secretion can also be managed medically with long-acting somatostatin analogs (see below).

Chapter 11

Administration of the analog lowers circulating GH and IGF-I levels, and also suppresses ectopic tumor elaboration of GHRH [94–96,103–107]. The drug therefore suppresses both pituitary GH as well as the peripheral tumor source of GHRH, thus attenuating the deleterious effects of chronic hypersomatotrophism. The peptide provides an effective option for medical management of carcinoid patients, especially those with recurrent disease. GH Hypersecretion

Ectopic Pituitary Adenomas Embryonal development of the anterior pituitary involves dorsal migration of fetal adenohypophyseal cells. Functional pituitary adenomas secreting GH may arise from these ectopic pituitary remnants in the sphenoid sinus and wing, petrous temporal bone and the nasopharyngeal cavity [108–110]. Residual tumor cells may also be dislodged after neurosurgical resection of invasive pituitary adenomas and give rise to subsequent recurrent ectopic adenomas. Alternatively, the very rare pituitary carcinoma may spread to the meninges cerebrospinal fluid or cervical lymph nodes, resulting in functional GH-secreting metastases which may also be diagnosed by radiolabelled octreotide imaging (octreoscan) (Fig. 11.2) [111]. Peripheral GH-secreting Tumors Immunoreactive GH has been identified in normal human tissues, including liver, kidney, lung, colon, stomach, and brain [112]. Extracts of lung adenocarcinoma, breast cancer, and ovarian tissues also contain immunoreactive GH without clinical evidence of acromegaly [113–114]. A GH-secreting intramesenteric pancreatic islet cell tumor was associated with acromegaly. Ectopic GH secretion by the tumor was unambiguously confirmed by a high arteriovenous gradient of GH across the tumor [70], rapid decrease of GH and IGF-I to normal levels within 2 hours after tumor resection, positive immunoperoxidase tumor staining for GH, demonstration of in vitro GH synthesis and release, and expression of human GH (hGH) mRNA. Postoperative GH suppression after glucose and stimulation by GHRH were also appropriate. Based on the features of this unique case, the very rare patients with ectopic GH secretion would be expected to exhibit a normal-sized or small pituitary gland on imaging, absent GH response to TRH injection, and normal levels of circulating plasma GHRH. Acromegaloidism

Patients who manifest clinical features of acromegaly but do not harbor a demonstrable pituitary or extrapituitary tumor have been termed “acromegaloid”. These patients exhibit soft tissue and skin changes usually associated with acromegaly and some may even have bony features of the disorder, and occasionally hyperglycemia. GH and IGF-I levels are normal in these patients and they respond appropriately to dynamic pituitary testing. Pachydermoperiostosis should be considered in the differential diagnosis. A unique growth

Acromegaly

425

factor, partially characterized by bioassay, stimulates colony formation by human erythroprogenitor cells [115]. Insulin resistance and defective IGF-I binding have been demonstrated in cells derived from two patients with acromegaloidism and acanthosis nigricans [116]. Treatment is directed at relief of peripheral clinical signs and symptoms. Genetic Syndromes (Table 5)

McCune–Albright Syndrome Polyostotic fibrous dysplasia, cutaneous pigmentation, sexual precocity, hyperthyroidism, hypercortisolism, hyperprolactinemia, and acromegaly comprise a rare hypersecretory endocrinopathy [117]. The diagnosis of McCune–Albright syndrome requires the presence of two signs of the triad of polyostotic fibrous dysplasia, café-au-lait pigmentation, and precocious puberty. Excessive GH secretion in these patients may be due to disordered hypothalamic regulation, although circulating GHRH levels are apparently normal [118]. Only about 10 patients have had definitive evidence for a pituitary adenoma, although most dynamic GH responses are indistinguishable from patients harboring GH-secreting somatotroph adenomas. In four of eight patients, G a mutations were detected in both endocrine and non-endocrine organs [119]. Management of GH hypersecretion in these patients includes medical treatment with somatostatin analogs, or pituitary irradiation. Multiple Endocrine Neoplasia GH-cell pituitary adenoma causing acromegaly is a well-documented component of the autosomal dominant multiple endocrine neoplasia I (MEN-1) syndrome which also includes parathyroid and pancreatic tumors. The disorder is associated with germ cell inactivation of the MENIN tumor suppressor gene which maps to chromosome 11q13 [120,121], and appears to be appropriately expressed in sporadic GH-cell adenomas [122]. Few functional pancreatic tumors in patients with MEN-1 also express excess circulating GHRH [103,123,124]. Familial Acromegaly

Familial acromegaly may occur in association with MEN-1 syndrome, or the Carney complex which maps to chromosome 2p [125], (Table 11.2). Recently, several families with isolated familial somatotropinomas have been analyzed [127–130]. These families consist of isolated related cases of acromegaly and/or gigantism and harbor a mutation in chromosome 11q13 distinct from MENIN. Gigantism

The diagnosis of pituitary gigantism should be considered in children who are >3 standard deviations (SD) above normal mean height for age, or >2 SDs over their adjusted mean parental height. The biochemical diagnosis is similar to that for acromegaly, i.e., GH levels are in excess of 1 mg/L after a glucose load and serum IGF-I concentrations are

426

SECTION 3

Table 11.2.

Pituitary Tumors

Familial acromegaly syndromes*

Syndrome

Clinical features

Chr. location

Gene

Protein

Proposed function/defect

Multiple endocrine neoplasia type I (MEN-1)

Tumors of parathyroid, endocrine pancreas, anterior pituitary

11q13

men1

Menin

Familial Acromegaly McCune-Albright syndrome

Somatotropinomas Polyostotic fibrous dysplasia, Skin pigment patches

11q13 and other locus 20q13.2 (mosaic)

Not men1 GNAS1 (gsp)

– GSa

Menin tumor suppressor protein interacts with JunD, represses transcriptor – Signal transduction/inactive GTPase results in constitutive adenylate cyclase independent of GHRH

2p16

–

–

Carney syndrome

Endocrine abnormalities: precocious puberty, somatotropinomas Skin and cardiac myxomas, Cushing syndrome, somatotropinomas

Protein kinase A signaling defect for GH activation

* Adapted from Prezant [126].

elevated. Gigantism may be caused by a variety of conditions [131] (Table 11.3). Familial tall stature, redundancy of Y chromosomes, Marfan’s syndrome, and homocystinuria should all be ruled out prior to considering the endocrine causes of tall stature. About 20% of patients with gigantism are associated with the McCune–Albright syndrome, with somatotroph hyperplasia or true pituitary adenomas. Somatotroph hyperplasia and acidophilic stem cell adenomas have been reported in cases of gigantism beginning in infancy or early childhood, suggesting early hypersecretion of GHRH or disordered pituicyte cell differentiation accounting for the hypersomatotrophism [72,131]. In children undergoing pubertal growth spurts, however, GH response to glucose may be paradoxical and serum IGF-I concentrations are often physiologically elevated. If pituitary imaging reveals the presence of an adenoma, it should be resected surgically. Somatostatin analogs with or without dopamine agonists have successfully been employed in treating these children [132,133]. Radiation therapy should be considered for failed responses to surgery and medical treatment (Table 11.4). CLINICAL FEATURES OF ACROMEGALY The manifestations of acromegaly may be due to either central pressure effects of the pituitary mass, or peripheral actions of excess GH and IGF-I. Central features of the expanding pituitary mass are common to all pituitary masses [134]. They include headache, visual dysfunction due to chiasmal compression, and rarely hypothalamic and frontal lobe dysfunction. The headache is often severe and sometimes debilitating. Lateral extension may impinge upon the cranial nerves III, IV, and VI with diplopia, or nerve V leading to facial pain; temporal lobe invasion may also occur. Inferior extension of the mass may cause cerebrospinal fluid rhinorrhea and nasopharyngeal sinus invasion [135]. These

Table 11.3.

Causes of tall stature*

Genetic Familial Sex chromosome redundancy Marfan’s syndrome Homocystinuria Neurofibromatosis Endocrine-metabolic Growth hormone-secreting pituitary adenomas or hyperplasia Hyperinsulinism Lipoatrophic diabetes Hyperthyroidism Prepubertal sex steroid excess Unclassified Cerebral gigantism * Adapted from Daughaday [131].

local signs are especially important in acromegaly, as most series report a relatively higher preponderance of macroadenomas (>65%) in acromegaly, as compared to a preponderance of microadenomas for PRL-secreting tumors [136–138].

Effects of Excessive GH Secretion The protean clinical manifestations of hypersomatotrophism are caused by elevated GH and/or IGF-I levels (Table 11.5). Effects of hypersomatotrophism on acral and soft tissue growth, as well as metabolic function, may occur insidiously over several years [140] (Fig. 11.3). The elusiveness of the symptomatology often results in the disease being diagnosed only when patients seek care for dental, orthopedic, or

Chapter 11 Table 11.4.

427

Acromegaly

Therapeutic outcome of reported cases of gigantism Patients

Sex

Age (yrs)

PRL (ng/ml)

RX

Chromophobe adenoma

M

171/2

193 (+2 SD)

Eosinophilic adenoma

F

31 mo

–

74

ND

Surgery

Postoperative GH > 1.0

355

60–109

Elevated

Surgery

GH remained high, IGF-I normal, growth stopped

356

Eosinophilic adenoma

F

12

180

100

100

Surgery Radiotherapy Bromocriptine

Growth stopped

359

Esinophilic adenoma

M

13

187.5 (+3.57 SD)

26–35 (mean 25)

n/a

Surgery

GH normalized “acceptable growth” achieved

Adenoma packed with pleomorphic GH & PRL cells

M

13

186 (+4 SD)

89–150

100–130

Surgery Bromocriptine

GH and PRL normalized

358

Mammosomatotroph hyperplasia

F

4

>95th %ile

44–55

128–195

Bromocriptine Octreotide Surgery

GH normalized

361

Pituitary adenoma (+ve for GH and PRL)

M

21/4

112

29.6

1070

Surgery Bromocriptine Octreotide

GH and PRL normalized

358

Somatotroph, lactotroph and mammosomatotroph hyperplasia; somatotroph and lactotroph adenoma

M

>95th %ile

73

77

Octreotide Bromocriptine Surgery Radiotherapy

GH remained elevated, needed radiotherapy Panhypopituitarism, needed replacement therapy

352

Acidophilic adenoma

F

4.5

>95th %ile

42

>150

Surgery Radiotherapy Bromocriptine Octreotide

PRL normalized GH remained elevated

353

Acidophilic stem cell adenoma

F

151/2

179 (>95th %ile)

71

8700

Surgery Cabergoline Octreotide LAR

PRL, GH, and IGF normalized

135

Mammosomatotroph adenoma positive for GH > PRL

M

8

140.5 (+2.5 SD)

28

120

Surgery Bromocriptine

Patient doing well

362

Pituitary GH adenoma

F

2

+4.4 SD

135

370

Surgery

GH normalized

358

McCune–Albright syndrome

M

6

149.7 (+5.9 SD)

1316 mIU

Surgery Octreotide

Growth started after surgery, but stopped on octreotide

363

GRFoma from foregut with metastases liver

F

15

n/a

>120

Surgery GRFoma resected Octreotide

GH and GRF suppressed Growth stopped 21/2 months after SMS start

359

Unknown (no surgery)

M

12

+4.2 SD

15

52

Bromocriptine Octreotide

Normalized GH, IGF-I, PRL and growth velocity

354

Unknown (no surgery)

M

159.9 (+4 SD)

17–40

>60

Bromocriptine Radiotherapy

GH near normal

360

Pathology

Ht (cm)

GH (ng/ml)

Outcome

Author*

Unclear tumor type

21

Mixed GH and PRL cells

11

Other

71/2

44.9 340–450

* Adapted from Maheshwari et al. [133]. Abbreviations: GH: growth hormone, PRL: prolactin, IGF-I: insulin-like growth factor-1, n/a: not available.

428

SECTION 3

Pituitary Tumors

rheumatologic disorders (Table 11.6). In a study in the UK, only 13% of 256 acromegalic patients diagnosed during a 20-year period, presented with primary symptoms of altered facial appearance or enlargement of extremities [136]. In a review of several hundred patients worldwide, 98% were reported with acral enlargement, while hyperhidrosis was prominent in 70% [140]. Morever, the time between onset of symptoms and diagnosis of acromegaly ranges from 6.6 to 10.2 years, with a mean delay of almost 9 years [8,135]. Generalized visceromegaly occurs with enlargement of the tongue, bones, salivary glands, thyroid, heart, liver, and spleen. Clinically apparent hepatosplenomegaly, however, is rare. Patients have characteristic facial features, large fleshy nose, spade-like hands, and frontal bossing. Some patients, if presenting early, may have subtle facial and peripheral features. Serial review of old photographs often accentuates the progress of these subtle physical changes [141]. Increase in shoe, ring, or hat size is commonly reported. Progressive

Table 11.5.

Clinical features of acromegaly

Local tumor effects Pituitary enlargement Visual field defects Cranial nerve palsy Headache Somatic Acral enlargement Thickening of soft tissue of hands and feet Musculoskeletal Prognathism Malocclusion Arthralgias Carpal tunnel syndrome Acroparesthesia Proximal myopathy Hypertrophy of frontal bones Skin Hyperhidrosis Oily Skin tags Colon Polyps Cardiovascular Left ventricular hypertrophy Asymmetric septal hypertrophy Hypertension Congestive heart failure Sleep disturbances Sleep apnea Narcolepsy

Visceromegaly Tongue Thyroid Salivary gland Liver Spleen Kidney Endocrine-metabolic Reproduction Menstrual abnormalities Galactorrhea Decreased libido, impotence, low sex hormone-binding globulin Multiple endocrine neoplasia (1) Hyperparathyroidism Pancreatic islet cell tumors Carbohydrate Impaired glucose tolerance Insulin resistance and hyperinsulinemia Diabetes mellitus Lipids Hypertriglyceridemia Mineral Hypercalciuria, increased 1,25 (OH)2 vitamin D3 Urinary hydroxyproline Electrolyte Low renin Increased aldosterone Thyroid Low thyroxine-binding globulin

* The mean delay to diagnosis from onset of symptoms is 8.7 years.

acral changes will, if untreated, lead to severe facial and skeletal disfigurement especially if the excess GH secretion begins prior to closure of the epiphyses (Fig. 11.4) [142–144]. Skeletal Changes

Periosteal new bone formation in response to IGF-I [145] results in skeletal overgrowth leading to mandibular overgrowth with prognathism, maxillary widening, teeth separation, frontal bossing, jaw malocclusion and overbite, and nasal bone hypertrophy [149]. Characteristic voice deepening with a sonorous resonance occurs because of laryngeal hypertrophy and enlarged paranasal sinuses. Arthropathy occurs in about 70% of patients with acromegaly, most of whom exhibit objective signs of joint swelling, hypermobility and cartilaginous thickening [5,147]. Up to half of patients experience joint symptoms severe enough to limit or impair daily activities [148–153]. Severe joint pain unusually signifies irreversible joint degeneration. Knees, hips, shoulders, lumbosacral joints, elbows, and ankles are affected in decreasing order of frequency. Joint involvement may be mono- or polyarticular, and although crepitus, stiffness, tenderness, and hypermobility are common, joint effusions are rarely encountered [144,152]. Local periarticular fibrous tissue thickening may cause subsequent joint stiffening, deformities, and nerve entrapment. Neural enlargement, local fluid retention and swelling of wrist soft tissues may lead to carpal tunnel syndrome, a painful entrapment median neuropathy, which occurs in up to half of all patients. This condition generally resolves early

Table 11.6.

Presentation of acromegaly*

Presenting chief complaint

Frequency (%)

Menstrual disturbance Change in appearance/acral growth Headaches Paresthesias/carpal tunnel syndrome Diabetes mellitus/impaired glucose tolerance Heart disease Visual impairment Decreased libido/impotence Arthopathy Thyroid disorder Hypertension Gigantism Fatigue Hyperhidrosis Somnolence Other Chance (detected by unrelated physical or dental examination or X-ray)

13 11 8 6 5 3 3 3 3 2 1 1 0.3 0.3 0.3 5 40

* From Molitch [143], based on 310 patients.

Chapter 11

Acromegaly

429

(c) (a),(b)

(d)

(f) (e) FIGURE 11.3. Clinical signs of hypersomatotrophism. (a) Original figure depicting earliest illustration of clinical features of acromegaly by Minkowski in 1887. Note acromegalic facies, fleshy fingers and toes, and frontal bossing. (b) Acromegaly in a young male with active perspiration, oily skin, acne, and widened tooth gap. (c) Prominent skin tags may be associated with the presence of colon polyps. (d) Jaw overbite and widening of spaces between incisors due to mandibular growth in acromegaly. (e) X-ray image of bony “tufting” seen at ends of terminal phalanges indicates bony overgrowth. (f) Increased heal pad thickness. (d) and (f) from Melmed and Braunstein [139].

after treatment. Spinal involvement including osteophytosis, disc space widening, and increased anteroposterior vertebral length may lead to dorsal kyphosis [151]. Pathology of Arthropathy

Proliferation of chondrocytes with subsequent increased joint space occurs early in response to increased GH and IGF-I levels. Presumably, induction of local IGF-I by GH stimulates uneven chondrocyte growth. Ulcerations and fissures present on the weight-bearing areas of new cartilage are often accompanied by new bone formation. This process eventually results in debilitating osteoarthritis associated

with bone remodeling, osteophyte formation, subchondral cysts, narrowed joint spaces, and lax periarticular ligaments. Osteophytes are commonly seen at the tufts of the phalanges and over the anterior aspects of spinal vertebrae. Ossification of ligaments and periarticular calcium pyrophosphate deposition are also found [147]. Although the duration of hypersomatotrophism appears to directly correlate with the severity of the joint changes, it is unclear whether higher GH levels are associated with increased severity of articular disease [151]. Responses to therapy (see below) will usually depend upon the degree of irreversible cartilage degeneration already in place.

430

SECTION 3

Pituitary Tumors

FIGURE 11.4. Severe skeletal disfigurement in three patients with growth hormone-secreting pituitary tumors. From Whitehead et al. [142].

Skin Changes

Hyperhidrosis and oily skin with an unpleasant odor are common early signs, occurring in up to 70% of patients. Patients often relate the need to increase their use of deodorant or cosmetic powders. Facial wrinkles, nasolabial folds and heel pads are increased in thickness, and body hair may become coarsened [154,155]. These effects may correlate with IGF-1 levels, and improve after treatment. Thickening of the skin has been attributed to glycosaminoglycan deposition [156], while connective tissue collagen production is also increased [160]. Skin tags are common and these may be important markers for the concomitant presence of adenomatous colonic polyps [158]. Raynaud’s phenomenon may also be present in up to one-third of patients. Cardiovascular Complications

Cardiovascular disease is a major cause of morbidity and mortality [159–169] with symptomatic cardiac disease present in about 20% of patients. Arterial hypertension, accelerated atherosclerosis, sodium and fluid retention leading to expanded extracellular fluid volume, and cardiac arrhythmias are the common cardiovascular manifestations. About half of patients with active acromegaly have hypertension, and 50% of these have evidence of left ventricular dysfunction [169]. Interestingly, left ventricular hypertrophy is also reported in about half of normotensive acromegalic patients. Although asymmetric septal hypertrophy is common, cardiac failure with early or mild cardiomegaly may occur in the absence of obvious causes of myocardial failure. Patients may exhibit subclinical left ventricular diastolic dysfunction, consistent with unique pathologic findings including myocardial hypertrophy, interstitial fibrosis, and lymphocytic myocardial infiltrates. Electrocardiograms are abnormal in about 50% of patients, with S-T segments,T-wave abnormalities, conduction defects and arrhythmias accounting for most changes. Plasma renin

levels are suppressed and endogenous plasma digitalis-like activity with chronic volume expansion has been identified [170]. Coexisting hypertension and coronary artery disease account for most of the cardiovascular disease encountered in patients with acromegaly, while a GH- or IGF-1mediated specific cardiomyopathy may also be present [164]. Cardiovascular disease is the most important cause of mortality in acromegaly, accounting for approximately 60% of deaths [159]. The presence of cardiovascular disease at the time of diagnosis is associated with high mortality rates, and effective control of GH and IGF-I levels results in improved cardiac function [172]. Respiratory Complications

Prognathism, thick lips, macroglossia, and hypertrophied nasal structures may result in significant airway obstructions [173–175]. Additional clinical features of acromegaly contribute to impaired upper respiratory function. Irregular hypertrophy of laryngeal mucosa and cartilage may lead to unilateral or bilateral vocal cord fixation or laryngeal stenosis with accompanying voice changes [173]. Tracheal calcification and cricoarytenoid joint arthropathy may also be present. These obstructive features may necessitate tracheostomy either to maintain adequate baseline airway function, or especially at the time of surgical anesthesia. Difficulty in tracheal intubation is often encountered in patients undergoing anesthesia. Central respiratory center depression as well as upper airways obstruction may contribute to the development of paroxysmal daytime sleep (narcolepsy), sleep apnea and habitual excessive snoring [173]. The obstructive sleep apnea syndrome, characterized by excessive daytime sleepiness with at least five episodes of obstructive apnea per hour, is an important cause of daytime somnolence in men with acromegaly. These patients may also have a ventilation perfusion defect with hypoxemia. The sleep apnea of acromegaly may be due to either obstruction of the respi-

Chapter 11

ratory tract, or central in origin. Interestingly, the central form of sleep apnea is associated with higher GH and IGFI levels, possibly reflecting a loss of central somatostatin tone accounting for the disorder [176–178]. Neuromuscular Changes

Peripheral acroparesthesias occur in almost half of all patients. Synovial edema and hyperplastic wrist ligaments and tendons contribute to painful median nerve compression with the resultant carpal tunnel syndrome [180]. A true symmetrical peripheral neuropathy has also been described. This rare mixed motor and sensory impairment should be distinguished from characteristic diabetic neuropathy, which may occur secondarily to acromegaly. The pathologic features of median neuropathy have been ascribed to increased edema, rather than extrinsic compression [181]. About half of all patients develop proximal myopathy which may be accompanied by myalgias and cramps and nonspecific electromyogram (EMG) myopathic changes. Histologic examination reveals hypertrophy and necrosis of skeletal muscle fiber in patients with proximal muscle weakness and elevated creatine phosphokinase (CPK) levels [182]. Although bony overgrowth of frontal bones may mask eye changes, true exophthalmos may be present. Open angle glaucoma may also result from impaired aqueous filtration through hypertrophied tissue surrounding the canal of Schlemm. Psychologic Changes

Self-esteem may diminish with progressive facial and bodily disfigurement. It is unclear whether reported depression, mood swings and apathy result from these physical effects or whether they are intrinsic central effects of high GH levels. There is no clear evidence for an increased incidence of psychologic disorders in acromegaly [183,184]. Morbidity and Mortality in Acromegaly

The impact of the disease on mortality outcome has recently become apparent, and a significant increased (approximately threefold) mortality has been reported in several studies [8,9,159,160,185–190]. In a retrospective study reported in 1966, 50% of patients died before the age of 50, with cardiovascular disease being the most common cause of death (Table 11.7). In 194 patients with acromegaly, a reduced life expectancy was found, with cardiovascular disorders accounting for 24% of deaths followed by respiratory (18%), and cerebrovascular disease (14%). Diabetes mellitus, found in 20% of patients, was associated with 2.5 times the predicted risk of death, while hypertension had been present in 45% of patients with acromegaly [8,9,159]. Analysis of more recent reports indicates that cardiovascular disease, respiratory disorders, diabetes and malignancy account for mortality in acromegaly. The most significant determinants of mortality appear to be the GH level and the presence of coexisting cardiac disease [159]. Moreover, control of GH levels to <2.5 mg/L after surgery or medical treatments

Table 11.7.

431

Acromegaly

Acromegaly: outcome determinants

Causes of death

%

Survival determinants

p

Cardiovascular Respiratory Malignancy

60 25 15

Last GH Hypertension Cardiac disease Diabetes Symptom duration

<0.0001 <0.02 <0.03 <0.03 <0.04

Documented determinants of mortality outcome in retrospective studies of acromegaly. Data integrated from Wright [185]; Alexander [8]; Nabarro [136]; Bengtsson [9]; Bates [160]; Rajasoorya [159]; Swearingen [187]; Abosch [188]; Freda [189].

appears to reverse adverse mortality rates [187,188]. It is now clear from these studies that effective biochemical control of acromegaly significantly reduces both morbidity and mortality. GH and Tumor Formation

The early practice of hypophysectomy in the management of metastatic carcinoma was based on experimental evidence implicating GH as a causative factor in the development of tumors. When high doses of impure GH were administered daily to rats for up to 70 weeks, neoplasms developed in multiple organs, including lymphosarcomas of the lung, adrenocortical and adrenomedullary carcinomas, solid ovarian, and breast tumors [191]. GH and IGF-I stimulate proliferation of several normal and transformed human cells [193] and the IGF-I receptor appears to be an important determinant of cell transformation [194]. GH induces hepatic and renal c-myc expression in hypophysectomized rats, prior to induction of IGF-I mRNA transcripts [192]. These observations imply that GH and/or IGF-I may possess direct or indirect mitogenic effects on mammalian cells. GH and IGF-I, also act as permissive growth stimulators of cells previously exposed to other growth factors [193,194]. IGF-I is expressed in lung, colon and breast carcinomas, while IGF-I receptors are present on Tlymphoblasts, pancreatic tumor cells, and breast cancer cells [195]. As IGF-I is also produced locally, GH and IGF-I may participate in intracrine, autocrine, paracrine, and classic endocrine pathways to regulate cellular proliferation [196]. IGFBP3, also induced by GH [197,198] inhibits cell proliferation and actually promotes apoptosis [202]. Thus, the ultimate impact of hypersomatotrophism on cell proliferation reflects a balance of apoptotic versus growthpromoting signals [200]. Acromegaly and Development of Neoplasms Several benign and malignant tumor types have been reported in association with acromegaly and retrospective studies have indicated a threefold increased risk for gastrointestinal malignancies in acromegaly [201,202]. Nevertheless, a compelling

432

SECTION 3

Pituitary Tumors

cause–effect relationship of acromegaly with cancer has not been established (Table 11.8) [203–220]. Reports of high prevalence of colonic polyps in acromegaly may reflect increased physician awareness in screening for these tumors, as well as the use of diagnostic colonoscopy. Prospectively, ~45% of patients with acromegaly harbor colonic polyps (Table 11.9). A recent controlled study in 161 patients revealed no increase in polyp incidence in acromegaly [219]. Polyposis coli and Gardner’s syndrome are also associated with acromegaly. Acrochordons (skin tags) have been noted

Table 11.8. analysis

a

Females Males Total b

in most patients found to harbor colonic lesions [158,206]. The presence of more than three skin tags in patients aged over 50 years and in whom the disease has been present for more than 10 years is a reliable screen for the presence of colonic polyps. However, no clear correlation between serum levels of GH or IGF-I and colonic polyps is apparent [206]. Although elevated IGF-I levels may correlate with colon polyp prevalence when patients are retested [220], a recent controlled prospective study of 151 patients showed no increased colon polyp incidence in acromegaly [219]. As hypertrophic mucosal folds and colonic hypertrophy are commonly present in acromegaly, barium radiography is not helpful for diagnosis of colonic lesions, and colonoscopy is warranted in these patients once every 3–5 years after diagnosis, depending on the presence of other risk factors. Timely diagnosis and resection of premalignant polyps is prudent for improved morbidity in this relatively high-risk group of patients [197]. Although a coexistence of acromegaly and meningioma has been reported, meningiomas also develop at sites of previous head trauma, inflammation, or irradiation [221]. No association has been reported between acromegaly and other intracranial neoplasms. These and other recent studies indicate that mortality from colon cancer is largely related to GH levels, rather than enhanced incidence of the disease in acromegaly (Table 11.10). In a large survey of 1362 patients in the UK, cancer incidence was in fact lower than expected, and enhanced colon cancer mortality in acromegaly correlated with GH levels [186]. As patients with

Acromegaly and cancer incidence: multicenter

Person-years at risk

N 95 128

Cancers Observed

1351 1630

8 5

223

2981

13

4822

21740

178

O/E

p

1.33 1.30

ns ns

1.3 0.76–3.4

–

a

Multicenter analysis of cancer incidence in patients with acromegaly ranging in age from 1 to 79 years. Adapted from Mustacchi [217]. b Analysis of 9 retrospective published reports (1956–1998) of cancer incidence in patients with acromegaly. (Included are data from [185]; [8]; [136]; [9]; [202]; [364]; [351]; [217]. O/E: Observed/expected ratio.

Table 11.9.

Colon polyps in acromegaly Polyps

N

M:F

Mean age

17 12 29 23 54 50 49 31 103 129 115 66c

10 : 7 11 : 11 – 12 : 11 26 : 28 25 : 25 30 : 19 11 : 20 49 : 54 68 : 60 63 : 69 –

49 56 – 47 47 25–70 54 52 51 57 55b 33

678

a

Adenoma

Hyperplastic

Total

5 2 4 8 5 11 11 11 23 33 27 25

3 1 0 1 11 12 5 8 25 42 18 18

8 3 4 9 19 23 16 16 48 75 45 43

165 (24%)

144 (21%)

309 (45%)

Carcinoma 2 2 2 0 0 1 0 0 0 6 3 1

Referencea 203 207 204 206 211 214 213 212 210 215 219 220

17 (2.5%)

Adapted from Melmed [200]. Median age. c Repeat colonoscopy. Incidence of colonic lesions in 524 patients prospectively studied in 12 studies. Up to 40% of asymptomatic males aged >50 yrs harbor colon adenomas. – = not ascertainable. b

Chapter 11 Table 11.10. acromegaly

Posttreatment GH levels and mortality in

Posttreatment GH (ng/mL) <2.5 n = 541

2.5–9.9 n = 493

>10 n = 207

Overall

1.10 (0.89–1.15)

1.41 (1.16–1.69)

2.12 (1.70–2.62)

<0.0001

Cancerrelated

0.96 (0.63–1.41)

0.81 (0.50–1.24)

1.81 (1.13–2.74)

<0.05

Mortality

p

Posttreatment GH levels correlate with mortality in acromegaly. Standardized mortality ratios are depicted for overall mortality and for cancer-related mortality. Adapted from Orme [186].

acromegaly are living longer due to improved biochemical control, it is apparent that long-term prospective controlled studies are required to resolve this question. Endocrine Complications

Elevated serum PRL levels, with or without galactorrhea, are found in about one-third of patients with acromegaly, some of whom present with PRL levels >100 mg/L [138,222]. Several mechanisms may explain the hyperprolactinemia in these patients. Functional pituitary stalk compression by a pituitary adenoma may prevent hypothalamic dopamine from reaching the normal pituitary lactotroph cell, resulting in release of lactotroph cells from tonic hypothalamic inhibition [222]. GH-secreting adenoma types may also concomitantly secrete PRL, including mixed GH-cell and PRL-cell plurihormonal adenomas, monomorphous mammosomatotroph adenomas, and acidophilic stem cell adenomas [28]. In patients with galactorrhea and normal PRL levels, elevated GH levels may “spill over” and behave as an agonist for PRL binding sites in the breast. Hypopituitarism may also develop as a result of the tumor mass impinging upon the surrounding normal pituitary tissue. Over half of patients will have amenorrhea or impotence [138,223], while up to 20% may in fact have secondary thyroid or adrenal failure. Gonadal function may also be an important determinant of bone density in these patients [224]. Carbohydrate intolerance is caused by the direct antiinsulin effects of GH, and patients may develop insulinrequiring diabetes mellitus [225]. Carbohydrate intolerance and insulin requirements improve remarkably after lowering of GH by surgery or somatostatin analog therapy. Hypertriglyceridemia (type IV), hypercalciuria, and hypercalcemia are also commonly found [226]. Pituitary hypersecretion of associated hormones by mixed somatotroph tumors may commonly result in hyperprolactinemia and rarely in Cushing’s disease (ACTH hypersecretion) or hyperthyroidism (TSH hypersecretion). IGF-I is a determinant of thyroid cell growth and possibly of thyrocyte function

Acromegaly

433

[227]. Thyroid dysfunction in acromegaly may be due to diffuse or nodular toxic or nontoxic goiter, or Graves’ disease [228,230]. Associated manifestations of MEN-I may be present in affected individuals. These include hypercalcemia with hyperparathyroidism or pancreatic tumors. Benign prostatic hypertrophy has been documented in acromegaly with no apparent increase in prostate cancer rates [230,231].

DIAGNOSIS OF ACROMEGALY

Measurement of GH Levels Basal morning (a.m.) and random GH levels are usually elevated in acromegaly [232–235]. Because of the episodic nature of GH secretion, however, serum concentrations may normally fluctuate from “undetectable” up to 30 mg/L [171]. When GH is sampled every 5 minutes, GH levels are undetectable in about half of samples collected over 24 hours [235,236]. In acromegaly, however, samples collected over 24 hours contain detectable levels of GH (>2 mg/L) [184,185], and mean 24 hour integrated GH levels <2.5 mg/L exclude acromegaly [237]. Serum GH levels invariably do not suppress to <1 mg/L within 1–2 hours of an oral glucose (75 g) load; glucose may actually stimulate GH secretion in about 10% of patients [238]. Although the episodic basal pattern of GH secretion is sustained in acromegaly, normal diurnal variation of GH is absent with a loss of sleep-related rise in GH [239]. These patients also exhibit a higher episodic GH pulse frequency which often persists after surgical adenoma resection. Using highly sensitive GH assays [240], random GH levels in patients with acromegaly may be <1.0 mg/L, and even as low as 0.37 mg/L when IGF-I levels are still elevated postoperatively [241] (Fig. 11.5). Thus, biochemical exclusion of acromegaly requires a random GH <0.4 mg/L or a GH nadir during OGTT of <1 mg/L, both with normal IGF-I levels [238] (Table 11.11). Responses to GHRH infusions, are not of diagnostic utility [242]. Serum IGF-I levels are invariably high in acromegaly [243], and the degree of elevation correlates well with the log of serum GH determinations [233]. Age- and sexmatched IGF-I elevations may persist for several months when GH levels are apparently controlled after treatment [244]. Pregnancy and late puberty are also associated with elevated IGF-I levels. A high IGF-I level is highly specific for acromegaly in the nonpregnant adult and correlates with clinical indices of disease activity [243] (Figs 11.6 and 11.7). IGFBP-3 levels are usually elevated in acromegaly, but provide little added diagnostic value [243]. IGF-1-binding protein (IGFBP-1) levels are low in acromegaly and are inversely correlated with GH levels [245]. IGFBP-1 may be directly inhibited by high levels of IGF-I or insulin, both of which are known to regulate this binding protein [246]. As IGFBP-1 may mediate cellular actions of IGF-I either by

434

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Pituitary Tumors Table 11.12. Factors resulting in discordant circulating IGF-I and GH values* • • • • • •

Unreliable or imprecise definition of “normal” GH values Delayed normalization of IGF-I levels following therapeutic intervention GH secretory pattern that more effectively stimulates IGF-I production Persistently elevated and erratic GH pulse frequency following treatment Contribution of local IGF-I production to circulating IGF-I levels Variable sensitivity and reproducibility of assays employed

* Adapted from Drange and Melmed [244].

Differential Diagnosis of Acromegaly

FIGURE 11.5. Ultrasensitive GH immunoradiometric assay distinguishes acromegaly status in postoperative patients. Adapted from Freda [241].

Table 11.11.

Diagnosis of acromegaly*

Random GH >0.4 mg/L and elevated IGF-I or GH nadir during OGTT >1 mg/L * Reproduced from Giustina [238].

attenuating or stimulating IGF-I effects, monitoring changes in IGFBP-1 levels may become useful in determining responses to therapy [247]. Although discordant GH responses to TRH and gonadotropin-releasing hormone (GnRH) administration have been described in up to 50% of patients, these imprecise adjunctive tests are rarely indicated to confirm the diagnosis. Urinary GH

Urinary GH levels can be measured by highly sensitive immunoassays with a minimal detectable level of 1.5 pg GH/ml. Normal subjects secrete 0.4–15 ng GH/g creatinine, while untreated acromegalic patients secrete >40 ng GH/g creatinine [248]. In the absence of renal disease, urinary GH levels appear to correlate with serum GH profiles. Measurement of urinary GH may therefore offer a relatively easy assessment of integrated GH secretion during the period of collection. The utility of this screening test still requires controlled confirmation.

The approach to diagnosis of the various forms of acromegaly [22] is outlined in Figure 11.8. Over 95% of acromegalic patients harbor a GH-cell pituitary adenoma [22]. The rare diagnosis of extrapituitary acromegaly should therefore only be considered in a small number of patients. Nevertheless, distinction of pituitary vs extrapituitary acromegaly is extremely important in planning effective management. Regardless of the cause, GH and IGF-I levels are invariably elevated and GH levels fail to suppress (<1 mg/L) after an oral glucose load in all forms of acromegaly [249]. Patients with true clinical features of acromegaly, normal GH and IGF-I levels and no evidence for extrapituitary tumor probably represent “burned out” acromegaly associated with an infarcted pituitary adenoma, often with resultant empty sella. As further dynamic tests are not useful in diagnosis, if a pituitary mass is indeed present, these patients may benefit from surgical resection. Four percent of consecutive patients with proven GH-cell adenomas had normal GH and elevated IGF-I levels [250]. Discordant circulating IGF-I and GH levels may be encountered (Table 11.12), and these may reflect assay precision, or persistently elevated bioactive GH levels despite apparent appropriate glucose suppression. Dynamic pituitary tests are not helpful in distinguishing GH-secreting pituitary tumors from extrapituitary tumors [251]. GH responses to TRH do not distinguish the various forms of acromegaly, as GH levels are usually stimulated in most patients and its diagnostic use is not cost effective. GH responses to dopamine agonists, and to GHRH administration, do not provide useful information for identifying the source of excess GH secretion [252,253]. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumors, and are normal or low in patients with pituitary acromegaly [253]. Measuring GHRH plasma levels therefore provides a precise and cost-effective test for the diagnosis of ectopic acromegaly. Unique and unexpected clinical features in an acromegalic patient, including respiratory wheezing or dyspnea, facial flushing, peptic ulcers, or renal stones will sometimes be helpful in alerting the physician to diagnosing nonpituitary endocrine tumors. Specific biochemical markers of an underlying ectopic tumor (including hypoglycemia, hyper-

Chapter 11

Acromegaly

435

FIGURE 11.6. Circulating insulin-like growth factor-I levels in acromegaly. From Clemmons et al. [243].

FIGURE 11.7.

IGF-I levels correlate with indices of clinical activity in acromegaly. Adapted from [243].

insulinemia, hypergastrinemia, and rarely hypercortisolism) are not usually encountered in pituitary acromegaly, and their presence should alert the physician to search for an extrapituitary source of GH excess. Anatomic localization of the pituitary or extrapituitary tumor is achieved using imaging techniques, including magnetic resonance imaging (MRI) and computed tomography (CT) scanning. As routine abdominal or chest imaging will yield a very low incidence of true positive cases of ectopic tumor, such screening of these patients is not recommended as being cost effective. Definitive preoperative localization and diagnosis of extrapituitary tumors by abdominal or chest imaging of all patients with acromegaly would, however, prevent unnecessary pituitary surgery in the rare patient. Nevertheless, the relatively low incidence of extrapituitary acromegaly makes this expensive screening approach difficult to justify. Elevated circulating GHRH levels, a normal or small-sized pituitary gland, or clinical and biochemical features of other tumors known to be associated with

extrapituitary acromegaly are indications for extrapituitary imaging. An enlarged pituitary is, however, often found on MRI of patients with peripheral GHRH-secreting tumors, and the radiologic diagnosis of a pituitary adenoma may be difficult to exclude. Exceedingly rare miscellaneous conditions associated with acromegaly, including acromegaloidism and the McCune– Albright syndrome should be considered only after definitive exclusion of pituitary and extrapituitary tumors.

TREATMENT OF ACROMEGALY

Aims A strategy for managing patients with acromegaly should aim to comprehensively manage the pituitary mass, suppress hypersecretion of GH and IGF-I, and prevent long-term sequelae of hypersomatotrophism [238,254] (Table 11.13). The mortality associated with untreated or partially treated

436

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Pituitary Tumors

acromegaly is about double the expected mortality rate of age-matched healthy subjects, and it is therefore important to achieve optimally effective GH control. Recent evidence has confirmed that elevated GH levels per se are associated with increased morbidity and account for the single most important determinant of mortality [159,186–188] (Fig. 11.9).

functions. A statistically significant “lowering” of peripheral GH levels is not an adequate therapeutic end-point for the complex of pituitary and peripheral disease associated with the disorder. An effective management strategy for patients with acromegaly should address the comprehensive goals of eliminating morbidity and reducing mortality rates to those expected for age- and sex-adjusted control populations [227].

Goals of Therapy

Besides the local mass effects of the pituitary tumor, acromegaly results in multiple metabolic and growth dys-

1. Selective resection or shrinkage of the pituitary tumor should be accompanied by correction of any

FIGURE 11.8. Diagnosis of acromegaly. Adapted from Melmed S, Anterior Pituitary in Current Practice of Medicine, S. Korenman (ed), 1996.

1.0 Matched population

0.8

Survival probability

Survival probability

1.0

0.6 p = 0.001 0.4

Acromegaly

0.2

0.8

GH < 2µg/l

0.6 GH ≥ 2µg/l

0.4 0.2 p = 0.02

0 (a)

0

5

10

15

20

25

Follow up (years)

30

35

0

40 (b)

0

4

8

12

16

20

24

Follow up (years)

FIGURE 11.9. Survival of patients with acromegaly is diminished (a), and is largely determined by GH levels (b). Adapted from Rajasoorya [159] and Holdaway in Management of Pituitary Tumors, 1998.

28

Chapter 11 Table 11.13. Effective management of growth hormonesecreting adenomas • • • • •

Suppress autonomous GH secretion to <1 ng/ml after a glucose load Normalize IGF-I levels to age- and gender matched controls Remove or reduce pituitary tumor mass Correct visual and neurologic defects Preserve pituitary trophic hormone function

• • • •

Treat acral, cardiovascular, pulmonary and metabolic complications Prevent systemic sequelae of long-term hypersomatotrophism Prevent biochemical or local recurrence Restore mortality rates to expected age-matched controls

associated parasellar local pressure effects and growth recurrence of the pituitary mass should ideally be prevented. 2. Anatomic or functional ablation of the disordered pituitary mass should not compromise residual anterior pituitary trophic function, especially the adrenal, thyroid, and gonadal axes. 3. The morbid effects of hypersomatotrophism, including glucose intolerance, hypertension, soft tissue swellings, nerve entrapments, and arthritis should be ameliorated or reversed [254]. These disorders are often neglected in the context of specialized neurosurgical or endocrine management, which tends to rely on objective radioimaging or hormone assay criteria. As patients with acromegaly are living longer, their metabolic, acral, and soft tissue manifestations will require careful diagnosis and management, if they cannot in fact be prevented. 4. The integrated 24-hour secretion of GH should be normalized, serum GH levels should be suppressed to <1 ng/ml after an oral glucose load and serum IGF-I levels should also be normalized. GH levels in healthy subjects range from 0.25 to 30 ng/ml, and are below the sensitivity of many routine clinical GH assays. Ideally, a cured patient should also have a “normal” 24-hour integrated secretion of GH (<2 mg/L), restored circadian rhythm and exhibit appropriate responses of GH to provocative stimuli including L-dopa, stress, sleep, and exercise. Unfortunately, older published series do not satisfactorily report a biochemical “end-point” compatible with controlled acromegaly, and results should therefore be interpreted as “lowering” of GH rather than biochemical control. The long-term adverse implications of mildly elevated (1–2.5 mg/L) integrated GH levels are presently unclear. Nevertheless, based upon in vitro animal and limited human data, chronic exposure to higher than physiologic concentrations of GH and/or IGF-I should be viewed as undesirable [256]. In older individuals GH is usually not measurable for most

Acromegaly

437

of the day and despite a random GH of 2 mg/L, the disease may still be active, with elevated IGF-I levels. 5. Long-term follow-up should ideally be designed for prevention of both biochemical and anatomic recurrences. Early detection of undesirable late sequelae of hypersomatotrophism is essential to prevent irreversible systemic changes including cardiovascular disorders, debilitating arthritis, and diabetes mellitus. The three therapeutic modes currently available for management of acromegaly, including surgery, irradiation, and medical treatment, in and of themselves do not comprehensively fulfill these goals. Their respective side effects and complications also require careful consideration when choosing an appropriate therapeutic strategy [197].

Surgical Management Selective transsphenoidal surgical resection is the indicated treatment for well-circumscribed somatotroph cell adenomas [267] (Fig. 11.10). The uses of the operative microscope, microinstrumentation, sophisticated head immobilization techniques, and accurate MRI localization have all combined to achieve a high level of expert success with this procedure. Residual pituitary function is usually intact after resection of well-encapsulated tumors that are totally confined within the pituitary fossa. The success of surgery is largely dependent upon the expertise and experience of the neurosurgeon. Surgery reverses the signs of preoperative compression and the compromised trophic hormone secretion is often restored. The skilled surgeon will balance the extent of maximal tumor tissue removal with the need to preserve anterior pituitary function. This is especially important in managing large invasive tumors. Metabolic dysfunction and soft tissue swelling start improving almost immediately, as GH levels return to normal levels within 1 hour of successful tumor resection. Resection of well-encapsulated small tumors usually results in unimpaired anterior pituitary function. Surgical outcome can be correlated with the size of the adenoma and the preoperative serum GH level. In patients with tumors less than 5 mm in diameter and totally confined to the sella, and in whom preoperative serum GH levels are <40 ng/ml, a favorable surgical response is portended. Fifty to 90% of patients with microadenomas achieve postoperative GH levels <2.5 mg/L, while <50% of all-sized macroadenomas had postoperative GH levels <2 ng/ml after glucose [260]. Sixty percent of 1360 patients undergoing transsphenoidal surgery for acromegaly worldwide had random GH levels less than 5 mg/L postoperatively [259] (Table 11.14). Less than onethird of all patients with adenomas larger than 10 mm in diameter were surgically “cured” by biochemical criteria. Using normalized IGF-I as a criterion, about 75% of patients with GH <5 mg/L appear to be in postoperative

438

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Pituitary Tumors

FIGURE 11.10. Transsphenoidal surgery in acromegaly. (a) Depiction of standard transsphenoidal midline approach to secreting pituitary tumors; (b) schematic depiction of midline tumor curettage; (c) schematic depiction of lateral parasellar curettage. From Fahlbusch et al. [260].

remission, while more recent series indicate improved biochemical results (Table 11.15). Unique surgical problems encountered in acromegaly include difficulties in endotracheal intubation due to macroglossia and/or kyphosis. Rarely, tracheostomy may be required for anesthesia. Recently, endoscopic transnasal surgery has been reported for resection of pituitary tumors [268]. Long-term results of this potentially less invasive procedure are not yet available. Side Effects of Surgery

New hypopituitarism develops in up to approximately 20% of patients undergoing transsphenoidal surgery reflecting

operative damage to the surrounding normal pituitary tissue [269]. Although often transient, these complications may require lifelong pituitary hormone replacement. Other complications, including permanent diabetes insipidus, cerebrospinal fluid leaks, hemorrhage, and meningitis occur in up to 10% of patients (Table 11.14). Secondary empty sella may also develop postoperatively. The incidence of local complications depends upon the size of the tumor, the extent of local invasiveness, and neurosurgical skill. Experienced pituitary surgeons report significantly lower postoperative complication rates [269]. Recurrence (approximately 7% over 10 years) or persistence of acromegaly after surgery

Chapter 11 Table 11.14. Cumulative results of transsphenoidal surgery in 1360 patients worldwide* Outcome

Percentage

Postoperative growth hormone <5 mg/L New hypopituitarism Permanent diabetes insipidus Local complications Deaths

60 18 3 7 1

* From Ross and Wilson [259].

Table 11.15. Percentage of patients with acromegaly achieving GH levels <2.5 mg/L after transsphenoidal surgery in selected series Patients (n) 224 76 78 100 72 162 139 66

Microadenomas in remission 72 84 54 61 59 91 91 86

Macroadenomas in remission 49 73 30 30 14 48 46 52

Year 1992 1994 1950 1996 1998 1998 1999 1999

Reference* 260 258 191 264 265 189 262 266

* Adapted from Stewart [267].

usually indicates incomplete surgical removal of adenomatous tissue, persistent inaccessible cavernous sinus tissue, or nesting of functional tumor tissue within the dural sellar lining, which is difficult to visualize and resect. Rarely, true surgical “failures” may require reoperation.

Radiation Treatment Conventional external deep X-ray therapy as well as heavyparticle (proton-beam) irradiation is employed as primary or adjuvant therapies for acromegaly [254]. High-energy ionizing radiation can be delivered to the pituitary tumor by megavoltage radiation sources [270–276]. Factors important in balancing maximal tumor radiation with minimal soft tissue damage include precise MR image localization, effective simulation and isocentral rotational techniques, and high voltage (6–15 MeV) delivery. Indications for use of radiation as primary therapy is a highly individualized choice, depending upon the expertise and experience of the treating radiotherapist, as well as the willingness of the patient to choose the benefits of the therapy vs. its potential risks. Patients undergoing conventional radiation therapy are administered up to 5000 rads in split doses of 180 rad fractions divided over 6 weeks. Tumor growth is invariably arrested and most

Acromegaly

439

pituitary adenomas shrink [276]. GH levels begin falling gradually during the first year after treatment, and after 10 years, GH levels are <10 mg/L in 70% of patients and are still elevated in 10–15% of patients [270–271]. After 20 years, however, the National Institute of Health’s experience is that over 90% of patients will have GH levels of <5 ng/ml [270]. Biochemical response to radiation is directly correlated with pretreatment GH levels. When these were >100 ng/ml, only 60% of patients had GH <5 ng/ml after 18 years [206]. This slow rate of biochemical response is the major disadvantage of this form of treatment. During the initial years after irradiation, over half of all patients may continue to be exposed to unacceptably high levels of circulating GH and IGF-I. During the first 7 years after irradiation, <5% of patients normalize IGF-I levels [273], while approximately 70% of patients exhibit normal IGF-I levels when tested during longer follow-up [274]. Side Effects of Radiotherapy

About 50% of all patients receiving radiotherapy develop pituitary trophic hormone disruption within the first 10 years of the treatment [270,271] (Table 11.16). This incidence increases annually thereafter [277]. Replacement of gonadal steroids, thyroid hormone and/or cortisone are necessary in these patients. Side effects of conventional radiation include hair loss, cranial nerve palsies, tumor necrosis with hemorrhage, and rarely loss of vision due to optic nerve damage or pituitary apoplexy. These effects have been documented in 1–2% of patients [277–281]. Lethargy, impaired memory and personality changes may also occur [282]. The incidence of local complications have been markedly diminished by use of highly reproducible simulators, precise rotational isocentric arc capability and doses of <5000 rad [277]. Proton-beam therapy (Bragg Peak) [283] is performed in a limited number of specialized centers and is contraindicated in patients with suprasellar extension of their tumors due to exposure of the optic tracts to the radiation field. Recently, stereotactic ablation of pituitary tumors by the y-knife has been reported [284,285]. While highly promising, this form of therapy awaits further investigation, especially as regards potential long-term side effects [286]. Although secondary brain neoplasms occurring following radiation are considered very rare, the development of second brain tumors in these patients has been reported [287,288]. These tumors, which arise within the radiation field region, appear to occur at a cumulative risk frequency of 1.9% over 20 years. In summary, radiation therapy is highly effective in shrinking over 95% of GHcell adenomas and in effectively lowering GH levels over 20 years in over 90% of patients. Because of the commonly observed side effects, especially hypopituitarism, as well as the rarely encountered but serious additional side effects, it should be reserved as adjuvant therapy for patients who are not clinically and biochemically controlled by surgical or medical management, or for those who refuse surgery or octreotide.

440

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Pituitary Tumors

Table 11.16.

Pituitary function after treatment of acromegaly with irradiation* Percentage of patients with acquired hypopituitarism

Years postirradiation

Mean growth hormone level (ng/ml)

Hypothyroid

Hypoadrenal

Male

Female

0 2 5 10

52 23 12 9

9 14 12 19

6 12 30 38

13 32 41 58

24 29 44 50

Hypogonadal

* From Eastman et al. [270].

DOPAMINE AGONISTS

Bromocriptine and Cabergoline Dopamine inhibits GH secretion in about one-third of patients with acromegaly. Bromocriptine, a dopamine agonist, or cabergoline (a longer-acting analog) have been used as either a primary or adjuvant therapy for acromegaly [289]. Usually, up to 20 mg/day bromocriptine is required to suppress GH in these patients, a dose higher than required to suppress PRL in patients harboring prolactinomas. Up to about 15% of acromegalic patients worldwide have been reported to suppress their GH levels to less than 5 mg/L when taking the medication [291]. The drug results in minimal tumor shrinkage, which occurs in only about 15% of patients. About 75% of patients, however, experience subjective clinical improvement and report reduced perspiration, decreased soft tissue swelling, and improved fatigue and headache, despite the persistence of elevated serum GH and/or IGF-I levels in most patients. Side effects of bromocriptine especially with the high doses required, include gastrointestinal upset, transient nausea and vomiting, headache, transient postural hypotension with dizziness, nasal stuffiness and, rarely, cold-induced peripheral vasospasm. Cabergoline

Cabergoline, a long-acting dopamine agonist, has proven highly effective in suppressing PRL hypersecretion and shrinking prolactinoma tumor mass. Limited published experience indicates that GH is suppressed to <2 ng/ml, and IGF-I normalized in up to a third of patients with acromegaly [293–295]. No reports of symptom relief have been documented. Side effects of cabergoline include gastrointestinal symptoms, dizziness, headache and mood disorders [295]. SRIF Receptor Ligands

Hypothalamic SRIF inhibits pituitary GH secretion, attenuates insulin secretion and also regulates multiple gastrointestinal secretions and functions [296,297]. Of the five SRIF receptor subtypes, SSTR2 and SSTR5 are preferentially expressed on somatotroph and thryotroph cell surfaces and mediate GH and TSH secretion [298–300]. Several SRIF

ligands have been employed as approved or investigational drugs for treating acromegaly.

Octreotide Octreotide, an octapeptide SRIF analog, binds predominantly to SSTR2 and SSTR5 and differs from the native hormone in potency, specificity, and duration of action [301,302]. Octreotide inhibits GH secretion with a potency 45 times greater than native SRIF, while its potency for inhibiting insulin release is only 1.3-fold that of SRIF. Because of its relative resistance to enzymatic degradation, the in vivo half-life of the analog is prolonged (up to 2 hours) after subcutaneous injection [303]. Furthermore, rebound GH hypersecretion seen following SRIF infusion is not encountered after octreotide. These pharmacologic differences provide unique advantages for using the analog in the long-term therapy of acromegaly [304–312]. A single subcutaneous administration of 50 or 100 mg subcutaneous octreotide suppresses both basal and stimulated GH secretion for up to 5 hours [302]. Although, as expected, the TSH response to TRH is also blocked by octreotide, PRL response to TRH is not attenuated. Secretion of pancreatic hormones, including insulin and glucagon and gastrointestinal hormones such as gastrin, vasoactive intestinal polypeptide and secretin, are suppressed by octreotide. Hence, the peptide has been effectively used to treat hypersecretory gastroenteropancreatic tumors [313]. Effects of SRLs in Acromegaly

In a double-blind, placebo-controlled trial subcutaneous octreotide administered as 8-hourly injections significantly attenuated GH and IGF-I levels in over 90% of patients [311] (Fig. 11.11). Integrated GH secretion measured over 5 hours after injection is suppressed to <5 mg/L in about 50% of all patients, and to <2 mg/L in 25% of acromegalic patients after 6 months [311] (Fig. 11.12). The medication normalizes IGF-I levels in about 70% of patients. In those harboring GH secreting microadenomas, integrated GH and pooled IGF-I levels are almost invariably normalized [311], while the response in larger tumors is less pronounced.

Chapter 11

Octreotide binds predominantly to SSTR2 receptor subtypes, and the GH secretory response to octreotide correlates with SRIF binding sites on pituitary tumor tissue [314]. In vivo imaging of SRIF receptors utilizing radiolabeled octreotide has indicated that GH responsiveness to the medication directly correlates with the presence of demonstrable pituitary receptors [315,316]. Patients not responding to octreotide do not have visible in vivo receptor binding sites (Fig. 11.13). Insufficient adenoma SRIF

Acromegaly

441

binding sites, or possibly a postreceptor defect, may be present in the small fraction (approximately 5%) of patients not responding to octreotide. In vivo imaging by octreoscan is not cost-effective for therapeutic screening and tumor remnants or normal pituitary tissue may also exhibit positive scintillation [317]. Several patients who appear to benefit in a complementary fashion from a combination of octreotide and bromocriptine have been reported [318]. Combined therapy with these two medications induces a

FIGURE 11.11. Effect of octreotide or placebo on hourly growth hormone levels in acromegaly. Mean percentage changes (±SE of basal values) of serum growth hormone (GH) concentrations in patients with acromegaly treated with either 100 mg octreotide subcutaneously every 8 hours (n = 52) (a) or placebo (n = 47) (b) subcutaneously every 8 hours. Blood was sampled before an injection and every hour for 8 subsequent hours before treatment (“baseline”), at the end of weeks 2 and 4 of treatment, and 4 weeks after discontinuation of treatment (“washout”). Octreotide or placebo was administered just after the 0-hour sampling. From Ezzat et al. [311].

(a)

(b)

FIGURE 11.12. Effect of low- and high-dose octreotide on integrated growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. Integrated mean GH and IGF-1 concentrations sampled during 8 hours in acromegalic patients treated with subcutaneous octreotide 100 mg every 8 hours (n = 50) (a) or 250 mg every 8 hours (n = 54) (b) for up to 6 months followed by 1 month of washout. ***indicates P < 0.001 compared with baseline. From Ezzat et al. [311].

442

SECTION 3

Pituitary Tumors

significantly additive suppression of GH and IGF-I levels compared with separate administration of similar doses of either drug. Factors that determine the efficacy of octreotide action in acromegaly include frequency of drug administration, total daily dose, the size of the pituitary tumor, and pretreatment GH levels. It may well be that smaller tumors secreting less GH in fact harbor higher numbers of SRIF receptors. Increasing the frequency of administration to 2hourly subcutaneous injections provided a more rapid and effective suppression of GH levels than similar total daily doses administered every 8 hours [319]. In fact, continuous subcutaneous infusion of up to 600 mg/day provides effective sustained GH control [320]. Total daily doses of 300– 1500 mg octreotide offer optimal responses, and further dose increases are usually not beneficial in patients resistant to therapy [312]. The lower the initial GH level, the more likely the patient is to respond to octreotide. Elderly male patients appear to be particularly sensitive to the GHlowering effects of octreotide [321]. In the long term, patients are not desensitized to octreotide and GH suppression is effectively maintained [322]. Long-acting Somatostatin Analogs

Two long-acting somatostatin analogs are available. These long-acting formulations provide a safe therapy that faciliates patient acceptance, enhances compliance and allows maximal biochemical control of the disorder. Sandostatin LAR is a sustained release intramuscular depot preparation of octreotide [323–327]. Injection of 20–30 mg results in peak drug level at 28 days, with integrated GH levels effectively suppressed for up to 49 days [323] (Fig. 11.14). Monthly injections for 18 months in 14 patients who were known to respond to s.c. octreotide, reduced integrated serum GH levels to <2 ng/ml in nine patients [325]. In an open-label study of 151 patients responsive to octreotide, the drug suppressed serum GH

levels to <2.5 ng/ml in approximately 70% of all patients [327]. Overall, IGF-I levels are normalized in 60–70% of patients receiving the long-acting analog. Lanreotide is a slow release (SR), long-acting depot preparation, at a fixed 30 mg injectable does every 7, 10 or 14 days [328–330]. GH levels <2.5 ng/ml were achieved in 60% of 56 patients treated for 48 weeks while IGF-I levels were normalized in almost two-thirds of patients [330]. Lanreotide is not yet approved for use in the USA. Effects of SRLs on Pituitary Adenoma Size

About one-third of all patients receiving octreotide experience a reduction of pituitary adenoma size [311,331,332]. The magnitude of this decrease ranges from 20% to 80% and at least in some studies does appear to be does-related. If shrinkage does occur, it should be evident relatively rapidly, and if tumors do not shrink within 16 weeks of initiating therapy, further treatment will probably not impact on adenoma size. Increasing the does to 750 mg/day may provide maximal benefit in shrinking adenomas [311]. In a randomized study, of 59 patients undergoing pituitary surgery, 22 patients received preoperative octreotide for 3–6 months and demonstrated improved postoperative biochemical control and reduced hospital length of stay [333,334]. Effects of Octreotide on Clinical Features of Acromegaly (Fig. 11.15)

The reduction in GH and IGF-I levels observed during chronic administration of octreotide are accompanied by marked improvements in many of the signs and symptoms of acromegaly [335,336]. Patients experience a general feeling of well-being and many features associated with soft tissue swelling resolve, as swelling dissipates within several days of initiating treatment in over 70% of patients [311]. Paresthesias, numbness and tenderness due to nerve entrapments dissappear, swollen facial features improve, and

FIGURE 11.13. Growth hormone (GH) responses to a single 100 mg subcutaneous dose of octreotide in eight acromegalic patients. All patients were imaged with in vivo radiolabeled octreotide.
= scan negative,  = scan positive. From Ur et al. [316].

Chapter 11

Acromegaly

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Side Effects

SRIF analogs are generally safe and well-tolerated [304]. As SRIF suppresses pancreatic secretions, gastrointestinal motility and splanchnic blood flow, gastrointestinal side effects of SRIF analogs predominate. These include loose stools, nausea, mild malabsorption, and flatulence in about onethird of all patients. These effects are often short-lived and may not be sustained. Hypoglycemia or hyperglycemia are not commonly encountered and insulin requirements in diabetic patients with acromegaly are dramatically reduced within hours of receiving octreotide. The most significant side effects of the drug relate to its action on the gallbladder. The drug attenuates gallbladder contractility and delays emptying, leading to the formation of sludge as evidenced by ultrasonography in up to 25% of patients [342,343]. These are usually cholesterol deposits and they disappear within 30 days of stopping the medication. Frank cholecystitis is not commonly encountered. The incidence of gallbladder sludge or stones appears to be geographically variable, with higher rates reported in China [343], Australia [308] and the UK [336]. In the USA, it would appear that up to 30% of all patients will experience at least one demonstrable ultrasonographic evidence of echogenic gallbladder deposits, within the first 18 months of treatment. Thereafter, further episodes of sludge formation are not usually encountered [322]. GH Receptor Antagonist FIGURE 11.14. Pharmacodynamics of octreotide LAR injection in acromegaly. (From Lancranjan et al. Metabolism 1996;45:67). Long-term GH responses to monthly LAR injections in 12 patients. From Stewart [327].

swelling of feet and hands resolves. Increased oily perspiration at rest also diminishes. Headaches, a common symptom in acromegaly, usually resolve rapidly [337], often within minutes of injection. Asymptomatic patients without cardiac, renal, or liver disease experienced a significant decrease of blood pressure, heart rate, and left ventricular wall thickness [172,338]. Octreotide treatment of patients with acromegaly and cardiac failure reduces systemic arterial resistance, oxygen consumption and fluid volume and restores functional activity. This effect appears to be rapidly reversible after drug withdrawal. In 30 patients with acromeagly, octreotide-induced GH suppression to <2.5 ng/ml was associated with improved left ventricular ejection fraction, with unchanged diastolic filling. Persistently elevated GH levels after a year were associated with increased systolic blood pressure [172]. Joint function and crepitus improve during chronic therapy [340], and ultrasound evidence of bone or cartilage repair has been demonstrated [146]. Sleep apnea is improved after several months’ treatment with octreotide.

GH action is mediated by ligand-induced dimerization and subsequent signaling of the GH receptor [344]. Failure of receptor dimerization leads to inactivation of the postreceptor GH signal. Trovert, a GH-receptor antagonist, blocks receptor dimerization and subsequent IGF-I generation [345]. Daily injections of Trovert, (20 mg) a PEGylated GH mutant molecule, normalizes IGF-I levels in over 90% of patients, and results in dose-dependent decreased fatigue, soft tissue swelling, as assessed by ring size, and perspiration [344]. The drug, which has not yet been approved in the USA, may be particularly useful in patients resistant to somatostatin receptor ligand therapy, as it effectively normalizes IGF-I levels in these patients [346].

Choice of Therapy The goal of therapy is tight control of GH secretion as adverse mortality rates correlate strongly with GH levels. A suggested approach to decision-making for therapy of the patient with acromegaly is shown in Figure 11.16. Each treatment modality has their respective advantages and disadvantages which are summarized in Table 11.17 and these should be weighed carefully to individualize patient care. Selective surgical excision of a well-defined pituitary microadenoma is the primary treatment of choice for most patients. Because of the invariably favorable biochemical response of small GH-secreting adenomas to octreotide, this option, with its potential side effects described, should be

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FIGURE 11.15. Clinical effects of octreotide on: (a) tumor size; (b) joint pain; (c) perspiration; (d) headache; and (e) middle finger circumference in acromegalic patients after 6 months’ treatment with octreotide (100 or 250 mg 8-hourly). From Ezzat et al. [311].

offered to patients refusing surgery. Macroadenomas and locally invasive tumors present a difficult surgical challenge, as remission rates in these patients are unacceptably low. Successful medical debulking of the sellar or parasellar mass

prior to surgery would therefore be highly desirable. Preoperative octreotide treatment for up to 16 weeks to shrink the pituitary adenoma appears to be warranted in these patients, although controlled prospective studies are required

Chapter 11

FIGURE 11.15.

Acromegaly

445

Continued.

to confirm the validity of this approach. Up to 50% of patients exhibit some degree of tumor shrinkage, thus potentially improving surgical morbidity and possibly enhancing subsequent postoperative results. This is especially important for those patients with relatively inaccessible tumor tissue and cavernous sinus invasion. Postoperatively, patients who fail the criteria of “control” can be treated with bromocriptine; although the efficacy of this drug is low, it is relatively inexpensive and free of major side effects. Somatostatin analogs (500–100 mg) should be injected and GH and IGF-I measured after 2 hours [347]. Sandostatin LAR (10, 20, or 30 mg) is initiated if GH levels suppress by more than 50% after s.c. octreotide to confirm responsiveness [325]. Patients may require more frequent dosing schedules rather than an increase in total drug dose. Some patients may benefit by addition of bromocriptine or cabergoline with octreotide. Patients who respond well to octreotide but develop gallbladder sludge may require prophylactic anticholelithogenic agents or even laparoscopic cholecystectomy. Patients receiving octreotide should undergo a gallbladder ultrasonographic examination if

symptoms develop, and postprandial glucose levels should be assessed every 3 months. Primary therapy with SRIF receptor ligands may be offered to those patients who refuse surgery or who find the risks of surgery or anesthesia unacceptable. Patients with invasive macroadenomas will invariably have persistently elevated postoperative GH levels and will require postoperative somatostatin analog treatment. Therefore, in patients whose pituitary lesion does not impinge on vital structures, primary medical management may be an informed therapeutic option [348]. Radiation therapy should be administered to patients who fail to respond to SRIF analogs, who cannot tolerate the medication, or who prefer not to receive long-term injections. After external irradiation, patients require medication for several years until GH levels are effectively lowered. GH-secreting pituitary tumors that recur despite medical therapy or irradiation may rarely require reoperation. Treatment of acromegaly should be focused on the myriad of patient concerns outlined in Table 11.18. Impor-

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FIGURE 11.16. Flowchart for decision-making in the treatment of acromegaly.

Table 11.17.

Treatment options for acromegaly*

Surgery Efficacy 80% of microadenomas: GH controlled <50% of macroadenomas: GH controlled IGF-I normalized in ~50%

Advantages • Rapid onset • One-time cost • Maybe permanent control

Disadvantages • New hypopituitarism (10%) • Diabetes insipidus (2–3%) • Local complications (~6%) • Cranial nerve or CNS damage (~1%) • Tumor persistence

Somatostatin analog

Radiotherapy

GH controlled in ~65% of patients within weeks

GH <5 ng/ml in 90% of patients in 18 years

GH <5 ng/ml in 15%

Normal IGF-I in ~70%

Normal IGF-I in <5%

Normal IGF-I in <10% of patients

•

No hypopituitarism Rapid onset Continued efficacy in long term

• • •

Permanent One-time cost Good patient compliance

•

Cost of drug and monitoring Asymptomatic gallstones (25%) Injections required

•

Ineffective and slow onset Hypopituitarism (50%) Visual and CNS dysfunction (~2%) Cost of interim medical therapy

• •

• •

•

• •

•

* Adapted from Melmed S, Jackson I, Kleinberg D, Klibanski A [254].

Dopamine agonists (high dose)

• •

•

Oral administration Low cost No hypopituitarism

Relatively ineffective • Adverse events (~30%) • High dose required

Chapter 11

tantly, patients require careful counseling for anxiety and interpretation of laboratory test results. Although tight GH control is critical, these additional clinical issues must also be addressed. The criteria for effective control of hypersomatotrophism include a suppressed GH of less than 1 ng/ml after oral glucose and normalized IGF-I levels. Patients should be followed quarterly until biochemical control is achieved. Thereafter, hormone evaluation should be performed semiannually, while in those patients who are biochemically in remission and in whom no residual tumor tissue is present, MRI should be repeated every 1 to 2 years [349]. Comprehensive physical examination should include evaluations of new skin tag and lipoma growth, as well as nerve entrapments and jaw overbites. Rheumatologic, dental, and cardiac evaluations will usually be required in Table 11.18. acromegaly • • • • • • • • • • •

Patient-focused treatment targets for

Arthralgias and headache Cardiac failure and hypertension Diabetes Sleep apnea Endocrine replacement Side effects of therapy Patient self-image Maxillofacial surgery Anxiety Fertility Interpret laboratory testing

Table 11.19.

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addition to the metabolic follow-up. In patients with evidence for residual tumor, or in those requiring hormone replacement or medical treatment, visual field perimetry and reserve testing of the adrenal, gonadal, and thyroid axes should be repeated semiannually and pituitary MRI annually. Mammography and colonoscopy should be performed annually in patients over the age of 50, especially in those harboring skin tags. An integrated approach to therapy and biochemical and clinical control takes advantage of the benefits of available therapeutic options, while balancing potential side-effects of the treatments. Maximal and sustained long-term control of GH and IGF-I should ameliorate the deleterious clinical effects of these hormones. This control can be achieved by judicious use of the treatment modalities described (Table 11.19). Novel peptide delivery systems [350] and new stereotactic neurosurgical techniques will provide improved therapeutic choices offering optimal long-term biochemical and clinical cure. REFERENCES

Acromegaly treatment outcomes*

Outcome

Criteria

Management

Controlled

Nadir GH <1 mg/L Age-sex-normalized IGF-I No clinical activity

Assess GH/IGF-I axis Evaluate pituitary function Periodic MRI No treatment or no change in current treatment

Inadequately controlled

Nadir GH >1 mg/L Elevated IGF-I Clinically inactive

Assess GH/IGF-I axis Evaluate pituitary function Periodic MRI Assess cardiovascular metabolic and tumoral comorbidity Weigh treatment benefit or consider new treatment vs low risk of elevated GH

Poor control

Nadir GH >1 mg/L Elevated IGF-I Clinically active

Assess GH/IGF-I axis Evaluate pituitary function Periodic MRI Actively treat or change treatment

* Adapted from Giustina et al. JCEM [238].

Acromegaly

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96 Drange M, Melmed S. Long-acting lanreotide induces clinical and biochemical remission of acromegaly caused by disseminated growth hormone-releasing hormone-secreting carcinoid. J Clin Endocrinol Metab 1998;83:3104 –3109. 97 Rivier J, Spiess J, Thorner M et al. Characterization of a growth hormone releasing factor from a human pancreatic islet tumor. Nature 1982;300: 276–280. 98 Bostwick DG, Quan R, Hofftnan AR et al. Growth hormone-releasing factor immunoreactivity in human endocrine tumors. Am J Pathol 1984;117:167–170. 99 Yamaguchi K, Abe K, Suzuki M et al. Production of immunoreactive pancreatic growth hormone-releasing factor in small cell carcinoma of the lung. J Clin Invest 1983;74:814–817. 100 Dayal Y, Lin HD, Tallberg K et al. Immunocytochemical demonstration of growth hormone-releasing factor in gastrointestinal and pancreatic endocrine tumors. Am J Clin Pathol 1986;85:13–20. 101 Oberg K, Norheim I, Wide L. Serum growth hormone in patients with carcinoid tumors; basal levels and response to glucose and thyrotrophin releasing hormone. Acta Endocrinol 1985;109:13–18. 102 Frohman LA, Thominet JL, Webb CB et al. Metabolic clearance and plasma disappearance rates of human pancreatic tumor growth hormone releasing factor in man. J Clin Invest 1984;73:1304–1311. 103 Ramsay JA, Kovacs K, Asa SL et al. Reversible sellar enlargement due to growth hormone releasing hormone (GRH) production by pancreatic endocrine tumors in an acromegalic patient with multiple endocrine neoplasia-I (MEN-1) syndrome. Cancer 1988;62:445–450. 104 Wilson DM, Hoffman AR. Reduction of pituitary size by the somatostatin analogue SMS 201-995 in a patient with an islet cell tumor secreting growth hormone releasing factor. Acta Endocrinol 1986;113:23–28. 105 Gomez-Pan A, Scanlon MF, Thomer MO et al. Effect of somatostatin on abnormal growth hormone and prolactin secretion in patients with the carcinoid syndrome. Clin Endocrinol 1979;10:575–581. 106 von Werder K, Losa M, Muller OA et al. Treatment of metastasing GRHproducing tumor with a long-acting somatostatin analogue. Lancet 1984;ii:282–283. 107 Moller DE, Moses AC, Jones K et al. Octreotide suppresses both growth hormone (GH) and GH-releasing hormone (GHRH) in acromegaly due to ectopic GHRH secretion. J Clin Endocrinol Metab 1989;68:499–504. 108 Lloyd RV, Chandler WF, Kovacs K et al. Ectopic pituitary adenomas with normal anterior pituitary glands. Am J Surg Path 1986;10:546–552. 109 Warner BA, Santen RJ, Page RB. Growth hormone and prolactin secretion by a tumor of the pharyngeal pituitary. Ann Int Med 1982;96:65–66. 110 Corenblum B, Le Blanc FE, Watanabe M. Acromegaly with an adenomatous pharyngeal pituitary. JAMA 1980;243:1456–1457. 111 Greenman Y, Woolf P, Coniglio J et al. Remission of acromegaly caused by pituitary carcinoma following surgical excision of GH secreting metastasis detected by 111-indium pentetreotide scan. J Clin Endocrinol Metab 1996;81:1628–1633. 112 Kyle CV, Evans MC, Odell WD. Growth hormone-like material in normal human tissues. J Clin Endocrinol Metab 1981;53:1138–1144. 113 Kaganowicz A, Farkoub NH, Frantz AG et al. Ectopic human growth hormone in ovaries and breast cancer. J Clin Endocrinol Metab 1979;48:5–8. 114 Greenberg PB, Martin TJ, Beck C et al. Synthesis and release of human growth hormone from lung carcinoma in cell culture. Lancet 1972;i:350–352. 115 Ashcraft MW, Hartzband PI, Van Herle A et al. A unique growth factor in patients with acromegaloidism. J Clin Endocrinol Metab 1983;57:272–276. 116 Low L, Chernausek SD, Sperling MA. Acromegaloid patients with Type A insulin resistance: parallel defects in insulin and insulin-like growth factor-I receptors and biological responses in cultured fibroblasts. J Clin Endocrinol Metab 1988;69:329–337. 117 McCune DJ. Osteitis fibrosa cystica: the case of a nine-year-old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am J Dis Child 1936;52:743–756. 118 Cuttler L, Jackson JA, uz-Zafar MS et al. Hypersecretion of growth hormone and prolactin in McCune–Albright syndrome. J Clin Endocrinol Metab 1989;68:1148–1154. 119 Weinstein LS, Shenker A, Gejman PV et al. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N Engl J Med 1991;325:1688–1695. 120 Chandrasekharappak SC, Guru SC, Manickam P et al. Positional cloning of the gene for multiple endocrine neoplasia type 1. Science 1997;276: 404–406. 121 Teh BT, Kytola S, Farnebo F et al. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab 1998;83:2621–2626. 122 Prezant TR, Levine J, Melmed S. Molecular characterization of the MEN-1

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tumor suppressor gene in sporadic pituitary tumors. J Clin Endocrinol Metab 1998;83:1388–1391. Roth KA, Wilson DM, Eberwine J et al. Acromegaly and pheochromocytoma: a multiple endocrine syndrome caused by a plurihormonal adrenal medullary tumor. J Clin Endocrinol Metab 1986;63:1421–1426. Sano T, Yamasaki R, Saito H et al. Growth hormone-releasing hormone (GHRH)-secreting pancreatic tumor in a patient with multiple endocrine neoplasia Type 1. Am J Surg Pathol 1987;11:810 – 819. Stratakis CA, Carney JA, Lin JP et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 1996;97:699–705. Prezant T, Melmed S. Pathogenesis of pituitary tumors. In: Besser M, Thorner M, eds. Comprehensive Clinical of Endocrinology, 3rd ed. Harcourt Publications, Kent, 2001. Gadelha MR, Prezant TR, Une KN et al. Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene. J Clin Endocrinol Metab 1999;84:249–256. Benlian P, Giraud S, Lahlou N et al. Familial acromegaly: a specific clinical entity—further evidence from the genetic study of a three-generation family. Eur J Endocrinol 1995;133;451– 456. Ackermann F, Krohn K, Windgassen M et al. Acromegaly in a family without a mutation in the menin gene. Exp Clin Endocrinol Diabetes 1999; 107:93–96. Yamada S, Yoshimoto K, Sano T et al. Inactivation of the tumor suppressor gene on 11q13 in brothers with familial acrogigantism without multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 1997;82:239–242. Daughaday WH. Pituitary gigantism. Endocrinol Metab Clin North Am 1992;3:633– 647. Zimmerman D, Young WF, Ebersold MJ et al. Gigantism due to growth hormone-releasing hormone (GHRH) excess and pituitary hyperplasia with adenomatous transformation. J Clin Endocrinol Metab 1993;76:216–222. Maheshwari H, Prezant TR, Herman-Bonert V et al. Long-acting peptidomimergic control of gigantism caused by pituitary acidophilic stem cell adenoma. J Clin Endo Metab 2000;85:3409–3416. Gelber SJ, Heffez DS, Donohoue PA. Pituitary gigantism caused by growth hormone excess from infancy. J Pediatr 1992;120:931–934. Melmed S, Braunstein GD, Chang RJ, Becker DP. Pituitary tumors secreting growth hormone and prolactin [clinical conference]. Ann Intern Med 1986;105(2):238–253. Nabarro JDN. Acromegaly. J Clin Endocrinol 1987;26:481–512. Jadresic A, Banks LM, Child DF et al. The acromegaly syndrome. Q J Med 1982;202:189–204. Drange MR, Fram NR, Bonert VH, Melmed S. Pituitary tumor registry: a novel clinical resource. J Clin Endocrinol Metab 2000;85:168–174. Melmed S, Braunstein G. Stein’s Textbook of Medicine, 5th ed. St Louis: Mosby, 1998;1773–1788. Molitch ME. Clinical manifestations of acromegaly. Clin Endocrinol Metab 1992;21:597– 614. Reichlin S. Acromegaly. Medical Grand Rounds 1982;1:9–24. Whitehead EM, Shalet SM, Davies D et al. Pituitary gigantism: a disabling condition. Clin Endocrinol 1982;17:271–277. Lieberman SA, Hoffman AR. Sequelae to acromegaly: reversibility with treatment of the primary disease. Horm Metab Res 1990;22:313–318. Colao A, Marzullo P, Vallone G et al. Reversibility of joint thickening in acromegalic patients: An ultrasonography study. J Clin Endocrinol Metab 1998;83:2121–2125. McCarthy TL, Centrella M, Canalis E. Regulatory effects of insulin-like growth factors I and II on bone collagen synthesis in rat calvarial cultures. Endocrinology 1989;124:301–309. Scillitani A, Chinodine I, Carnevale V et al. Skeletal involvement in female acromegalic subjects: the effects of growth hormone excess in amenorrhea and menstruating patients. J Bone Miner Res 1997;12:1729–1736. Lieberman SA, Bjorkengren AG, Hoffman AR. Rheumatologic and skeletal changes in acromegaly. Endo Metab Clin 1992;21:615–631. Layton MW, Fudman EJ, Barkan A et al. Acromegalic arthropathy. Characteristics and response to therapy. Arthritis Rheum 1988;31:1022–1028. Ibbertson HK, Manning PJ, Holdaway IM et al. The acromegalic rosary. Lancet 1991;337:154–156. Detenbeck LC, Tressler HA, O’Duffy JD et al. Peripheral joint manifestations of acromegaly. Clin Orthop 1973;91:119–127. Dons RF, Roseelet P, Pastakia B et al. Arthropathy in acromegalic patients before and after treatment: a long-term follow-up study. Clin Endocrinol 1988;28:515–524.

152 Bluestone R, Bywaters EG, Hartog M et al. Acromegalic arthropathy. Ann Rheum Dis 1971;30:243–258. 153 Kellgren JH, Ball J, Tutton GK. The articular and other limb changes in acromegaly. Q J Med 1952;21:405–432. 154 Kho KM, Wright AD, Doyle FH. Heel pad thickness in acromegaly. Br J Radiol 1970;43:119–125. 155 MacSweeny JE, Baxter MA, Joplin GF. Heel pad thickness is an insensitive index of biochemical remission in acromegaly. Clin Radiol 1990;42:348–350. 156 Matsuoka LY, Wortsman J, Kupchella CE et al. Histochemical characterization of the cutaneous involvement of acromegaly. Arch Intern Med 1932;142:1820–1833. 157 Verde GG, Santi I, Chiodini P et al. Serum type III procollagen propeptide levels in acromegalic patients. J Clin Endocrinol Metab 1986;63:1406–1410. 158 Leavitt J, Klein I, Kendricks F et al. Skin tags: a cutaneous marker for colonic polyps. Ann Int Med 1983;98:928–930. 159 Rajasoorya C, Holdaway IM, Wrightson P et al. Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol 1994;41:95–102. 160 Bates AS, Van’t Hoff W, Jones JM et al. An audit of outcome of treatment in acromegaly. Q J Med 1993;86:293–299. 161 Lombardi G, Colao A, Marzullo P et al. Is growth hormone bad for your heart? Cardiovascular impact of GH deficiency and of acromegaly. J Endocrinol 1997;155:S33–S39. 162 Sacca L, Cittadini A, Fazio S. Growth hormone and the heart. Endocr Rev 1994;15:555–573. 163 Colao A, Cuocolo A, Marzullo P et al. Impact of patient’s age and disease duration on cardiac performance in acromegaly: a radionuclide angiography study. J Clin Endocrinol Metab 1999;84:1518–1523. 164 Lopez-Velasco R, Escobar-Morreale HF, Vega B et al. Cardiac involvement in acromegaly: specific myocardiopathy or consequence of systemic hypertension? J Clin Endocrinol Metab 1997;82:1047–1053. 165 Hamwi GJ, Skillman TG, Tufts KC Jr. Acromegaly. Am J Med 1960;29:690. 166 Rodrigues EA, Caruana MP, Lahirl A et al. Subclinical cardiac dysfunction in acromegaly: evidence for a specific disease of heart muscle. Br Heart J 1989;62:185–194. 167 Ritchie CM, Sheridan B, Fraser R et al. Studies on the pathogenesis of hypertension in Cushing’s disease and acromegaly. Q J Med 1990;280: 855–867. 168 Savage DD, Henry WL, Eastman RC et al. Echocardiographic assessment of cardiac anatomy and function in acromegalic patients. Amer J Med 1979;67:823–829. 169 Luboshitzki R, Hammerman H, Barzilai D et al. The heart in acromegaly: correlation of echocardiographic and clinical findings. Isr I Med Sci 1980;16:378–383. 170 Deray G, Rieu M, Devynck MA et al. Evidence of an endogenous digitalislike factor in the plasma of patients with acromegaly. N Engl J Med 1987;316:575–580. 171 Hartman ML, Veldhuis JD, Vance ML et al. Somatotropin pulse frequency and basal concentrations are increased in acromegaly and are reduced by successful therapy. J Clin Endocrinol Metab 1990;70:1375–1384. 172 Colao A, Cuocolo A, Marzullo P et al. Effects of 1-year treatment with octreotide on cardiac performance in patients with acromegaly. J Clin Endocrino Metab 1999;84:17–23. 173 Trtoman-Dickenson B, Weetman AP, Hughes JMB. Upper airflow obstruction and pulmonary function in acromegaly: relationship to disease activity. Q J Med 1991;79:527–533. 174 Bames AJ, Pallis C, Joplin GF. Acromegaly and narcolepsy. Lancet 1979;ii:332–333. 175 Pekkarinen T, Partinen M, Pelkonen R et al. Sleep apnoea and daytime sleepiness in acromegaly: relationship to endocrinological factors. Clin Endocrinol 1987;27:649–654. 176 Grunstein RR, Ho KY, Sullivan CE et al. Sleep apnea in acromegaly. Ann Intern Med 1991;115:527–532. 177 Grunstein RR, Ho KY, Berthon-Jones M et al. Central sleep apnea is associated with increased ventilatory response to carbon dioxide and hypersecretion of growth hormone in patients with acromegaly. Am J Respir Crit Care Med 1994;150:496–502. 178 Rosenow F, Reuter S, Deuss U et al. Sleep apnea in treated acromegaly: relative frequency and predisposing factors. Clin Endocrinol 1996;45:563–569. 179 Grunstein RR, Ho KK, Sullivan CE. Effect of octreotide, a somatostatin analog, on sleep apnea in patients with acromegaly. Ann Intern Med 1994;121:478–483. 180 O’Duffy JD, Randall RV, MacCarty CS. Median neuropathy (carpal-tunnel syndrome) in acromegaly. A sign of endocrine overactivity. Ann Intern Med 1973;78:379–383.

Chapter 11 181 Jenkins JP, Sohaib SA, Akker S et al. The pathology of median neuropathy in acromegaly. Ann Ant Med 2000;133:197–201. 182 Nagulesparen M, Trickey R, Davies MJ et al. Muscle changes in acromegaly. Br Med J 1976;2:914–915. 183 Abed RT, Clark J, Elbadawy MHF et al. Psychiatric morbidity in acromegaly. Acta Psychiatr Scand 1987;75:635–639. 184 Furman K, Ezzat S. Psychological features of acromegaly. Psychother Psychosom 1998;67:147–153. 185 Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med 1970;39:1–16. 186 Orme SM, McNally RJQ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab 1998;83:2730–2734. 187 Swearingen B, Barker FG, Katznelson L et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 1998;83:3419–3426. 188 Abosch A, Tyrrell JB, Lamborn KR et al. Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab 1998;83:3411–3418. 189 Freda PU, Wardlaw SL, Post KD. Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly. J Neurosurg 1998;89:353–358. 190 Jenkins D, O’Brien I, Johnson A et al. The Birmingham pituitary database: auditing the outcome of the treatment of acromegaly. Clin Endocrinol 1995;43:517–522. 191 Moon HD, Simpson ME, Li CH, Evans HM. Neoplasms in rats treated with pituitary growth hormone 1. Pulmonary and lymphatic tissues. Cancer Res 1950;10:297–308. 192 Murphy LJ, Bell GI, Friesen HG. Growth hormone stimulates sequential induction of c-myc and insulin-like growth factor I expression in vivo. Endocrinology 1987;12:1806–1812. 193 Stewart CEH, Rotwein P. Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiological Reviews 1996;76:1005–1026. 194 Melmed S, Yamashita S, Yamasaki H et al. IGF-I receptor signaling: lessons from the somatotroph. Recent Prog Horm Res 1996;51:189–215. 195 Cullen KJ, Yee D, Sly WS et al. Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 1990;50:48–53. 196 Daughaday WH. The possible autocrine/paracrine and endocrine roles of insulin-like growth factors of human tumors. Endocrinology 1990;127:1–4. 197 Grinspoon S, Clemmons D, Swearingen B et al. Serum insulin-like growth factor-binding protein-3 levels in the diagnosis of acromegaly. J Clin Endocrinol Metab 1995;80:927–932. 198 van der Lely AJ, de Herder WW, Janssen JA et al. Acromegaly: the significance of serum total and free IGF-I and IGF-binding protein-3 in diagnosis. J Endocrinol 1997;155:S9–13; discussion S15–6. 199 Cohen P, Peehl DM, Graves HC, Rosenfeld RG. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J Endocrinol 1994;142:407–415. 200 Melmed S. Acromegaly and cancer: not a problem? J Clin Endocrinol Metab 2001;86:2929–2934. 201 Ron E, Gridley G, Hrubec Z et al. Acromegaly and gastrointestinal cancer. Cancer 1991;68:1673–1677. 202 Cheung NW, Boyages SC. Increased incidence of neoplasia in females with acromegaly. Clin Endocrinol 1997;47:323–327. 203 Klein I, Parveen G, Gavaler JS, Vanthiel DH. Colonic polyps in patients with acromegaly. Ann Int Med 1982;97:27–30. 204 Brunner JE, Johnson CC, Zafar S et al. Colon cancer and polyps in acromegaly: increased risk associated with family history of colon cancer. Clin Endocrinol 1990;32:65–71. 205 Ritter MM, Richter WO, Schwandt P. Acromegaly and colon cancer. Ann Intern Med 1987;106:636–637. 206 Ezzat S, Strom C, Melmed S. Colon polyps in acromegaly. Ann Intern Med 1991;114:754-758. 207 Ituarte EA, Petrini J, Hershman JM. Acromegaly and colon cancer. Ann Int Med 1984;101:627–628. 208 Pines A, Rozen P, Ron Z, Gilat T. Gastrointestinal tumors in acromegalic patients. Am J Gastroenterol 1985;80:266–269. 209 Ezzat S, Melmed S. Are patients with acromegaly at increased risk for neoplasia? J Clin Endocrinol Metab 1991;72:245–249. 210 Delhougne B, Deneux C, Abs R et al. The prevalence of colonic polyps in acromegaly: a colonoscopic and pathological study in 103 patients. J Clin Endocrinol Metab 1995;80:3223–3226. 211 Ladas SD, Thalassinos NC, Ioannides G, Raptis SA. Does acromegaly really

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predispose to an increased prevalence of gastrointestinal tumours? Clin Endocrinol (Oxf) 1994;41(5):597–601. Terzolo M, Tappero G, Borretta G et al. High prevalence of colonic polyps in patients with acromegaly. Influence of sex and age. Arch Intern Med 1994;154(11):1272–1276. Vasen HFA, Erpecum KJ, Roelfsema F et al. Increased prevalence of colonic adenomas in patients with acromegaly. European Journal of Endocrinology 1994;131:235–237. Colao A, Balzano A, Ferone D et al. Increased prevalence of colonic polyps and altered lymphocyte subset pattern in the colonic lamina propria in acromegaly. Clin Endocrinol (Oxf) 1997;47(1):23–28. Jenkins PJ, Fairclough PD, Richards T et al. Acromegaly, colonic polyps and carcinoma. Clin Endocrinol (Oxf) 1997;47(1):17–22. Jenkins PJ, Besser GM, Fairclough PD. Colorectal neoplasia in acromegaly. Gut 1999;44(5):585–587. Mustacchi P, Shimkin MB. Occurrence of cancer in acromegaly and in hypopituitarism. Cancer 1956;1:100–104. Jenkins PJ. Acromegaly and colon cancer in Growth Horm IGF Res 2000;10 Suppl A:35–36. Renehan AG, Bhaskar P, Painter JE et al. The prevalence and characteristics of colorectal neoplasia in acromegaly. J Clin Endocrinol Metab 2000;85(9): 3417–3424. Jenkins PJ, Frajese V, Jones AM et al. Insulin-like growth factor I and the development of colorectal neoplasia in acromegaly. J Clin Endocrinol Metab 2000;85(9):3218–3221. Bunick EM, Mills LC, Rose LI. Association of acromegaly and meningiomas. JAMA 1978;240:1267–1268. Barkan AL. Acromegaly diagnosis and therapy. Endocrinol Metab Clin 1989;18:277–310. Kaltsas GA, Mukherjee JJ, Jenkins PJ et al. Menstrual irregularity in women with acromegaly. J Clin Endocrinol Metab 1999;84:2731. Lesse GP, Fraser WD, Farquharson R et al. Gonadal status is an important determinant of bone density in acromegaly. Clin Endocrinol (Oxf) 1998;48:59–65. Melmed S. Unwanted effects of growth hormone excess in the adult. J Ped Endocrinol Metab 1996;9:369–374. James RA, Moller N, Chatterjee S et al. Carbohydrate tolerance and serum lipids in acromegaly before and during treatment with high dose octreotide. Diabetic Med 1991;8:517. Giustina A, Barkan A, Casanueva FF et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 2000;85:526–529. Robbins RJ, Melmed S, eds. Acromegaly: a Century of Scientific Progress. New York: Plenum Press, 1987. Kasagi K, Shimatsu A, Miyamoto S et al. Goiter associated with acromegaly: Sonographic and scintigraphic finding of the thyroid gland. Thyroid 1999;9:791. Colao A, Marzullo P, Ferone D et al. Prostatic hyperplasia: an unknown feature of acromegaly. J Clin Endocrinol Metab 1998;83:775–779. Colao A, Marzullo P, Spiezia S et al. Effect of growth hormone (GH) and insulin-like growth factor I on prostate diseases: an ultrasonographic and endocrine study in acromegaly, GH deficiency, and healthy subjects. J Clin Endocrinol Metab 1999;84:1986–1991. Barkan AL, Berlins IZ, Kelch RP. Plasma insulin-like growth factor/somatomedin C in acromegaly: correlation with degree of growth hormone hypersecretion. J Clin Endocrinol Metab 1988;67:69–73. Chang-Demoranvflle BM, Jackson IMD. Diagnosis and endocrine testing in acromegaly. Endocrinol Metab Clin 1992;21:649–668. Colao A, Ferone D, Cappabianca P et al. Effect of octreotide pretreatment on surgical outcome in acromegaly. J Clin Endocrinol Metab 1997;82:3308. Ho KY, Veldhuis JD, Johnson ML et al. Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 1988;81:968–975. Ho KY, Evans WS, Blizzard RM et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 1987;64:51–58. Duncan E, Wass JAH. Investigation protocol: acromegaly and its investigation. Clin Endocrinol (Oxf) 1999;50:285–293. Giustina A, Barkan A, Casanueva F et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 2000;85:526–529. Barkan AL, Stred SE, Reno K et al. Increased growth hormone pulse frequency in acromegaly. J Clin Endocrinol Metab 1989;69:1225–1233. Veldhuis JD, Liem AY, South S et al. Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in

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men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab 1995;80:3209–3222. Freda PU, Post KD, Powell JS, Wardlaw SL. Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly. J Clin Endocrinol Metab 1998;83:3808–3816. Losa M, Chiodini PG, Liozzi A et al. Growth hormone-releasing hormone infusion in patients with active acromegaly. J Clin Endocrinol Metab 1986;63:88–93. Clemmons DR, Van Wyk JJ, Ridgway E et al. Evaluation of acromegaly by radioimmunoassay of somatomedin C. N Engl J Med 1979;301: 1138–1142. Drange MR, Melmed S. IGFs in the evaluation of acromegaly. In: Rosenfeld RG, Roberts CT, eds. The IGF System: Molecular Biology, Physiology, and Clinical Applications. Totowa, NJ: Human Press 1999:699–720. Holly JMP, Cotterill AM, Jemmott RC et al. Inter-relations between growth hormone, insulin, insulin-like growth factor-I (IGF-1), IGF binding protein1(IGFBP-1), and sex hormone-binding globulin in acromegaly. Clin Endocrinol 1991;34:275–280. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:3–34. Ezzat S, Ren S, Braunstein GD et al. Octreotide stimulates insulinlike growth factor binding protein-1 (IGFBP-1) levels in acromegaly. J Clin Endocrinol Metab 1991;73:441–443. Winer L, Shaw MA, Baumann G. Urinary GH secretion rates in normal and acromegalic man: a clinical appraisal of its potential clinical utility. J Endocrinol Inv 1989;12:461–467. Melmed S, Ho K, Klibanski A et al. Recent advances in pathogenesis, diagnosis and management of acromegaly. J Clin Endocrinol Metab 1995;80:3395–3402. Brockmeier SJ, Buchfelder M, Adams EF et al. Acromegaly with “normal” serum growth hormone levels: clinical features, diagnosis and results of transsphenoidal microsurgery. Horm Metab Res 1992;24:392–396. Melmed S. Extrapituitary acromegaly. Endocrinol Metab Clinics North Am 1991;20:1–9. Barkan AL, Snenker Y, Grekin RJ et al. Acromegaly due to ectopic growth hormone (GH)-releasing hormone (GHRH) production: dynamic studies of GH and ectopic GHRH secretion. J Clin Endocrinol Metab 1986;63:1057–1064. Frohman LA. Ectopic hormone production by tumors. Clinical Neuroendocrine Perspectives 1984;3:201–224. Melmed S, Jackson I, Kleinberg D, Klibanski A. Current treatment guidelines for acromegaly. J Clin Endocrinol Metab 1998;83:2646–2652. Barkan A. Controversies in the diagnosis and therapy of acromegaly. Endocrinologist 1997;7:300–307. Melmed S. Tight control of growth hormone: an attainable outcome for acromegaly treatment. J Clin Endocrinol Metab 1998;83:3409–3410. Laws ER, Jr, Thapar K. Pituitary surgery. Endocrinol Metab Clin North Am 1999;28(1):119–131. Osman IA. Factors determining the long-term outcome of surgery for acromegaly. Q J Med 1994;87:617–623. Ross DA, Wilson CB. Results of transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas in a series of 214 patients. J Neurosurg 1988;68:854–867. Fahlbusch R, Honegger J, Buchfelder M. Surgical management of acromegaly. Endocrinol Metab Clin North Am 1992;21:669–692. Davis DH, Laws JrER, Ilstrup DM et al. Results of surgical treatment for growth hormone-secreting pituitary adenomas. J Neurosurg 1993;79:70–75. Ahmed S, Elsheikh M, Stratton IM et al. Outcome of transsphenoidal surgery for acromegaly and its relationship to surgical experience [In Process Citation]. Clin Endocrinol (Oxf) 1999;50:561–567. Long H, Beauregard H, Somma M et al. Surgical outcome after repeated transsphenoidal surgery in acromegaly. J Neurosurg 1996;85:239–247. Sheaves R, Jenkins P, Blackburn P et al. Outcome of transsphenoidal surgery for acromegaly using strict criteria for surgical cure. Clin Endocrinol 1996;45:407–413. Lissett CA, Peacey SR, Laing I et al. The outcome of surgery for acromegaly: the need for a specialist pituitary surgeon for all types of growth hormone (GH) secreting adenoma. Clin Endocrinol 1998;49:653–657. Gittoes NJL, Sheppard MC, Johnson AP, Stewart PM. Outcome of surgery for acromegaly—the experience of a dedicated pituitary surgeon. Q J Med 1999;92:741–745. Stewart PM. Current therapy for acromegaly. Trends in Endocrinology and Metabolism 2000;11:128–132. Jho HD, Carrau RL. Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. J Neurosurg. 1997;87:44–51.

269 Ciric I, Ragin A, Baumgartner C et al. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 1997;40:225–236. 270 Eastman RC, Gorden P, Glatstein E, Roth J. Radiation therapy of acromegaly. Endocrinol Metab Clin North Am 1992;21:693–712. 271 Eastman RC, Gordon P, Roth J. Conventional supervoltage irradiation is an effective treatment for acromegaly. J Clin Endocrinol Metab 1979;48:931–940. 272 Feek CM, McLellan J, Seth J et al. How effective is external pituitary irradiation for growth hormone-secreting pituitary tumors? Clin Endocrinol 1984;20:401–408. 273 Barkan AL, Halasz I, Dornfeld KJ et al. Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab 1997;82:3187–3191. 274 Powell JS, Wardlaw SL, Post KD, Freda PU. Outcome of radiotherapy for acromegaly using normalization of insulin-like growth factor I to define cure. J Clin Endocrinol Metab 2000;85:2068–2071. 275 Barrande G, Pittino-Lungo M, Coste J et al. Hormonal and metabolic effects of radiotherapy in acromegaly: long-term results in 128 patients followed in a single center. J Clin Endocrinol Metab 2000;85:3779–3785. 276 Biermasz NR, van Dulken H, Roelfsema F. Long-term follow-up results of postoperative radiotherapy in 36 patients with acromegaly. J Clin Endocrinol Metab 2000;85:2476–2482. 277 van der Lely AJ, Herder WW, Lamberts SWJ. Editorial: the role of radiotherapy in acromegaly. J Clin Endocrinol Metab 1997;82:3185–3186. 278 Millar JL, Spry NA, Lamb DS, Delahunt J. Blindness in patients after external beam irradiation for pituitary adenomas: two cases occurring after small daily fractional doses. Clin Oncol 1991;3:291–294. 279 Alexander MJ, DeSalles AA, Tomiyasu U. Multiple radiation-induced intracranial lesions after treatment for pituitary adenoma. Case report. J Neurosurg 1998;88:111–115. 280 Ahmed M, Kanaan I, Rifai A et al. An unusual treatment-related complication in a patient with growth hormone-secreting pituitary tumor. J Clin Endocrinol Metab 1997;82:2816–2820. 281 Al-Mefty O, Kersh JE, Routh A et al. The long-term side effects of radiation therapy for benign brain tumors in adults. J Neurosurg 1990;73:502–512. 282 Crossen JR, Garwood D, Glatstein E et al. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 1994;12:627–642. 283 Kjellberg RN, Kliman B, Swisher BJ. Radiosurgery for pituitary adenoma with bragg peak proton beam. In: Derome PJ, Jedynak CP, Peillon F, eds. Pituitary Adenomas. Paris: Asclepios Publishing, 1980:209–217. 284 Laws JE, Vance ML. Radiosurgery for pituitary tumors and craniopharyngiomas. Neurosurg Clin N Am 1999;10:327–336. 285 Landolt AM, Haller D, Lomax N et al. Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy. J Neurosurg 1998;88:1002–1008. 286 Pan L, Zhang N, Wang E et al. Pituitary adenomas: the effect of gamma knife radiosurgery on tumor growth and endocrinopathies. Stereotact Funct Neurosurg 1998;70:119–126. 287 Brada M, Ford D, Ashley S et al. Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. Br Med J 1992; 304:1343–1346. 288 Tsang RW, Laperriere NJ, Simpson WJ et al. Glioma arising after radiation therapy for pituitary adenoma. A report of four patients and estimation of risk [published erratum appears in Cancer 1994 Jan 15;73(2):492]. Cancer 1993;72: 2227–2233. 289 Vance ML, Evans WS, Thorner MO. Bromocriptine. Ann Int Med 1984; 100:78–91. 290 Wass JA, Thorner MO, Morris DV et al. Long term treatment of acromegaly with bromocriptine. Br Med J 1977;1:875–878. 291 Jaffe CA, Barkan AL. Treatment of acromegaly with dopamine agonists. Endocrinol Metab Clin 1992;3:713–735. 292 Colao A, Ferone D, Marzullo P et al. Effect of different dopaminergic agents in the treatment of acromegaly. J Clin Endocrinol Metab 1997;82: 518–523. 293 Jackson SN, Fowler J, Howlett TA. Cabergoline treatment of acromegaly: a preliminary dose finding study. Clin Endocrinol (Oxf) 1997;46:745–749. 294 Muratori M, Arosio M, Gambino G et al. Use of cabergoline in the long-term treatment of hyperprolactinemic and acromegalic patients. J Endocrinol Invest 1997;20:537–546. 295 Abs R, Verhelst J, Maiter D et al. Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab 1998;83:374–378. 296 Reichlin S. Somatostatin. N Engl J Med 1983;309:1495–1501. 297 Kelijman M, Williams TC, Downs TR, Frohman LA. Comparison of the

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sensitivity of growth hormone secretion to somatostatin in vivo and in vitro in acromegaly. J Clin Endocrinol Metab 1988;67:958–963. Greenman Y, Melmed S. Heterogenous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab 1994;78: 398–403. Greenman Y, Melmed S. Expression of three somatostatin receptor subtypes in pituitary adenomas: Evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab 1994;79: 724–729. Shimon I, Taylor JE, Dong JZ et al. Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. J Clin Invest 1997;99(4):789–798. Plewe C, Beyer J, Krauve U et al. Long-acting and selective suppression of growth hormone secretion by somatostatin analogue SMS 201-995 in acromegaly. Lancet 1984;i:782–784. Lamberts SWJ. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev 1988;9:417–436. Wass JAH. Octreotide treatment of acromegaly. Horm Res 1990; I(suppl.):1–5. Lamberts SWJ, van der Lely AJ, de Herder WW et al. Octreotide. N Engl J Med 1996;334:246–254. Lamberts SWJ, Uitterlinden P, Verschoor L et al. Long-term treatment of acromegaly with the somatostatin analogue SMS 201-995. N Engl J Med 1985;313:1576–1580. Comi RJ, Gordon P. The response of serum growth hormone levels to the long acting somatostatin analog SMS 201-995 in acromegaly. J Clin Endocrinol Metab 1987;64:37–42. Barnard LB, Grantham WG, Lamberton P et al. Treatment of resistant acromegaly with long-acting somatostatin analogue (SMS 201-995). Ann Int Med 1986;105:856–861. Ho KY, Weissberger AJ, Marbach P et al. Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety. Ann Intern Med 1990;112:173–181. McKnight JA, McCance DR, Sheridan B et al. A long-term doseresponse study of somatostatin analogue (SMS 201-995, octreotide) in resistant acromegaly. Clin Endocrinol 1991;34:119–125. Sassolas G, Harris AG, James-Deidier A et al. Long-term effect of incremental doses of the somatostatin analog SMS 201-995 in 58 acromegalic patients. J Clin Endocrinol Metab 1990;71:391–397. Ezzat S, Snyder PJ, Young WE et al. Octreotide treatment of acromegaly: a randomized, multicenter study. Ann Int Med 1992;117:711–718. Quabbe HJ, Plockinger U. Dose response study and long-term effect of the somatostatin analog octreotide in patients with therapy-resistant acromegaly. J Clin Endocrinol Metab 1989;68:873–881. Gorden P, Comi RJ, Maton PN, Go VL. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormonesecreting tumors of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Ann Intern Med 1989;110:35–50. Reubi JC, Landolt AM. The growth hormone responses to octreotide in acromegaly correlate with adenoma somatostatin receptor status. J Clin Endocrinol Metab 1989;68:844–850. Lamberts SWJ, Bakker WH, Reubi JC et al. Somatostatin-receptor imaging in the localization of endocrine tumors. N Engl J Med 1990;323:1246–1249. Ur E, Mather SJ, Bomanji J et al. Pituitary imaging using a labelled somatostatin analogue in acromegaly. Clin Endocrinol 1992;36:147–150. Chanson, P. Predicting the effects of long-term medical treatment in acromegaly. At what cost? For what benefits? Eur J Endocrinol 1997; 136:359–361. Lamberts SWJ, Zweens M, Verschoor L, del Pozo E. A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201-995, bromocriptine, and the combination of both drugs. J Clin Endocrinol Metab 1986;63:16–20. Wang C, Lam KSL, Arceo E, Chan FL. Comparison of the effectiveness of 2hourly versus 8-hourly subcutaneous injections of a somatostatin analog (SMS 201-995) in the treatment of acromegaly. J Clin Endocrinol Metab 1989;69: 670–677. Tauber JP, Babin TH, Tauber MT et al. Long-term effects of continuous subcutaneous infusion of the somatostatin analog octreotide in the treament of acromegaly. J Clin Endocrinol Metab 1988;68:917–924. van der Lely AJ, Harris AG, Lamberts SWJ. The sensitivity of growth hormone secretion to medical treatment in acromegalic patients: influence of age and sex. Clin Endocrinol 1992;37:181–185.

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322 Newman CB, Melmed S, Snyder PJ et al. Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients—a clinical research center study. J Clin Endocrinol Metab 1995;80: 2768–2775. 323 Flogstad AK, Halse J, Haldorsen T et al. Sandostatin LAR in acromegalic patients: a dose-range study. J Clin Endocrinol Metab 1995;80:3601–3607. 324 Gillis JC, Noble S, Goa KL. Octreotide long-acting release (LAR): a review of its pharmacological properties and therapeutic use in the management of acromegaly. Drugs 1997;53:618–699. 325 Flogstad AK, Halse J, Bakke S et al. Sandostatin LAR in acromegalic patients: long term treatment. J Clin Endocrinol Metab 1997;82:23–28. 326 Stewart PM, Kane KF, Stewart SE et al. Depot long-acting somatostatin analog (Sandostatin-LAR) is an effective treatment for acromegaly. J Clin Endocrinol Metab 1995;80:3267–3272. 327 Lancranjan I, Atkinson AB and the Sandostatin LAR Group. Results of a European multicentre study with Sandostatin LAR in acromegalic patients. Pituitary 1999;1:105–114. 328 Giusti M, Gussoni G, Cuttica CM et al. Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly: six-month report on an Italian Multicenter Study. Italian Multicenter Slow Release Lanreotide Study Group. J Clin Endocrinol Metab 1996;81:2089–2097. 329 Caron P, Morange-Ramos I, Cogne M et al. Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J Clin Endocrinol Metab 1997;38:18-22. 330 Giusti M, Ciccarelli E, Dallabonzan D et al. Clinical results of long-term slowrelease lanreotide treatment of acromegaly. Eur J Clin Invest 1997;27:277–284. 331 Barakat S, Melmed S. Reversible shrinkage of a growth hormone secreting pituitary adenoma by a long-acting somatostatin analog octreotide. Arch Int Med 1989;149:1443–1445. 332 Barkan AL, Lloyd RV, Chandler WE et al. Preoperative treatment of acromegaly with long-acting somatostatin analog SMS 201-995. Shrinkage of invasive pituitary macroadenomas and improved surgical remission rate. J Clin Endocrinol Metab 1988;67:1040–1048. 333 Colao A, Ferone D, Cappabianca P et al. Effect of octreotide pretreatment on surgical outcome in acromegaly. J Clin Endocrinol Metab 1997;82:3308–3314. 334 Biermaz NR, vanDulkin H, Roelfsema F. Direct postoperative and follow-up results of transsphenoidal surgery in 19 acromegalic patients pretreated with octreotide compared to those in untreated matched controls. J Clin Endocrinol Metab 1999;84:3551–3555. 335 Colao A, Marzullo P, Ferone D et al. Cardiovascular effects of depot longacting somatostatin analog sandostatin LAR in acromegaly. J Clin Endocrinol Metab 2000;85:3132–3140. 336 Page MD, Millward ME, Taylor A et al. Long-term treatment of acromegaly with a long-acting analogue of somatostatin, octreotide. Q J Med 1990;274: 189–201. 337 Pascual J, Freijanes J, Berciano J, Pesquera C. Analgesic effect of octreotide in headache associated with acromegaly is not mediated by opioid mechanisms. Pain 1991;47:341–344. 338 Chanson P, Timsit J, Masquet C et al. Cardiovascular effects of the somatostatin analog octreotide in acromegaly. Ann Int Med 1990;113:921–923. 339 Lombardi G, Colao A, Ferone D et al. Cardiovascular aspects in acromegaly: effects of treatment. Metabolism Clinical and Experimental 1996;45:57–60. 340 Layton MW, Fudman EJ, Barkan A et al. Acromegalic arthropathy: characteristics and response to therapy. Arthritis Rheum 1988;31: 1022–1028. 341 Van Liessum PA, Hopman WPM, Pieters GFFM et al. Post-prandial gallbladder motility during long term treatment with the long acting somatostatin analog SMS 201-995 in acromegaly. J Clin Endocrinol Metab 1989;69:557–562. 342 Melmed S, Dowling RH, Frohman L et al. Consensus statement: benefits vs. risks of medical therapy for acromegaly. Am J Med 1994;97:468. 343 Shi Y-F, Zhu XF, Harris AG et al. Prospective study of long-term effects of somatostatin analog (Octreotide) on gallbladder function and gallstone formation in chinese acromegalic patients. J Clin Endocrinol Metab 1993;76: 32–37. 344 Chen WY, Wight DC, Wagner TE, Kopchick JJ. Expression of a mutated bovine growth hormone gene suppresses growth of transgenic mice. Proc Natl Acad Sci USA 1987:5061–5065. 345 Trainer PJ, Drake WM, Katznelson L et al. Treatment of acromegaly with the growth hormone receptor antagonist pegvisonmant. N Eng J Med 2000; 342:1171–1177. 346 Herman-Bonert VS, Zib K, Scarlett JA, Melmed S. Growth hormone receptor antagonist therapy in acromegalic patients resistant to somatostatin analogs. J Clin Endocrinol Metab 2000;85:2958–2961.

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347 Lamberts SWJ, Uitterlinden P, Schuijff PC, Khjn JGM. Therapy of acromegaly with sandostatin. The predictive value of an acute test, the value of serum somatomedin-C measurements in dose adjustment and the definition of a biochemical “cure”. Clin Endocrinol 1988;29:411–420. 348 Newman C, Melmed S, George A et al. Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab 1998;83:3034–3040. 349 Shimon I, Melmed S. Management of pituitary tumors. Ann Int Med 1998; 129:472–483. 350 Weeke J, Christensen SE, Orskow H et al. A randomized comparison of intranasal and injectable octreotide administration in patients with acromegaly. J Clin Endocrinol Metab 1992;75:163–169. 351 Barzilay J, Heatley GJ, Cushing GW. Benign and malignant tumors in patients with acromegaly. Arch Intern Med 1991;151(8):1629–1632. 352 Moran A, Asa SL, Kovacs K et al. Gigantism due to pituitary mammosomatotroph hyperplasia. N Engl J Med 1990;323(5):322–327. 353 Gelber SJ, Heffez DS, Donohoue PA. Pituitary gigantism caused by growth hormone excess from infancy. J Pediatr 1992;120(6):931–934. 354 Fazekas I, Pasztor E, Slowik F et al. Pathological and experimental investigations in a case of gigantism. Acta Neuropathol 1993;85(2): 167–174. 355 Fraiser SD, Kogut MD. Adolescent acromegaly: studies of growth-hormone and insulin metabolism J Pediatr 1967;71:832–839. 356 Espiner EA, Carter TA, Abbott GD, Wrightson P. Pituitary gigantism in a 31

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month old girl: endocrine studies and successful response to hypophysectomy. J Endocrinol Invest 1981;4(4):445–50358. Zampieri P, Scanarini M, Sicolo N et al. The acromegaly-gigantism syndrome. Report of four cases treated surgically. Surg Neurol 1983;20(6):498–503. Ritzen EM, Wettrell G, Davies G, Grant DB. Management of pituitary gigantism. The role of bromocriptine and radiotherapy. Acta Paediatr Scand 1985;74(5):807–814. von Werder K, Losa M, Muller OA et al. Treatment of metastasising GRFproducing tumour with a long-acting somatostatin analogue. Lancet 1984; 2(8397):282–283. Anniko M, Ritzen EM. Pituitary tumour causing gigantism. Morphology and in vitro hormone secretion. ORL J Otorhinolaryngol Relat Spec 1986; 48(3):180–190. Blumberg DL, Sklar CA, David R et al. Acromegaly in an infant. Pediatrics 1989;83(6):998–1002. Lu PW, Silink M, Johnston I et al. Pituitary gigantism. Arch Dis Child 1992; 67(8):1039–1041. Zimmerman D, Young WF Jr, Ebersold MJ et al. Congenital gigantism due to growth hormone-releasing hormone excess and pituitary hyperplasia with adenomatous transformation. J Clin Endocrinol Metab 1993;76(1):216–222. Popovic V, Damjanovic S, Micic D et al. Increased incidence of neoplasia in patients with pituitary adenomas. The Pituitary Study Group. Clin Endocrinol (Oxf) 1998;49(4):441–445.

C h a p t e r

12 Prolactinoma Mark E. Molitch

PATHOPHYSIOLOGY AND PATHOGENESIS

INTRODUCTION

Classification

At the same time that prolactin (PRL) was initially being characterized in the early 1930s by Riddle and coworkers (see Chapter 4), so too the first clinical reports of a syndrome of amenorrhea coupled with galactorrhea were appearing [1,2]. Over the ensuing 20 years, three distinct clinical syndromes were described (Table 12.1): (i) the Chiari–Frommel Syndrome—amenorrhea, galactorrhea and low urinary gonadotropins occurring post-partum [3]; (ii) the Ahumada–Argonz–del Castillo syndrome—nonpuerperal amenorrhea, galactorrhea and low urinary gonadotropins with no evidence of a pituitary tumor on standard skull X-rays [1,4]; and (iii) the Forbes–Henneman– Griswold–Albright syndrome—nonpuerperal amenorrhea, galactorrhea and low urinary gonadotropins in association with a chromophobe adenoma [5]. Overproduction of PRL was postulated in both of the last two syndromes [4,5]. Although Kleinberg and Frantz initially reported elevated serum bioassayable PRL levels in blood in patients with galactorrhea [6], it was Friesen et al. [7] who first demonstrated elevated radioimmunoassayable PRL levels in the serum of a patient with a prolactinoma, the fall in such levels with partial tumor resection, and the production of PRL by the tumor in vitro. The now recognized insensitivity of standard skull X-rays, along with a better understanding of the pathophysiology of prolactinomas, have rendered obsolete this early eponymic classification of prolactin disorders. Prolactinomas have been considered to be the most common of the hormone-secreting pituitary tumors in both autopsy and surgical series [8]. Recent data suggest that gonadotroph cell adenomas may be as common, however (see Chapter 14).

Prolactinomas are generally classified clinically by size: microadenomas, less than 10 mm in diameter; macroadenomas, more than 10 mm in diameter; and macroadenomas with extrasellar extension. The direction and degree of extrasellar extension are of obvious clinical importance, but whether more detailed classification of such extension and/or invasiveness is of clinical or biologic importance is open to question. Hardy [9] has published a classification schema that is generally used for the size and extent of extra sellar extension. In this schema (Fig. 12.1), Grade I refers to microadenomas, Grade II to macroadenomas that may have suprasellar extension but have no gross radiologic invasiveness of surrounding boney structures, Grade III to those tumors with localized boney invasiveness, and Grade IV refers to those with diffuse invasion of bone structures. As will be discussed below, the larger the tumor and the more invasive it is, the more likely it is that surgery will fail to provide a complete cure. The importance of radiologic demonstration of invasion is unclear, as 88% of macroadenomas and 69% of microadenomas show evidence of dural invasion when examined histologically [10]. In general, serum PRL levels parallel the size of the tumors [11]. Rare patients have large tumors that stain densely for PRL using immunohistochemical techniques but have only modestly elevated serum PRL levels by radioimmunoassay [12], possibly due to a defect in the release mechanism for PRL. However, when two-site immunoradiometric assays (IRMA) or chemiluminometric (ICMA) assays are used, patients with very high PRL levels may appear to have PRL levels that are only moderately elevated, i.e. in the order of 30– 200 mg/L, due to the “hook effect” [13,14]. This can cause confusion with clinically nonfunctioning adenomas, which 455

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may cause a similar elevation of PRL due to interference with dopamine reaching the normal lactotrophs and a “disinhibition” of PRL secretion [15–17]. This confusion can be avoided by always remeasuring the PRL in such patients at 1 : 100 dilution, as PRL levels in samples with the “hook effect” will then increase dramatically.

Natural History of Prolactinomas Autopsy Studies

Pituitary adenomas have been found at autopsy in 1.5–27% of subjects not suspected of having pituitary disease while alive [18–37] (Table 12.2). The average frequency of finding an adenoma for these studies, which examined a total of 12,411 pituitaries, was 10.9%. In the studies in which PRL immunohistochemistry was performed, 44% of the 325 pituitaries stained positively for PRL [22,24, 25,29,32–34,36,37]. The tumors were distributed equally throughout the age groups (range 16–86 years) and between the sexes. In these postmortem studies, all but three of the tumors (99.97%) were less than 10 mm in diameter (Table 12.2), and these three were less than 15 mm in diameter. Thus, microprolactinomas are present in about 5–10% of the adult

Table 12.1. syndromes

Eponymic classification of hyperprolactinemic

Chiari–Frommel syndrome Amenorrhea, galactorrhea and low urinary gonadotropins occurring postpartum Ahumada–Argonz–del Castillo syndrome Amenorrhea, galactorrhea and low urinary gonadotropins occurring nonpuerperally with no evidence of pituitary tumor Forbes–Henneman–Griswold–Albright syndrome Amenorrhea, galactorrhea and low urinary gonadotropins associated with evidence of a pituitary tumor

population. The relative lack of macroadenomas in these studies suggests that growth from micro- to macroadenomas must be an uncommon event and/or that virtually all macroadenomas come to clinical attention and therefore are not included in autopsy findings. A population study performed by the Mayo Clinic for Olmstead County, Minnesota found a mean annual incidence of diagnosis of pituitary tumors of 8.2 per 100,000 women aged 15 or more [39]. This figure is only about 0.1% of the actual frequency of tumors known from the autopsy studies. Even giving such women a hypothetical 50 years of further life expectancy in which to have this diagnosis made, we find that only about 400 per 100,000 (50 times 8.2 per 100,000 per year) or 0.4% of the population will have a prolactinoma diagnosed during their lifetimes. This means, therefore, that at most only 5–10% of tumors (known to be present from the autopsy studies) ever come to clinical attention. In the early published series of patients with prolactinomas (i.e. the prebromocriptine period in which most patients with diagnosed tumors came to surgery), about two-thirds of patients operated on had microadenomas and one-third macroadenomas [40–43]. Therefore, only about 3% (onethird of the 5–10% of tumors that ever come to clinical attention) of microadenomas would be expected to grow to become macroadenomas, assuming that virtually all such tumors that grow become sufficiently symptomatic so as to come to clinical attention and therefore not show up in autopsy statistics. The rest of the microadenomas remain small, either being clinically insignificant or being discovered as microadenomas. PRL-secreting macroadenomas are sometimes found incidentally during life, however (Fig. 12.2). Natural History of Untreated Prolactinomas

Six series of patients with microadenomas being observed for long periods without treatment have been published (Table 12.3). In these series [44–49], women with prolactinomas documented by sella tomography or computed

FIGURE 12.1. Growth patterns of adenomas. From Hardy [9]

Chapter 12 Table 12.2.

Study Susman [18] Costello [19] Sommers [20] McCormick and Halmi [21] Kovacs et al. [22] Landolt [23] Mosca et al. [24] Burrow et al. [25] Parent et al. [26] Muhr et al. [27] Schwezinger and Warzok [28] Coulon et al. [29] Chambers et al. [30] Siqueira and Guembarovski [31] El-Hamid et al. [32] Scheithauer et al. [33] Marin et al. [34] Mosca et al. [35] Sano et al. [36] Teramoto et al. [37] Total

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457

Frequency of pituitary adenomas found at autopsy

Pituitaries examined (n)

Adenomas found (n)

Frequency (%)

Macroadenomas found (n)

Stain for prolactin (%)

260 1,000 400 1,600

23 225 26 140

8.8 22.5 6.5 8.8

– 0 0 0

– – – –

152 100 100 120 500 205 5,100

20 13 24 32 42 3 485

13.2 13.0 24.0 26.7 8.4 1.5 9.5

2 0 0 0 1 0 0

53 – 23 41 – – –

100 100 450

10 14 39

10.0 14.0 8.7

0 0 0

60 – –

486 251 210 111 166 1,000

97 41 35 13 15 51

20.0 16.3 16.7 11.7 9.0 5.1

0 0 0 0 0 0

48 66 32 – 47 30

12,411

1,348

10.9

3

44

From Molitch [38].

FIGURE 12.2. After a CT scan carried out to rule out lesions of internal auditory canals causing deafness showed a possible sellar mass, this MRI scan was performed to more definitively characterize this incidentally found macroadenoma. The sagittal (left) and coronal (right) cuts show a large macroadenoma with suprasellar and lateral parasellar extension. This 30 year old man was eventually found to have panhypopituitarism and a prolactin of 2200 ng/ml. His deafness was subsequently found to be due to Wegener’s granulomatosis.

tomography (CT) who refused surgery and/or medical treatment were followed for a period of up to 8 years. Of the total of 139 women, there was evidence of tumor growth by these methods in only nine (6.5%). In retrospect, we now know the high false-positive and false-negative rates of polytomography [25]. In a similar 2–6 year follow-up of 140 patients with hyperprolactinemia and no radiologic

evidence of tumor (idiopathic hyperprolactinemia), only 22 developed evidence of microadenomas [48–52]. Except for the study by Sisam et al. [48], in which high-resolution CT was used throughout, these other studies employed both sella polytomography and CT, often axial, for the assessment of tumor size, especially at the earliest examinations. At later examinations, high resolution CT with coronal sections had

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Table 12.3.

Study von Werder et al. [44] March et al. [45] Weiss et al. [46] Koppleman et al. [47] Sisam et al. [48] Schlechte et al. [49] Total

Natural history of untreated prolactinomas

Patients (n) 10 43 27 8 38 13

Radiologic technique Tomograms CT + + + + +

139

+ + + + + +

Evidence of tumor growth (n)

Length of follow-up (yrs)

1 2 3 1 0 2

4 4 6 2.5–7.5 4 5.3

9 (6.5%)

2.5–8.0

From Molitch [63].

become the preferred method of evaluation. Because of this change in techniques from those with low sensitivity and specificity to one with better sensitivity and specificity, the true rates of progression from normal sellas or those with minimal abnormalities to documentation of the presence of a tumor cannot be determined accurately, and it is likely that the numbers given above are overestimates rather than underestimates. This very low risk of 6.5% for progression of microadenomas to macroadenomas (Table 12.3) in these carefully followed patients is close to the figure of 3% derived from the autopsy studies cited above. Obviously, macroadenomas have to develop from microadenomas but it appears that 93–97% of microadenomas stay small. One may pose the question, therefore, as to whether microadenomas and macroadenomas are two separate disease entities. In addition to their differences in natural history, two other pieces of data support the hypothesis that microadenomas and macroadenomas are different disease entities. The first is their strikingly different responses in tumor size to bromocriptine treatment, macroadenomas often decreasing markedly in size whereas little size change is usually seen in microadenomas (see below). This may reflect the fact that macroadenomas appear to be more sensitive than microadenomas to inhibition of PRL secretion by dopamine (DA) both in vivo and in vitro [53,54]. The second is the fact that the frequency of capillaries in macroadenomas is decreased (9.3 capillaries/ 0.1 mm2) compared to normal pituitaries (62.0 capillaries/ 0.1 mm2) and microadenomas (51.1 capillaries/0.1 mm2) [55]. Erroi et al. [55] have hypothesized that this decreased blood supply in the macroadenomas may permit these tumors to be less inhibited by PRL inhibitory factors. However, it is also possible that these large tumors have just outgrown their blood supply, so that this finding may be a result of rapid tumor growth rather than causative [55]. These two features may be interlinked, in that decreased exposure of the macroadenoma to the usual amounts of DA traversing the portal system because of the decrease in blood supply may both allow the tumors to get better, escaping from this partial inhibition, and make the tumors super-

sensitive to additional dopamine, a “denervation hypersensitivity.” (See below for further discussion of this point.) Two studies have attempted to correlate biologic invasiveness and size of prolactinomas in vivo with assessment of cell proliferation potential in vitro. Nagashima et al. [56] gave 5-bromodeoxyuridine intravenously to patients at the start of transsphenoidal surgery to label tumor cells in the DNA synthesis phase (S-phase). They were unable to find a correlation between the percentage of cells in the S-phase with the size of the tumors. Landolt et al. [57] and Delgrange et al. [58] assessed tumors for the immunohistochemical presence of the proliferation-associated nuclear antigen Ki-67, which is expressed throughout the cycle of proliferating normal and neoplastic cells but is absent in resting cells (Go-phase) and correlates with the growth rate of human tumors. Although they did not find a correlation between the percentage of cells expressing Ki-67 and tumor size, they did find a correlation with the presence of dural invasion as determined histologically but not as determined by the surgeon or by preoperative CT. Relationship to Oral Contraceptives

The increasing frequency with which prolactinomas were being diagnosed in the 1970s [39,43,59] paralleled the use of oral contraceptives in women, leading to the hypothesis that estrogens may promote the growth or stimulate the formation of prolactinomas [39,60]. This hypothesis is buttressed by the experimental findings in animals showing estrogens to be stimulatory to DNA synthesis, mitotic activity, PRL mRNA levels and PRL synthesis (see Chapter 4). Furthermore, the hormonal milieu of pregnancy can stimulate the growth of prolactinomas (see below) and oral contraceptives and postmenopausal estrogen replacement can cause a 1.5 to twofold increase in circulating PRL levels [61]. In some series of patients with prolactinomas, an increased frequency of prior oral contraceptive use was found but this was not substantiated in other studies (see [62] for review). To try to answer the question as to whether oral contraceptive use can be implicated in the development of

Chapter 12 Table 12.4.

459

Relationship of oral contraceptive use to prolactinomas Patients with prolactinomas

Study

Prolactinoma

Total

Using OC (n)

Frequency (%)

Controls Total

Using OC (n)

Frequency (%)

67 65 74 72 65

12 20 70 303 212

8 4 48 148 128

67 20 68 49 60

81

100

83

83

Case-control studies using amenorrheic, normoprolactinemic women as controls Tolis et al. [70] 17* 8 47 65 29 Jones et al. [71] 26† 20 77 41 27 Maheux et al. [65] 70*‡ 52 74 70 51 Franks et al. [72] 42† 23 55 202 112

49 66 73 55

Case-control studies using normal women as controls Coulam et al. [66] 3 2 Tepperman et al. [64] 20* 13 Maheux et al. [65] 70*‡ 52 Shy et al. [67] 72† 52 Pituitary Adenoma 212† 138 Study Group [68] Sherman et al. [69] 100† 81

OC, oral contraceptives. * Diagnoses of prolactinomas all established at surgery. † Diagnoses of prolactinomas established by surgery or sella tomography. ‡ Same prolactinoma patients, different control groups. From Molitch [63].

prolactinomas, a number of careful case control studies have been performed (Table 12.4). In two of these studies, using normal women as controls and having adequate numbers of patients (20 and 72) for analysis, increased frequencies of prior oral contraceptive use in prolactinoma patients were found [64,65]. In other studies, totaling 382 patients, however, no such risk was found [66–69]. Because women with amenorrhea in general may be treated by some physicians with oral contraceptives as a method of inducing menses, four other case-control comparisons have been done using women with nonhyperprolactinemic amenorrhea as controls. In these studies, totaling 155 patients, no excess use of oral contraceptives by prolactinoma patients could be found [65,69–72]. It should be recognized that in most of these studies, the diagnosis of prolactinoma was made by surgery and/or radiology, the techniques being used in the latter case having known poor sensitivity and specificity [25]. In summary, most of these studies do not support the hypothesis that the clinical appearance of prolactinomas is related to prior oral contraceptive use. Furthermore, in the long-term British prospective surveys [73] of women using oral contraceptives (Oxford Family Planning Association Study and Royal College of General Practitioners’ Study), no increased risks have been found for developing prolactinomas in oral contraceptive users (110,612 women-years of observation) compared with women never having used oral contraceptives (111,252 women-years of observation). In other studies, Corenblum and Donovan administered estrogens to 18 women with microadenomas and 19 with

idiopathic hyperprolactinemia, finding no tumor enlargement in any over a period of years [74]. Similarly, Testa et al. found no evidence of tumor enlargement in eight women with microadenomas and eight with idiopathic hyperprolactinemia when using oral contraceptives over a 2 year period [75]. However, individual cases with enlargement of tumors during estrogen therapy have been reported [76–78], so that such patients should be followed carefully with periodic monitoring of PRL levels. PATHOGENESIS OF PROLACTINOMAS The role of the hypothalamus in the pathogenesis of prolactinomas is controversial. A primary defect in hypothalamic regulation of PRL secretion, such as a defect in dopaminergic tone, has been hypothesized to either cause or facilitate the growth of most prolactinomas [79,80] (Fig. 12.3). Others hypothesize that most changes in hypothalamic function in patients with tumors are secondary to the tumors, the tumors arising de novo as intrinsic disorders of the pituitary. Because the predominant regulatory influence of the hypothalamus on PRL secretion is inhibitory (see Chapter 4), primarily due to DA, the postulated hypothalamic defect is one of a decrease in dopaminergic tone. Whether this is a functional defect [79] or an alteration in lactotroph sensitivity to DA because of a postulated estrogen-induced alteration in pituitary blood supply [81] has been debated. Fine and Frohman [79] postulated a hypothalamic defect in DA secretion as the cause of prolactinomas. This was

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FIGURE 12.3. Possible mechanisms leading to the formation of a prolactinoma. Top: normal regulation. Middle: tumors could arise because of an increase in prolactin (PRL)releasing factor (PRF) or a decrease in PRLinhibiting factor (dopamine). Bottom: tumors could arise de novo without hypothalamic influence. From Molitch [63]

Chapter 12

FIGURE 12.4. Rationale of the L-dopa and carbidopaprimed L-dopa tests. When L-dopa is given alone (top panel), it can be converted to dopamine in the periphery and in the central nervous system. This dopamine can then act on the lactotrophs, either directly or via the hypothalamus. When peripheral decarboxylation of L-dopa is prevented by carbidopa (which does not cross the blood–brain barrier), only dopamine formed in the central nervous system has inhibitory activity on the pituitary (bottom panel). From Molitch et al. [84]

based on their studies with a test that determined the degree of PRL inhibition by L-dopa with and without pretreatment with the dopa decarboxylase inhibitor carbidopa (Fig. 12.4). Because dopa decarboxylase is present in both pituitary and hypothalamus, administration of L-dopa can cause augmentation of the amount of DA reaching the lactotrophs directly in the pituitary or via the hypothalamic tuberoinfundibular dopaminergic (TIDA) pathways. However, carbidopa, which blocks dopa decarboxylase, cannot cross the blood–brain barrier and therefore, pretreatment with this drug causes administered L-dopa to augment only DA coming from the TIDA pathways and blocks peripheral conversion of this L-dopa to DA. Their study [79] showed that carbidopa pretreatment greatly diminished the PRL response to L-dopa in patients with prolactinomas, implying

Prolactinoma

461

a defect in DA generating ability within the hypothalamus in such patients. Subsequent studies, however, suggest that these findings need to be reinterpreted, in that this decreased response to L-dopa with carbidopa is reversible when the prolactinoma is surgically removed [84,85] (see below). Another possible way in which there could be a decreased amount of DA reaching the pituitary would be if there were an altered blood supply such that the amount of blood coming from the portal vessels were diluted by blood coming from elsewhere. Schechter et al. [86] have provided electron microscopic data suggesting that prolactinomas contain arteries, whereas the anterior pituitaries from normal subjects do not. However, Gorczyca and Hardy [87] showed that up to 81% of normal pituitaries contain endarteries by injection studies. On the other hand, Erroi et al. [55] using electron microscopy, found no evidence of arteries in either prolactinomas or normal pituitary tissue. Thus this question of abnormal tumor vascularity remains controversial at this point. A number of studies investigating the sensitivity of prolactinomas to DA suppression have been carried out but the results are conflicting. Some suggest that such tumors are resistant to DA suppression [53,88,89] and others that there is no such resistance [79,90–92]. Of the latter group of studies only those of Ho et al. [91,92] used submaximal doses of DA. The mechanism of this possible decreased DA sensitivity is likely related to the decrease in the number of high affinity DA receptors in prolactinomas compared to normal pituitary tissue [93]. Serri et al. [53] found that patients with hyperprolactinemia due to hypothalamic/stalk disruption and clear defective DA transmission were “supersensitive” to DA suppression. Thus, evidence regarding hypothalamic DA suggests that hypothalamic DA generation is likely to be at least normal in patients with prolactinomas, although their prolactinomas may have as an intrinsic defect, a decreased ability to respond to the normal inhibition by DA. Whether there is an altered blood supply to the tumors in patients with prolactinomas is an issue that still needs confirmation. There are a number of other ways to examine the question of whether there is primary hypothalamic dysfunction that causes prolactinomas, including: (i) examination of the nontumorous portion of the gland to detect hyperplasia of the lactotrophs; (ii) evaluation of abnormalities of hypothalamic regulation of PRL secretion after selective adenoma resection; (iii) determination of the rate of new tumor formation following adenoma resection; (iv) clonal analysis to determine whether such tumors are polyclonal rather than monoclonal; and (v) evaluation of the tumors for specific mutations resulting in monoclonal proliferation. These questions will now be addressed. Is there Hyperplasia of the Nonneoplastic Lactotrophs in Patients with Prolactinomas?

Pathologic evaluation of the nonneoplastic portion of pituitaries containing prolactinomas has been performed in a

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limited number of patients. In studies using immunohistochemistry, Säeger and Lüdecke [94] found that in patients with tumors of enough clinical significance to warrant surgical resection, lactotroph hyperplasia was seen in the nonneoplastic portions of the pituitaries in 18.8% of 32 patients with prolactinomas, 23.9% of 46 patients with growth hormone (GH), adrenocorticotropic hormone (ACTH) and nonsecreting adenomas, and in 20% of 15 patients whose normal pituitaries were being removed as palliative therapy for cancer. These proportions with hyperplasia were not statistically different. Kovacs and coworkers [95,96], using PRL immunohistochemistry, found that at autopsy of 40 pituitaries containing incidental prolactinomas that had not been suspected clinically there was failure of involution of the lactotrophs in the nontumorous portions of the glands, but there was no actual hyperplasia. Landolt found that in five patients studied in this fashion using immunohistochemistry and electron microscopy, the secretory activity of surrounding lactotrophs appeared to be less than in the adjacent adenoma [97]. However, in another publication [98] Landolt and Minder state that there was hyperplasia of paraadenomatous lactotrophs in 14 of 24 patients having transsphenoidal surgery for their clinically significant prolactinomas. Thus, the data regarding this point are conflicting and a firm conclusion cannot be drawn. Are Abnormal PRL Secretory Dynamics in Patients with Prolactinomas Explained by Underlying Hypothalamic Dysfunction or are they due to the Tumor Itself?

Our own studies of PRL secretory dynamics before and after transsphenoidal selective adenoma resection indicate a normalization of PRL secretory dynamics when patients appeared to be “cured” by surgery [98,99]. Detailed preoperative and postoperative tests of PRL secretory dynamics were carried out in 44 patients. Of the 44 women, 31 were “cured” by surgery, as defined by a fall in PRL levels to normal, a return of normal menses, and cessation of galactorrhea. The remaining 13 women failed to meet one or more of these criteria and were not considered “cured.” In the “cured” group, blunted PRL responses to thyroidstimulating hormone (TRH) (Fig. 12.5) and insulininduced hypoglycemia returned toward normal but those with elevated PRL levels postoperatively had persistently blunted PRL responses to TRH and hypoglycemia. In other similar studies, preoperative PRL responses to TRH and hypoglycemia were blunted and in most [85,100–102], but not all [103,104], the PRL responses to these secretogogues returned to normal following curative surgery. An L-dopa/carbidopa test was carried out in 23 patients before and after adenomectomy (Fig. 12.6). In this test, the percentage inhibition of PRL achieved by L-dopa alone is compared with that achieved by L-dopa after pretreatment with the dopa decarboxylase inhibitor carbidopa [79]. In normals, the degree of PRL inhibition is similar with Ldopa alone or after carbidopa pretreatment [79]. Prior to surgery, carbidopa pretreatment caused a blunting of L-dopa

FIGURE 12.5. Prolactin responses to thyrotropin-releasing hormone in patients with prolactinomas before and after transsphenoidal selective microadenomectomy. In “cured” patients (n = 28), the blunted responses were brought toward the normal but in “noncured” (n = 10), this did not occur. From Reichlin and Molitch [98]

inhibition of PRL secretion. Surgical cure was followed by restoration to normal of the blunted L-dopa/carbidopa test but the blunting by carbidopa of the L-dopa effect persisted in patients who were not cured [84]. Similar findings have been reported by Barbarino et al. [85]. Several other workers have evaluated the dopaminergic system in patients with adenomas postoperatively using a variety of agonists and antagonists, such as chlorpromazine, metoclopramide, domperidone, nomifensine and monoiodotyrosine [101, 105–110]. The results are conflicting and these discrepancies are probably due to differences in action of these agents. Taken as a whole, our results and those of others suggest that prolactin secretory dynamics return to or towards normal in most patients who have had curative resection of their tumors. It is likely that in most patients with prolactinomas the underlying hypothalamic prolactin regulatory system is normal and that abnormalities of PRL response to TRH, dopamine agonists and antagonists, and less specific stimulation such as hypoglycemia are either due to intrinsic abnormalities of the tumor itself or due to alteration of hypothalamic function secondary to the tumor by shortloop feedback activation of dopamine secretion (see Chapter 4). Tumor-induced altered hypothalamic function may last for several months and may account for the quantitatively

Chapter 12

Prolactinoma

463

FIGURE 12.6. Prolactin suppression with L-dopa alone and L-dopa after prior treatment with the decarboxylase inhibitor carbidopa pre- and postoperatively in patients cured (n = 18) by surgery (top panel) and patients not cured (n = 5) by surgery (bottom panel). L-dopa was given at time zero. The values shown are the percentage of basal PRL levels. Each bar represents the mean ± SEM. In the patients cured by surgery, note how the blunted response to carbidopa and L-dopa returns to normal after surgery. From Molitch et al. [84]

incomplete return of function in some patients when testing is performed within a few months of surgery. The possibility that the persisting hyperprolactinemia and abnormal PRL secretory dynamics in some cases are due to an underlying hypothalamic abnormality cannot be excluded, however. Can the Hyperprolactinemia be Permanently Cured by Prolactinoma Resection or does Hypothalamic Dysfunction cause Recurrent Tumor Formation?

If tumors arise as a result of hypothalamic dysfunction, then there should be a high incidence of new tumor formation following successful transsphenoidal selective adenomectomy. In our own series of 42 patients with microadenomas undergoing transsphenoidal selective adenomectomy, 37 had return of PRL levels to normal postoperatively. We were

able to obtain long-term follow-up in 29 of these patients, finding that PRL levels remained normal in 24 at a mean of 50 ± 3 months (range 11–81 months) following surgery [99]. Five patients became hyperprolactinemic again after intervals of 6, 8, 12 and 18 months following surgery (Fig. 12.7), but in no case was there evidence of recurrent tumor by CT [79]. Although Serri et al. [111] reported a 50% recurrence rate of hyperprolactinemia at 4 ± 1.3 years of follow-up after transsphenoidal surgery, the recurrence rates for eight other series varied from 0% to 39% [85,101–103,110,112–122]. Schlechte et al. [118] have reported early and late time patterns of recurrence. Seven of their 12 patients had recurrence of hyperprolactinemia within 12 months of surgery but five had normal PRL levels for as long as 2–3 years after surgery and at that time again became hyperprolactinemic. Because the recurrence of

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Pituitary Tumors Table 12.5. Potential sites for mutations that could be implicated in prolactinoma tumorigenesis Oncogenes Release and inhibitory hypophysiotropic factor receptors Releasing factor (TRH, VIP, Other PRF) receptors (activating mutations) Inhibitory factor (Dopamine) receptors (inactivating mutations) Signal transduction mechanisms G-proteins Adenylyl cyclase/cAMP/CREB Protein kinase C Transcription factors Pit-1 Prop-1 Other Heparin-binding secretory transforming gene (hst) Pituitary tumor transforming gene (PTTG) Ras, myc, myb, fos, jun Cyclins Tumor suppressor genes Menin

FIGURE 12.7. Postoperative course in patients with late relapse. Included are data from five patients who had microadenomas and one patient with a macroadenoma. One patient became pregnant and had a transient rise in PRL (indicated by “P” in figure) before having a permanent rise in PRL. From Rodman et al. [99]

hyperprolactinemia usually occurs within 1–2 years of surgery in most patients in these series, it seems more likely that recurrence was due to regrowth of tumor remnants left at surgery rather than new tumor formation, given the known very slow rate of growth of these tumors and the known high rate of dural invasion of such tumors [10,123]. The lack of continuing and increasing rate of relapse with greater length of follow-up argues against a primary hypothalamic dysfunction as causative in the majority of patients. Are Prolactinomas Polyclonal or Monoclonal?

If prolactinomas are due to hypothalamic dysregulation, presumably there would be a stimulation of a number of cells, first resulting in hyperplasia and eventually in tumor formation. Accordingly, if the tumors are examined for clonality, such tumors should show that they developed from multiple clones of cells, i.e. they will be polyclonal. On the other hand, if a tumor originally arises because of a spontaneous mutation in one cell, the tumor should be monoclonal. Recent developments in molecular biology have allowed the determination of monoclonality vs polyclonality in heterozygous women with prolactinomas. This involves X-chromosomal inactivation analysis using determination of restriction fragment length polymorphisms [124] and differential methylation patterns in the genes for hypoxanthine phosphoribosyl transferase and phosphoglycerate kinase, which are X-linked [125]. In a study by

Other (p53, p21, p16, p27Rb, nm23)

Herman et al. [125], four of four prolactinomas examined were found to be monoclonal, whereas control normal pituitary tissue was polyclonal. In a similar study, Jacoby et al. [126] found one of one prolactinomas to be monoclonal. This preliminary data in a small number of cases is very strong evidence for sporadic mutation within the pituitary cells as being the primary etiology and strong evidence against the primary defect being within the hypothalamus. As Herman et al. state, however, these findings “do not exclude a facilitory role for the hypothalamus in pituitary tumorigenesis, perhaps by inducing clonal expansion of a genomically altered cell [125].” Have Specific Mutations been Found that can be Implicated in Tumorigenesis?

A large number of potential mutations that could be pathogenetic for prolactinomas in humans have been investigated (Table 12.5). Because dopamine is the primary suppressor of lactotroph growth and function, mutations causing loss of function in the dopamine D2 receptor have been looked for without success [127]. By similar reasoning, activating mutations of the TRH receptor have been sought, again without success [128,129]. Evaluation of prolactinomas for mutations in the G proteins coupling the D2 receptor to adenyl cyclase and the TRH receptor to its intracellular activating pathways have also been unsuccessful [130,131], although prolactinomas resistant to bromocriptine may have decreased levels of the Gi2a protein that couples the D2 receptor to adenyl cyclase [130]. As noted below, bromocriptineresistant prolactinomas also have a decrease in the short D2

Chapter 12

receptor isoform, resulting in decreased inhibition of adenyl cyclase [132]. Thus, these alterations in D2 isoforms and Gi2a may play a role in the pathogenesis of dopamine resistant prolactinomas, but those tumors comprise only 8–15% or prolactinomas [130]. Pit-1 and Prop-1 are pituitary-specific transcription factors necessary for the initial development and subsequent proliferation of lactotrophs, somatotrophs and thyrotrophs during embryogenesis (see Chapter 4). Because of their importance in lactotroph cell proliferation, pathogenetic mutations in Pit-1 and Prop-1 genes have been sought in prolactinomas. Although both Pit-1 and Prop-1 are expressed in prolactinomas [133–137], mutations of neither transcription factor have been found in such tumors [137,138]. Many other studies have examined prolactinomas for putative oncogenes and tumor suppressor genes. No evidence for amplification or rearrangements have been found for the oncogenes N-ras, H-ras, K-ras, myc II, N-myc, c-myc, myb, blc1, h-SF1, p16, p27, p53, sea, nm23, or c-fos [139–144]. Because of the occurrences of prolactinomas in MEN-1 (see below), mutations in the menin tumor suppressor gene [145] have been looked for in both MEN-1 and sporadic cases. Initial studies showed an increased frequency of loss of heterozygosity (LOH) for the 11q13 region, the site of the menin gene, in both MEN-1 associated and sporadic prolactinomas in some studies [139,146–148] but not for other chromosomal locations, and the LOH was associated with a greater degree of tumor invasiveness [147]. However, the menin gene appears to be intact in sporadic tumors [148–150]. In addition to the menin gene, the 11q13 region also contains the transforming gene hst (heparin-biding secretory transforming gene) which encodes fibroblast growth factor 4 (FGF-4). Although normal adult tissues do not express the hst gene, Gonsky et al. [151] showed that this gene is expressed in prolactinomas. In subsequent studies, Shimon et al. [152] demonstrated that rat pituitary cultures transfected with the hst gene had enhanced basal secretion of PRL and also proliferated faster, and hst-transfected cells injected subcutaneously into athymic nude mice caused aggressive lactotroph tumor formation. Shimon et al. [153] have also shown that five of 14 prolactinomas stained for FGF-4, compared to normal pituitary cells. Moreover, in the prolactinomas, hst positivity seemed to be associated with tumor invasiveness as determined by MRI. Another putative oncogene, pituitary tumor transforming gene (PTTG), has been localized to chromosome 5q33 [154,155]. PTTG is overexpressed in rat GH4 pituitary tumor cells and it induces tumor formation in athymic nude mice [154,155]. Zhang et al. [155,156] found PTTG to be expressed in normal human adult and fetal tissue and in all human malignant cells as well as in all human pituitary tumors. No mutations in the PTTG coding region were found. However, when PTTG was transfected and expressed in 3T3 cells, large colonies are found and when such cells are injected into athymic nude mice tumor formation

Prolactinoma

465

occurred and no tumor stimulation was found with mutated PTTG [155]. In further studies, Zhang et al. [156] found PTTG mRNA to be present in increased amounts in 21 of 30 nonfunctioning adenomas, 13 of 13 GH-secreting, nine of 10 prolactinomas and one of one ACTH secreting tumors, and that the quantity appeared to correlate with tumor invasiveness in hormone-secreting but not nonfunctioning adenomas. The exact roles and potential interrelationships between hst, PTTG and menin genes and their products in the pathogenesis of prolactinomas and/or the stimulation of their growth still remain unclear. Conclusions

In summary, it appears that the majority of prolactinomas arise de novo as intrinsic pituitary disease and are not the result of hypothalamic dysfunction. Because of the findings of persistent PRL secretory dynamic abnormalities in some patients despite normal basal PRL levels and the small number of late relapses, it is possible that some tumors arise because of hypothalamic dysregulation. The specific somatic mutations that result in prolactinoma formation and growth are still unknown but a number of interesting candidate genes are being actively investigated.

Prolactinomas in Multiple Endocrine Neoplasia Type I Prolactinomas occur in about 20% of patients with Multiple Endocrine Neoplasia Type 1 (MEN-1) [157]. The MEN1 (menin) gene has been identified on chromosome 11q13 [145] and is thought to function as a constitutive tumor suppressor gene, so an inactivating mutation results in tumor development. As noted above, similar mutations have not been found in sporadic prolactinomas. The fact that in only a subset of MEN-1 patients do prolactinomas develop, suggests that there may be a secondary modifying gene at a locus different from that of the menin gene that acts with the menin gene to produce prolactinomas [157]. There is also a suggestion that the prolactinomas in patients with MEN-1 may be more aggressive than sporadic prolactinomas [158]. When patients with apparently sporadic prolactinomas were screened for hypercalcemia, 14.3% in one series were found to have hyperparathyroidism and one-third of those were found to have gastrinomas upon screening for pancreatic tumors [159]. This figure is higher than the 2–3% reported previously [160,161]. However, even a 2% figure suggests that obtaining a careful family history and measuring calcium levels are useful in the evaluation of all prolactinoma cases. Familial cases of prolactinomas without MEN-1 have also been reported [162]. PATHOLOGY The majority of prolactinomas have cells that are sparsely granulated on electron microscopy [8]. The cells are irreg-

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Pituitary Tumors

ular, have large nuclei with prominent nucleoli and have an abundant rough endoplasmic reticulum and Golgi apparatus [8,163–167]. Immature secretory granules are pleomorphic but mature storage granules are spherical with a diameter of 150–500 nm [8,166]. A characteristic feature of these cells is “misplaced exocytosis,” i.e. extrusion of the secretory granules into the extracellular space [8,168]. Among the various features of the cells, increased endocrine activity is associated with a high frequency of exocytosis, a decreased number of granules per cell and marked development of the rough endoplasmic reticulum, but there are no correlations of endocrine activity with granule size or development of the Golgi [169]. Densely granulated prolactinomas are more rare. Although the rough endoplasmic reticulum is not as abundant as in the sparsely granulated tumors, the Golgi is well developed and high density, large (200–1200 nm) secretory granules are present [8,164]. In general, densely granulated prolactinomas are more closely associated with lower secretory activity and lower serum PRL levels than are sparsely granulated tumors [164,166]. It is not clear that the sparsely and densely granulated cell types are clearly different cell types or whether they can transform into each other [170]. Calcification occurring in prolactinomas is relatively common [8] and cases where there is almost complete ossification of such tumors have been reported [171,172]. Amyloid may also be present [173,174]. Rarely, a prolactinoma may have the structure of an “oncocytoma,” with the characteristic oncytic feature of abundant, hyperplastic, abnormal mitochondria [175]. As will be discussed below, prolactinomas can invade local tissues and may have varying histologic features, but they cannot be termed truly malignant unless metastases distant from the original tumor can be demonstrated. Fortunately, true malignant prolactinomas are exceedingly rare and just over 25 have been reported [176–178]. The presence of distant metastases must be differentiated from two simultaneously occurring intrapituitary prolactinomas, which may occur rarely [179,180] or the primary tumor being primarily located ectopically [181]. PRL secreting tumors may also secrete other hormones. The most common combination is PRL plus GH, about 25–40% of GH-secreting tumors being found to make PRL (see Chapter 10). One particular variant of these PRL plus GH-secreting tumors is the acidophil stem cell adenoma. These tumors have irregular, elongated cells with irregular nuclei and may have oncytic changes with very large mitochondria. In contrast to the other tumors secreting both hormones, patients with these tumors have more marked elevations of PRL than GH and usually present with menstrual abnormalities, galactorrhea, decreased libido or impotence and may have little in the way of acromegalic features [182]. These tumors are usually macroadenomas at the time of presentation and generally have had a relatively short course [182]. Other hormone combinations include PRL and ACTH, PRL and thyroid-stimulating hormone

(TSH), and PRL and follicle-stimulating hormone (FSH) [183–188]. ANIMAL MODELS OF PROLACTINOMAS

Prolactinomas in Aging Rats Prolactinomas develop spontaneously in up to 80% of aging Sprague–Dawley rats [189,190]. It has been hypothesized that such tumors may arise because of a number of defects in dopaminergic inhibition of the lactotrophs. Sarkar et al. [190,191] demonstrated a degeneration of TIDA neurons with a decrease in portal blood DA concentrations in aging rats who developed prolactinomas, with intermediate levels in those who did not develop prolactinomas compared to young rats. However, in these experiments it was not clear that the DA neuronal degeneration was primary in causing the prolactinoma, secondary to short-loop negative feedback of the elevated, autonomously secreted PRL, or just an associated finding that does not play a role in the pathogenesis of the tumors. The usual effect of PRL negative feedback is to increase hypothalamic DA turnover (see Chapter 4). The decrease in DA levels in aging rats is compatible with the concept and other experimental findings suggesting that the short-loop negative feedback of PRL on TIDA neurons is decreased in aging compared to younger rats [192]. In other experiments, mediobasal hypothalamic lesions which eliminate DA inhibition result in hypertrophy and hyperplasia of lactotrophs in rats but not true prolactinoma formation [193].

Estrogen-induced Prolactinomas Estrogens given long-term to rats also induces the formation of pituitary tumors [194,195]. With repeated passages, the tumors can become completely autonomous [196]. Estrogens given for 30 days causes only hyperplasia [197,198] but 60 days treatment causes true neoplasia [198]. Some strains of rats are particularly sensitive to estrogens in the induction of such tumors, such as the Fischer 344 and ACI strains [199,200] and some strains, such as the Holtzman, do not develop prolactinomas at all in response to estrogens [201]. Although both Fischer 344 and Holtzman rats increase PRL synthesis in response to estrogen exposure, only the Fischer 344 rats respond with tumor formation [201]. This discrepancy suggests that actual tumor formation may require some mitogenic factor in addition to the effect on PRL synthesis. As with prolactinomas associated with aging, estrogeninduced tumors are also associated with damaged TIDA neurons and lowered median eminence and portal vessel DA levels [190,191,202], and decreased TIDA negative feedback effects of PRL [203]. The antidopaminergic effects of estrogens are thought to represent both a direct stimulatory ability of estrogens on PRL gene transcription plus an intracellular site of true antidopaminergic action (see Chapter 4).

Chapter 12

Although a direct hypothalamic effect on decreasing DA release into the portal system was initially postulated [204], this effect does not occur in hypophysectomized rats, suggesting that the effect is mediated by the elevated PRL levels. In a study of the simultaneous measurement of hypothalamic DA activity and pituitary PRL levels in Fischer 344 rats treated with estrogen implants for varying periods of time, Morgan et al. [205] found elevated DA activity in the first 14 days of estrogen treatment along with increased PRL levels, but decreased DA activity by 30 days, suggesting that there was an initial normal negative feedback effect of the elevated PRL levels that, perhaps, resulted in possible exhaustion of the TIDA neurons with decreased DA response to PRL and even cellular damage over time. The fact that such tumors respond negatively to dopamine agonists such as bromocriptine, supports a role for this late loss of DA in the progression of such tumors [205]. However, in support of the concept that the decrease in DA inhibition is not primary with regard to actual tumor formation, Wiklund et al. [201] found that the differences in tumorigenesis between the Fischer 344 and Holtzman rats persists even when their pituitaries are transplanted to beneath the kidney capsule, getting rid of direct hypothalamic influence. Once tumors occur, they are accompanied by an increase in vascularity [198]. These new vessels are arterial and transmit blood from the general circulation, rather than blood deriving from portal vessels, thus diluting any DA coming from the hypothalamus [81]. These findings also support a role for a late decrease in DA permitting further growth of the tumors but do not support a role for abnormal vasculature or a decrease in DA as being primary in tumor initiation.

Dopamine-resistant Tumor Cell Lines Some rat PRL-secreting tumor cell lines do not respond to DA in vitro; a number of possible explanations exist. Thus, GH3 cells do not respond because of an absence of DA receptors [206,207]. The 7315a and MtTW15 prolactinoma cell lines are refractory to inhibition of PRL secretion by DA but have DA receptors [208,209]. Although Cronin et al. [208,209] and DiPaolo and Bernier [210] found highaffinity DA binding sites to be present, Bouvier et al. [211] found only low-affinity sites to be present. Further studies suggest that in these two DA resistant tumors the associations of the DA receptor with the guanine nucleotidebinding inhibitory proteins G0 and Gi-2 are altered, and for the Go protein this is due to a selective decrease or absence of its a0 subunit [211,212].

Conclusions—Relationship of Animals to Human Prolactinomas A number of insights may be gained from inspection of these animal models with respect to the pathogenesis and growth of human prolactinomas. First, although a dopamin-

Prolactinoma

467

ergic defect appears to accompany the development of the aging and estrogen-induced tumors, it appears to be a secondary rather than a primary event, although it may be permissive in promoting further tumor growth. It is tempting to compare the arterialization of the estrogen-induced tumors found by Elias and Weiner [81] and resultant decrease in DA reaching the tumorous lactotrophs with the decrease in overall vascularity and thus decrease in dopamine reaching the tumorous lactotrophs in human macroprolactinomas found by Erroi et al. [55]. Schlechter et al. [86] also suggested an increase in tumor arterialization in human prolactinomas, but these results are controversial. Second, the dopaminergic defect and increased PRL synthesis and secretion may be differentiated from true neoplastic change, as evidenced by the differences in the Fischer 344 and Holtzman rats. While considerable effort has gone into trying to demonstrate a primary dopaminergic defect in human prolactinomas in the past, it is reasonable that future efforts should continue to look for specific cell mutations that could cause neoplastic change. LOCAL MASS EFFECTS As mentioned previously, about 95% of prolactinomas are microadenomas, having a tumor diameter less than 10 mm. There may be local or even diffuse invasion of the dura and bone of the sella turcica but this does not usually give rise to clinically apparent symptoms. Although headaches are common in patients with microadenomas, we found them to be no more common than in women with galactorrhea and normal sella radiology with or without associated hyperprolactinemia [213]. On the other hand, Kemman and Jones [214] found that 58% of hyperprolactinemic women with normal radiologic studies had more than one headache per week in comparison to only 27% of a control group. Local mass effects may well cause symptoms in patients with macroadenomas, depending upon size and extent of extrasellar extension. The frequency of such symptoms is much lower than in patients with nonsecreting tumors because prolactinoma patients usually present with symptoms of reproductive/sexual dysfunction (see below). Visual field defects due to chiasmal compression depend upon the amount of suprasellar extension. In one series of macroadenoma patients of all types reported, the average amount of suprasellar extension of patients with visual disturbances was 18.5 mm whereas the average amount of such extension without visual disturbances was 9.5 mm [215]. It should be remembered that generally there is about 10 mm between the top of the normal pituitary and the chiasm [216]. Because of the great variation in how these tumors grow superiorly with respect to the location of the chiasm, visual field defects can range from the classical complete bitemporal hemianopsia to small, partial quadrantic defects to scotomas ([216]; for more details, see Chapter 21). There are no specific types of visual field defects peculiar to prolactinomas compared to other types of tumors.

468

SECTION 3

Pituitary Tumors

Ophthalmoplegias are relatively uncommon, being due to invasion of the cavernous sinus with entrapment of cranial nerves III, IV and VI. The first and second division of the trigeminal nerve (V1 and V2) and the carotid artery are other major structures in the cavernous sinus that can be involved. In some patients a cavernous sinus syndrome may develop, consisting of ophthalmoplegia and pain or hyperesthesia in the distribution of V1 [217]. The carotid artery may be encased within the tumor. Pituitary tumors are an uncommon cause of the cavernous sinus syndrome, being the etiology in only six of 102 patients with this syndrome reported from the Mayo Clinic [218]. Shrinkage of these tumors with dopamine agonists can be quite dramatic and satisfying [217,219,220], as surgery is rarely curative and is potentially fraught with complications [221,222]. Extensive invasion of the floor of the skull with massive destruction of bone occasionally occurs, occasionally causing problems by entrapping cranial nerves and compressing vital brain structures [220,221,223–225]. Extrasellar extension in other directions may cause temporal lobe epilepsy and hydrocephalus [221,226]. These large, invasive tumors are uncommon but not rare and should be differentiated from true carcinomas; a demonstration of metastases distant from the primary tumor is necessary for the latter diagnosis. Histologically, these invasive tumors have no specific features to differentiate them from noninvasive prolactinomas [221]. Many of these patients respond quite well to dopamine agonists, occasionally shrinking to the point where no tumor is even detectable on scan and PRL levels are normal [217,219,220,224,226]. Rarely, these tumors function as a “cork” at the base of the skull so that with substantial tumor shrinkage CSF leaks may occur, giving rise to the potential for meningitis [225]. Surgery is never curative and may be dangerous [220,222,223]. Some patients may respond well to irradiation, substantial tumor shrinkage occurring over many years [221]. Local mass effects may also cause hypopituitarism because of direct pituitary compression or hypothalamic/stalk dysfunction. The larger the tumor, the more likely there is to be one or more hormonal deficits [40,42,120,221,227–233]. Because of the varying sizes of these tumors in the various reports and differences in assessment techniques it is difficult to be precise in estimating the frequencies of hormonal deficits with varying sizes of tumors. With the Grade III–IV tumors (Hardy classification) with suprasellar extension, clinically significant deficits in ACTH and TSH are found in 10–30% of patients [40,120,227,229,231]. Certainly all patients with macroadenomas need to be evaluated for possible deficits in pituitary function. CLINICAL MANIFESTATIONS The clinical manifestations due to hyperprolactinemia and their pathophysiology are discussed extensively in Chapter 4. The frequencies with which various clinical manifestations occur in patients with prolactinomas varies depending

upon referral patterns. Currently, in many centers, such as my own, most patients with microadenomas are now taken care of by gynecologists and general internists and the endocrinologist only sees patients not responsive to dopamine agonists or those with very large macroadenomas.

Women In older series, almost all premenopausal women presented because of symptoms of galactorrhea, amenorrhea, or infertility. In a summary of 21 series of 1621 women with prolactinomas undergoing transsphenoidal surgery (Table 12.6), the frequency of oligoamenorrhea was 92.9% and of galactorrhea was 84.7% [29,42,43,101–104,112,114,115,120, 122,230,231,234–240]. Although the usual situation is that of secondary amenorrhea, primary amenorrhea may also occur (see Chapter 4). Presentation because of severe headaches or visual field disturbance due to large tumors is uncommon in women, who usually initially seek medical attention because of their menstrual dysfunction or their galactorrhea which generally occur even with minimal PRL elevations and long before the tumors have grown large [241]. Postmenopausal women with prolactinomas usually present with mass effects from large tumors [217], although others are found simply because of a history of “premature” menopause [242].

Table 12.6. Amenorrhea and galactorrhea in women with prolactinomas having transsphenoidal adenomectomies

Study Post et al. [40] Randall et al. [42] Hardy [43] Tucker et al. [101] Jacquet et al. [102] Camanni et al. [103] Samaan et al. [104] Faria and Tindall [114] Giovanelli et al. [115] Nelson et al. [120] Antunes et al. [230] Bevan et al. [231] Wiebe et al. [234] Rawe et al. [235] Schlechte et al. [236] Smallridge and Martins [237] Nicola et al. [238] Woosley et al. [239] Thomson et al. [240] Feigenbaum et al. [112] Turner et al. [122] Total

Patients (n) 30 84 300 45 21 58 26 100 48 40 25 48 14 30 73 22 101 34 77 409 36 1409

With amenorrhea (n) 29 84 270 42 19 56 26 97 48 34 21 43 14 30 72 19 93 32 57 389 31 1324 (94.0%)

With galactorrhea (n) 29 73 270 35 18 54 23 84 38 32 17 19 10 28 62 21 84 27 45 389 15 1373 (84.7%)

Chapter 12

Men Men with prolactinomas often present because of symptoms due to the size of the tumor rather than impotence, loss of libido or infertility (Table 12.7). In a summary of 16 series comprising 444 men with prolactinomas, not all of whom went to surgery, 77.9% were impotent, 36.6% had visual field defects, 33.8% had partial or complete hypopituitarism, 29.1% complained of headaches, and only 10.9% had galactorrhea [41–43,103,228,231,242–252]. Thus, about onethird of men had symptoms due to tumor size. Radiologic investigation demonstrates a macroadenoma in 80–90% of cases in most series [40–42,103,228,231,242–247, 250–253]. There has been considerable speculation regarding the considerably greater proportion of men having macroadenomas compared to women. One hypothesis suggests that men tend to ignore symptoms of sexual dysfunction longer than women do, writing off impotence and decrease in libido to “aging” [250]. Thus, the prolonged course without therapy permits tumors to grow large. This line of reasoning ignores the data from women regarding the rather uncommon occurrence of progression of size of microadenomas. As discussed above, such progression is quite uncommon, appearing to occur in somewhat less than 7% of untreated cases over a 4–6 year period of observation. This observation would point to a more fundamental biologic difference in the growth of prolactinomas between the sexes. The difference is unlikely to be due to the differences in target organ sex hormones, i.e. estrogens and testosterone, as estrogens tend to be strongly growth-promoting (see below). Because the gonads of both sexes are suppressed when hyperprolactinemia is present, it is unlikely that gonadal inhibitory peptides such as inhibin or follistatin are

Table 12.7.

469

important in this regard. Although tumors in men and older women who had predominantly macroadenomas have higher MIB-1 labeling than do the microadenomas seen in younger women [254], this simply reflects the fact that larger tumors have a greater propensity for cellular proliferation compared to smaller tumors, but does not really shed light on fundamental pathogenetic differences. Another possibility to explain the apparent overall increased prevalence of prolactinomas in women as well as the relatively decreased proportion of microadenomas and idiopathic hyperprolactinemia in men is the possibility that the reproductive axes have differential sensitivity to hyperprolactinemia. Amenorrhea and galactorrhea are commonly seen in women with PRL levels only marginally elevated (25–50 ng/ml). Perhaps the male reproductive axis is much more resistant, so that PRL levels have to be, for example, >100 ng/ml to cause impotence or decreased libido. However, the data from Spark et al. [246] argue against this formulation, in that they had a number of men with impotence and mild hyperprolactinemia (PRL levels 19, 27, 37, 39, 40, 57, 72, 82, 90 ng/ml) whose impotence was cured with lowering PRL levels into the normal range with bromocriptine. Whether there are tumor growth factors that might have a differential effect on prolactinoma growth in the different sexes is unknown. Further examination of these issues may yield important information regarding the pathophysiology of these tumors.

Children and Adolescents Children and adolescents may present with growth arrest, pubertal delay, or primary amenorrhea in addition to the more standard presentations of galactorrhea, oligo/amenorrhea, and mass effects such as headaches or visual distur-

Presenting symptoms in men with prolactinomas

Study Domingue et al. [29] Randall et al. [30] Hardy [31] Camanni et al. [83] Goodman et al. [174] Bevan et al. [177] Franks [184] Carter et al. [185] Grisoli et al. [186] Spark et al. [187] Prescott et al. [188] Dupuy et al. [209] Murray et al. [216] Hulting et al. [250] Berezin et al. [251] Walsh and Pullan [252] TOTAL

Prolactinoma

Patients (n) 5 16 55 11 10 17 21 22 22 26 6 80 10 37 53 53 444

With impotence (n) 2 9 46 8 9 9 8 20 21 26 6 55 8 29 45 45 346 (77.9%)

With galactorrhea (n) 2 – 6 2 1 1 0 3 4 – 1 15 1 2 2 4 44 (10.9%)

With headaches (n) – 4 – 7 4 8 1 6 16 – 1 10 – 16 23 6 102 (29.1%)

With hypopit. (n) – 8 7 3 4 2 0 8 10 14 2 48 – 18 7 6 137 (33.8%)

With vis. field abn. (n) 1 7 9 3 5 6 6 9 12 5 0 49 – 16 22 9 159 (36.6%)

470

SECTION 3

Table 12.8.

Pituitary Tumors

Size of tumors in children and adolescents with prolactinomas Total

Study Grisoli et al. [255] Fraioli et al. [256] Howlett et al. [257] Maira and Anile [258] Haddad et al. [259] Billaud et al. [260] Dyer et al. [261] Partington et al. [262] Minderman et al. [263] Colao et al. [266] Artese et al. [265] TOTAL

Females

Total

Micro

Macro

Total

Micro

8 4 14 22 13 9 18 15 66 26 34

1 0 5 12 4 3 5 4 22 11 11

7 4 9 10 9 6 13 11 44 15 23

7 4 10 – 11 7 11 – 55 17 29

1 0 2 – 4 2 4 – 20 10 11

219

78

151

54

151 (66%)

bances [255–266]. In contrast to the distribution of patients in adults, there is a disproportionately large number of patients who have macroadenomas (64%), even allowing for possible selection bias because of reporting from neurosurgical units (Table 12.8). Furthermore, the percentage of patients resistant to dopamine agonists may be higher than in adults, with Colao et al. [266] reporting that PRL levels were normalized in only 10 of 26 children and adolescents taking bromocriptine, five of 15 taking quinagolide, and 15 of 20 taking cabergoline. The reasons for the high percentage of large macroadenomas and the relative resistance to dopamine agonists are not known, but it is tempting to speculate that these peculiarities may be linked. HORMONE HYPERSECRETION—DIAGNOSIS AND TESTING The differential diagnosis of hyperprolactinemia is quite broad and is dealt with extensively in Chapter 4, as is diagnostic testing. Through a careful history and physical examination as well as routine blood chemistry and thyroid function testing, most of these disorders can be excluded, save those dealing with hypothalamic/pituitary disease. Some investigators have found the PRL responses to various stimulatory and inhibitory agents to be helpful in the differential diagnosis of hyperprolactinemia [267,268]. However, as outlined in Chapter 4, present experience shows that the blunted responses of PRL to TRH, hypoglycemia, carbidopa/L-dopa are nonspecific and are seen with other types of hyperprolactinemia as well [269]. Other series have similarly reported that dynamic testing of PRL secretion is of no more help than basal PRL levels alone in the differential diagnosis of hyperprolactinemia [270–274]. As mentioned in Chapter 4, a critical distinction to be made is between PRL secreting macroadenomas and “non-secreting” macroadenomas that cause a PRL elevation

Males Macro

Total

Micro

Macro

6 4 8 – 7 5 7 – 35 7 18

1 – 4 – 2 2 7 – 11 9 5

0 – 3 – 0 1 1 – 2 1 0

1 – 1 – 2 1 6 – 9 8 5

97 (64%)

41

8

33 (80%)

because of hypothalamic/stalk dysfunction. Generally, large PRL secreting macroadenomas will have PRL levels above 250 ng/ml and virtually all will be above 100 ng/ml. Nonsecreting macroadenomas commonly cause PRL elevations in the 25–250 ng/ml levels, most being <100 ng/ml. Those with PRL levels between 100 and 250 ng/ml may prove quite troublesome in this differential diagnosis [15–17,272,275]. A case of a patient with a PRL of 662 ng/ml whose tumor did not stain for PRL has been welldocumented [276] but cases with such high PRL levels must be extraordinarily rare. IMAGING All patients with hyperprolactinemia in whom nonhypothalamic/pituitary disorders have been excluded deserve imaging of the hypothalamic/pituitary area with high resolution CT with contrast or magnetic resonance imaging (MRI) with gadolinium. The latter technique is somewhat better in our hands and affords better information about surrounding vasculature, the optic chiasm and invasion of the cavernous sinus [277]. One potential problem in investigating patients with mild hyperprolactinemia is the finding of a false positive CT or MRI scan. Because these techniques are now able to detect incidental nonsecreting tumors, cysts, infarcts, etc. [38], the finding of a “microprolactinoma” on scan in a patient with elevated PRL levels may not always be a true positive finding. Thus a patient with idiopathic hyperprolactinemia may have a “tumor” found on scan that, when removed, still leaves the patient hyperprolactinemic. This may contribute to the relatively low rate of surgical cure for these lesions. For most patients with microadenomas, surgery will not be performed and such lesions can then be followed with serial imaging, if necessary. Alternatively only PRL levels can be followed in patients with microadenomas and imaging repeated only if PRL levels rise.

Chapter 12

In recent years, imaging using 123I-labeled ligands that bind to the DA D2 receptor have investigated with singlephoton emission tomography [278]. Although visualization is seen with very large macroadenomas, no visualization is yet possible with microadenomas [278]. Further improvements in sensitivity will be necessary before this technique will be useful in the differential diagnosis of sellar lesions. The subject of imaging is reviewed extensively in Chapter 24. Current policy has been to perform visual fields (Goldmann perimetry) in patients whose tumors are adjacent to or pressing on the optic chiasm, as visualized on MRI scan. If a clear distance of >2 mm is seen, then we do not perform such scans. The subject of ophthalmologic evaluation of tumor patients is reviewed extensively in Chapter 25.

TREATMENT

Observation The indications for therapy in patients with prolactinomas may be divided into two categories: (i) effects of tumor size, and (ii) effects of hyperprolactinemia. In about 95% of patients, microprolactinomas do not enlarge over a 4–6 year period of observation (see above). Thus, the simple argument that therapy is indicated for a microadenoma to prevent it from growing is fallacious. On the other hand, if a documented adenoma exists, it needs to be followed closely to determine if it is growing. It is very unlikely for a prolactinoma to grow significantly with no increase in serum PRL levels, although this phenomenon has been reported [279]. Therefore, after an initial scan showing a microadenoma, most patients can just be followed with serial PRL levels. If PRL levels rise or the patient develops symptoms of mass effects such as headaches, then repeat scanning is indicated, although one patient with a tremendous increase in PRL levels from 250 to 1528 ng/ml with no change in tumor size by CT scan has been reported [280]. Certainly a microadenoma that is documented to be growing demands therapy for the size change alone, as it may be one of the 7% that will grow to be a macroadenoma. Patients with macroadenomas have already indicated that the tumor has a propensity to grow. Therefore, one is loath just to observe these unless there are specific contraindications to therapy. Local or diffuse invasion or compression of adjacent structures, such as the stalk or optic chiasm, are additional indications for therapy. Other indications for therapy are relative, being due to the hyperprolactinemia itself. These include decreased libido, menstrual dysfunction, galactorrhea, infertility, hirsutism, impotence and premature osteoporosis and have been discussed in detail in Chapter 4. In a woman with a microadenoma with normal menses and libido and galactorrhea that is not bothersome, there is no specific reason for therapy. On the other hand, in a woman with amenor-

Prolactinoma

471

rhea and anovulation who wishes to become pregnant, therapy clearly is indicated. However, if such a woman did not wish to become pregnant, then therapy to prevent osteoporosis or to improve libido clearly is only relatively indicated. The ability to follow a patient closely with PRL levels, CT or MRI scans, and estimations of bone mineral density and rather precise estimates of the efficacy of various modes of therapy (see below) allow a highly individualized way of following patients and choosing the proper timing and mode of therapy.

Surgery Transsphenoidal surgery is the surgical procedure used for microadenomas and most macroadenomas. Rarely is craniotomy performed. The surgical success rates are highly dependent upon the experience and skill of the surgeon as well as the size of the tumor. Surgical results from 34 published series are summarized in Table 12.9. Care has been taken to record only the results from the latest series from a given neurosurgical/endocrine team, omitting data from earlier papers. The papers were further selected so that the size of the tumor (microadenoma vs macroadenoma) had to be specified [41–44,99,101,104,110,113–115,117,119, 120,122,215,222,229–231,234–240,245,281–285]. In these series, 973 of 1321 (73.7%) microadenomas and 415 of 1279 (32.4%) macroadenomas were reported as being curatively resected, i.e. having PRL levels normalized by 1–12 weeks following surgery. Within these series the surgical success rates were quite variable. For series with at least 10 patients, the surgical cure rate varied from 38% to 91% for microadenomas and from 11% to 80% for macroadenomas. From a mail survey of 80 neurosurgeons, Zervas reported surgical cure rates of 74% of 1518 PRL secreting microadenomas and 30% of 1022 PRL secreting macroadenomas [286]. This latter report is not clear, however, in how microadenomas and macroadenomas were classified, as these patients were also reported as being divided by PRL levels greater than or less than 200 ng/ml. Clearly, for the macroadenomas the success rate in large part was dependent on the size of tumors chosen for surgery. In many series, the object was, appropriately, debulking of a very large tumor rather than cure and in other series very large tumors were not operated upon. In a number of series, it was the impression that PRL levels were more a determining factor of surgical success than actual size of the tumor. Patients with serum PRL levels >200 ng/ml were found to have a decreased chance for cure at surgery even when stratified within micro- and macroadenoma groups [42,119,234,235,281,282]. Although PRL levels >200 ng/ml do appear to be a risk factor for poor surgical outcome independent of tumor size, the reason for this has never been addressed. In general, increased hormone production per given mass of tissue suggests high efficiency and better tissue differentiation, characteristics that usually imply a lesser degree of neoplastic

472

SECTION 3

Table 12.9.

Pituitary Tumors

Surgical cure rates for prolactinomas Tumors operated

Study Domingue et al. [41] Randall et al. [42] Hardy [43] Von Werder [44] Rodman et al. [99] Tucker et al. [101] Samaan et al. [104] Arafah et al. [110] Faria and Tindall [114]* Giovanelli et al. [115] Parl et al. [117] Charpentier et al. [119] Nelson et al. [120] Ciric et al. [215] Guidetti et al. [222] Pelkonen et al. [229] Antunes et al. [230] Bevan et al. [231] Wiebe et al. [234] Rawe et al. [235] Schlechte et al. [236] Smallridge and Martins [237] Grisoli et al. [245] Nicola et al. [238] Landolt [281] Woosley et al. [239] Dupuy et al. [248] Thomson et al. [240] Fahlbusch and Buchfelder [282] Brabant et al. [283] Scanlon et al. [284] Turner et al. [122] Massoud et al. [113] Soule et al. [285] TOTAL

Microadenomas

Tumors cured

Macroadenomas

67 54 186 31 42 27 26 74 72 48 – 58 28 – 34 6 9 39 13 21 30 19 – 70 33 22 2 61 108 19 15 32 64 11

25 46 89 – 23 18 – 46 28 – – 289 11 41 120 53 8 28 – 9 24 5 20 40 37 14 78 8 139 37 20 – – 23

1321

1279

Microadenomas

Macroadenomas

46 39 143 20 37 20 20 67 55 38 13 36 21 – 20 3 3 27 5 17 20 12 – 47 25 16 2 46 66 11 10 25 58 5

10 13 34 – 9 8 – 29 13 – 11 134 4 11 11 6 3 8 – 3 11 0 6 16 10 5 7 4 15 14 16 – – 4

973 (73.7%)

415 (32.4%)

Recurrence Microadenomas – – 12/24 – 5/29 3/24 – 5 4/30 10 4 2 8 – 8 – – 1 – – 8 – – – – 1 – 8/41† 8/50 – 0 1 25 1 114/544 (21.0%)

Macroadenomas – – 4/5 – 1/5 – – 10 4/11 – 10 10 1 – 4 – – 1 – – 4 – – – – 0 – 0 1/15 – 0 – – 0 50/253 (19.8%)

* Classified on the basis of PRL <200 ng/ml (81% microadenomas) or >200 ng/ml (86% macroadenomas) rather than tumor size. † Long-term recurrence rate reported in a later paper [121].

change and, presumably, a better chance for complete tumor removal. Thus, this finding is paradoxical and, at present, is without explanation. It would be interesting to correlate the extent of dural invasion, histologic differentiation of the tumor, and serum PRL levels in a series of patients. The criterion for cure specified above was return of PRL levels to normal. When this happens, there is almost a 100% return to normal of gonadal function in both sexes [40,249,287,288]. Analysis of LH pulsatility shows that both the number and amplitude of peaks gradually increase postoperatively (Fig. 12.8) [288]. Often normal reproductive function is obtained even with PRL levels slightly above

normal, but since such patients appear to have a much greater chance of recurrence of more significant hyperprolactinemia (see below), they cannot be deemed as being truly cured. Patients with macroadenomas of all types may be hypopituitary before surgery and, because of the extent of surgery sometimes performed, may have significant changes in pituitary function postoperatively. In an analysis of 84 patients with macroadenomas (36 were prolactinomas), Nelson et al. [289] found that of those with normal preoperative pituitary function, only 78% retained normal function postoperatively. One-third with some pituitary deficits prior to surgery improved and one-third with such

Chapter 12

FIGURE 12.8. Pre- and postoperative serum luteinizing hormone (LH) concentrations following selective resection of a prolactinoma. The start of a LH pulse is indicated by an arrow. From Stevenaert et al. [288]

deficits had worsened pituitary function after surgery. None of the panhypopituitary patients improved following surgery [289]. Although the initial cure rates for microadenomas are usually in the 65–85% range with experienced neurosurgeons, postoperative recurrence of hyperprolactinemia has been a problem. Because most recurrences of hyperprolactinemia occur within the first year following surgery, this has been attributed to regrowth of tumor remnants (see above). Recurrence rates vary from 0% (44) to 50% [111]. From the series compiled in Table 12.8, recurrence rates for microadenomas (114 of 544 = 21.0%) and macroadenomas (50 of 253 = 19.8%) are similar. It should be stressed here that for virtually all of these recurrences, the recurrence is that of hyperprolactinemia and not documented radiologic evidence of tumor regrowth. With recurrence of the hyperprolactinemia there usually also is a recurrence of

Prolactinoma

473

sexual/reproductive dysfunction that usually is an indication for medical therapy to reduce PRL levels. In a series of patients with microadenomas operated upon by Dr. Jules Hardy, of 58 patients with a normal PRL postoperatively, 25 had a relapse of hyperprolactinemia after a mean of 3.3 years, but only 10 of these 25 had a recurrence of amenorrhea or galactorrhea and CT scans showed evidence of a recurrence of the microadenoma in only two [113]. Based on the cure rate of 73.7% and the recurrence rate of 21.0% cited above, the ultimate, long-term surgical cure rate for microadenomas, using a normal PRL level as the criterion, is 58.2%, and this is a number that can be given to patients when counseling them with respect to choices of therapy. For patients with macroadenomas, with a cure rate of 32.4% and a recurrence rate of 19.8%, the long-term cure rate is 26.0%, understanding that these numbers are derived from patients in whom the neurosurgeon thought there was a possibility of cure. For patients with giant prolactinomas and those with considerable cavernous sinus invasion, the chance for surgical cure is essentially zero. Complications from transsphenoidal surgery for microadenomas are quite infrequent, the mortality rate being at most 0.27%, the major morbidity rate being about 0.4% (visual loss 0.1%, stroke/vascular injury 0.2%, meningitis/ abscess 0.1% and oculomotor palsy 0.1%) and CSF rhinorrhea occurring in 1.3% [286,290]. The mortality rate for transsphenoidal surgery for all types of secreting and nonsecreting macroadenomas is 0.9%, the major morbidity rate is 6.5% (visual loss 1.5%, stroke/vascular injury 0.6%, meningitis/abscess 0.5% and oculomotor palsy 0.6%), and rate of CSF rhinorrhea is 3.3% [286,290]. Transient diabetes insipidus (DI) is quite common with transsphenoidal surgery for both micro- and macroadenomas and permanent DI occurs in about 1% of surgeries on macroadenomas [286]. Hypopituitarism is common in patients with macroadenomas prior to surgery as a result of mass effects, occurring in more than 50% of patients [279]. With surgery, both further worsening or improvement may occur [279]. Surgery involving craniotomy is much more hazardous. Although visual field defects and reduction in visual acuity can be improved in 74% of patients whose macroadenomas abut the optic chiasm [291], a small number of patients with normal visual fields may have a reduction of vision after surgery due to herniation of the chiasm into an empty sella, direct injury or devascularization of the optic apparatus, fracture of the orbit, postoperative hematoma, or cerebral vasospasm [292].

Radiotherapy Because of the excellent therapeutic responses to transsphenoidal surgery and medical therapy (see below), radiotherapy is generally not considered to be a primary mode of treatment for prolactinomas. Just over 250 patients (Table 12.10) have been reported who had been treated with conventional radiotherapy alone or in combination with

474

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Pituitary Tumors

T a b l e 1 2 . 1 0.

Effects of conventional radiation therapy on prolactinomas Length of follow-up (yr)

Number hypopituitary

Study

Associated therapy

Antunes et al. [230] Kleinberg et al. [293] Grossman et al. [232] Tsagarakis et al. [300] Carter et al. [243]

None Surgery Bromocriptine

6 11 36

0 1 8 16

– 4 5.4 8.5

– – 2 8

None Surgery None

1 11 8

0 0 5

– – 9.4

1 5 1

Surgery None Bromocriptine Surgery + bromocriptine Bromocriptine Surgery + bromocriptine Surgery + bromocriptine

13 2 3 9 10 11 25

3 1 0 5 6

2.25 9 – 9 6

2 3 8 4/10

8

4

–

None Bromocriptine Surgery + bromocriptine

11 1 63

3 16

5 10

3 22

Gomez et al. [294] Mehta et al. [298] Sheline et al. [296] Johnston et al. [297]

Wang et al. [299] Wallace and Holdaway [301] Zierhut et al. [302] Tsang et al. [303]

bromocriptine for their prolactinomas or after failure of surgical cure [230,232,243,293–303]. Three series reported small numbers of patients treated only with radiotherapy. Antunes et al. [230] and Kleinberg et al. [293] (these appear to be the same patients) reported that six patients so treated had a mean decrease to 12% of pretreatment levels of PRL but none had return of PRL levels to normal over a 1–6 year follow-up. Gomez et al. [294] and Mehta et al. [298] reported the long-term followup of eight women treated only with radiotherapy, finding that five had a return of PRL levels to normal at 2, 9, 10, 13 and 13 years of follow-up whereas two had no lowering of PRL levels over an 8 and 13 year follow-up and one had to have surgery because of rising PRL levels. Within their larger series of patients treated with combined modalities, Johnston et al. [297] reported two women treated with irradiation only in whom PRL levels reached normal in one after 13 years and remained elevated in the other after 14 years. When both irradiation and bromocriptine were used, eight of 36 patients (22%) developed normal PRL levels off bromocriptine after a mean of about 4 years in one study [232] and a later paper [300] showed that this figure increased to 16 patients after a mean of 8.5 years. In another study, five of 12 (42%) developed normal PRL levels after 9 years, nine of these 12 also having had prior surgery [297]. In a third study, six of 21 (29%) women had normal PRL levels after 6 years, with 11 also having had prior surgery

Number

Number cured

[228]. Because bromocriptine itself may cause a very significant, permanent lowering of PRL levels after therapy is discontinued (see below), it is uncertain in these latter series how much of the permanent PRL decreases were due to radiotherapy and how much were due to the bromocriptine. When radiotherapy is used after noncurative surgery, normalization of PRL levels is also quite infrequent. Antunes et al. [230] reported normalization of PRL levels in one of 11 patients (9%) over 0.25–16 years (mean 4 years) following radiotherapy. Of 11 similar patients so treated, Carter et al. [243] reported that none had normal PRL levels after 0.6–15 years (mean 5.8 years) following radiotherapy. Sheline et al. [296] found that of 13 patients irradiated at the University of California in San Francisco following incomplete surgical resection, three reached normal PRL levels with a mean follow-up for the whole group of 29 months. More recently, Zierhut et al. [302] found that only three of 11 patients achieved normal PRL levels a mean of 6.5 years after postoperative radiotherapy and Tsang et al. [303] found that only 25% of 45 patients treated with all three treatment modalities had normal PRL levels off bromocriptine at 10 years. The major side effect of radiotherapy is hypopituitarism. This complication has occurred with varying frequencies in theses series, ranging from 5.5% [230] to 12.5% [298] to 93.3% [297]. Additional complications that occur months to years after radiotherapy of pituitary adenomas include

Chapter 12

second malignancies, cerebrovascular accidents, optic nerve damage, radiation brain necrosis, neurologic dysfunction, and soft tissue reactions. Second malignancies have been reported to be significantly increased (relative risks of 9.38 and 16) years following the primary irradiation [304,305]. Radiation-induced optic atrophy occurs in 2–5% of patients and is due to ischemic damage to the optic apparatus [306]. Radiotherapy-induced encephalopathy is rare but can be devastating and seems to be dose-related [307]. A new form of radiotherapy which allows the precise delivery of a single, necrotizing dose to the tumor with little radiation to surrounding tissue is referred to as “stereotactic” radiotherapy and has had increasing use in recent years. The “gamma knife” uses cobalt-60 gamma radiation emitting sources that focus on a specific point and the linear accelerator (LINAC) uses photons and focuses on a single point using a moving gantry system [308]. Cranial nerves in the cavernous sinus are relatively radioresistant but the optic nerves, chiasm and tracts are radiosensitive [309,310], so that this type of treatment appears to be advantageous for postoperative tumor residing in the cavernous sinus, although some newer surgical approaches through the cavernous sinus are being evaluated [311]. Long-term experience with the use of the gamma knife is quite limited at this point, however. Data extending out to only 2–3 years on only about 50 patients suggests that this technique may be more effective at reducing hormone levels and tumor size with fewer complications than conventional radiotherapy [312–316], but additional time will be necessary with data collected in a clear, organized, prospective manner to be able to place this new therapy into the proper perspective. Thus, with radiotherapy only small numbers of patients reach normal levels of PRL and then only after many years. Radiotherapy seems best reserved as adjunctive therapy for those patients with enlarging lesions who have not responded to either medical or surgical treatment. Gamma knife or LINAC focused radiotherapy, compared to conventional radiotherapy, would appear to offer advantages of efficacy, rapidity of effect, and possibly less adverse effects and thus, at this point, would be the techniques of choice when radiotherapy is indicated.

Medical Therapy Bromocriptine

Bromocriptine (2-bromo-a-ergocryptine mesylate) is an ergot derivative developed by Flückiger and colleagues at Sandoz Pharmaceuticals in the late 1960s for the purpose of inhibiting PRL secretion without the uterotonic vasospastic properties of other ergots [317]. The development of this drug was a logical progression from work done years earlier by Shelesnyak [318] which documented the effect of a variety of ergot alkaloids on inhibiting the formation of deciduomas in rats, which is a PRL-medicated response. Bromocriptine was initially shown by Lutterbeck

Prolactinoma

475

et al. [319] to be clinically useful in suppressing nonpuerperal galactorrhea and shortly thereafter Besser et al. [320] showed that this beneficial effect was accompanied by a reduction in serum PRL levels. A great number of subsequent animal and clinical studies have confirmed this beneficial effect on galactorrhea and amenorrhea due to hyperprolactinemia as well as on the manifestations of hyperprolactinemia in men, and it became recognized that these effects were due to its activity as a long-acting dopamine receptor agonist [62,321,322]. At the same time as these studies were beginning, animal studies were just beginning to show an inhibitory effect of dopamine on PRL secretion (see Chapter 4). Initial attempts were made to lower PRL levels with L-dopa, the dopamine precursor used so successfully in the treatment of Parkinsonism. Unfortunately, L-dopa was found to have only a short-term effect on PRL secretion in humans with hyperprolactinemia and could not be used successfully for long term treatment [323,324]. Thus, there were no other effective medical treatments for the hyperprolactinemic syndromes besides bromocriptine for a number of years. In several large, early published studies (for a review, see [62]), totaling more than 400 hyperprolactinemic patients treated with bromocriptine, normoprolactinemia or return of ovulatory menses occurred in 80–90% of patients. When both PRL levels and return of menses were studied in the same patients, it was found that substantial reductions in PRL levels to still slightly elevated levels often was enough to restore ovulation and menses despite the fact that normal PRL levels were achieved in only 70–80% of treated patients. Patients without roentgenographic evidence of tumor responded somewhat better (88.6%) than patients with such evidence of tumor (80.7%). In other reviews of these early studies similar response rates of 80–85% were found [322,325]. During this period of demonstration of the efficacy of bromocriptine in reducing PRL levels, more basic studies elucidated the mechanism of action. Although L-dopa was found to increase PIF activity in the hypothalamus of rats [326], it was also found to decrease PRL secretion in pituitary cell cultures [327,328]. Bromocriptine stimulates hypothalamic dopamine receptors [329] but ergocryptine and bromocriptine were also found to decrease PRL synthesis in vitro [330–335]. Dopamine (D2) receptors have been demonstrated on normal and adenomatous lactotroph cells [336] and bromocriptine has been found to reversibly bind to this receptor with high affinity [337]. Schran et al. [338] have worked out the pharmacokinetics of bromocriptine reasonably well using a sensitive radioimmunoassay (RIA) for the drug. After a single oral dose of 2.5 mg, serum levels peaked after 3 hours and the nadir was observed at 7 hours, with very little bromocriptine detectable in the circulation after 11–14 hours. The biologic activity parallels the serum levels but there is a continued biologic effect even with undetectable serum levels. The absorption rate from the GI tract is 25–30% with

476

SECTION 3

Pituitary Tumors

a linear relationship between peak plasma levels and dose. Only the native compound is bioactive and metabolites are inactive. There is a very high first pass effect, with 93.6% of a dose being metabolized and only 6.5% of an absorbed dose reaching the systemic circulation unchanged [338]. In rats, measurable tissue levels of bromocriptine can be found in almost all organs 2 hours after an oral dose. Highest levels are found in liver, lung, kidney and pituitary. Despite its very low solubility in water, bromocriptine seems to penetrate most areas of the brain. Studies in pregnant rats show low, but significant transfer of bromocriptine across the placenta, with levels in the fetus about one-fourth of that found in maternal blood. Levels in the placenta are higher than levels in the fetus, suggesting that the placenta may act as a partial barrier to the transfer of bromocriptine. There is little intraindividual variability in the absorption and peak blood levels achieved, but there is considerable interindividual variability [338]. There is also considerable variability in the PRL lowering effects of a given dose of bromocriptine that does not correlate with serum bromocriptine levels, implying differences in sensitivity to the drug [339]. Decreased response to bromocriptine in vivo has been shown to correspond to decreased numbers of DA receptors on lactotroph cell membranes and decreased inhibition of

Tab le 1 2 . 1 1 .

adenyl cyclase when the same tumors are studied in vitro following surgery [340]. In vitro studies found that bromocriptine not only decreased PRL synthesis but also DNA synthesis, cell multiplication and tumor growth [341,342]. Later studies using DNA flow cytometry demonstrated that bromocriptine causes a decrease in cellular growth rate, an increase in the relative proportion of cells in the S phase and a reduced portion of cells in the G1 phase [343]. In 1972, Quadri et al. [344] also found that bromocriptine was able to decrease prolactinoma size in vivo, paving the way for human studies. The initial report that bromocriptine was able to reduce tumor size in humans was by Corenblum et al. [345]. Subsequently, several individual case reports documented such tumor size reduction and a number of series of patients have now been reported. Table 12.11 reports the tumor size responses to bromocriptine from 24 different series of patients, totaling 302 patients with macroadenomas [227,231,299,346–363]. Each series was examined carefully so that patients with combined GH and PRL secreting tumors and those who had prior radiotherapy were excluded. In almost all of the patients documentation of size reduction was by CT scan, although in a few of the patients in earlier studies pneumoencephalography was used; data

Macroadenoma size responses to bromocriptine Tumor size reduction

Study Molitch et al. [227] Bevan et al. [231] Wang et al. [299] McGregor et al. [346] Sobrinho et al. [347] Spark et al. [348] Blackwell et al. [408] Lamberts and Quik [414] Nissim et al. [349] Wass et al. [350] Wollesen et al. [351] Horowitz et al. [352] Corenblum et al. [353] Weiss et al. [354] Johnston et al. [355] Warfield et al. [356] Barrow et al. [357] Liuzzi et al. [358] Pullan et al. [359] Gasser et al. [360] Fahlbusch et al. [361] Walsh and Pullan [252] Höfle et al. [279] DeRosa et al. [439] TOTAL

Total

>50%

25–50%

0–25%

Not quantified

No change

Duration of treatment (mos.)

27 7 3 5 12 10 6 6 7 14 4 6 16 19 14 6 11 38 5 9 23 30 14 10

13 5 3 – – – – 0 4 – 4 – – – – – 3

5 2 0 – – – – 2 – – – – – 10 – – 2

9 0 0 – – – – 2 – – – – – 0 – – 0

4 – 9 – – –

0 – 11 – – –

1 – 2 – – –

– – – 5 9 8 4 – – 9 – 3 11 – 10 4 – 29 – 6 – 25 12 6

0 0 0 0 3 2 2 2 3 5 0 3 5 9 4 2 6 9 0 3 1 5 2 4

12 1.5 24–144 3 6 8–27 26 24 1.5 3–22 15–45 6 60–108 1.5 18–84 6 1.6 30–88 6–24 – 0.5–1.5 – 96 6

302

45

32

14

141

70

Chapter 12

from ordinary hypocycloidal polytomography and visual fields without these other studies were not considered acceptable for this data analysis. For some series, it appeared that patients has also been reported in earlier, less complete compilations. Only the latest publication was used, on the assumption that it represented the most complete collection of data and would prevent duplication of patients. It is possible that some of those earlier series represented different patients, but that was not clear from the publications. In some series estimates of the amount of size change were given whereas in others only the fact that some response occurred was noted. Of the 302 patients analyzed, 76.8% had some tumor size decrease in response to bromocriptine with periods of observation ranging from 6 weeks to over 10 years. In the large, multicenter trial conducted in the United States [227], 27 patients were followed prospectively for at least 12 months on varying doses of bromocriptine, CT scans being done at 6 weeks, 6 months, and 12 months. Of these 27 patients, 13 (48%) had a much greater than 50% reduction in size of their tumors (Fig. 12.9), five (18.5%) had a 25–50% reduction in tumor size, and nine (33.3%) had a <25% reduction in tumor size. In no patient was there no change. Nine other series quantitated their tumor size reductions as well [231,299,349,351,354,357,359,361,363]. Including our series, this gave a total of 112 patients, out of whom 45 (40.2%) had a >50% reduction in tumor size, 32 (28.6%) had a 25–50% reduction in tumor size, 14 (12.5%) had a <25% reduction, and 21 (18.7%) had no evidence of any reduction in tumor size. Two studies used high resolution CT scans to determine whether bromocriptine could also reduce the size of microadenomas. Bonneville et al. [362] found that of 15 such patients, six tumors disappeared completely, five decreased approximately 50% in volume and four remained

Prolactinoma

477

unchanged with treatment of 3–12 months. Demura et al. [363] reported a reduction in size in all patients. The time course of tumor size reduction is variable. Some patients may experience extremely rapid decrease in tumor size, significant changes in visual fields being noted with 24–72 hours and significant changes noted on scan with 2 weeks [364]. In others, little change may be noted at 6 weeks but scanning again at 6 months may show significant changes [227]. In the multicenter trial cited above, 19 patients had a tumor size reduction noted by 6 weeks but in eight others improvement was not noted until the 6 month scans. A progressive decrease was often noted between 6 months and 1 year. In many patients followed subsequently, and in other reports noted above, continued tumor size decreases were noted progressively after 1 year for up to several years. In the multicenter study [227] visual field improvement occurred in nine of the 10 patients with significant visual field abnormalities; 80–90% of patients have had substantial improvement in other studies as well [231,346,348,349, 354,356,358,359,361]. Visual field improvement generally parallels and often precedes the changes seen on scan [227,359]. It is often difficult to determine before treatment whether visual defects are temporary or permanent and only the response to therapy provides a final answer. These studies with medical therapy are reassuring, in that a relatively slow chiasmal decompression over several weeks provides excellent restoration of visual fields and that immediate surgical decompression is not necessary. Usually, when there is no significant change in visual fields despite significant evidence of tumor reduction on scan, subsequent surgery also does not improve these fields [361]. Analysis of data in the multicenter study [227] showed that the extent of tumor size reduction did not correlate with basal PRL levels, nadir PRL levels achieved, the

FIGURE 12.9. MRI scans from the patient shown in Fig. 12.2 after 5 years of bromocriptine treatment. Left: sagittal view, Right: coronal view. Note the marked decrease in tumor size.

478

SECTION 3

Pituitary Tumors

percentage fall in PRL or whether PRL levels reached normal. Some patients had excellent reduction in PRL levels into the normal but only modest changes in tumor size, while others had persistent hyperprolactinemia (although >88% suppression from basal values) with almost complete disappearance of tumor. A reduction in PRL levels always preceded any detectable change in tumor size and PRL nonresponders are also tumor size nonresponders. As Liuzzi et al. [358] have noted, once maximum size reduction is achieved, the dose of bromocriptine can often be substantially reduced, gradually. The reduction in tumor size is usually not only accompanied by improved visual fields and reduction of hyperprolactinemia but also by improvement in other pituitary function. In the multicenter study [227] estradiol levels improved markedly in 13 of 15 premenopausal women, and menses returned in all except these two. Testosterone levels were low in 11 men and increased in nine during treatment, but only to normal in four. Peak testosterone levels occurred between 6 and 12 months for most men. Warfield et al. [356] noted that two patients who were hypothyroid before bromocriptine treatment became euthyroid and one patient who was hypoadrenal became euadrenal. When the prolactinoma is present prepubertally, improved pituitary function allows resumption of normal growth and pubertal development [257,365]. The mechanism by which bromocriptine causes tumor size reduction is essentially a turning off of the intracellular PRL synthesizing machinery, i.e. an inhibition of transcription of PRL mRNA and PRL synthesis [334,342]. These changes can be tracked in vivo using positron emission tomography (PET) scanning using 11C-methionine to monitor amino acid incorporation into protein. Bergstrom et al. [366] have shown that within the first few hours of bromocriptine, the amino acid metabolism decreased by 40% and by 7–9 days this decreases by 70%, accompanied by marked tumor shrinkage. Morphologically, within the first 6 weeks there is a decrease in the number of exocytoses and an initial increase and later decrease in the number of PRL secretory granules, involution of the rough endoplasmic reticulum and Golgi with a decrease in cytoplasmic volume [357,367,368]. By 6 months there is a paucity of cellular organelles with numerous vacuoles, fragmented rough endoplasmic reticulum, many lysosomes and lipfuscin granules along with aggregated chromatin in the nucleus. At that point there is considerable breakdown of tumor cells with cytoplasmic fragmentation, macrophage infiltration and an increase in stromal tissue and collagen fibers between cells [369–371]. When bromocriptine is stopped for 1 week before surgery after 2 weeks of therapy, regrowth of tumor cells occurs with development of the rough ER and Golgi and a decrease in the number of secretory granules [368,371]. Prolactinomas that do not regress in size but do respond to bromocriptine with a normalization of serum PRL levels retain a considerably better tumor morphology [369].

Surgery Following Bromocriptine Treatment One additional pathologic finding of great importance is the development of fibrosis. Landolt et al. called attention to this phenomenon in 1982 [372], stating that his surgical results were much poorer in patients who had received bromocriptine. They subsequently showed an increase in perivascular fibrosis in treated patients [373]. Esiri et al. [374] demonstrated a striking, time-dependent increase in tumor fibrosis with bromocriptine, finding the fibrosis to be specific to prolactinomas, as it did not occur in similarly treated nonsecreting adenomas (Fig. 12.10). The development of this fibrosis may be important with regard to the ability of a surgeon to cure a patient surgically after bromocriptine treatment and also with regard to tumor re-expansion once bromocriptine is stopped. Landolt et al. found that for their patients with microadenomas bromocriptine resulted in a decrease in his surgical cure rate from 81% to 33% [372]. Other series have not corroborated this experience for microadenomas, however. Faglia et al. [375] reported that they had a 69% surgical cure rate for 29 patients with microadenomas that had never received bromocriptine and a 65% cure for 20 patients that had previously received bromocriptine. Fahlbusch et al. [376] found an 80% surgical cure rate for microadenoma patients with PRL levels less than 200 ng/ml not treated with bromocriptine and an 85% cure rate for such patients who had been treated with bromocriptine. On the other hand, the cure rate for 12 patients not treated with bromocriptine but with PRL levels more than 200 ng/ml was 58% and only 33% for 12 such patients treated with bromocriptine. Hubbard et al. [377] compared the results in their bromocriptine treated patients with historical controls [42], finding that the surgical cure rates from the bromocriptine treated patients were 68%, 17%, and 17% for microadenomas, diffuse expansive adenomas and invasive adenomas compared to 72%, 47% and 17% in the corresponding groups of patients not having been treated with bromocriptine in the previous paper. Bevan et al. [231] also found no significant difference in surgical cure rates for microadenomas between patients previously treated with bromocriptine (six of 10 patients) and those not receiving bromocriptine (eight of 14). On the other hand, Bevan et al. [231] found that the fibrosis that developed in the macroadenoma patients produced a tough tumor consistency, making surgical removal extremely difficult. For such patients the cure rate was only one in eight, whereas in such patients who had not been treated with bromocriptine it was seven in 20. Furthermore, these patients with fibrotic tumors had a much greater rate of surgical complications. Weiss et al. [354], however, pretreated all of their macroadenoma patients with bromocriptine for 6–12 weeks and found that of the 10 tumors that had >30% reduction in tumor size, the cure rate was 70% and of the nine tumors that did not respond with a significant size change, the cure rate was 22%. Thus, most series suggest that bromocriptine has little or no effect on later surgical results for microadenomas. For

Chapter 12

Prolactinoma

479

(c)

(a)(b) FIGURE 12.10. Microscopic appearance of reticulin-stained sections of prolactin-secreting adenomas from a patient who received no preoperative bromocriptine treatment (a); a patient who received 3 weeks of preoperative bromocriptine treatment (b); and a patient who received preoperative bromocriptine treatment for 36 weeks (c). (Magnification ¥ 250.) From Esiri et al. [374]

macroadenomas, there may be a problem with bromocriptine treatment longer than 6–12 weeks, at which point fibrosis becomes limiting to complete tumor removal. Retroperitoneal fibrosis has been found with very high doses of bromocriptine (30–140 mg daily) used to treat Parkinson’s disease [378,379] but has not been found in the doses used to treat hyperprolactinemia. An alternative to late surgical treatment is continued bromocriptine. Prolonged bromocriptine treatment for up to 10 years appears to be well-tolerated [299,353,355, 356,380,381] and the dose can often be reduced considerably [358,382]. Thorner et al. [383] pointed out that when bromocriptine is discontinued in a patient with a macroadenoma that has become reduced in size, the tumor can re-expand within 2 weeks. In the multicenter study [227], bromocriptine withdrawal after 1 year resulted in tumor reexpansion in three of four patients. In one of those, placement back on bromocriptine and withdrawal again after 4 years showed a similar re-expansion of tumor. Johnston et al. [355] systematically examined 15 patients treated with either bromocriptine or pergolide (see below) for 3.7 years for recurrence after stopping therapy. Hyperprolactinemia recurred in 14, symptoms related to hyperprolactinemia recurred in 13, but tumor size increased in only two. The

PRL levels after bromocriptine withdrawal were lower than pretreatment in 12 of 13 cases. Wang et al. [299] found that of 24 patients treated solely with bromocriptine for over 3.4 ± 2.3 years, serum PRL levels remained normal in five (24%) with no clinical symptoms after drug withdrawal. Only one patient with a macroadenoma had drug withdrawn and this patient had normal PRL levels and no evidence of tumor recurrence after 2 years. Ho et al. [381] found that four of 15 patients with prolactinomas maintained normal PRL levels off bromocriptine after 5.5 ± 0.6 years of treatment. Rasmussen et al. [384] found PRL levels to remain normal in four of 75 hyperprolactinemic women (mixed idiopathic and tumor) after a median of 24 months of therapy. Thus, 10–20% of patients can maintain normal PRL levels after stopping treatment, although 70–80% with marked tumor size reduction may not experience tumor reexpansion with stopping of therapy. With patients with very large tumors who have excellent tumor size reduction, stopping therapy must be done very cautiously, if at all. The best approach is probably to reduce the dose gradually, following PRL levels, and only discontinue the drug if there are no increases in PRL levels or tumor size on just 2.5 mg per day. Those with tumors that extend along the clivus and midbrain that have had substantial size reduction probably

480

SECTION 3

Pituitary Tumors

should never have their drug stopped, as a sudden enlargement could prove lethal. Side Effects of Bromocriptine Treatment Bromocriptine is certainly not without side effects but, in general, it is well tolerated. The most common side effects are nausea and sometimes vomiting; these are usually transient but may recur with each dose increase. Orthostatic hypotension usually is only a problem when initiating therapy and rarely recurs with dose increases. Limiting nausea and vomiting occurs in 3–5% of patients and digital vasospasm, nasal congestion and depression occur in rare patients when doses less than 7.5 mg/day are used [321,322]. Side effects can be minimized by starting with 1.25 mg daily with a snack at bedtime. The dose is gradually increased to 2.5 mg twice daily with meals over 7–10 days and PRL levels checked after 1–2 months. Oral prednisolone has been found to abolish the nausea occurring with long-acting preparations of bromocriptine [385] but it is not known whether this also works with oral bromocriptine. Most patients respond within 1–2 months if they are going to respond. Doses higher than 7.5 mg per day are usually not necessary except in some patients with very large tumors. One notable additional side effect is a psychotic reaction. Turner et al. [386] noted psychotic reactions in eight of 600 patients receiving either bromocriptine or lisuride (see below) from hyperprolactinemia or acromegaly. Symptoms included auditory hallucinations, delusional ideas and changes in mood. Rare reports of exacerbation of preexisting schizophrenia also exist and the drug should be given cautiously to such patients [387,388]. Psychotic reactions usually resolve within 72 hours of stopping the drug. It should be noted that phenothiazines given to such patients may blunt the action of bromocriptine on prolactinomas as well [227]. Rarely, the prolactinoma serves as a “cork” and tumor size reduction with bromocriptine may cause CSF rhinorrhea [389,390]. One concerning problem is the tumor that initially shrinks in response to bromocriptine and then enlarges. This is usually due to noncompliance, which is further worsened by the tendency for the patient and physician to resume the full dose instead of gradually restarting. This tends to make side effects worse, further exacerbating the noncompliance. However, Dallabonzana et al. [391] reported two such patients; one had a concomitant rise in PRL but the other did not. Although a similar patient was reported by Crosignani et al. [392], a 6 week period off treatment elapsed before the repeat radiologic evaluation. Delgrange et al. [393] also reported a man who had been responsive to bromocriptine for 5 years and then became resistant, only to subsequently respond to quinagolide and cabergoline. Pelligrini et al. [394] have shown that DA binding sites are markedly decreased in tumors that actually grow during bromocriptine treatment in comparison to those that respond and even to those that do not respond but do not grow. In other studies, Caccavelli et al. [395] have shown

that resistant cells express a decreased proportion of the short DA D2 receptor isoform which is coupled to phospholipase C more efficiently than the long DA D2 receptor isoform. Exactly how this defect in posttranslational processing occurs is not known. Although extremely rare, tumors that continue to enlarge while being treated with bromocriptine may turn out to be carcinomas (see above). A rare case of an adenoma transforming to a sarcoma during bromocriptine therapy has also been reported [396]. Reversible pleuropulmonary changes consisting of pleural effusions, pleural thickening and parenchymal lung changes have been reported in patients treated with high doses of bromocriptine for Parkinson’s disease [397]. These findings have not been reported with doses used for patients treated for hyperprolactinemia. Two alternative methods of giving bromocriptine have been tried. Vermesh et al. [398] reported that similar reductions in PRL levels are achieved with oral and intravaginal administration of oral bromocriptine tablets. However, the drug effect lasts for up to 24 hours with a single dose and gastrointestinal side effects were much less with the intravaginal route. Katz et al. [399] reported a woman intolerant of oral bromocriptine with a macroadenoma who responded well with tumor shrinkage to intravaginal bromocriptine. Many women have now been treated with intravaginal bromocriptine with similar results, although some develop local irritation at the site of tablet placement. Thus, the gastrointestinal side effects appear to be caused by local effects rather than being mediated centrally. A long-acting, injectable, depot preparation of bromocriptine (bromocriptine-LAR) causes high blood levels of drug within 5 hours with only minimal side effects. PRL levels fall to 10–20% of basal levels within 12–24 hours [400–405]. PRL levels stay down for 2–6 weeks and tumor shrinkage occurs rapidly in about 60–80% of patients [400–405]. Despite the obvious efficacy and appeal of this preparation, at present there are no plans to market this preparation in the USA. Pergolide

Another dopamine agonist that went through early trials demonstrating efficacy in the treatment of prolactinomas is pergolide (Permax®), which is approved by the US Food and Drug Administration for the treatment of Parkinson’s disease. Although such approval for the treatment of hyperprolactinemia is lacking, there is considerable experience with its use in prolactinoma patients and such use is well documented in the literature. Hyperprolactinemia can be controlled with single daily doses of 50–150 mg [406]. Several studies have shown comparability to bromocriptine with respect to tolerance and efficacy, including tumor size reduction [407–411]. Experience has shown that some patients who do not respond to bromocriptine do so to pergolide and vice-versa [412]. Only 39 patients from these series [409,410,414,414a] had sufficient data to quantitate tumor size reduction. Of these, 29 (75%) had a greater than

Chapter 12 Table 12.12. Comparison of efficacy of dopamine agonists in effecting tumor size reduction Tumor size reduction Dopamine agonist Bromocriptine Pergolide Quinagolide Cabergoline

Number of cases

>50%

25–50%

<25%

No change

112 29 105 320

40.2% 75% 48.1% 28.4%

28.6% 10% 20.2% 28.4%

12.5% 5% 17.3% 14.8%

18.7% 10% 14.4% 28.4%

50% reduction, four (10%) had 25–50% reduction, two (5%) had less than 25% reduction and four (10%) had no change in tumor size (Table 12.12). Quinagolide

Quinagolide (CV 205-502) is a nonergot dopamine agonist with similar tolerance and efficacy to bromocriptine and pergolide and can also be given once daily [233,415]. About 50% of patients who are resistant to bromocriptine respond to quinagolide [416–421]. Although side effects are similar, some patients appear to tolerate quinagolide better than bromocriptine [233,415–422]. Nine studies conducted worldwide have assessed the ability of quinagolide to reduce the size of PRL-secreting macroadenomas [415,416, 423–429]. In the US multicenter study [415], we studied 26 patients over a 24-week period, finding that two had a greater than 50% reduction in tumor size, eight had a 25–50% reduction in tumor size, 11 had a less than 25% reduction in tumor size while five had no reduction in tumor size. Eleven of the patients entered into that study, however, had been previously shown to be either intolerant or relatively resistant to bromocriptine. Return of menses occurred in 11 of 15 premenopausal women, accompanied by an increase in estradiol levels. In men, sexual function improved in five of seven with pretreatment abnormalities and testosterone levels increased in six of eight men. Improved spermatogenesis has been noted in other studies [422]. A total of 105 patients including our 26 patients have been assessed for tumor size reduction in a semiquantitative way in studies ranging from 2 to 36 months in duration [415,416,423–429]. Of these 105, 50 (48.1%) experienced a greater than 50% tumor size reduction, 21 (20.2%) experienced a 25–50% size reduction, 18 (17.3%) experienced a less than 25% reduction, and 15 (14.4%) had no change in tumor size (Table 12.12). The status of this drug in the US is uncertain at the present time. Cabergoline

Cabergoline(1-ethyl-3,3-[3¢-dimethylamino-propyl]3[6¢allylergoline-8b-carbonyl]urea diphosphate – Dostinex®) is different from the other dopamine agonists in that it has a very long half-life and can be given orally once or twice weekly. The long duration of action stems from its slow

Prolactinoma

481

elimination from pituitary tissue [430], its high affinity binding to pituitary dopamine receptors [431], and extensive enterohepatic recycling [432]. After oral administration, PRL lowering effects are initially detectable at 3 hours and gradually increase so that there is a plateau of effect between 48 and 120 hours [432–434] and with weekly doses there is a sustained reduction of PRL [435]. There is a linear dose – serum PRL level response [432]. A number of studies have now shown that cabergoline is at least as effective as and perhaps more effective than bromocriptine in lowering PRL levels, but with substantially fewer side effects [433–437]. In a prospective, double-blind comparison study of 459 women (279 microadenomas, three macroadenomas, 167 idiopathic hyperprolactinemia, 10 other), of women treated with cabergoline, 83% achieved normoprolactinemia, 72% achieved ovulatory cycles and 3% discontinued the medication because of adverse effects while of women treated with bromocriptine, 59% achieved normoprolactinemia, 52% achieved ovulatory cycles, and 12% stopped the drug because of adverse effects [438]. In other studies, cabergoline treatment of men caused a rapid improvement of sperm number and quality [439]. Rare patients experience limiting nausea and vomiting with cabergoline, and they may be treated with intravaginal cabergoline as well [440]. Several studies have assessed the effect of cabergoline on macroadenoma size [435–437,441–447a]. A total of 320 patients in these series had their tumor size assessed in a semiquantitative way in studies ranging from 3 to 24 months duration of treatment. Of these 320, 91 (28.4%) experienced a greater than 50% tumor size reduction, 91 (28.4%) had a 25–50% reduction, 47 (14.8%) had a less than 25% reduction, and 91 (28.4%) had no change in tumor size (Table 12.12). In several of these series many of the patients had been previously treated with other dopamine agonists, some being intolerant and others resistant, and that may color the findings. In the study of Colao et al. [446], only eight of the 23 macroadenoma patients had received short courses of bromocriptine previously and were only intolerant and not resistant to bromocriptine; of these 23, 12 (52%) had greater than 50% reduction in tumor size, 9 (39%) had a 25–50% reduction in tumor size, and 2 (9%) had a less than 25% reduction in tumor size. In a recent series of 27 patients, who had all been previously shown to be resistant to bromocriptine or quinagolide (CV205-502), Colao et al. [448] showed that cabergoline was able to normalize PRL levels in 15 of 19 patients with macroadenomas and all eight patients with microadenomas; tumor shrinkage was documented in nine of the 19 macroadenomas and four of the eight microadenomas [448]. In a similar series, Delgrange et al. [442] showed that cabergoline was able to normalize PRL levels in five of eight patients intolerant of bromocriptine and two of three patients unresponsive to bromocriptine. Other Dopamine Agonists

A number of other dopamine agonists have developed to treat hyperprolactinemia over the years. Although efficacy

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has been found for a number of these medications, they have not been approved and do not appear to be near such approval for clinical use in the USA for a variety of reasons. Such drugs include lergotrile [449], lisuride [450], metergoline [450], mesulergine [451], dihydroergocristine [452], dihydroergocriptine [453], hydergine [454], terguride [455], and CQP 201–403 [456].

Conclusions Regarding Treatment Microadenomas

As discussed above, the risk of progression of microadenoma to macroadenoma is probably under 5%. Thus, the patient not desiring fertility has no pressing need for therapy. On the other hand, long-term hypogonadism due to hyperprolactinemia may be associated with premature osteoporosis in both sexes (see Chapter 4); treatment reverses the increased rate of bone loss. For the woman with continued menses and no hypoestrogenemia, the risk of osteoporosis is not increased (see Chapter 4). For the correction of gonadal function with prevention of osteoporosis and restoration of libido, most patients should be treated unless they have normal estrogen/testosterone function. If fertility is not an issue, then estrogen replacement therapy or a dopamine agonist could be tried. Because of its efficacy in reducing PRL levels, its favorable adverse effect profile, and once or twice weekly dosing, cabergoline appears to be the initial drug of choice for most patients with prolactinomas. If fertility is the primary reason to restore ovulation, then bromocriptine may be better because of its more established safety profile (see below). However, the cost of treatment and the necessity of taking medications for many years make some patients choose transsphenoidal surgery as their primary option. Also, about 10% of patients either just cannot tolerate or do not respond to dopamine agonists. Although there was some initial concern that bromocriptine-induced tumor fibrosis might hinder later surgical success, this has not proven to be so in most series, so that this should probably not be a concern if a patient decides to have surgery later. Based on the compilation of surgical series listed above, the initial surgical cure rates for microadenomas appear to be in the 65–85% range, with a later recurrence for hyperprolactinemia of about 20%. Thus the ultimate cure rate is in the 60% range. Radiation therapy has a very limited role in patients with microadenomas, being limited to those who do not respond to dopamine agonists and who are not cured by surgery. Macroadenomas

Because of their excellent results and the rather poor results of surgery in most patients, DA agonists are recommended as the initial therapy for patients with PRL-secreting macroadenomas (Table 12.12). Surgery can be performed later in patients whose tumor responses to such medications

are not optimal. Even if this subsequent surgery is necessary for tumor debulking it is rarely curative, and a dopamine agonist is usually necessary for treatment of the hyperprolactinemia. Because of its better tolerability and generally better efficacy, cabergoline is the dopamine agonist of choice. Radiation therapy again has a very limited role here, being used for those who have no response to dopamine agonists or whose tumor was documented to actually grow while on dopamine agonists and after incomplete surgical removal. Stereotactic radiotherapy appears to be the best form of radiotherapy at this point, although long-term complications remain to be assessed fully. Whether surgery should be considered for removal of a shrunken tumor during dopamine agonist treatment is not established. As discussed above, some tumors show increased fibrosis after bromocriptine treatment and tumor removal has been found to be impaired in some series but not others. However, as complete surgical removal is rarely achieved and dopamine agonists will still be necessary for controlling the hyperprolactinemia, there seems to be little reason for any surgical intervention if there has been good tumor size reduction. In a study comparing patients treated with bromocriptine alone vs surgery plus bromocriptine, no differences were found in the outcomes of PRL levels and tumor size, with the additional adverse effects of surgery now added [279]. When dopamine agonist therapy is stopped, the prolactinoma may return to its original size, often within days to weeks. However, Johnston et al. [355] found no reexpansion in 13 of 15 patients in whom dopamine agonists were withdrawn, despite recurrence of hyperprolactinemia in 14 of the 15. This potential return to pretherapy size dictates extreme caution when withdrawing dopamine agonist therapy, as rapid tumor expansion may produce far more clinical symptoms than slow tumor enlargement. Often, however, the dose can be gradually tapered once maximal size reduction has occurred and, in suitable cases, stopped entirely if no re-expansion occurs. The anatomic response of tumors to dopamine agonist treatment must be monitored carefully by CT or MRI and by visual field examinations to detect tumors that do not respond, including the very rare carcinomas and cases of tumor reenlargement. PREGNANCY IN WOMEN WITH PROLACTINOMAS As discussed in Chapter 4, hyperprolactinemia is usually associated with anovulation and infertility, and correction of the hyperprolactinemia with dopamine agonists restores ovulation in about 90% of cases. When a woman harbors a prolactinoma as the cause of the hyperprolactinemia, two major issues arise when ovulation and fertility are restored: (i) the effects of the dopamine agonist on early fetal development occurring before a pregnancy is diagnosed; and (ii) the effect of the pregnancy itself on the prolactinoma.

Chapter 12

Effects of Bromocriptine on the Developing Fetus As a general principal, it is advised that fetal exposure to bromocriptine be limited to as short a period as possible. Most advise that mechanical contraception be used until the first two to three cycles have occurred, so that an intermenstrual interval can be established. In this way, a woman will know when she has missed a menstrual period, a pregnancy test can be performed quickly, and bromocriptine stopped. Thus, bromocriptine will have been given for only about 3–4 weeks of the gestation. When used in this fashion, bromocriptine has not been found to cause any increase in spontaneous abortions, ectopic pregnancies, trophoblastic disease, multiple pregnancies or congenital malformations (Table 12.13) [457,458]. Long-term follow-up studies of 64 children between the ages of 6 months and 9 years whose mothers took bromocriptine in this fashion have shown no ill effects [459]. Experience is limited to only just over 100 women, however, with the use of bromocriptine throughout the gestation, but no abnormalities were noted in the infants except one with an undescended testicle and one with a talipes deformity [457,460–462]. Few data are available on the safety during pregnancy of pergolide. Outcome data available on 265 pregnancies in which cabergoline was administered to facilitate ovulation do not show increased risks of preterm, ectopic, or multiple birth deliveries or malformations [463,464]. However, this data is relatively sparse compared to the data in over 6000 pregnancies with bromocriptine, so that at the moment bromocriptine use is favored when

Table 12.13.

Prolactinoma

483

fertility is the major reason for treatment. On the other hand, this data is encouraging so that the mother may be reassured if she gets pregnant while taking cabergoline, and over the next few years we will likely gain a sufficient amount of data so as to be able to recommend cabergoline for fertility without reservation.

Effect of Pregnancy on Prolactinoma Size Estrogens have a marked stimulatory effect on PRL synthesis and secretion and the hormonal milieu of pregnancy can stimulate lactotroph cell hyperplasia (see Chapter 4). Those autopsy studies showing lactotroph cell hyperplasia during pregnancy have now been corroborated in vivo, MRI scans showing a gradual increase in pituitary volume over the course of gestation, beginning by the second month and peaking the first week postpartum with a final height reaching to almost 12 mm in some cases [465,466]. Because of these known stimulatory effects of pregnancy on normal lactotrophs and the knowledge that estrogen receptors had been demonstrated in prolactinomas [467], it was not surprising when the first case reports began to appear of pregnancy-induced symptomatic enlargement of pituitary tumors in patients who had been treated with bromocriptine or other ovulation-inducing agents (Fig. 12.11) [468–476]. In some of these patients surgery was required to correct visual symptoms [468,469,471,476], but

Effect of bromocriptine on pregnancies Bromocriptine Normal population %

n

%

Pregnancies Spontaneous adortion Terminations Ectopic Hydatidiform moles

6239 620 75 31 11

100 9.9 1.25 0.5 0.2

0.5–1.0 0.05–0.7

Deliveries (known duration) At term (>38 weeks) Preterm (<38 weeks)

4139 3620 519

100 87.5 12.5

100 85 15

Deliveries (known outcome) Single births Multiple births

5120 5031 89

100 9.3 1.7

100 8.7 1.3

Babies (known details) Normal With malformations With perinatal disorders

5213 5030 93 90

100 96.5 1.8 1.7

100 95 3–4 >2

Modified from Krupp et al. [458]

100 10–15

FIGURE 12.11. Coronal and sagittal MRI scans of an intrasellar prolactin secreting macroadenoma in a woman prior to conception (above) and at 7 months of gestation (below). Note the marked tumor enlargement at the latter point, at which time the patient was complaining of headaches.

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in others the noted defects resolved after parturition [468,470,472,474]. Gemzell and Wang [477] summarized collected data on 187 patients with prolactinomas becoming pregnant; the data for 152 of these patients had not been published previously. There were 91 pregnancies in 85 women with microadenomas that had not received prior irradiation or surgery. Severe headache and visual field defects occurred in one patient at 12 weeks of gestation; the woman was treated conservatively and underwent transsphenoidal surgery after delivery at 36.5 weeks. Headaches developed in three other patients. All were treated conservatively and delivered at term. There were 56 pregnancies in 46 women with macroadenomas that had not received prior irradiation or surgery. Headaches or visual disturbances occurred in 19; 12 were treated conservatively; one received bromocriptine; one received high-dose glucocorticoids; and five underwent transsphenoidal surgery during pregnancy. In comparison, Gemzell and Wang found that of 70 women with macroadenomas treated with surgery and/or irradiation before becoming pregnant, only two developed headaches plus visual-field changes and three developed headaches alone. During the period of that review, Sandoz reported only nine cases of tumor enlargement in 137 pregnancies through 1978 [478]. Another review summarized 16 series reported between 1979 and 1985 totaling 246 women with microadenomas and 91 women with macroadenomas who became pregnant [479]. Subsequently, Kupersmith et al. [480] reported that in 54 patients with microprolactinomas no visual field defects were noted during pregnancy. However, in all four patients with macroprolactinomas, visual field defects occurred; in each of these four cases, the visual field defects resolved with bromocriptine or delivery [480]. In another series, no evidence of tumor enlargement during pregnancy was found in 22 patients with microprolactinomas or in five patients with macroprolactinomas [481]. Most recently, Musolino and Bronstein [481a] reported that of 41 patients with microadenoma only 1 patient had significant tumour enlargement, of 30 patients with macroadenoma who had no prior surgery, 11 had significant tumour enlargement, of 21 patients with macroadenomas who had no prior

Table 12.14.

surgery, none had significant enlargement. When these data [479–481a] are combined, only five of the 363 women (1.2%) with microadenomas had symptoms of tumor enlargement (headaches or visual disturbances or both) (Table 12.14). In no case was surgical intervention necessary. These series included 82 patients with macroadenomas who had not had prior surgery or irradiation. Of these, 20 (24.4%) had symptomatic tumor enlargement, two of the four patients reported by Kupersmith et al. [480] had visual field defects that were quite minor requiring either surgery (early series) or reinstitution of bromocriptine in many. Sixty-nine women with macroadenomas had been treated with irradiation or surgery before pregnancy; only two of the 48 (4.2%) had symptomatic tumor enlargement, and none had asymptomatic enlargement during gestation. Thus, the risk of clinically important microadenoma enlargement during pregnancy was 5.5% in the series reviewed by Gemzell and Wang [477] and only 1.4% in this newer compilation. However, for the macroadenomas, the risk of symptomatic tumor enlargement was considerably higher, ranging from 24.4% in this review to 35.7% [477,478]; the risk was considerably attenuated if there was prior irradiation or surgery. About 25–50% of the cases of symptomatic tumor enlargement required surgery before it was known that bromocriptine could reduce tumor size. More recently, however, bromocriptine has been used successfully during pregnancy to reduce symptomatic tumor enlargement in a number of cases [480,482–487]. No ill effects on the infant were observed in these cases. As stated above, no teratogenic or other untoward effects of bromocriptine on pregnancy have been noted when bromocriptine was stopped within a few weeks of conception. Experience is limited, however, with the use of bromocriptine throughout the gestation (see above) [457, 460–462,488–491]. In two studies in which bromocriptine was given before elective therapeutic abortions at 6–9 weeks [492] or 20 weeks [493] of gestation, there were no effects on estradiol, estriol, progesterone, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, cortisol or human placental lactogen. In all studies maternal and fetal PRL levels were suppressed but

Effect of pregnancy of prolactinomas

Tumor type

Prior therapy

Patients (n)

Symptomatic enlargement*

Microadenomas Macroadenomas Macroadenomas

None None Yes

363 82 69

5 (1.4%) 20 (24.4%) (2.9%)

* Requiring intervention—surgery or bromocriptine.

Chapter 12

in the three cases in which amniotic-fluid PRL was measured, it was suppressed in two [493] and normal in the third [489]. Thus, these few studies of bromocriptine treatment late in gestation suggest that such use is probably safe, but there have been no large-scale or long-term studies. The use of prophylactic bromocriptine throughout the pregnancy likely prevents tumor regrowth during the pregnancy in most cases. In some patients, postpartum PRL levels and tumor sizes are actually reduced as compared with values before pregnancy [494], but this has not been observed in all series [495]. Ikegami et al. [496] found that patients previously treated by transsphenoidal surgery had lower postpartum PRL levels than patients not cured by surgery and subsequently treated with bromocriptine and also those just treated with bromocriptine. These lower levels of PRL then contributed to decreased milk production and poorer breast feeding. In their study no nursing patient showed a sharp increase of PRL levels or complained of symptoms suggestive of tumor enlargement, such as headaches or visual disturbances. RECOMMENDATIONS FOR MANAGEMENT For the hyperprolactinemic woman with a microadenoma there are three possible choices to restore fertility: bromocriptine alone, transsphenoidal selective adenomectomy, or bromocriptine after surgery or irradiation. Bromocriptine is preferred as the primary treatment for such patients because of its efficacy in restoring ovulation and very low (1–2%) risk of clinically serious tumor enlargement. Bromocriptine is generally preferred to cabergoline because of its more extensive long-term safety record with respect to the fetus. Transsphenoidal surgery causes a permanent reduction of PRL levels in only 60% of cases and entails morbidity and mortality, albeit at the low rates discussed above. Pregnancy can generally be achieved in 80–85% of patients with bromocriptine or surgery [479,495,497]. Rare patients who do not respond to either modality may need additional hormonal maneuvers to facilitate ovulation, such as clomiphene citrate plus human chorionic gonadotropin [498,499] or pulsatile gonadotropin releasing hormone therapy [500,501]. Although radiotherapy has been advocated by some for patients with microadenomas before bromocriptine-induced pregnancy, it does not appear to be warranted, as the risk of tumor enlargement without radiotherapy is much lower than the risk of known, long-term sequelae of pituitary radiotherapy—viz. hypopituitarism (see above). A patient with a microadenoma treated only with bromocriptine should be carefully followed throughout gestation. PRL levels do not always rise during pregnancy in women with prolactinomas, as they do in normal women. Usually PRL levels rise over the first 6–10 weeks after stopping bromocriptine and then do not increase further [502]. PRL levels may also not rise with tumor enlargement [503].

Prolactinoma

485

Therefore, periodic checking of PRL levels is of no benefit. Because of the low incidence of tumor enlargement, routine, periodic visual field testing is not cost effective. Visual field testing and scanning are performed only in patients who become symptomatic. In the patient with tumor enlargement who does not respond to reinstitution of bromocriptine, surgery or early delivery may be required. For the patient with a small intrasellar or inferiorly extending macroadenoma, bromocriptine is also favored as the primary therapy. The likelihood that such a tumor will enlarge sufficiently to cause clinically serious complications is probably only marginally higher than the likelihood in patients with microadenomas. In a woman with a larger macroadenoma that may have suprasellar extension, there is a 15–35% risk of clinically serious tumor enlargement during pregnancy when only bromocriptine is used. There is no clear-cut answer as to the best therapeutic approach and this has to be a highly individualized decision that the patient has to make after a clear, documented discussion of the various therapeutic alternatives. The most conservative approach is to perform a prepregnancy transsphenoidal surgical debulking of the tumor. This should greatly reduce the risk of serious tumor enlargement, but cases with massive tumor expansion during pregnancy after such surgery have been reported [487]. After surgical debulking, bromocriptine is required to restore normal PRL levels and allow ovulation. Although radiotherapy before pregnancy, followed by bromocriptine, reduces the risk of tumor enlargement also, it is rarely curative (see above). Radiotherapy may also result in long-term hypopituitarism (see above), so that this approach seems less acceptable than transsphenoidal surgery plus bromocriptine. A third approach, that of giving bromocriptine continuously throughout gestation, has been advocated [462]. At this point, however, data regarding the effects of continuous bromocriptine therapy on the developing fetus are still quite meager, and such therapy cannot be recommended without reservation. Should pregnancy at an advanced stage be discovered in a woman taking bromocriptine, the data that exist are reassuring and would not justify therapeutic abortion. Yet another approach is to stop bromocriptine after pregnancy is diagnosed. For patients with macroadenomas treated with bromocriptine alone or after surgery or irradiation, careful followup with 1–3 monthly visual field testing is warranted. Repeat scanning is reserved for patients with symptoms of tumor enlargement and/or evidence of a developing visual field defect or both. Repeat scanning after delivery to detect asymptomatic tumor enlargement may be useful as well. Should symptomatic tumor enlargement occur with any of these approaches, reinstitution of bromocriptine is probably less harmful to the mother and child than surgery. There have been a number of cases reported where such reinstitution of bromocriptine has worked quite satisfactorily, causing rapid tumor size reduction with no adverse

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effects on the infant (see above). Any type of surgery during pregnancy results in a 1.5-fold increase in fetal loss in the first trimester and a fivefold increase in fetal loss in the second trimester, although there is no risk of congenital malformations from such surgery [504]. Thus, bromocriptine reinstitution would appear to be preferable to surgical decompression. However, such medical therapy must be very closely monitored, and transsphenoidal surgery or delivery (if the pregnancy is far enough advanced) should be performed if there is no response to bromocriptine and vision is progressively worsening. REFERENCES 1 Ahumada JC, del Castillo EB. Amenorréa y galactorréa. Bol Soc Obst Y Ginec 1932;11:64–67. 2 Krestin D. Spontaneous lactation associated with enlargement of the pituitary. Lancet 1932;1:928–930. 3 Mendel EB. Chiari-Frommel syndrome. Am J Obstet Gynecol 1946; 51:889–892. 4 Argonz J, Del Castillo EB. A syndrome characterized by estrogenic insufficiency, galactorrhea and decreased urinary gonadotropin. J Clin Endocrinol Metab 1953;13:79–87. 5 Forbes AP, Henneman PH, Griswold GC, Albright F. Syndrome characterized by galactorrhea amenorrhea and low urinary FSH: comparison with acromegaly and normal lactation. J Clin Endocrinol Metab 1954;14:265–271. 6 Kleinberg DL, Frantz AG. Human prolactin: measurement in plasma by in vitro bioassay. J Clin Invest 1971;50:1557–1568. 7 Friesen H, Webster BR, Hwang P et al. Prolactin synthesis and secretion in a patient with the Forbes–Albright syndrome. J Clin Endocrinol Metab 1972;34:192–199. 8 Horvath E, Kovacs K. The adenohypophysis. In: Kovacs K, Asa SL, eds. Functional Endocrine Pathology. Boston: Blackwell Scientific Publications, 1991:245–281. 9 Hardy J. Transsphenoidal surgery of hypersecreting pituitary tumors. In: Kohler PO, Ross GT, eds. Diagnosis and Treatment of Pituitary Tumors. New York: American Elsevier Publishing Co, 1973:179–194. 10 Selman WR, Laws ER, Scheithauer BW, Carpenter SM. The occurrence of dural invasion in pituitary adenomas. J Neurosurg 1986;64:402–407. 11 Klijn JGM, Lamberts SWJ, De Jong FH et al. The importance of pituitary tumour size in patients with hyperprolactinaemia in relation to hormonal variables and extrasellar extension of tumor. Clin Endocrinol 1980;12:341–355. 12 Molitch ME. Hyperprolactinemia. Medical Grand Rounds 1982;1:307–319. 13 St-Jean E, Blain F, Comtois R. High prolactin levels may be missed by immunoradiometric assay in patients with macroprolactinomas. Clin Endocrinol 1996;44:305–309. 14 Barkan A, Chandler WF. Giant pituitary prolactinoma with falsely low serum prolactin: the pitfall of the “high-dose hook effect”: case report. Neurosurgery 1998:9;13–15. 15 Molitch ME, Reichlin S. Hypothalamic hyperprolactinemia: neuroendocrine regulation of prolactin secretion in patients with lesions of the hypothalamus and pituitary stalk. In: Macleod RM, Thorner MO, Scapagnini U, eds. Prolactin. Basic and clinical correlates. Proceedings of the IVth International Congress on prolactin. Padova, Italy: Liviana Press, 1985:709–719. 16 Bevan JS, Burke CW, Esiri MM, Adams CBT. Misinterpretation of prolactin levels leading to management errors in patients with sellar enlargement. Am J Med 1987;82:29–32. 17 Kruse A, Astrup J, Gyldensted C, Cold GE. Hyperprolactinaemia in patients with pituitary adenomas. The pituitary stalk compression syndrome. Brit J Neurosurg 1995;9:453–457. 18 Susman W. Pituitary adenoma. Br Med J 1933;2:1215. 19 Costello RT. Subclinical adenoma of the pituitary gland. Am J Pathol 1936;12:205–215. 20 Sommers SC. Pituitary cell relations to body states. Lab Invest 1959;8:588–621. 21 McCormick WF, Halmi NS. Absence of chromophobe adenomas from a large series of pituitary tumors. Arch Pathol 1971;92:231–238. 22 Kovacs K, Ryan N, Horvath E et al. Pituitary adenomas in old age. J Gerontol 1980;35:16–22.

23 Landolt AM. Biology of pituitary microadenomas. In: Faglia G, Giovanelli MA, MacLeod RM, eds. Pituitary microadenomas. London: Academic Press, 1980:107–122. 24 Mosca L, Solcia E, Capella C, Buffa R. Pituitary adenomas: surgical versus post mortem findings today. In: Faglia G, Giovanelli MA, MacLeod RM, eds. Pituitary microadenomas. London: Academic Press, 1980:137–142. 25 Burrow GN, Wortzman G, Rewcastle NB et al. Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. N Engl J Med 1981;304:156–158. 26 Parent AD, Bebin J, Smith RR. Incidental pituitary adenomas. J Neurosurg 1981;54:228–231. 27 Muhr C, Bergstrom K, Grimelius L, Larsson S-G. A parallel study of the roentgen anatomy of the sella turcica and the histopathology of the pituitary gland in 205 autopsy specimens. Neuroradiology 1981;21:55–65. 28 Von Schwezinger G, Warzok R. Hyperplasien und adenome der hypophyse im unselektierten sektionsgut. Zbl Allg Pathol u Pathol Anat 1982;126:495–498. 29 Coulon G, Fellmann D, Arbez-Gindre F, Pageaut G. Les adenome hypophysaires latents. Etude autopsique. Sem Hop Paris 1983;59:2747–2750. 30 Chambers EF, Turski PA, LaMasters D, Newton TH. Regions of low density in the contrast-enhanced pituitary gland: normal and pathologic processes. Radiology 1982;144:109–113. 31 Siqueira MG, Guembarovski AL. Subclinical pituitary microadenomas. Surg Neurol 1984;22:134–140. 32 Abd El-Hamid MW, Joplin GF, Lewis PD. Incidentally found small pituitary adenomas may have no effect on fertility. Acta Endocrinol 1988;117:361–364. 33 Scheithauer BW, Kovacs KT, Randall RV et al. Effects of estrogen on the human pituitary: a clinicopathologic study. Mayo Clin Proc 1989;64:1077–1084. 34 Marin F, Kovacs KT, Scheithauer BW et al. The pituitary gland in patients with breast carcinoma: a histologic and immunocytochemical study of 125 cases. Mayo Clin Proc 1992;67:949. 35 Mosca L, Costanzi G, Antonacci C et al. Hypophyseal pathology in AIDS. Histol Histopathol 1992;7:291. 36 Sano T, Kovacs KT, Scheithauer BW et al. Aging and the human pituitary gland. Mayo Clin Proc 1993;68:971. 37 Teramoto A, Hirakawa K, Sanno N et al. Incidental pituitary lesions in 1000 unselected autopsy specimens. Radiology 1994;193:161. 38 Molitch ME. Pituitary incidentalomas. Endocrinol Metab Clin N Amer 1997;26:725–740. 39 Annegers JF, Coulam CB, Abboud CF et al. Pituitary adenoma in Olmsted County, Minnesota, 1935–1977. A report of an increasing incidence of diagnosis in women of childbearing age. Mayo Clin Proc 1978;53:641–643. 40 Post KD, Biller BJ, Adelman LS et al. Selective transsphenoidal adenomectomy in women with galactorrhea-amenorrhea. JAMA 1979;242:158–162. 41 Domingue JN, Richmond IL, Wilson CB. Results of surgery in 114 patients with prolactin-secreting pituitary adenomas. Am J Obstet Gynecol 1980; 137:102–108. 42 Randall RV, Laws ER, Abboud CF et al. Transsphenoidal microsurgical treatment of prolactin-producing pituitary adenomas. Mayo Clin Proc 1983; 58:108–121. 43 Hardy J. Transsphenoidal Microsurgery of prolactinomas. In: Black PM, Zervas NT, Ridgway EC, Martin JB, eds. Secretory tumors of the pituitary gland. New York: Raven Press: 73–81. 44 Von Werder K, Eversmann T, Fahlbusch R, Rjosk H-K. Development of hyperprolactinemia in patients with adenomas with and without prior operative treatment. Excerpta Med Int Congr Ser 1982;584:175–188. 45 March CM, Kletzky OA, Davajan V et al. Longitudinal evaluation of patients with untreated prolactin-secreting pituitary adenomas. Am J Obstet Gynecol 1981;139:835–844. 46 Weiss MH, Teal J, Gott P et al. Natural history of microprolactinomas: sixyear follow-up. Neurosurgery 1983;12:180–183. 47 Koppelman MCS, Jaffe MJ, Rieth KG et al. Hyperprolactinemia, amenorrhea, and galactorrhea. Ann Intern Med 1984;100:115–121. 48 Sisam DA, Sheehan JP, Sheeler LR. The natural history of untreated microprolactinomas. Fertil Steril 1987;48:67–71. 49 Schlechte J, Dolan K, Sherman B et al. The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 1989; 68:412–418. 50 Rjosk HK, Fahlbusch R, von Werder K. Spontaneous development of hyperprolactinaemia. Acta Endocrinol 1982;100:333–336. 51 Martin TL, Kim M, Malarkey WB. The natural history of idiopathic hyperprolactinemia. J Clin Endocrinol Metab 1985;60:855–858. 52 Pontiroli AE, Falsetti L. Development of pituitary adenoma in women with hyperprolactinaemia: clinical, endocrine, and radiological characteristics. Brit Med J 1984;288:515–518.

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pituitary adenomas using the reverse transcription polymerase chain reaction method. Clin Endocrinol 1996;45:263–270. Sanno N, Teramoto A, Matsuno A et al. Expression of Pit-1 and estrogen receptor messenger RNA in prolactin-producing pituitary adenomas. Mod Pathol 1996;9:526–533. Ikuyama S, Mu Y-M, Ohe K et al. Expression of an orphan nuclear receptor DAX-1 in human pituitary adenomas. Clin Endocrinol 1998;48:647–654. Nakamura Y, Usui T, Mizuta H et al. Characterization of Prophet of Pit-1 gene expression in normal pituitary and pituitary adenomas in humans. J Clin Endocrinol Metab 1999;84:1414–1419. Pelligrini-Bouiller I, Morange-Ramos A, Barlier A et al. Pit-1 gene expression in human pituitary adenomas. Horm Res 1997;47:251–258. Bogglid MD, Jenkinson S, Pistorello M et al. Molecular genetic studies of sporadic pituitary tumors. J Clin Endocrinol Metab 1994;78:387–392. Pei L, Melmed S, Scheithauer B et al. H-ras mutations in human pituitary carcinoma metastases. J Clin Endocrinol Metab 1994;78:842–846. Woloschak M, Roberts JL, Post K. c-myc, c-fos, c-myb gene expression in human pituitary adenomas. J Clin Endocrinol Metab 1994;79:253–257. Cai WY, Alexander JM, Hedley-Whyte ET et al. Ras mutations in human prolactinomas and pituitary carcinomas. J Clin Endocrinol Metab 1994;78:89–93. Clayton RN, Boggild M, Bates AS et al. Tumour suppressor genes in the pathogenesis of human pituitary tumours. Horm Res 1997;47:185–193. Shimon I, Melmed. Pituitary tumor pathogenesis. J Clin Endocrinol Metab 1997;82:1675–1681. Chandrasekharappa SC, Guru SC, Manickham P et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997;276: 404–407. Herman V, Drazin NZ, Gonsky R, Melmed S. Molecular screening of pituitary adenomas for gene mutations and rearrangements. J Clin Endocrinol Metab 1993;77:50–55. Bates AS, Farrell WE, Bicknell EJ et al. Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker. J Clin Endocrinol Metab 1997;82:818–824. Tanaka C, Kimura T, Yang P et al. Analysis of loss of heterozygosity on chromosome 11 and infrequent inactivation of the MEN1 gene in sporadic pituitary adenomas. J Clin Endocrinol Metab 1998;83:2631–2634. Prezant TR, Levine J, Melmed S. Molecular characterization of the Men1 tumor suppressor gene in sporadic pituitary tumors. J Clin Endocrinol Metab 1998;83:1388–1391. Asa SL, Somers K, Ezzat S. The MEN-1 gene is rarely down-regulated in pituitary adenomas. J Clin Endocrinol Metab 1998;83:3210–3212. Gonsky R, Herman V, Melmed S, Fagin J. Transforming DNA sequences present in human prolactin-secreting pituitary tumors. Mol Endocrinol 1991;5:1687–1695. Shimon I, Huttner A, Said J et al. Heparin-binding secretory transforming gene (hst) facilitates rat lactrotrope cell tumorigenesis and induces prolactin gene transcription. J Clin Invest 1996;97:187–195. Shimon I, Hinton DR, Weiss MH, Melmed S. Prolactinomas express heparinbinding secretory transforming gene (hst) protein product: marker of tumour invasiveness. Clin Endocrinol 1998;48:23–29. Pei L, Melmed S. Isolation and characterization of a pituitary tumor-specific transforming gene. Mol Endocrinol 1997;11:443–441. Zhang X, Horwitz GA, Prezant TR et al. Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol Endocrinol 1999; 13:156–166. Zhang X, Horwitz GA, Heaney AP et al. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 1999;84: 761–767. Burgess JR, Shepherd JJ, Parameswaran V et al. Prolactinomas in a large kindred with multiple endocrine neoplasia Type 1: clinical features and inheritance pattern. J Clin Endocrinol Metab 1996;81:1841–1845. Burgess JR, Shepherd JJ, Parameswaran V et al. Spectrum of pituitary disease in multiple endocrine neoplasia Type 1 (MEN 1): Clinical, biochemical, and radiological features of pituitary disease in a large MEN 1 kindred. J Clin Endocrinol Metab 1996;81:2642–2646. Corbetta S, Pizzocaro A, Peracchi M et al. Multiple endocrine neoplasia type 1 in patients with recognized pituitary tumours of different types. Clin Endocrinol 1997;47:507–512. Anderson HO, Jorgensen PE, Bardram L, Hilsted L. Screening for multiple endocrine neoplasia type 1 in patients with recognized pituitary adenoma. Clin Endocrinol 1990;33:771–775. Scheithauer BW, Laws E, Kovacs K et al. Pituitary adenomas of the multiple endocrine neoplasia type 1 syndrome. Sem Diagnostic Pathol 1987;4:205–211.

Chapter 12 162 Berezin M, Karasik A. Familial prolactinoma. Clin Endocrinol 1995;42:483–486. 163 Robert F, Hardy J. Prolactin-secreting adenomas. A light and electron microscopical study. Arch Pathol 1975;99:625–633. 164 Martinez AJ, Lee A, Moossy J, Maroon JC. Pituitary adenomas: clinicopathological and immunohistochemical study. Ann Neurol 1980; 7:24–36. 165 Kameya T, Tsumuraya M, Adachi I et al. Ultrastructure, immunohistochemistry and hormone release of pituitary adenomas in relation to prolactin production. Virchows Arch A Path Anat Histol 1980;387:31–46. 166 Lloyd RV, Gikas PW, Chandler WF. Prolactin and growth hormone-producing pituitary adenomas. Am J Surg Pathol 1983;7:251–260. 167 Asa S. The pathology of pituitary adenomas. Endocrinol Metab Clin N Amer 1999;28:13–43. 168 Horvath E, Kovacs K. Misplaced exocytosis. Distinct ultrastructural feature in some pituitary adenomas. Arch Pathol 1974;97:221–224. 169 Dingemans KP, Assies J, Jansen N, Diegenbach PC. Sparsely granulated prolactin cell adenomas of the pituitary gland. Virchows Arch Pathol Anat 1982; 396:167–186. 170 Kovacs K. The morphology of abnormal lactotrophs. In: Mena F, Valverde-R C, eds. Prolactin secretion: A multidisciplinary approach. New York: Academic Press, 1984:353–369. 171 Guay AT, Freeman R, Rish BL et al. Calcified pituitary tumor with hyperprolactinemia: selective removal by transsphenoidal adenectomy. Fertil Steril 1978;29:585–588. 172 Mukada K, Ohta M, Uozumi T et al. Ossified prolactinoma: case report. Neurosurgery 1987;20:473–475. 173 Kuratsu JI, Matsukado Y, Miura M. Prolactinoma of pituitary with associated amyloid-like substances. J Neurosurg 1983;59:1067–1070. 174 Kubota T, Kuroda E, Yamashima T et al. Amyloid formation in prolactinoma. Arch Pathol Lab Med 1986;110:72–75. 175 Kalyanaraman UP, Halmi NS, Elwood PW. Prolactin-secreting pituitary oncocytoma with galactorrhea-amenorrhea syndrome. Cancer 1980;46: 1584–1589. 176 Pernicone PJ, Scheithauer BW, Sebo TJ et al. Pituitary carcinoma. Cancer 1997;79:804–812. 177 Kaltsas GA, Grossman AB. Malignant pituitary tumours. Pituitary 1998;1:6981. 178 Hurel SJ, Harris PE, McNicol AM et al. Metastatic prolactinoma: effect of octreotide, cabergoline, carboplatin and etoposide; immunocytochemical analysis of proto-oncogene expression. J Clin Endocrinol Metab 1997; 2962–2965. 179 Powers SK, Wilson CB. Simultaneously occurring prolactinomas. J Neurosurg 1981;55:124–126. 180 Woosley RE. Multiple secreting microadenomas as a possible cause of selective transsphenoidal adenomectomy failure. J Neurosurg 1983;58:267– 269. 181 Warner BA, Santen RJ, Page RB. Growth hormone and prolactin secretion by a tumor of the pharyngeal pituitary. Ann Intern Med 1982;96:65–67. 182 Horvath E, Kovacs K, Singer W et al. Acidophil stem cell adenoma of the human pituitary: clinicopathologic analysis of 15 cases. Cancer 1981;47: 761–771. 183 Cunningham GR, Huckins C. An FSH and prolactin-secreting pituitary tumor: pituitary dynamics and testicular histology. J Clin Endocrinol Metab 1977;44:248–253. 184 Duello TM, Halmi NS. Pituitary adenoma producing thyrotropin and prolactin. Virchows Arch Path Anat Histol 1977;376:255–265. 185 Martinez D, Barthe D. Heterogeneous pituitary adenomas. Virchows Arch Pathol Anat 1982;394:221–233. 186 Jaquet P, Hassoun J, Delori P et al. A human pituitary adenoma secreting thyrotropin and prolactin: immunohistochemical, biochemical, and cell culture studies. J Clin Endocrinol Metab 1984;59:817–824. 187 Yamaji T, Ishibashi M, Teramoto A, Fukushima T. Hyperprolactinemia in Cushing’s disease and Nelson’s syndrome. J Clin Endocrinol Metab 1984;58:790–795. 188 Spertini F, Deruaz JP, Perentes E et al. Luteinizing hormone (LH) and prolactin-releasing pituitary tumor: possible malignant transformation of the LH cell line. J Clin Endocrinol Metab 1986;62:849–854. 189 Meites J. Changes in neuroendocrine control of anterior pituitary function during aging. Neuroendocrinology 1982;34:151–156. 190 Sarkar DK, Gottschall PE, Meites J. Damage to hypothalamic dopaminergic neuron is associated with development of prolactin-secreting pituitary tumors. Science 1982;218:684–686. 191 Sarkar DK, Gottschall PE, Xie QW, Meites J. Reduced tuberoinfundibular

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dopaminergic neuronal function in rats with in situ prolactin-secreting pituitary tumors. Neuroendocrinology 1984;38:498–503. Reymond MJ. Age-related loss of the responsiveness of the tuberoinfundibular dopaminergic neurons to prolactin in the female rat. Neuroendocrinology 1990;59:490–496. Cronin MJ, Cheung CY, Weiner RI, Goldsmith PC. Mammotroph and gonadotroph volume percentage in the rat anterior pituitary after lesion of the medial basal hypothalamus. Neuroendocrinology 1982;34:140–147. McEuen CS, Selyle H, Collip JB. Some effects of prolonged administration of oestrin in rats. Lancet 1936;1:775–776. Clifton KH, Meyer RK. Mechanism of anterior pituitary tumor induction by estrogen. Anat Rec 1956;125:65–81. Clifton KH, Furth J. Changes in hormone sensitivity of pituitary mammotropes during progression from normal to autonomous. Cancer Res 1961;21:913–920. Bartke A, Doherty PC, Steger RW et al. Effects of estrogen-induced hyperprolactinemia on endocrine and sexual functions in adult male rats. Neuroendocrinology 1984;39:126–135. El-Azouzi M, Hsu DW, Black PM et al. The importance of dopamine in the pathogenesis of experimental prolactinomas. J Neurosurg 1990;72:273–281. Dunning WF, Curtis MR, Segaloff A. Strain differences in response to diethylstilbestrol and the induction of mammary gland and bladder cancer in the rat. Cancer Res 1947;7:511–521. Stone JP, Holtzman S, Shellabarger. Neoplastic responses and correlated plasma prolactin levels in diethylstilbestrol-treated ACI and Sprague–Dawley rats. Canc Res 1979;39:773–778. Wiklund J, Wertz N, Gorski J. A comparison of estrogen effects on uterine and pituitary growth and prolactin synthesis in F344 and Holtzman rats. Endocrinology 1981;109:1700–1707. Casanueva F, Cocchi D, Locatelli V et al. Defective central nervous system dopaminergic function in rats with estrogen-induced pituitary tumors, as assessed by plasma prolactin concentrations. Endocrinology 1982;110: 590–599. Demarest KT, Riegle GD, Moore KE. Long-term treatment with estradiol induces reversible alterations in tuberoinfundibular dopaminergic neurons: a decreased responsiveness to prolactin. Neuroendocrinology 1984;39:193–200. Cramer OM, Parker CR, Porter JC. Estrogen inhibition of dopamine release into hypophysial portal blood. Endocrinology 1979;104:419–422. Morgan WW, Steger RW, Smith MS et al. Time course of induction of prolactin-secreting pituitary tumors with diethylstilbestrol in male rats: response of tuberoinfundibular dopaminergic neurons. Endocrinology 1985;116:17–24. Malarkey WB, Groshong JC. Defective dopaminergic regulation of prolactin secretion in a rat pituitary tumour cell line. Nature 1977;266:640–641. Cronin MJ, Faure N, Martial JA, Weiner RI. Absence of high affinity dopamine receptors in GH3 cells: a prolactin-secreting clone resistant to the inhibitory action of dopamine. Endocrinology 1980;106:718–723. Cronin MJ, Valdenegro CA, Perkins SN, MacLeod RM. The 7315a pituitary tumor is refractory to dopaminergic inhibition of prolactin release but contains dopamine receptors. Endocrinology 1981;109:2160–2166. Cronin MJ, Keefer DA, Valdenegro CA et al. Prolactin secretion and dopamine receptors of the MtTW15 transplantable pituitary tumour. J Endocrinol 1982;94:347–358. Di Paolo T, Bernier MA. Estradiol and guanine nucleotide modulation of dopamine receptor agonist and antagonist binding sites in 7315a pituitary tumors. Biochem Pharmacol 1988;37:2373–2379. Bouvier C, Lagacé, Potier M, Collu R. Structural differences between dopamine D2 receptors present in a rat pituitary adenoma and in transplantable rat pituitary tumors 7315a and MtTW15. J Neurochem 1990;54:815–822. Collu R, Bouvier C et al. Selective deficiency of guanine nucleotide-binding protein G0 in two dopamine-resistant pituitary tumors. Endocrinology 1988;122:1176–1178. Biller BJ, Boyd AE III, Molitch ME et al. Galactorrhea syndromes. In: Post KD, Jackson IMD, Reichlin S, eds. The pituitary adenoma. New York: Plenum Press, 1980:65–90. Kemmann E, Jones JR. Hyperprolactinemia and headaches. Am J Obstet Gynecol 1983;145:668–671. Ciric I, Mikhael M, Stafford T et al. Transsphenoidal microsurgery of pituitary macroadenomas with long-term follow-up results. J Neurosurg 1983; 59:395–401. Melen O. Neuro-ophthalmologic features of pituitary tumors. Endocrinol Metab Clin N Amer 1987;16:585–608. King LW, Molitch ME, Gittinger JW Jr et al. Cavernous sinus syndrome due

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to prolactinoma: resolution with bromocriptine. Surg Neurol 1983;19: 280–284. Thomas JE, Yoss RE. The parasellar syndrome: problems in determining etiology. Mayo Clin Proc 1970;45:617–623. Clayton RN, Webb J, Heath DA et al. Dramatic and rapid shrinkage of a massive invasive prolactinoma with bromocriptine: a case report. Clin Endocrinol 1985;22:573–581. Molitch ME. Medical treatment of giant pituitary prolactinomas. In: Al-Mefty O, ed. Controversies in neurosurgery. New York: Theime Medical Publishers, 1996:2–10. Lundberg PO, Drettner B, Hemmingsson A et al. The invasive pituitary adenoma. Arch Neurol 1977;34:742–749. Guidetti B, Fraioli B, Cantore GP. Results of surgical management of 319 pituitary adenomas. Acta Neurochir 1987;85:117–124. Witrak GA, Zlonis MS, Larson DM. A fatal invasive prolactin-producing pituitary adenoma causing hypoglossal nerve paresis. Arch Pathol lab Med 1986;110:1188–1189. Murphy FY, Vesely DL, Jordan RM et al. Giant invasive prolactinomas. Am J Med 1987;83:995–1002. Davis JRE, Sheppard MC, Heath DA. Giant invasive prolactinoma: a case report and review of nine further cases. Quart J Med 1990;74(275): 227–238. Zikel OM, Atkinson JLD, Hurley DL. Prolactinoma manifesting with symptomatic hydrocephalus. Mayo Clin Proc 1999;74:475–477. Molitch ME, Elton RL, Blackwell RE et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 1985;60:698–705. Goodman RH, Molitch ME, Post KD et al. Prolactin secreting tumors in the male. In: Post KD, Jackson IMD, Reichlin S, eds. The pituitary adenoma. New York: Plenum Press, 1980:91–108. Pelkonen R, Grahne B, Hirvonen E et al. Pituitary function in prolactinoma. Effect of surgery and postoperative bromocriptine therapy. Clin Endocrinol 1981;14:335–348. Antunes JL, Housepian EM, Frantz AG et al. Prolactin-secreting pituitary tumors. Annals of Neurol 1977;2:148–153. Bevan JS, Adams CBT, Burke CW et al. Factors in the outcome of transsphenoidal surgery for prolactinoma and non-functioning pituitary tumour, including pre-operative bromocriptine therapy. Clin Endocrinol 1987;26:541–556. Grossman A, Cohen BL, Charlesworth M. Treatment of prolactinomas with megavoltage radiotherapy. Brit Med J 1984;288:1105–1109. Vance ML, Lipper M, Klibanski A et al. Treatment of prolactin-secreting pituitary macroadenomas with the long-acting non-ergot dopamine agonist CV 205–502. Ann Intern Med 1990;112:668–673. Wiebe RH, Kramer RS, Hammond CB. Surgical treatment of prolactinsecreting microadenomas. Am J Obstet Gynecol 1979;134:49–55. Rawe SE, Williamson HO, Levine JH et al. Prolactinomas: surgical therapy, indications and results. Surg Neurol 1980;14:161–167. Schlechte J, Sherman B, Halmi N et al. Prolactin-secreting pituitary tumors in amenorrheic women: a comprehensive study. Endocrine Rev 1980;1: 295–308. Smallridge RC, Martins AN. Transsphenoidal surgery for prolactin-secreting pituitary tumors. So Med J 1982;75:963–968. Nicola GC, Tonnarelli GP, Griner A. One hundred and ten prolactin secreting adenomas: results of surgical treatment. In: Faglia G, Giovanelli MA, MacLeod RM, eds. Pituitary microadenomas. New York: Academic Press, 1980:483–486. Woosley RE, King JS, Talbert L. Prolactin-secreting pituitary adenomas: neurosurgical management of 37 patients. Fertil Steril 1982;37:54–60. Thomson JA, Teasdale GM, Gordon D et al. Treatment of presumed prolactinoma by transsphenoidal operation: early and late results. Brit Med J 1985;291:1550–1553. Franks S, Nabarro JDN, Jacobs HS. Prevalence and presentation of hyperprolactinaemia in patients with “functionless” pituitary tumours. Lancet 1977;1:778–780. Maor Y, Berezin M. Hyperprolactinemia in postmenopausal women. Fertil Steril 1997;67:693–696. Carter JN, Tyson JE, Tolis G et al. Prolactin-secreting tumors and hypogonadism in 22 men. N Engl J Med 1978;299:847–852. Peillon F, Bard H, Mowszowicz I et al. Les adénomes à prolactine chez l’homme. Ann d’Endocrinologie 1979;40:73–74. Grisoli F, Vincentelli F, Jaquet P et al. Prolactin secreting adenoma in 22 men. Surg Neurol 1980;13:241–247. Spark RF, Wills CA, O’Reilly G et al. Hyperprolactinaemia in males with and without pituitary macroadenomas. Lancet 1982;2:129–188.

247 Prescott RWG, Johnston DG, Kendall-Taylor P et al. Hyperprolactinaemia in men–response to bromocriptine therapy. Lancet 1982;1:245–248. 248 Dupuy M, Derome PJ, Peillon F et al. Prolactinoma in man. Pre- and postoperative study in 80 cases. Sem Hôp Paris 1984;60:2943–2954. 249 Murray FT, Cameron DF, Ketchum C. Return of gonadal function in men with prolactin secreting pituitary tumors. J Clin Endocrinol Metab 1984; 59:79–85. 250 Hulting A-L, Muhr C, Lundberg PO, Werner S. Prolactinomas in men: clinical characteristics and the effect of bromocriptine treatment. Acta Med Scand 1985;217:101–109. 251 Berezin M, Shimon I, Hadani M. Prolactinoma in 53 men: clinical characteristics and modes of treatment (male prolactinoma). J Endocrinol Invest 1996;18:436–441. 252 Walsh JP, Pullan PT. Hyperprolactinemia in males: a heterogeneous disorder. Aust NZ J Med 1997;27:385–390. 253 Ramot Y, Rapoport MJ, Hagag P, Wysenbeek AJ. A study of the clinical differences between women and men with hyperprolactinemia. Gynecol Endocrinol 1996;10:397–400. 254 Calle-Rodriguez RDP, Giannini C, Scheithauer BW et al. Prolactinomas in male and female patients: a comparative clinicopathologic study. Mayo Clin Proc 1998;73:1046–1052. 255 Grisoli F, Guibout M, Jaquet P et al. Les adénomes à prolactine péripubertaires. 8 observations. Nouv Presse Méd 1978;7:1819–1825. 256 Fraioli B, Ferrante L, Celli P. Pituitary adenomas with onset during puberty. J Neurosurg 1983;59:590–595. 257 Howlett TA, Wass JAH, Grossman A et al. Prolactinomas presenting as primary amenorrhea and delayed or arrested puberty: response to medical therapy. Clin Endocrinol 1989;30:131–140. 258 Maira G, Anile C. Pituitary adenomas in childhood and adolescence. Can J Neurol Sci 1990;17:83–87. 259 Haddad SF, VanGilder JC, Menez AH. Pediatric pituitary tumors. Neurosurgery 1991;29:509–514. 260 Billaud L, Cousin I, Guilhaume B, Luton JP. Adénomes à prolactine développés pendant la puberté. Diagnostic et évolution à long terme. 9 observations. La Presse Méd 1993;22:299–303. 261 Dyer EH, Civit T, Visot A et al. Transsphenoidal surgery for pituitary adenomas in children. Neurosurgery 1994;34:207–212. 262 Partington MD, Davis DH, Laws ER Jr, Scheithauer BW. Pituitary adenomas in childhood and adolescence. Results of transsphenoidal surgery. J Neurosurg 1994;80:209–216. 263 Mindermann T, Wilson CB. Pediatric pituitary adenomas. Neurosurgery 1995;36:259–269. 264 Poussaint TY, Barnes PD, Anthony DC et al. Hemorrhagic pituitary adenomas of adolescence. Am J Neuroradiol 1996;17:1907–1912. 265 Artese R, D’Osvaldo DH, Molocznik I et al. Pituitary tumors in adolescent patients. Neurol Res 1998;20:415–417. 266 Colao AM, Loche S, Cappa M et al. Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up. J Clin Endocrinol Metab 1998;83:2777–2780. 267 Cowden EA, Ratcliffe JG, Thomson JA et al. Tests of prolactin secretion in diagnosis of prolactinomas. Lancet 1979;1:1155–1158. 268 Marrs RP, Bertolli SJ, Kletzky OA. The use of thyrotropin-releasing hormone in distinguishing prolactin-secreting pituitary adenoma. Am J Obstet Gynecol 1980;138:620–625. 269 Molitch ME, Reichlin S. Neuroendocrine studies of prolactin secretion in hyperprolactinemic states. In: Mena F, Valverde-Rodriguez C, eds. Prolactin secretion: A multidisciplinary approach. New York: Academic Press, 1984:393–421. 270 Vance ML, Thorner MO. Prolactinomas. Endocrinol Metab Clin N Amer 1987;16:731–753. 271 Lamberts SWJ, Birkenhäger JC, Kwa HG. Basal and TRH-stimulated prolactin in patients with pituitary tumours. Clin Endocrinol 1976;5:709–711. 272 Klijn JGM, Lamberts SWJ, DeJong FH, Birkenhäger. The value of the thyrotropin-releasing hormone test in patients with prolactin-secreting pituitary tumors and suprasellar non-pituitary tumors. Fertil Steril 1981;35:155–161. 273 Frantz AG. Endocrine diagnosis of prolactin-secreting pituitary tumors. In: Black PM, Zervas NT, Ridgway EC et al. eds. Secretory tumors of the pituitary gland. New York: Raven Press, 1984:45–52. 274 Prescott RWG, Johnston DG, Taylor PK, Haigh J. The inability of dynamic tests of prolactin and TSH secretion to differentiate between tumorous and non-tumorous hyperprolactinemia. J Endocrinol 1985;8:49–54. 275 Balagura S, Frantz AG, Housepian EM, Carmel PW. The specificity of serum prolactin as a diagnostic indicator of pituitary adenoma. J Neurosurg 1979;51:42–46.

Chapter 12 276 Albuquerque FC, Hinton DR, Weiss MH. Excessively high prolactin level in a patient with a nonprolactin-secreting adenoma. J Neurosurg 1998; 89:1043–1046. 277 Naidich MJ, Russell EJ. Current approaches to imaging of the sellar region and pituitary. Endocrinol Metab Clin N Amer 1999;28:45–79. 278 De Herder WW, Reijs AEM, Kwekkeboom DJ et al. In vivo imaging of pituitary tumours using a radiolabelled dopamine D2 receptor radioligand. Clin Endocrinol 1996;45:755–767. 279 Höfle G, Gasser R, Mohsenipour I, Finkenstedt G. Surgery combined with dopamine agonists versus dopamine agonists alone in long-term treatment of macroprolactinoma: a retrospective study. Exp Clin Endocrinol Diabetes 1998;106:211–216. 280 Sisam DA, Sheehan JP, Schumacher OP. Lack of demonstrable tumor growth in progressive hyperprolactinemia. Am J Med 1986;80:279–280. 281 Landolt AM. Surgical treatment of pituitary prolactinomas: postoperative prolactin and fertility in seventy patients. Fertil Steril 1981;35:620–625. 282 Fahlbusch R, Buchfelder M. Present status of neurosurgery in the treatment of prolactinomas. Neurosurg Rev 1985;8:195–205. 283 Brabant G, Brennecke I, Herrmann H et al. Hyperprolactinämie und Prolactinome. Dtsch Med Wschr 1985;110:1564–1567. 284 Scanlon MF, Peters JR, Thomas JP et al. Management of selected patients with hyperprolactinaemia by partial hypophysectomy. Brit Med J 1985;291: 1547–1550. 285 Soule SG, Farhi J, Conway GS et al. The outcome of hypophysectomy for prolactinomas in the era of dopamine agonist therapy. Clin Endocrinol 1996;44:711–716. 286 Zervas NT. Surgical results for pituitary adenomas: results of an international survey. In: Black P McL, Zervas NT, Ridgway EC, Martin JB, eds. Secretory tumors of the pituitary gland. New York: Raven Press, 1984;377–385. 287 Arafah BM, Manni A, Brodkey JS et al. Cure of hypogonadism after removal of prolactin secreting adenomas in men. J Clin Endocrinol Metab 1981;52:91–94. 288 Stevenaert A, Beckers A, Vandalem JL, Hennen G. Early normalization of luteinizing hormone pulsatility in women with microprolactinomas. J Clin Endocrinol Metab 1986;62:1044–1047. 289 Nelson AT Jr, Tucker HSG Jr, Becker DP. Residual anterior pituitary function following transsphenoidal resection of pituitary macroadenomas. J Neurosurg 1984;61:577–580. 290 Laws ER. Pituitary surgery. Endocrinol Metab Clin N Amer 1987;16:647–665. 291 Cohen AR, Cooper PR, Kupersmith MG et al. Visual recovery after transsphenoidal removal of pituitary adenomas. Neurosurgery 1985;17:446–452. 292 Barrow DL, Tindall GT. Loss of vision after transsphenoidal surgery. Neurosurgery 1990;27:60–68. 293 Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977;296:589–600. 294 Gomez F, Reyes FI, Faiman C. Nonpuerperal galactorrhea and hyperprolactinemia. Am J Med 1977;62:648–660. 295 De Schryver A, VandeKerckhove D, Debruyne G. Prolactin-secreting pituitary adenoma. Acta Radiol Oncol 1980;19:169–175. 296 Sheline GE, Grossman A, Jones AE, Besser GM. Radiation therapy for prolactinomas. In: Black P McL, Zervas NT, Ridgway EC, Martin JB, eds. Secretory tumors of the pituitary gland. New York: Raven Press, 1984:93–108. 297 Johnston DG, Hall K, Kendall-Taylor P et al. The long-term effects of megavoltage radiotherapy as sole or combined therapy for large prolactinomas: studies with high definition computerized tomography. Clin Endocrinol 1986;24:675–685. 298 Mehta AE, Reyes FI, Faiman C. Primary radiotherapy of prolactinomas. Am J Med 1987;83:49–58. 299 Wang C, Lam KSL, Ma JTC et al. Long-term treatment of hyperprolactinaemia with bromocriptine: effect of drug withdrawal. Clin Endocrinol 1987;27:363–371. 300 Tsagarakis S, Grossman A, Plowman PN et al. Megavoltage pituitary irradiation in the management of prolactinomas: long-term follow up. Clin Endocrinol 1991;34:399–406. 301 Wallace EA, Holdaway IM. Treatment of macroprolactinomas at Auckland Hospital 1975–1991. N Zealand Med J 1995;108:50–52. 302 Zierhut D, Flentje M, Adolph J et al. External radiotherapy of pituitary adenomas. Int J Radiation Oncol Biol Phys 1995;33A:307–314. 303 Tsang RW, Brierley JD, Panzarella T et al. Role of radiation therapy in clinical hormonally-active pituitary adenomas. Radiother Oncol 1996;41:45–53. 304 Brada M, Ford D, Ashley S et al. Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. Br Med J 1992;302:1343–1346. 305 Tsang RW, Laperriere NJ, Simpson WJ et al. Glioma arising after radiation

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360 Gasser RW, Holzner-Mueller E, Skrabal F et al. Macroprolactinomas and functionless pituitary tumours. Immunostaining and effect of dopamine agonist therapy. Acta Endocrinol 1987;116:253–259. 361 Fahlbusch R, Buchfelder M, Schrell U. Short-term preoperative treatment of macroprolactinomas by dopamine agonists. J Neurosurg 1987;67:807–815. 362 Bonneville JF, Poulignot D, Cattin F et al. Computed tomographic demonstration of the effects of bromocriptine on pituitary microadenoma size. Radiology 1982;143:451–455. 363 Demura R, Kubo O, Demura H et al. Changes in computed tomographic findings in microprolactinomas before and after bromocriptine. Acta Endocrinol 1985;110:308–312. 364 Thorner MO, Martin WH, Rogol AD et al. Rapid regression of pituitary prolactinomas during bromocriptine treatment. J Clin Endocrinol Metab 1980;51:438–445. 365 Dalzell GW, Atkinson AB, Carson DJ, Sheridan B. Normal growth and pubertal development during bromocriptine treatment for a prolactinsecreting pituitary macroadenoma. Clin Endocrinol 1987;169–172. 366 Bergström M, Muhr C, Lundberg PO et al. Rapid decrease in amino acid metabolism in prolactin-secreting pituitary adenomas after bromocriptine treatment: A PET study. J Comp Asst Tomography 1987;11:815–819. 367 Tindall GT, Kovacs K, Horvath E, Thorner MO. Human prolactin-producing adenomas and bromocriptine: a histological, immunocytochemical, ultrastructural, and morphometric study. J Clin Endocrinol Metab 1982;55:1178–1183. 368 Niwa J, Minase T, Mori M, Hashi K. Immunohistochemical, electron microscopic, and morphometric studies of human prolactinomas after shortterm bromocriptine treatment. Surg Neurol 1987;28:339–344. 369 Anniko M, Wersäll J. Clinical and morphological findings in two cases of bromocriptine-treated prolactinomas. Acta Path Microbiol Scand 1981;89:41–47. 370 Bassetti M, Spada A, Pezzo G, Giannattasic G. Bromocriptine treatment reduces the cell size in human macroprolactinomas: a morphometric study. J Clin Endocrinol Metab 1984;58:268–273. 371 Mori H, Mori S, Saitoh Y et al. Effects of bromocriptine on prolactinsecreting pituitary adenomas. Cancer 1985;56:230–238. 372 Landolt AM, Keller PJ, Froesch ER, Mueller J. Bromocriptine: does it jeopardise the result of later surgery for prolactinomas? Lancet 1982;2:657–658. 373 Landolt AM, Osterwalder V. Pervascular fibrosis in prolactinomas: is it increased by bromocriptine? J Clin Endocrinol Metab 1984;58:1179–1183. 374 Esiri MM, Bevan JS, Burke CW, Adams CBT. Effect of bromocriptine treatment on the fibrous tissue content of prolactin-secreting and nonfunctioning macroadenomas of the pituitary gland. J Clin Endocrinol Metab 1986;63:383–388. 375 Faglia G, Moriondo P, Travaglini P, Giovanelli MA. Influence of previous bromocriptine therapy on surgery for microprolactinoma. Lancet 1983;1: 133–134. 376 Fahlbusch R, Buchfelder M. Influence of preoperative bromocriptine therapy on success of surgery for microprolactinoma. Lancet 1984;2:519–520. 377 Hubbard JL, Bernd MD, Scheithauer W et al. Prolactin-secreting adenomas: the preoperative response to bromocriptine treatment and surgical outcome. J Neurosurg 1987;67:816–821. 378 Demonet JF, Rostin M, Dueymes JM et al. Retroperitoneal fibrosis and treatment of Parkinson’s disease with high doses of bromocriptine. Clin Neuropharmacol 1986;9:200–201. 379 Bowler JV, Ormerod IE, Legg NJ. Retropertioneal fibrosis and bromocriptine. Lancet 1986;2:466. 380 Johnston DG, Prescott RWG, Kendall-Taylor P et al. Hyperprolactinemia: long-term effects of bromocriptine. Am J Med 1983;75:868–874. 381 Ho KY, Smythe GA, Compton PJ, Lazarus L. Long-term bromocriptine therapy may restore the inhibitory control of prolactin release in some patients with pathological hyperprolactinemia. Aust NZ J Med 1985;15:213–219. 382 Soto-Albors CE, Randolph JF, Ying YK et al. Medical management of hyperprolactinemia: a lower dose of bromocriptine may be effective. Fertil Steril 1987;48:213–217. 383 Thorner MO, Perryman RL, Rogol AD et al. Rapid changes of prolactinoma volume after withdrawal and reinstitution of bromocriptine. J Clin Endocrinol Metab 1981;53:480–483. 384 Rasmussen C, Bergh T, Wide L. Prolactin secretion and menstrual function after long-term bromocriptine treatment. Fertil Steril 1987;48:550–554. 385 Jenkins PJ, Jain A, Jones SL et al. Oral prednisolone supplement abolishes the acute adverse effects following initiation of depot bromocriptine therapy. Clin Endocrinol 1996;45:447–451. 386 Turner TH, Cookson JC, Wass JAH et al. Psychotic reactions during

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treatment of pituitary tumours with dopamine agonists. Brit Med J 1984;289:1101–1103. Le Feuvre CM, Isaacs AJ, Frank OS. Bromocriptine-induced psychosis in acromegaly. Brit Med J 1982;285:1315. Procter AW, Littlewood R, Fry AH. Bromocriptine induced psychosis in acromegaly. Brit Med J 1983;286:50–51. Afshar F, Thomas A. Bromocriptine-induced cerebrospinal fluid rhinorrhea. Surg Neurology 1982;18:61–63. Kok JG, Bartelink AKM, Schulte BPM et al. Cerebrospinal fluid rhinorrhea during treatment with bromocriptine for prolactinoma. Neurology 1985;35:1193–1195. Dallabonzana D, Spelta B, Oppizzi G et al. Reenlargement of macroprolactinomas during bromocriptine treatment: report of two cases. J Endocrinol Invest 1983;6:47–50. Crosignani PG, Mattei A, Ferrari C, Giovanelli MA. Enlargement of a prolactin-secreting pituitary microadenoma during bromocriptine treatment. Brit J Obstet Gynecol 1982;89:169–170. Delgrange E, Crabbé J, Donckier J. Late development of resistance to bromocriptine in a patient with macroprolactinoma. Horm Res 1998;49:250–253. Pellegrini I, Rasolonjanahary R, Gunz G et al. Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab 1989;69:500–509. Caccavelli L, Feron F, Morange I et al. Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinol 1994;60:314–322. Nagasaka T, Nakashima N, Furui A et al. Sarcomatous transformation of pituitary adenoma after bromocriptine therapy. Human Pathol 1998;29:190–193. McElvaney NG, Wilcox PG, Churg A, Fleetham JA. Pleuropulmonary disease during bromocriptine treatment of Parkinson’s disease. Arch Intern Med 1988;148:2231–2236. Vermesh M, Fossum GT, Kletzky OA. Vaginal bromocriptine: pharmacology and effect on serum prolactin in normal women. Obstet Gynecol 1988;72: 693–698. Katz E, Schran HF, Adashi EY. Successful treatment of a prolactin-producing pituitary macroadenoma with intravaginal bromocriptine mesylate: a novel approach to intolerance of oral therapy. Obstet Gynecol 1989;73:517–520. Montini M, Pagani G, Gianola D et al. Long-lasting suppression of prolactin secretion and rapid shrinkage of prolactinomas after a long-acting, injectable form of bromocriptine. J Clin Endocrinol Metab 1986;63:266–268. Van’t Verlaat JW, Lancranjan I, Hendriks MJ, Croughs RJM. Primary treatment of macroprolactinomas with Parlodel LAR. Acta Endocrinol 1988;199:51–55. Ciccarelli E, Miola C, Avataneo T et al. Long-term treatment with a new repeatable injectable form of bromocriptine, Parlodel LAR, in patients with tumourous hyperprolactinemia. Fertil Steril 1989;52:930–935. Kocijancic A, Prezelj J, Vrhovec I, Lancranjan I. Parlodel LAR in the treatment of macroprolactinomas. Acta Endocrinol 1990;122:272–276. Tsagarakis S, Tsiganou E, Tzavara I et al. Effectiveness of a long-acting injectable form of bromocriptine in patients with prolactin and growth hormone secreting macroadenomas. Clin Endocrinol 1995;42:593–599. Colao AM, Merola B, Srnacchiaro F et al. Comparison among different dopamine-agonists of new formulation in the clinical management of macroprolactinomas. Horm Res 1995;44:222–228. Lemberger L, Crabtree R, Callaghan JT. Pergolide, a potent long-acting dopamine-receptor agonist. Clin Pharmacol Ther 1980;27:642–651. Franks S, Lynch SS, Horrocks PM, Butt WR. Treatment of hyperprolactinaemia with pergolide mesylate: acute effects and preliminary evaluation of long-term treatment. Lancet 1981;2:659–661. Blackwell RE, Bradley EL, Kline LB et al. Comparison of dopamine agonists in the treatment of hyperprolactinemic syndromes: a multicenter study. Fertil Steril 1983;39:744–748. Kendall-Taylor P, Hall K, Johnston DG, Prescott RWG. Reduction in size of prolactin-secreting tumours in men treated with pergolide. Brit Med J 1982;285:465–467. Kleinberg DL, Boyd AE III, Wardlaw S et al. Pergolide for the treatment of pituitary tumors secreting prolactin or growth hormone. N Engl J Med 1983;309:704–709. Grossman A, Bouloux P-MG, Loneragan R et al. Comparison of the clinical activity of mesulergine and pergolide in the treatment of hyperprolactinaemia. Clin Endocrinol 1985;22:611–616. Kletzky OA, Borenstein R, Mileikowsky GN. Pergolide and bromocriptine for the treatment of patients with hyperprolactinemia. Am J Obstet Gynecol 1986;154:431–435.

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413 Ahmed SR, Shalet SM. Discordant responses of prolactinoma to two different dopamine agonists. Clin Endocrinol 1986;244:421–426. 414 Lamberts SW, Quik RF. A comparison of the efficacy and safety of pergolide and bromocriptine in the treatment of hyperprolactinemia. J Clin Endocrinol Metab 1991;72:635–641. 414a Freda PU, Andreadis CI, Khandj, AG et al. Long-term treatment of prolactin-secreting macroadenomas with pergolide. J Clin Endocrinol Metab 2000;85:8–13. 415 Vance ML, Cragun JR, Reimnitz C et al. CV 205–502 treatment of hyperprolactinemia. J Clin Endocrinol Metab 1989;68:336–339. 416 Van der Lely AJ, Brownell J, Lamberts SWJ. The efficacy and tolerability of CV 205–502 (a nonergot dopaminergic drug) in macroprolactinoma patients and in prolactinoma patients intolerant to bromocriptine. J Clin Endocrinol Metab 1991;72:1136–1141. 417 Duranteau L, Chanson P, Lavoinne A et al. Effect of the new dopaminergic agonist CV 205–502 on plasma prolactin levels and tumour size in bromocriptine-resistant prolactinomas. Clin Endocrinol 1991;34:25–29. 418 Brue T, Pellegrini I, Gunz G et al. Effects of the dopamine agonist CV 205–502 in human prolactinomas resistant to bromocriptine. J Clin Endocrinol Metab 1992;74:577–584. 419 Glaser B, Nesher Y, Barziliai S. Long-term treatment of bromocriptineintolerant prolactinoma patients with CV 205–502. J Reprod Med 1994;39:451–454. 420 Merola B, Sarnacchiaro F, Colao A et al. Positive response to compound CV 205–502 in hyperprolactinemic patients resistant to or intolerant of bromocriptine. Gynecol Endocrinol 1994;8:175–181. 421 Morange I, Barlier A, Pellegrini I et al. Prolactinomas resistant to bromocriptine: long-term efficacy of quinagolide and outcome of pregnancy. Eur J Endocrinol 1996;135:413–420. 422 Colao AM, DeRosa M, Sarnachhiaro F et al. Chronic treatment with CV 205–502 restores the gonadal function of hyperprolactinemic males. Eur J Endocrinol 1996;135:548–552. 423 Van’t Verlaat JW, Croughs RJM, Brownell J. Treatment of macroprolactinomas with a new non-ergot, long-acting dopaminergic drug, CV 205–502. Clin Endocrinol 1990;33:619–624. 424 Serri O, Beauregard H, Lesage J et al. Long term treatment with CV 205–502 in patients with prolactin-secreting pituitary macroadenomas. J Clin Endocrinol Metab 1990;71:682–687. 425 Khalfallah Y, Claustrat B, Grochowicki M et al. Effects of a new prolactin inhibitory, CV 205–502, in the treatment of human macroprolactinomas. J Clin Endocrinol Metab 1990;71:354–349. 426 Barnett PS, Palazidou E, Miell JP et al. Endocrine function, psychiatric and clinical consequences in patients with macroprolactinomas after long-term treatment with the new non-ergot dopamine agonist CV 205–502. Quart J Med 1991;81:891–906. 427 Svoboda T, Luger A, Knosp E, Geyer G. Prolactinom-behandlung mit einem neuen dopaminagonisten. Dtsch Med Wchr 1991;116:1224–1227. 428 Crottaz B, Uske A, Reymond MJ et al. CV 205–502 treatment of macroprolactinomas. J Endocrinol Invest 1991;14:757–762. 429 Kvistborg A, Halse J, Bakke S et al. Long-term treatment of macroprolactinomas with CV 205–502. Acta Endocrinol 1993;128:301–307. 430 DiSalle E, Ornati G, Giudici D. A comparison of the in vivo and in vitro duration of prolactin lowering effect in rats of FCE 21336, pergolide and bromocriptine. J Endocrinol Invest 1984;7(Suppl 1):32. 431 Strolin BM, Doster P, Barone D et al. In vivo interaction of CAB with rat brain dopamine receptors labelled with 3H-N-n-propylinorapomorphine. Eur J Pharmacol 1990;187:399–408. 432 Andreotti AC, Pianezzola E, Persiani S et al. Pharmacokinetics, pharmacodynamics, and tolerability of cabergoline, a prolactin-lowering drug after administration of increasing oral doses (0.5, 1.0, and 1.5 milligrams) in healthy male volunteers. J Clin Endocrinol Metab 1995;80:841. 433 Ferrari C, Barbieri C, Caldara R et al. Long-lasting prolactin-lowering effect of cabergoline, a new dopamine agonist, in hyperprolactinemic patients. J Clin Endocrinol Metab 1986;63:941–945. 434 Melis GB, Gambacciani M, Paoletti AM et al. Dose-related prolactin inhibitory effect of the new long-acting dopamine receptor agonist cabergoline in normal cycling, puerperal, and hyperprolactinemic women. J Clin Endocrinol Metab 1987;65:541–545. 435 Ciccarelli E, Gayest M, Miola C et al. Effectiveness and tolerability of long term treatment with cabergoline, a new long-lasting ergoline derivative, in hyperprolactinemic patients. J Clin Endocrinol 1989;69:725–728. 436 Ferrari C, Mattei A, Melis GB et al. Cabergoline: long-acting oral treatment of hyperprolactinemic disorders. J Clin Endocrinol Metab 1989;68:1201– 1206.

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Pituitary Tumors

437 Ferrari C, Paracchi A, Mattei AM et al. Cabergoline in the long-term therapy of hyperprolactinemic disorders. Acta Endocrinol 1992;126:489–494. 438 Webster J, Piscitelli G, Polli A et al. The efficacy and tolerability of long-term cabergoline therapy in hyperprolactinaemic disorders: an open, uncontrolled, multicentre study. European Multicentre Cabergoline Study Group. N Engl J Med 1994;331:904–909. 439 DeRosa M, Colao A, DiSarno A et al. Cabergoline treatment rapidly improves gonadal function in hyperprolactinemic males: a comparison with bromocriptine. Eur J Endocrinol 1998;138:286–293. 440 Motta T, Colombo N, de Vincentiis S et al. Vaginal cabergoline in the treatment of hyperprolactinemic patients intolerant to oral dopaminergics. Fertil Steril 1996;65:440–442. 441 Biller BMK, Molitch ME, Vance ML et al. Treatment of prolactin-secreting macroadenomas with the once-weekly dopamine agonist cabergoline. J Clin Endocrinol Metab 1996;81:2338–2343. 442 Delgrange E, Maiter D, Donckier J. Effects of the dopamine agonist cabergoline in patients with prolactinoma intolerant or resistant to bromocriptine. Eur J Endocrinol 1996;134:454–456. 443 Motta T, Maggi G, D’Alberton A et al. Twice weekly cabergoline treatment of macroprolactinoma. J Obstet Gynecol 1989;9:334–335. 444 Page SR, Nussey SS. Cabergoline therapy of a large prolactinoma in a bromocriptine-intolerant patient. J Obstet Gynecol 1989;10:156–158. 445 Melis GB, Mais V, Gambacciani M et al. Reduction in the size of prolactinproducing pituitary tumor after cabergoline administration. Fertil Steril 1989;52:412–415. 446 Colao A, DeSarno A, Landi ML et al. Long-term and low-dose treatment with cabergoline induces macroprolactinoma shrinkage. J Clin Endocrinol Metab 1997;82:3574–3579. 447 Ferrari CI, Abs R, Bevan JS et al. Treatment of macroprolactinoma with cabergoline: a study of 85 patients. Clin Endocrinol 1997;46:409–413. 447a Verhelst J, Abs R, Maiter D et al. Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab 1999;84:2518–2522. 448 Colao A, DiSarno A, Sarnacchiaro S et al. Prolactinomas resistant to standard dopamine-agonists respond to chronic cabergoline treatment. J Clin Endocrinol Metab 1997;82:876–883. 449 Thorner MO, Ryan SM, Wass JAH et al. Effect of the dopamine agonist, lergotrile mesylate, on circulating anterior pituitary hormones in man. J Clin Endocrinol Metab 1978;47:372–378. 450 Crosignani PG, Ferrari C, Liuzzi A et al. Treatment of hyperprolactinemic states with different drugs: a study with bromocriptine, metergoline, and lisuride. Fertil Steril 1982;37:61–67. 451 Hesla JS, Rodman EF, Molitch ME et al. The effect of the ergoline derivative, CU 32–085, on prolactin secretion in hyperprolactinemic women. Fertil Steril 1987;48:555–559. 452 Scarduelli C, Cavioni V, Galparoli C et al. Clinical use of an antiprolactinaemic drug: dihydroergocristine. J Obstet Gynecol 1987;7:225–227. 453 Faglia G, Conti A, Muratori M et al. Dihydroergocriptine in management of microprolactinomas. J Clin Endocrinol Metab 1987;65:779–784. 454 Tamura T, Satoh T, Minakami H, Tamada T. Effect of hydergine in hyperprolactinemia. J Clin Endocrinol Metab 1989;69:470–474. 455 Venturini PL, Horowski R, Valenzano M et al. Effect of terguride on prolactin levels in normal, puerperal and hyperprolactinaemic women. Eur J Clin Pharmacol 1986;30:195–197. 456 Hanssen LE, Brownell J, Halse J et al. CQP 201–403 a new dopamine agonist in the treatment of hyperprolactinemia. Acta Endocrinol 1988;117;552–556. 457 Krupp P, Monka C. Bromocriptine in pregnancy: safety aspects. Klin Wochenschr 1987;65:823–827. 458 Krupp P, Monka C, Richter K. The safety aspects of infertility treatments. Program of the Second World Congress of Gynecology and Obstetrics, Rio de Janeiro, October, 1988. 459 Raymond JP, Goldstein E, Konopka P et al. Follow-up of children born of bromocriptine-treated mothers. Hormone Res 1985;22:239–246. 460 Konopka P, Raymond JP, Merceron RE, Seneze J. Continuous administration of bromocriptine in the prevention of neurological complications in pregnant women with prolactinomas. Am J Obstet Gynecol 1983;146:935–938. 461 Canales ES, García IC, Ruíz JE, Zàrate A. Bromocriptine as prophylactic therapy in prolactinoma during pregnancy. Fertil Steril 1981;36:524–526. 462 Ruiz-Velasco V, Tolis G. Pregnancy in hyperprolactinemic women. Fertil Steril 1984;41:793–805. 463 Robert E, Musatti L, Piscitelli G, Ferrari CI. Pregnancy outcome after treatment with the ergot derivative, cabergoline. Reprod Toxicol 1996;10:333–337.

464 Pharmacia and Upjohn, Inc: Data on File, October, 1997. 465 Elster AD, Sanders TG, Vines FS, Chen MYM. Size and shape of the pituitary gland during pregnancy and post partum: measurement with MRI imaging. Radiology 1991;181:531–535. 466 Dinç H, Esen F, Demirci A et al. Pituitary dimensions and volume measurements in pregnancy and post partum. Acta Radiologica 1998;39:64–69. 467 Pichon MF, Bression D, Peillon F, Milgrom E. Estrogen receptors in human pituitary adenomas. J Clin Endocrinol Metab 1980;51:897–902. 468 Radwanska E, McGarrigle HHG, Little V et al. Induction of ovulation in women with hyperprolactinemic amenorrhea using clomiphene and human chorionic gonadotropin or bromocriptine. Fertil Steril 1979;32:187–192. 469 Kajtar T, Tomkin GH. Emergency hypophysectomy in pregnancy after induction of ovulation. Br Med J 1971;4:88–90. 470 Swyer GIM, Little V, Harries BJ. Visual disturbance in pregnancy after induction of ovulation. Br Med J 1971;4:90–91. 471 Falconer MA, Stafford-Bell MA. Visual failure from pituitary and parasellar tumours occurring with favourable outcome in pregnant women. J Neurol Neurosurg Psychiatry 1975;38:919–930. 472 Lamberts SWJ, Seldenrath HJ, Kwa HG, Birkenhäger JC. Transient bitemporal hemianopsia during pregnancy after treatment of galactorrheaamenorrhea syndrome with bromocriptine. J Clin Endocrinol Metab 1977; 44:180–184. 473 Corbey RS, Crysberg JRM, Rolland R. Visual abnormalities in a pregnancy following bromocriptine medication. Obstet Gynecol 1977;50:69–71. 474 Jewelewicz R, Zimmerman EA, Carmel PW. Conservative management of a pituitary tumor during pregnancy following induction of ovulation with gonadotropins. Fertil Steril 1977;28:35–40. 475 Burry KA, Schiller HS, Mills R et al. Acute visual loss during pregnancy after bromocriptine-induced ovulation. Obstet Gynecol 1978;52:19–22. 476 Nelson PB, Robinson AG, Archer DF, Maroon JG. Symptomatic pituitary tumor enlargement after induced pregnancy. J Neurosurg 1978;49:283–287. 477 Gemzell C, Wang CF. Outcome of pregnancy in women with pituitary adenoma. Fertil Steril 1979;31:363–372. 478 Griffith RW, Turkalj I, Braun P. Pituitary tumours during pregnancy in mothers treated with bromocriptine. Br J Clin Pharmacol 1979;7:393–396. 479 Molitch ME. Pregnancy and the hyperprolactinemic woman. N Engl J Med 1985;312:1365–1370. 480 Kupersmith MJ, Rosenberg C, Kleinberg D. Visual loss in pregnant women with pituitary adenomas. Ann Intern Med 1994;121:473–477. 481 Rossi A-M, Vilska S, Heinonen PK. Outcome of pregnancies in women with treated or untreated hyperprolactinemia. Eur J Obstet Gynecol Reprod Biol 1995;63:143–146. 481a Musolino NRC Bronstein MD. Prolactinomas and pregnancy. In: Bronstein M, ed. Pituitary Tumors in Pregnancy. Boston, Kluwer 2001:91–108. 482 Bergh T, Nillius SJ, Wide L. Clinical course and outcome of pregnancies in amenorrhoeic women with hyperprolactinaemia and pituitary tumours. Br Med J 1978;1:875–880. 483 Thorner MO, Edwards CRW, Charlesworth M et al. Pregnancy in patients presenting with hyperprolactinaemia. Br Med J 1979;2:771–774. 484 Van Roon E, van der Vijver JCM, Gerretsen G et al. Rapid regression of a suprasellar extending prolactinoma after bromocriptine treatment during pregnancy. Fertil Steril 1981;36:173–177. 485 Maeda T, Ushiroyama T, Okuda K et al. Effective bromocriptine treatment of a pituitary macroadenoma during pregnancy. Obstet Gynecol 1983;61:117–121. 486 Crosignani P, Ferrari C, Mattei AM. Visual field defects and reduced visual acuity during pregnancy in two patients with prolactinoma: rapid regression of symptoms under bromocriptine. Case reports. Br J Obstet Gynecol 1984;91: 821–823. 487 Belchetz PE, Carty A, Clearkin LG et al. Failure of prophylactic surgery to avert massive pituitary expansion in pregnancy. Clin Endocrinol 1986;25: 325–330. 488 Modena G, Portioli I. Delivery after bromocriptine therapy. Lancet 1977; 2:558. 489 Espersen T, Ditzel J. Pregnancy and delivery under bromocriptine therapy. Lancet 1977;2:985–986. 490 Yuen BH. Bromocriptine, pituitary tumours, and pregnancy. Lancet 1978;2:1314. 491 Bigazzi M, Ronga R, Lancranjan I et al. A pregnancy in an acromegalic woman during bromocriptine treatment: effects on growth hormone and prolactin in the maternal, fetal, and amniotic compartments. J Clin Endocrinol Metab 1979;48:9–12. 492 Ylikorkala O, Kivinen S, Rönnberg L. Bromocriptine treatment during early human pregnancy: effect on the levels of prolactin, sex steroids and placenta lactogen. Acta Endocrinol 1980;95:412–415.

Chapter 12 493 Lehmann WD, Musch K, Wolf AS. Influence of bromocriptine on plasma levels of prolactin and steroid hormones in the twentieth week of pregnancy. J Endocrinol Invest 1979;2:251–255. 494 Crosignani PG, Mattei AM, Scraduelli C et al. Is pregnancy the best treatment for hyperprolactinaemia? Human Reprod 1989;4:910–912. 495 Samaan NA, Schultz PN, Leavens TA et al. Pregnancy after treatment in patients with prolactinoma: operation versus bromocriptine. Am J Obstet Gynecol 1986;155:1300–1305. 496 Ikegami H, Aono T, Koizumi K et al. Relationship between the methods of treatment for prolactinomas and the puerperal lactation. Fertil Steril 1987;47:867–869. 497 Laws ER, Fode NC, Randall RV et al. Pregnancy following transsphenoidal resection of prolactin-secreting pituitary tumors. J Neurosurg 1983;58: 685–688. 498 McGarrigle HHG, Sarris S, Little V et al. Induction of ovulation with clomiphene and human chorionic gonadotrophin in women with hyperprolactinaemic amenorrhoea. Br J Obstet Gynecol 1978;85:692–697.

Prolactinoma

495

499 Radwanska E, McGarrigle HHG, Little V et al. Induction of ovulation in women with hyperprolactinemic amenorrhea using clomiphene and human chorionic gonadotropin of bromocriptine. Fertil Steril 1979;32:187–192. 500 Bergh T, Skarin G, Nillius SJ, Wide L. Pulsatile GnRH therapy—an alternative successful therapy for induction of ovulation in infertile normoand hyperprolactinaemic amenorrhoeic women with pituitary tumours. Acta Endocrinol 1985;110:440–444. 501 Gindoff PR, Loucopoulos A, Jewelewicz R. Treatment of hyperprolactinemic amenorrhea with pulsatile gonadotropin-releasing hormone therapy. Fertil Steril 1986;46:1156–1158. 502 Narita O, Kimura T, Suganuma N et al. Relationship between maternal prolactin levels during pregnancy and lactation in women with pituitary adenoma. Acta Obst Gynael Jpn 1985;37:758–762. 503 Divers WA Jr, Yen SSC. Prolactin-producing microadenomas in pregnancy. Obstet Gynecol 1983;61:425–429. 504 Brodsky JB, Cohen EN, Brown BW Jr et al. Surgery during pregnancy and fetal outcome. Am J Obstet Gynecol 1980;138:1165–1167.

C h a p t e r

13 Cushing’s Disease Xavier Bertagna Marie-Charles Raux-Demay François Girard

Jean-Pierre Luton

PATHOPHYSIOLOGY Cushing’s syndrome refers to the manifestations of chronic glucocorticoid excess and may result from various causes (Table 13.1). In Cushing’s disease pituitary adrenocorticotropic hormone (ACTH) oversecretion induces bilateral adrenocortical hyperplasia and excess production of cortisol, adrenal androgens, and 11-deoxycorticosterone which together provoke the clinical and biologic features of the disease.

EPIDEMIOLOGY Cushing’s disease is the most frequent cause of spontaneous Cushing’s syndrome in adults. In most series its prevalence is approximately 70% with a definite female preponderance, the female/male ratio ranging between 3 : 1 and 10 : 1 [1–4]. In our series of 809 adult patients with spontaneous Cushing’s syndromes, Cushing’s disease accounts for 68% of the cases, and the female/male ratio is 2.8 (Table 13.2). Distribution of the age at diagnosis shows a peak in adult females in the 25–45-year range (Fig. 13.1). In children, the causes of Cushing’s syndrome have a different distribution. Primary adrenocortical tumors are more frequent and Cushing’s disease accounts for about 30% of the cases. Children with this condition are usually older than 9 with an equal sex ratio [5–7]. Cushing’s disease is rare; its true incidence which varies with age and sex is difficult to evaluate. Incidence data are available on pituitary [8,9] and adrenocortical [10,11] tumors. The prevalence of corticotroph tumors in the former [12] and that of Cushing’s syndrome in the latter [13–15] provide an indirect means whereby the incidence of Cushing’s disease may be roughly estimated to be in the range of 0.1 to 1 new cases per 100,000 per year. 496

Brigitte Guilhaume

CHRONIC ACTH AND PROOPIOMELANOCORTIN (POMC) PEPTIDES OVERSECRETION BY THE PITUITARY

Normal Synthesis and Secretion of ACTH Mechanisms of ACTH Biosynthesis

The mechanisms of ACTH biosynthesis have been fully elucidated in the last 15 years: a high-molecular-weight ACTH-precursor molecule was identified and characterized in the ACTH-producing AtT-20/D16-v mouse tumor cell line [16]. Recombinant DNA methods unravelled the primary structure of this precursor [17]—called POMC— in many species including humans [18–20]. This is fully described in Chapter 2. The overall mechanism of POMC gene expression in man is shown schematically in Figure 13.2: a single POMC gene per haploid genome is present on the distal region (2p23–25) of the short arm of chromosome 2 [21,22]; it consists of three exons, the coding regions (in black) being present only on exons 2 and 3; after the splicing of the primary transcript a mature messenger RNA (mRNA) of 1072 nucleotides (nt) is generated and a poly (A)+ tail of about 200 nt is added. A pre-POMC molecule is first translated starting with a 26-amino acid signal peptide necessary for the translocation of the nascent protein through the membrane of the rough endoplasmic reticulum. Within the Golgi apparatus and the secretory granule the POMC molecule undergoes a series of proteolytic cleavages and chemical transformations which together result in the maturation or processing of the precursor [23]: proteolysis occurs at pairs of basic amino acids. Among the nine potential cleavage sites of the human POMC only four are utilized in the anterior pituitary, generating the N-terminal fragment [24,25] the joining peptide [26–28], ACTH [29–31], b-lipotropin (b-LPH), and a small amount of

Chapter 13 Table 13.1.

Cushing’s Disease

497

Causes of Cushing’s syndrome

Spontaneous ACTH-dependent Pituitary ACTH oversecretion Cushing’s disease Primary corticotroph Anterior pituitary adenoma Anterior pituitary mixed adenoma Anterior pituitary cancer Ectopic corticotroph adenoma Multiple endocrine neoplasia type 1 Intermediate lobe pituitary adenoma? Primary hypothalamic dysfunction CRH-producing tumors Hypothalamic CRH-producing tumor Ectopic CRH-producing tumor Nonpituitary ACTH oversecretion Ectopic ACTH syndrome Endocrine tumors Mononuclear cells Cortisol hyperreactive syndrome?

FIGURE 13.1. Cushing’s disease.

Patient age at the time of diagnosis of

ACTH-independent (adrenal Cushing’s syndrome) Unilateral adrenocortical tumors Adrenocortical adenoma Adrenocortical carcinoma Bilateral adrenocortical disorders Primary pigmented nodular adrenal disease ACTH-independent macronodular adrenal hyperplasia (AI-MAH) Gonadal tumors Iatrogenic Exogenous glucocorticoids Exogenous Cortrosyn CRH, corticotropin-releasing hormone.

Table 13.2. Etiology of 809 spontaneous Cushing’s syndromes in adults

Cushing’s disease Primary adrenocortical tumor Benign adrenocortical adenoma Adrenocortical carcinoma Ectopic ACTH syndrome Primary adrenocortical nodular dysplasia

Number of patients (%)

Female/male ratio

550 (68) 199 (25) 111 (14) 88 (11) 58 (7) 2 (0.2)

2.8 4.2 0.5 3.6 1.4 –

g-LPH and b-endorphin (b-end) [31,32]. Other chemical transformations include glycosylation of the N-terminal fragment [33], C-terminal amidation of the joining peptide [27,28,34,35], and partial phosphorylation of ACTH on Ser31 [36,37]. An alternate mode of nonprimate POMC processing takes place in the intermediate lobe of the pituitary releasing smaller peptides such as b-melanocyte

FIGURE 13.2. Schematic view of the human proopiomelanocortin (POMC) gene expression. Black bars denote the protein coding regions of the DNA and messenger RNA (mRNA). Hatched bars denote the peptide fragments found in the human anterior pituitary.

stimulating hormone (b-MSH), corticotrophin-like intermediate lobe peptide (CLIP), and a-MSH [38,39]. It does not normally occur in the human pituitary where the intermediate lobe is only fully present in the fetus [40].

498

SECTION 3

Pituitary Tumors

POMC gene expression also occurs in many normal nonpituitary tissues [41,42]; it does so at a very low level and predominantly through an alternate mode of gene transcription [43–45], generating negligible amounts of POMC peptide [46–48]. It is assumed that the highly predominant if not the sole source of circulating ACTH and POMC peptides in humans, under normal circumstances, is the anterior pituitary corticotroph cell. The coordinate proteolysis of POMC and the equimolar secretion of the various POMC peptides has two implications: any of the non-ACTH POMC peptides can be assayed in blood as an alternate marker of the overall pituitary corticotroph activity; a specific pattern of POMC peptides is associated with the pituitary corticotroph, and any qualitative abnormality suggests a pathologic nonpituitary source [49–51]. Regulation of ACTH Secretion

The normal circadian rhythm of plasma cortisol is directly driven by the pituitary corticotroph activity [52–54]. Its pattern is derived by variations in the number and amplitude of episodic ACTH bursts [55,56]. Pituitary corticotroph activity increases in the second half of the night, around 2–4 a.m., peaks at waking-up, and gradually falls during the morning [57]. Various physical and psychologic stresses can interrupt this normal rhythm, at any time, with an acute ACTH rise. Both the normal circadian rhythm and the stress-induced changes are central nervous system (CNS) mediated under the primary—although not exclusive— control of hypothalamic corticotropin-releasing hormone (CRH) [58]. CRH [59] acts directly on the corticotroph cell through specific receptors that activate the adenylyl cyclase and increase intracellular cyclic adenosine monophosphate (cAMP) formation [60,61]. Arginine vasopressin (AVP), through its own specific V1 type receptors, also acts on the corticotroph cell to activate the phospholipase C leading to increased phosphoinositides turnover, Ca2+ release, and protein kinase C activation [62]. The action of AVP potentiates that of CRH [63] by further increasing cAMP formation [64–66]: crosstalk between the two transducing systems provides the synergistic action that promotes the maximal ACTH response by increasing both POMC gene transcription and secretory granule exocytosis [67–69]. This phenomenon, thoroughly studied in vitro on animal models, is also observed in humans: the simultaneous administration of CRH and AVP (or its analog lysine vasopressin, LVP) induces a maximal ACTH rise, higher than that obtained by either secretagog alone or their sum [70–72]. Glucocorticoids exert a negative feedback on pituitary ACTH [73]. In patients with primary adrenal deficiency, basal and stimulated ACTH are increased. On the other hand, excess glucocorticoid administration or secretion by a primary adrenocortical tumor inhibit basal and stimulated ACTH. Prolonged glucocorticoid suppression of the hypothalamic–corticotroph axis characteristically induces long-

lasting unresponsiveness, which may extend for months or years after the source of excess glucocorticoid has been withdrawn. Glucocorticoids inhibit hypothalamic CRH production [74] and also act directly at the corticotroph cell as demonstrated in various animal models. They inhibit basal and stimulated ACTH release [75,76], as well as POMC gene transcription in a dose-dependent manner [77]. Interestingly this inhibition is not complete and a small proportion of POMC transcription is not suppressed, even by very high amounts of glucocorticoids [68,78]. A proposed neuro-immuno-endocrine loop is emerging which suggests that corticotroph function not only acts on immunocompetent cells—through cortisol production—but is itself the target of various immunomodulators [79]. Data obtained in the rat show that interleukin-1 and -6 both exert a stimulatory action on ACTH release at the hypothalamic and pituitary levels [80–82]. It is suggested that they participate in the physiologic ACTH rise in acute infectious stress, as they experimentally mediate that which occurs after bacterial lipopolysaccharide injections. Both cytokines are normally present in the rat anterior pituitary, apparently in a subpopulation of thyroid-stimulating hormone (TSH) cells and in folliculostellate cells for interleukin-1 and interleukin-6, respectively, thus raising the possibility that they act as local paracrine factors [83,84]. Further studies are obviously needed to establish the exact significance of these data, the effects of other regulatory peptides found in the pituitary [85] and their possible implication on the physiology and pathophysiology of ACTH release in humans [86,87].

Oversecretion of ACTH in Cushing’s Disease Cushing’s Hypothesis

The proposition that the pituitary was responsible for the clinical features of Cushing’s disease was convincingly expressed for the first time in Harvey Cushing’s classic monograph of 1932:The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism) [88]. Cushing was recognizing that “. . . striking clinical effects might be produced by minute, symptomatically predictable (pituitary) adenomas. So it is the degree of secretory activity of an adenoma which may be out of all proportion to its dimension, that evokes the recognizable symptomcomplex in all hypersecretory states . . .” he was still wondering however “. . . if the polyglandular features of the disorder are partly due, as premised, to a secondary hyperplasia of adrenal cortex. . . .” Much uncertainty remained at that time on the fine pathophysiologic mechanism of this disorder, yet the crucial clinical and pathologic observations had been made and the pertinent questions had been asked. Today it is recognized

Chapter 13

that chronic oversecretion of cortisol, androgens, and 11deoxycorticosterone by hyperplastic adrenocortical glands is directly responsible for the clinical features of Cushing’s disease, a phenomenon which is primarily driven by pituitary ACTH oversecretion.

Cushing’s Disease

499

tory action of CRH and/or AVP in spite of the hypercortisolic state [93,106,107]. These observations are of utmost importance. Not only do they provide the basis for the pathophysiologic understanding of ACTH oversecretion, but they also support the rationale of the diagnostic procedures [108].

Demonstrating ACTH Oversecretion

When plasma ACTH became measurable by bioassay [89] it was found to be normal or slightly elevated in patients with Cushing’s disease [90–92]. ACTH radioimmunoassay [52] came as an illuminating tool for the fine exploration of these patients. A majority of patients with Cushing’s disease have normal plasma ACTH values in the morning, although as a group their mean ACTH value is significantly higher than that of normal subjects [91,93–95]. However, even a normal ACTH value is inappropriately high or not normally restrained in view of the hypercortisolic state; repeated ACTH measurements over 24 hours show that patients with Cushing’s disease have high evening values with a lack of the normal circadian rhythm [53,54,96]. Continuous sampling with a persistaltic pump has not been performed to study the 24-hour integrated plasma ACTH, as has been done for cortisol [97,98]. The fragility of the molecule in blood probably precluded this approach, which might be performed by measuring other, more stable, POMC peptides such as b- and g-LPHs [99]. ACTH Secretion is Dysregulated, not Autonomous

Besides being increased, corticotroph activity has acquired altered regulatory mechanisms that are the hallmark of Cushing’s disease. Plasma ACTH—and cortisol—classically have lost their normal circadian periodicity; yet episodic fluctuations occur and in some cases a significant circadian variation may still be present [54,100–102] (Fig. 13.3). They are unresponsive to stress [103,104]; they have become partially resistant to the suppressive action of glucocorticoids [105]; they are—inappropriately—sensitive to the stimula-

The Source and Mechanism of ACTH Oversecretion in Cushing’s Disease The Classic Anterior Pituitary Corticotroph Adenoma

That Cushing’s disease is a primary pituitary disorder caused by a corticotroph adenoma is based on the frequency with which such adenomas are found at surgery and the histologic, biochemical, and clinical evidences for a suppressed hypothalamic CRH. Prevalence Since the late 1970s many groups have reported the high frequency of pituitary microadenomas found at surgery in patients who were systematically subjected to sellar exploration by the transsphenoidal route, whether or not a pituitary tumor had been suspected by prior X-ray, computed tomography (CT) scanning, or, more recently, magnetic resonance imaging (MRI). As a rule such tumors are found in more than 80% of the cases [109–117]. Although small, and “silent,” corticotroph tumors are sometimes found at autopsy of non-Cushing’s patients, the prevalence of such adenomas is definitively higher in patients with Cushing’s disease [118]. Histology The basophilic adenomas of Cushing’s disease have variable sizes; a large majority of them are microadenomas arbitrarily defined as being less than 10 mm with a mean of approximately 5 mm [12,112,119] (Fig. 13.4). Most are localized to a primary right- or left-sided position within the gland, but a significant proportion (ca. 15%) are situated centrally [112]. Some are found outside the pituitary fossa and develop from the uppermost part of the

FIGURE 13.3. Twenty-four-hour profile of cortisol (Cort.) and adrenocorticotropic hormone (ACTH) in a normal woman (Left panel) and a woman with Cushing’s disease (right panel). From Liu et al. [54].

500

SECTION 3

Pituitary Tumors

pituitary gland (pars tuberalis), above the diaphragma being out of reach of the neurosurgeon via the transsphenoidal route, and several cases of Cushing’s disease have been reported with an ectopic corticotroph adenoma [120–122], in the mucosa of the sphenoidal sinus [123], and even in an ovarian teratoma [124]. The classic basophilic adenoma is not encapsulated and composed of compact cords of more or less homogeneous cells. The granule content is responsible for its basophilic and PAS-staining properties: the latter is now explained since non-ACTH POMC peptides (the N-terminal fragment) are glycosylated [33]. Electron microscopy shows secretory granules which are highly variable in size (from 100 to 700 nm) and in amounts [125] (Fig. 13.5). Occasionally the paucity of the granule content explains that some adenomas appear chromophobe at the light microscope. Within the same tumor a variable pattern of granule load and size may be observed. In some adenomas [126] tumor cells show characteristic features of the Crooke’s cell

[127] as depicted in the normal corticotroph of patients treated with corticosteroids: a ring-shaped homogeneous dense hyaline area constitutes an amorphous zone that repels the granules to the margin of the cell and close to the nucleus; ultrastructural studies show that it is made of filaments [128]. Immunocytochemistry has recently provided the ultimate means to recognize corticotroph cells by the specific immunodetection of their content [125,129]. For a given antibody the signal is generally correlated to the cell granule load (Fig. 13.6a,b). The sensitivity of the method sometimes allows the detection of an immune signal in what appeared to be a chromophobe adenoma [125]. Many adenomas will, unsurprisingly, react with different antisera directed against different POMC fragments, though some will respond only to a given antiserum. Although this type of observation may point to some peculiar mode of POMC processing in a particular tumor which would not generate a generally accessible epitope to the antibody, as has been described for

FIGURE 13.4. Pituitary gland from a necropsy in a patient with Cushing’s disease (horizontal section ¥ 10). A prominent microadenoma is located within the anterior lobe, in the vicinity of the posterior lobe (only a small portion of which is recognizable on this section: PL). Two invasive extensions (Ex) of the tumor are progressing within the neighboring tissues of the sella turcica. Courtesy of L. Olivier.

(a)

(b) FIGURE 13.5. Ultrastructural study of two surgically removed microadenomas, exhibiting completely different cytological features (same magnification, bars = 1 mm). (a) This tumor is homogeneously constituted of poorly granulated cells (SG, secretory granules; L, lysosomal formations) with a large clear nucleus and a narrow ring of cytoplasm. (b) On the contrary, the second tumor is composed of granulated cells. The secretory granules (SG) vary in size, and are generally distributed along the plasma membrane. The tumor cells harbor a dense nucleus with a prominent nucleolus, and more or less developed bundles of filaments (F). Courtesy of E. Vila-Porcile.

Chapter 13

Cushing’s Disease

501

(a)

(b)

(c) FIGURE 13.6. Cytologic study of surgically removed corticotroph microadenomas. (a) Immunofluorescence with an anti-ACTH25–39 antibody: in this tumor, immunoreactive cells are scattered among unlabeled cells. Immunoreaction varies from cell to cell, and only concerns the cytoplasm, the nuclei thus appearing as dark dots (¥350). (b) Immunofluorescence with an anti-b-endorphin antibody: in this second tumor, all the cells are heavily immunoreactive, and are densely clustered around a capillary (large dark area). The bright immunofluorescent labeling is homogeneous and is restricted to the cytoplasm (¥350). Courtesy of L. Olivier. (c) In situ hybridization of human corticotroph tumor cells with a 32 P-labeled proopiomelanocortin (POMC) DNA prode. Diffuse hybridization signal indicated by the black silver grains localize high concentrations of POMC mRNA in the tumor cells. Courtesy of P.L. Texier.

example in endorphin adenomas [130], it should be kept in mind that different antisera may show variable sensitivities. More recently the specific recognizition of POMC RNA by in situ hybridization has been achieved in human corticotroph adenomas (Fig. 13.6c). The periadenomatous tissue shows a variable density of corticotroph cells, with frequent and typical Crooke’s cells [128]. The coexistence of corticotroph hyperplasia and adenoma has been reported [131–134]. Suppressed Hypothalamic CRH A crucial clue to the pathophysiologic mechanism of ACTH oversecretion in Cushing’s disease is that pituitary corticotroph adenomas are associated with a series of histologic, biochemical, and clinical arguments that hypothalamic CRH is chronically suppressed: (i) histologically, examination of the periadenomatous tissue does not show—in the vast majority of the cases—a specific evidence of corticotroph cell hyperplasia [135–137]; (ii) biochemically, measurement of POMC peptides by various radioimmunoassays (RIAs) reveals low concentrations in periadenomatous tissue in comparison with the adenoma and also with normal human pituitaries [138,139]; and (iii) clinically, suppressed hypothalamic CRH is supported by the lack of response to stress (insulininduced hypoglycemia) in Cushing’s disease in contrast to other situations of ACTH hypersecretion which are thought

to be CRH-dependent (depression . . .) [103,104]. It is supported also by the clinical evaluation after selective pituitary surgery in case of both success and failure. In the former case, successful removal of the adenoma results in a state of selective pituitary corticotroph deficiency that spontaneously resumes its activity over months or years: all parameters of normality will be restored including perfect conservation of circadian rhythm [111,140–145]. Even the cases of failure are interesting; in such patients it was found that 24-hour urinary cortisol excretion and plasma ACTH were unchanged from preoperative values despite removal of a significant, generally half, portion of the anterior pituitary. This was taken as an indication that an adenoma was present but missed since, if the disease were due to diffuse corticotroph hyperplasia, it would be expected that partial hypophysectomy would have induced at least a partial decrease in ACTH and cortisol productions. [111]. POMC Gene Expression is Qualitatively Unaltered Numerous studies performed in vitro show that in the vast majority of corticotroph adenomas the products of POMC gene transcription and of POMC processing are identical with those in the normal human anterior pituitary. The gene transcription shows no gross abnormality and the POMC transcripts in pituitary tumors are similar to

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those in the normal pituitary [49,146–148]: A 1200-nt POMC mRNA is the highly predominant, if not sole, transcript (Fig. 13.7). A small percentage (<5%) of transcripts result from an alternate mode of RNA splicing adding 30 nt at the 5¢ end of the second exon. It has no implication on the open reading frame, which is not modified. Fewer than 1% of transcripts result from the use of an upstream promoter at -369 nt [149]. The N-terminal fragment [150], the joining peptide [27], authentic ACTH1–39 [29,30,50,51], b-LPH and variable amounts of g-LPH and b-endorphin [51,151,152] are the normal end-products of POMC processing found both in tumor extracts and in culture media. A somewhat higher proportion of b-endorphin over b-LPH—and g-LPH over b-LPH—has been reported [49,140]. Yet the recruitment of proteolytic sites that are not normally activated in the normal pituitary is not observed and peptides like CLIP and a-MSH are neither produced nor released. This general finding supports the use of highly specific immunoradiometric assays (IRMAs) for plasma ACTH detection as a valid and significant means to evaluate patients with Cushing’s disease [153]. In rare instances qualitative alterations of POMC gene expression have been described, in silent corticotroph adenomas, and in pituitary cancers [154–156]. Thus tumor POMC peptides, including ACTH, usually show no peculiar or unexpected molecular forms, in contrast with what is often found when POMC expression occurs in a nonpituitary tumor (Fig. 13.8). Any of them can be used alternatively for the clinical investigation, all their plasma values being highly correlated [157].

nants which are not exclusive of each other may theoretically provoke and maintain unrestrained hormone production: (i) the set-point defect at the cell level; and (ii) the tumoral mass at the tissue level. These pathophysiologic mechanisms have been thoroughly studied in vivo and in vitro in various models such as primary hyperparathyroidism where the two determinants cooperate [158]. In the case of human corticotroph tumors, in vitro studies offer obvious difficulties: the latter tumors are much rarer and direct comparison between the tumoral and the normal corticotroph cell is seldom achieved. Yet a number of experimental and human studies provide insight for a pathophysiologic explanation of the phenomenon. The Set-point Defect or Partial Resistance to Glucocorticoid The hallmark of ACTH oversecretion in Cushing’s disease is its partial resistance to the normal suppressive effect of glucocorticoids [105,159]. The dose–response curve between administered dexamethasone and plasma ACTH or endogenous cortisol production is shifted to the right (Fig. 13.9). Because ACTH secretion by the pituitary tumor is not normally restrained, ACTH is overproduced with subsequent chronic hypercortisolism. Since peripheral tissues

POMC Gene Expression is not Normally Restrained

The Determinants of ACTH Oversecretion In a system normally regulated by a negative feedback loop, two determi-

FIGURE 13.7. Northern blot analysis of RNAs from human pituitary corticotroph adenomas. (a) Lanes 1–11, 1 mg total RNA from pituitary tumors; lane P, 2 mg total RNA from a normal human pituitary. (b) In black, the pHOX3 probe used for hybridization corresponding to most of the coding region of exon 3.

FIGURE 13.8. Immunodetection of adrenocorticotropic hormone (ACTH)-like peptides after Sephadex G-50 gel exclusion chromatography of tissue extracts. Left panel: only ACTH1–39 is detected (Ø) in one normal pituitary and four corticotroph adenomas. Right panel: variable amounts of corticotrophin-like intermediate lobe peptides (CLIP) ( — ) are present in five nonpituitary tumors responsible for the ectopic ACTH syndrome. | |

Chapter 13

FIGURE 13.9. Variations (mean ± SEM) of plasma cortisol, adrenocorticotropic hormone (ACTH), and lipotropin (LPH) in response to increasing daily doses of dexamethasone administered for 2 days in 15 normal subjects (
) and in 16 patients with Cushing’s disease ()

have retained their normal sensitivity to the action of cortisol [160,161] they appropriately develop the features of Cushing’s disease. In vitro studies have confirmed that pituitary corticotroph adenomas are not autonomous and have indeed retained some sensitivity to the suppressive effect of glucocorticoids which invariably decrease basal and/or stimulated ACTH release [162–168]. A direct comparison between the responses of normal and tumoral cells in vitro is lacking most of the time. A single study measured the effects of two doses of dexamethasone (1 and 10 mg/dl) on both ACTH release and POMC mRNA content in cultured cells obtained either from corticotroph adenomas or from their (presumably normal) periadenomatous tissues. Whereas dexamethasone efficiently reduced both parameters in the periadenomatous cells, its suppressive effect was reduced in the tumoral cells [146]. Schematically normal secretion of ACTH results from a fine equilibrium within the corticotroph cell between two opposite regulators with stimulatory (cAMP and protein kinase C pathways driven by CRH and AVP) and inhibitory (glucocorticoid pathway) actions. A subtle imbalance between the two regulators should lead to ACTH dysregulation and, in the case overproduction, to an apparent state of resistance to glucocorticoids. Thus variable, and probably numerous, mechanisms may provoke a set-point defect. A gross abnormality in the nature of the glucocorticoid receptor in the tumoral corticotroph cell has not yet been demonstrated [169]. The recent elucidation of a molecular alteration responsible for the syndrome of general resistance to glucocorticoids [170] may pinpoint more precise targets for future studies on the DNA and/or mRNA coding for the human glucocorticoid receptor in the tumor. Alternatively the functional activity of a structurally normal glucocorticoid receptor may be reduced by a variety of

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intracellular defects. Among many other causes, it is decreased in experimental animal models where v-mos and Ha-ras oncoproteins are overexpressed [171,172]; recent data have elucidated a general mechanism whereby the activated glucocorticoid receptor and the products of the protooncogenes c-fos and c-jun inhibit each other’s action at the gene level [173,174]. A set-point defect might also be caused by the exaggerated activation of cAMP and/or protein kinase C pathways. In vitro studies on rat anterior pituitary cells show that whenever one of these two pathways is stimulated, ACTH suppression by glucocorticoids is diminished [68,75,175]. Increased cAMP formation in AtT-20 cells directly blunts the suppressive effect of glucocorticoids on POMC synthesis through the inhibition of glucocorticoid receptor binding to DNA [176]. A subset of human growth hormone (GH)producing pituitary tumors is associated with increased production of cAMP [177]: it has been shown to result from the intrinsic activation of their Gs protein by a single base mutation which suppresses the GTPase activity of the asubunit [178]. This precise type of acquired genetic alteration has so far not been found in corticotroph tumors [179]. An alternate hypothesis, already suggested for other types of endocrine tumors, is that the tumoral cell acquires an abnormal sensitivity to non-CRH hypothalamic neurohormones [118]. In vivo studies have claimed that various hypothalamic factors like thyrotropin-releasing hormone (TRH) and luteinizing hormone (LH)-releasing hormone (LHRH) would increase ACTH release in occasional patients [180–182]. The significance of these results suffer from the inescapable drawback of uncontrolled trials. Very few studies reported the data in vivo and in vitro in the same patient. Few cases, however, have been described which still make it possible that some rare tumor has acquired this unexpected sensitivity [164,183,184]. More and more growth factors also seem to play a role in an autocrine or paracrine fashion within the pituitary [85]; their involvement in the pathogenesis of tumor formation is not yet established. The Tumor Mass At the tissue level, the mass of the tumor is another determinant of the final level of ACTH oversecretion. In vitro studies on rat anterior pituitary cells show that increasing glucocorticoids cannot totally suppress the rate of POMC gene transcription [68,78]. Although these studies should not be simply transposed to a pathologic human condition, it should not be totally ruled out that some inescapable POMC gene expression contributes to the unrestrained ACTH secretion, especially when the tumor mass becomes important. Both clinical and experimental observations show that situations where maximal ACTH secretion is chronically solicited induce an increase in corticotroph cell mass. Rare cases of poorly controlled Addisonian patients have apparently developed pituitary enlargement [185–188]. A large increase in corticotroph cell area is observed in the anterior

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pituitary of adrenalectomized rats [189,190]. It is possible that glucocorticoids exert a direct inhibitory action on the growth of corticotroph cells [191], their deprivation being a direct stimulus for growth. It is thought however that corticotroph cell growth is driven by the action of CRH. Indeed the growth-promoting effect of various hypothalamic neurohormones is well documented, like that of GHRH on GH cells for example, which may proceed through the activation of cellular oncogenes [192]. Longterm administration of CRH in experimental animals also leads to corticotroph cell hyperplasia [193,194] and hypertrophy [189]. To explain the growth of a pituitary corticotroph adenoma on these grounds would imply two necessary conditions: (i) that the adenoma be sensitive to the action of CRH and (ii) that CRH be present, as least at some time of the development of the adenoma. Pituitary corticotroph adenomas remain sensitive to the stimulatory actions of CRH [106,107,195,196] and AVP [92,197] in vivo. These actions are used as investigational tools to target the pituitary origin of ACTH oversecretion. In vitro studies have largely confirmed that the tumoral cells are the direct target of these secretagogs [162–166,198]. A synergistic effect of AVP has also been observed [165]. Quantitatively the responses of the tumor cells have rarely been compared to that of normal human corticotroph cells. A single study reported that 9 of 16 such tumors had identical sensitivity to CRH as the paired nonadenomatous tissue, and seven a lower sensitivity [164]. In addition to its action on the adenylyl cyclase, CRH has been shown to modulate action potential firing and to increase intracellular calcium on cultured cells obtained from human corticotroph adenomas [199,200] It may seem paradoxical to invoke a role for CRH in the growth of a corticotroph adenoma when much evidence suggests that it is suppressed in Cushing’s disease. This contradiction is only apparent. It is conceivable that, although

it is not originally responsible, CRH contributes, at least at the beginning of the disease, to the progression of a pituitary tumor resulting from a clonal event primarily responsible for a set-point defect with secondary tumor growth (Fig. 13.10). Does a Pituitary Clonal Event Lead to Both a Set-point Defect and Tumor Growth? The clonal origin of various human endocrine tumors has been recognized, based on the study of genetic markers borne by the X chromosome in female heterozygous patients. Recent techniques using DNA probes directed at various genetic markers (hypoxanthine phosphoribosyl transferase and/or phosphoglycerate kinase) studied the X-inactivation pattern in peripheral and tumoral tissues through the combined DNA digestion with a methylation-specific enzyme and the restriction enzyme giving rise to a restriction fragment length polymorphism. They have shown the monoclonal nature of all nonfunctioning pituitary tumors [201,202]. Recent studies performed on functioning tumors [203] showed a monoclonal pattern in three of three GH-secreting adenomas, four of four PRL-secreting adenomas, and three of four corticotroph adenomas; the fourth corticotroph adenoma was substantially contaminated by interspersed normal adenohypophyseal tissue that may have induced an apparent polyclonal pattern. More recent studies using another anonymous marker of the X chromosome, the M27b probe, have confirmed these results in pituitary corticotroph adenomas [204–206]. Whatever its mechanism, the occurrence of a state of partial resistance to glucocorticoids in a clone of pituitary corticotroph cells could theoretically have the following consequences (Fig. 13.10). 1. At the beginning the small tumoral clone would secrete only a minor amount of ACTH with no subsequent increase in cortisol. Persistent CRH

FIGURE 13.10. Pathogenesis of Cushing’s disease. Schematic view of a tentative pituitary hypothesis. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; F, cortisol.

Chapter 13

action on “cortisol-deprived” clonal cells would constitute an ideal stimulatory condition for their further growth. Thus the adenoma would develop and tumoral ACTH would progressively override nontumoral ACTH with subsequent increased cortisol production and ultimate extinction of hypothalamic CRH. 2. The full-blown expression of Cushing’s disease would be attained. This scheme could be extended to the situation where bilateral total adrenalectomy would constitute a further stimulus for tumor progression by restoring normal cortisol (exogenously administered) and eventually CRH. 3. Two conditions that would concur again to stimulate the growth of the tumor, possibly leading to the Nelson’s syndrome. The set-point defect and the tumor growth potential would be linked. This scheme explains how CRH could have a transient role in the progression of the adenoma. It shows how at some time a pituitary might contain both an adenoma and still normal corticotroph cells, as has been occasionally seen on histologic examination [131–134]. Variants of the Anterior Pituitary Corticotroph Adenoma

Pituitary Carcinomas Although corticotroph adenomas often show invasive features and sometimes a high mitotic index, the existence of primary pituitary carcinomas is still a subject of debate. The presence of extraneural metastases are required for this diagnosis. Several such patients have been reported [207–210], including cases where immunocytochemistry of distant metastases (liver, bone) proved the presence of POMC peptides [210]. This situation is more frequently, but not exclusively, associated with Nelson’s syndrome, occurs equally in males and females, and the mean age is relatively low. Caution should be exerted to eliminate the possibility that an occult nonpituitary tumor secreting ACTH has metastasized to different sites, including the pituitary. Because the growth aggressiveness of the pituitary tumor may be the ultimate prognostic factor [211], methods to predict it via the mitotic index, nuclear aneuploidy, or other means would certainly be helpful. Mixed Adenomas Concurrent secretion of another pituitary hormone by corticotroph adenomas, although rare, has been reported. It is seldom of clinical significance and most often a chance discovery through global immunocytochemical testing of the surgically removed tissue. Prolactin (PRL) [212], TSH, LH, and a-subunits have been found to coexist in an occasional corticotroph adenoma [213]. Curiously cholecystokinin (CCK) [214], neuromedin U [215], and more recently galanin [216] have been found to be specifically present in corticotroph adenomas as well as in normal human corticotrophs. The significance of this colocalization is unknown. Not unexpectedly other proteins which are ubiquitous biochemical markers of neurosecre-

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tory granules such as chromogranin A [217], secretogranin I, and II, and 7B2 are present in all pituitary tumors, including corticotroph adenomas [218,219]. Whether they exert any peripheral, autocrine or paracrine function also needs to be demonstrated. Some of them, like chromogranin A and secretogranin I, have numerous potential proteolytic sites that may be natural substrates for maturation enzymes. In several systems [220,221] including AtT-20 cells [222] a maturation product of chromogranin A, pancreastatin [220], exerts an inhibitory effect on the resident hormone release and may be part of an ultra-ultra short autocrine negative feedback. Other peptides such as parathyroid hormone (PTH)related protein [223], and bombesin [224] have been occasionally found associated with pituitary corticotroph adenomas. Again the significance of these associations is not known. Because bombesin has been attributed a growth effect it may be of pathophysiologic relevance. Silent Corticotroph Adenomas The development of immunocytochemistry revealed that some pituitary tumors unexpectedly contained immunoreactive ACTH, although the patients had no clinical or biologic evidence of hypercortisolism [225–228]; hence the name “silent” corticotroph adenomas. Most often these tumors present as macroadenomas, revealed clinically because of their space-occupying effect. Thorough studies through electron microscopy level have separated various subtypes: some are morphologically indistinguishable from the classical basophilic adenoma, others show subtle differences in granule size, and loss of some type of microfilaments. In some tumors immunoreactive ACTH cells are rare and associated with other cell populations containing GH, PRL, LH, FSH, and TSH [229]. No abnormality has been observed that would alter the quality of the POMC message [148]. The most likely explanation for the clinical silence lies on two molecular bases: the low levels of POMC mRNA on the one hand and the occasional alteration in POMC processing on the other [154,155]. Yet some tumors show no evidence of any such abnormality. It is then speculated that an intrinsic traffic or export defect is responsible, as suggested by reports of increased lysosomal activities [226]. These tumors emphasize the notion that the growth and secretory activities of a corticotroph tumor need not be concordant. They raise the possibility that growthpromoting factors are operating which are not linked to POMC overexpression. Different types of mutations of Gsa have already been described in a subset of GH-secreting pituitary adenomas [178]. Thus it is likely that variability in the genetic causes of pituitary corticotroph adenomas will be the rule with a range of consequences. At one end of the spectrum, a given mutation may essentially alter the sensitivity to glucocorticoid; at the other end another mutation may alter mainly the growth regulation leading to a silent corticotroph tumor.

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It should be kept in mind that the clinical silence of these tumors should only be asserted after a well-designed hormonal investigation. The secondary occurrence of florid Cushing’s disease has indeed been reported in patients who have harbored such tumors for many years [230–232]. Adenomas of the Multiple Endocrine Neoplasia Type I (MEN I) This familial disease transmitted as an autosomal dominant trait combines the occurrence of tumoral lesions in the parathyroids, the pancreas, and the pituitary although all endocrine tissues may not be simultaneously involved [233]. Pituitary lesions have been reported to occur in 15–50% of the cases with a high predominance of PRL and GH hypersecretory syndromes and nonfunctional tumors [234,235]. In a recent study of 16 patients with the Zollinger–Ellison syndrome and MEN I, three (19%) were found to have Cushing’s disease with biologic and imaging evidence of a pituitary origin [236]. In the three cases the hypercortisolism was mild and might have escaped the diagnosis had it not been systematically looked for. This is a unique situation where familial cases of Cushing’s disease have recently been reported [237]. Cushing’s disease of MEN I must be distinguished from Cushing’s syndrome, which often occurs in the sporadic form of Zollinger– Ellison where an ectopic ACTH syndrome originates from the pancreatic tumoral lesion. The interesting feature of MEN I is the insight on tumor formation that has recently emerged. The pancreatic lesions are also characterized by islet-cell hyperplasia but with concomitant multifocal clonal tumors. Tumor transformation in the pancreas was associated with the deletion of specific DNA regions on chromesome 11, pointing to a possible new antioncogene responsible for endocrine tumor formation induced by the loss of its two alleles [238]. This specific gene alteration, also found in occasional sporadic pituitary tumors, was absent in four examined corticotroph adenomas [239]. The Intermediate Lobe Pituitary Adenoma

Besides the classic anterior pituitary corticotroph cells, a second type of POMC-producing cells form clusters of a-MSH immunoreactive cells arranged in follicles in the colloid cyst region in the human gland. They are thought to be the remnants of the fetal intermediary lobe and may generate the cellular cords that penetrate the pituitary posterior lobe [240]. The diversity of POMC-producing cells in the normal human pituitary logically suggested that each of them could give rise to a different subtype of pituitary adenoma with specific localization and secretory pattern, both in terms of POMC peptide molecular forms and dynamic regulation. Supporting the hypothesis that some human corticotroph adenomas arise from remnants of the pars intermedia are two animal models of Cushing’s disease: the dog and the horse both develop the disease spontaneously in association with tumors of the pars intermedia (in at least 30% of the

dogs and in all cases of the horses) [118,241,242]. These tumors logically process POMC into essentially intermediate-like peptides: although ACTH is only a minor product, its plasma concentrations reach abnormal levels because of the high biosynthetic activity and the mass of the tumor. The tumoral secretion is unresponsive to the classical regulators of anterior pituitary corticotroph like dexamethasone, CRH, and vasopressin. As expected, dopaminergic agonists are effective therapeutic agents [243,244]. Evidence for an identical subtype of intermediate-like pituitary adenoma in man has been advanced in a single study [245]. Based on histologic data showing the close association of argyrophil fibers with nests of tumoral cells, and the hormonal workup showing responses more like those expected of an intermediate lobe tumor, it was suggested that these tumors arose from intermediate lobe remnants, were more often associated with hyperplastic lesions, were less amenable to surgical cure, and were driven by a general hypothalamic defect with decreased dopamine turnover. Investigation of a specific POMC peptide pattern was not performed, and others could not confirm these data [246,247]. Although dopaminergic agents have been claimed to be effective in an occasional patient [183,248], controlled studies clearly establish that this condition, if it indeed exists, is rare [249,250] and these patients do not necessarily harbor an intermediate lobe pituitary adenoma [251]. Hypothalamus-dependent Cushing’s Disease

Although it is becoming increasingly clear that a vast majority of the patients with Cushing’s disease harbor a corticotroph adenoma in their pituitary there are still some cases—including patients from Cushing’s monograph of 1932 [88]—where pituitary lesions were apparently absent. Therefore two questions remain to be solved: (i) is there a subset of patients with Cushing’s disease where pituitary ACTH oversecretion is caused by a primary hypothalamic dysfunction creating simple diffuse corticotroph hyperplasia?; and (ii) in the vast majority of patients who harbor a pituitary corticotroph adenoma, does the lesion result from prior hyperplasia caused by a primary hypothalamic dysfunction? Is there a Subset of Patients with Cushing’s Disease due to Primary Hypothalamic Dysfunction? Abnormalities in the quantitative and qualitative aspects of various CNS and anterior pituitary functions have been interpreted as evidence for a primary (and general?) hypothalamic dysfunction that would include CRH overproduction with subsequent ACTH oversecretion. Classically cited are the loss of normal ACTH circadian rhythm, the decreased suppressive effect of glucocorticoids, altered secretory patterns of GH, TSH, PRL, and gonadotropins, and modified sleep electroencephalography (EEG) patterns [2,118,252]. A detailed statistical analysis (performed retrospectively on already published studies) showed that the distribution of parameters of plasma cortisol fluctuations was compatible

Chapter 13

with the existence of two populations of patients with Cushing’s disease. It was hypothesized that highly fluctuating cortisol concentrations were of hypothalamic origin, low fluctuations of primary pituitary origin [253]. Also in favor of a primary hypothalamic disorder were the apparent, and sometimes persistent, cure of some patients treated with drugs acting directly at the CNS such as the serotonin antagonist cyproheptadine and the g-aminobutyric acid (GABA)-ergic sodium valproate [2,118], All these lines of evidence can be seriously challenged. Many are simply attributable to the hypercortisolic state: altered EEG patterns, abnormal GH, PRL, gonadotropin, and TSH secretory patterns all return to normal when the source of hormone excess is removed [2,140,141,143]. The beneficial effect of CNS-directed drugs is debated particularly because it was based on uncontrolled studies: subsequent elegant studies have shown that many Cushing’s disease have spontaneous fluctuations with longlasting periods of apparent total remission—whether or not the patients are treated with CNS-directed or dopaminergic drugs [254]. Corticotroph cell hyperplasia has been reported in pituitaries of patients with Cushing’s disease [135–137,255,256]. Because CRH exerts a growth stimulatory action on corticotroph cells in animals [193,194] and because corticotroph cell hyperplasia has been observed in pituitaries obtained from patients with Cushing’s syndrome resulting from chronic CRH oversecretion by hypothalamic [257] or ectopic [258,259] tumors, this histologic finding is generally taken as a strong argument for CRH involvement [260]. Establishing this histologic diagnosis is of utmost difficulty [12]. It should not be accepted when obtained on limited surgical materials: some adenoma may escape surgical exploration because of an ectopic location, and the difficult histologic diagnosis of corticotroph hyperplasia certainly requires that the whole gland be thoroughly examined since the corticotroph cells are not scattered randomly in the gland, but rather show clusters of densely aggregated cells [129,261]. If this histologic diagnosis can be demonstrated under the necessary scrutiny in a patient with the clinical and biologic features of Cushing’s disease, then it probably offers the best evidence of a CRH dependence. Yet it would still need to be proven that CRH is of hypothalamic origin, and not from an occult ectopic source, and if so, that it is not merely a functional and transient hypothalamic CRH dysfunction associated with disorders like depression, chronic stress, and general resistance to glucocorticoids. Even the finding of corticotroph cell hyperplasia is not definitive proof that it is CRH-mediated. Evidence has been provided for the existence of primary multinodular corticotroph hyperplasia [262]. Thus the ultimate proof still requires the unambiguous demonstration that hypothalamic CRH is indeed overproduced. Plasma CRH is normal or low in patients with Cushing’s disease, although the significance of these peripheral plasma values may not be

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absolutely relevant [263,264]. CRH rather appears to be low in the cerebrospinal fluid (CSF) of patients with Cushing’s disease [265], in contrast with depressed patients [266,267]. Although CRH analogs that exert an antagonist activity have been used in the rat [268], such a molecule remains to be constructed for human studies. It certainly would constitute a unique heuristic tool and the sole way to definitively establish a pathophysiologic role for CRH in Cushing’s disease. Does Corticotroph Cell Hyperplasia Precede Adenoma Formation? That hyperplasia often precedes the formation of a clonal tumor has long been recognized in animal models and in humans, and brilliantly demonstrated by the recent use of powerful transgenic animal models [269]. Sitedirected expression of the SV40T antigen in the mouse pancreatic b cell first induces hyperplasia of the endocrine cells [270]. As a result of a second and spontaneous event, an occasional clonal b-cell tumor develops. It is thought that this experimental model somehow reproduces the longproposed two-step theory of Knudson for spontaneous oncogenesis [271]. In humans the familial form of medullary thyroid cancer (Sipple syndrome) provides the best example of a naturally occurring endocrine cancer where tumoral transformation is preceded by a state of general hyperplasia of C cells [272]. The molecular mechanisms responsible for the different steps have been unravelled in privileged situations in humans, such as the retinoblastoma. In most other cases they are still unknown. The local expression of angiogenic compounds may be the tumor-promoting factor [273]. On these grounds it is interesting to remember that a recently characterized angiogenic factor, vascular endothelial growth factor or vasculotropin, was isolated from pituitary folliculostellate cells [274,275] and the mouse corticotroph cell line AtT-20 [276]. Increasingly, the pituitary is becoming the target of site-directed oncogenesis in various transgenic animals. Transgenic mice expressing the human GHRH gene develop selective hyperplasia of the GH cells [277,278]. It will be of major interest to observe if authentic tumors eventually develop with time. Various genes have been targeted to pituitary corticotroph cells in transgenic mice using transgenes placed under the promoter of the rat POMC gene [279,280]. Expression of SV40T antigen provoked marked development of both anterior pituitary corticotrophs and intermediate-lobe melanotrophs [281]; whether true clonal tumors secondarily develop is not yet known. Other approaches have been used recently that create experimental models of Cushing’s disease in transgenic animals [282]. ACTH-producing pituitary tumors were generated with the polyoma early region promoter linked to a cDNA encoding the polyoma large T antigen [283]. Chronic ACTH and corticosteroid overproduction was induced by targeting the expression of an antisens message to the glucocorticoid receptor type II [284], and in transgenic mice overexpressing CRH [285]. In this latter experimental model pituitary

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corticotroph hyperplasia was observed. It will be crucial to determine if adenomatous lesions ultimately develop. In humans, the evidence that hyperplasia precedes the formation of a pituitary adenoma is still scant: although pregnancy is a condition with PRL cell hyperplasia, no association is clearly found to suggest that it is a risk factor for subsequent development of a PRL-secreting tumor. The ectopic GHRH syndrome is almost always associated with GH cell hyperplasia when pituitary examination is performed [286]. Similarly, pituitary enlargement occurring in states of longlasting peripheral hormone deprivation (hypothyroidism, hypogonadism) is, as a rule, associated with hyperplasia and reverses under adequate treatment. Whether true tumors have really developed under such conditions remains to be established unequivocally. The evidence that primary CRH hyperactivity may be responsible for corticotroph cell hyperplasia secondarily initiating the formation of an adenoma is based on theoretical, histologic, and clinical grounds: (i) CRH exerts a growth stimulatory action on corticotroph cells; (ii) associations of a corticotroph adenoma and corticotroph hyperplasia have been found [131–134]; and (iii) an increased number of stressful events have been found in patients with Cushing’s disease [287,288]. It suggested that prolonged CRH overactivity eventually led to the formation of the adenoma. Clinical experience does not indicate that depressed patients are particularly at risk for Cushing’s disease. More interesting are the patients whose disease recurs after “successful” removal of a pituitary adenoma [111,289]. It is speculated that the original hypothalamic CRH overactivity had been transiently silenced by the hypercortisolism, and recovers its activity after removal of the pituitary adenoma. In fact, there is simply no way to be sure that the recurrence is not due to the regrowth of a small amount of tumoral cells that had escaped the surgeon’s skill and which can be removed by a second pituitary surgery [290,291]. Thus, although such a mechanism remains a possibility (Fig. 13.11), there is certainly at the present time no definitive proof that corticotroph cell hyperplasia is a prerequisite condition leading to the formation of a pituitary adenoma. Progress in this field might come from new experimental approaches generating chronic pituitary stimulation by CRH in animals [285,292] and whenever and anti-CRH analog will be available for clinical studies.

EFFECTS OF CHRONIC ACTH AND POMC PEPTIDES OVERSECRETION

Effects on the Adrenal Effects of ACTH on Corticosteroid Secretion

Steroidogenesis in the zona fasciculata and the zona reticularis of the adrenal cortex is regulated predominantly, if not exclusively, by ACTH. Binding of the pituitary peptide to its specific membrane receptor induces an immediate secretion of glucocorticoids, androgens, and mineralocorticoids

FIGURE 13.11. Pathogenesis of Cushing’s disease. Schematic view of a tentative hypothalamic hypothesis. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; F, cortisol.

[293,294]. The primary mediator of ACTH action is cAMP and cAMP-dependent protein kinase; protein kinase C does not directly mediate the actions of ACTH although interactions between the two kinase systems have been described [295]. Because little steroid is stored in the gland, increased secretion is the reflection of increased synthesis [294]. ACTH primarily acts to increase the rate-limiting step of steroid synthesis (the conversion of cholesterol to pregnenolone) by enhancing the accessibility of cholesterol to the substrate-binding site of cytochrome 450P. This action requires a rapid protein synthesis and a labile protein called steroidogenesis activator polypeptide (SAP) has recently been characterized [296]. In the long term, ACTH action also involves a stimulatory effect on the expression of various key enzymes of steroidogenesis, most likely at the transcriptional level [297,298]. In contrast with some other endocrine functions in humans, chronic adrenocortical stimulation by ACTH does not induce a desensitization state. Indeed the opposite occurs; the adrenocortical response is amplified [299]. This long-recognized phenomenon had been attributed to a “trophic” effect of ACTH though recent knowledge has shed a molecular explanation. Adrenocotrical cells exposed to ACTH in vitro acquire an increased number of ACTH receptors and an increased rate of protein Gs expression [300–303]. Thus the binding of ACTH and the transducing apparatus are both amplified, explaining the higher

Chapter 13

sensitivity and the greater response potential of chronically stimulated cells. Fascinating results have recently unmasked an autocrine network that operates on adrenocortical cells. In response to ACTH various growth factors are secreted. Insulin-like growth factor-I (IGF-I) is secreted [304,305], and acts on its own receptors to stimulate the differentiated functions of adrenocortical cells [306,307]. In contrast, transforming growth factor-b (TGF-b) exerts inhibitory effects, its receptors being also regulated by ACTH. Moreover ACTH favors the release of angiogenic factors such as fibroblast growth factor (bFGF) and IGF-II thus stimulating the growth of the adrenals and of their vascular system as well [295]. Although much work remains to be done to unravel the physiologic relevance of each individual system and their integrated implications in the final adrenocortical response, these autocrine factors stress the importance of the adrenal glands as potential amplifiers of the corticotroph activity. In comparison with normal cells, hyperplastic adrenocortical cells of Cushing’s disease have particular qualities: (i) they are more sensitive to low doses of ACTH; and (ii) their response to ACTH stimulation is higher and longer [299,308]. If Cushing’s disease is defined as a set-point defect at the pituitary level, it is conceivable that increased responsiveness of chronically stimulated adrenal glands may lower the amount of ACTH needed to maintain the same degree of cortisol oversecretion. Diminished ACTH secretion would thus occur in parallel with adrenal hyperresponsiveness, sometimes to the point where plasma immunoreactive ACTH reaches the lower limit of sensitivity of a given RIA. This reciprocal interaction between the adrenals and the pituitary adenoma may explain why no good correlation is found between plasma ACTH levels and the level of cortisol over-production in patients with Cushing’s disease [309]. The mechanisms of adrenal androgens secretion grossly parallel those of cortisol [294]. Thus dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and D-4-androstenedione are elevated in Cushing’s disease [310]. Their peripheral transformation to testosterone and dihydrotestosterone may lead to a moderate state of androgen excess in females [311]. Dissociation between cortisol and adrenal androgens is observed however in the particular situation of patients resuming normal corticotroph function after successful pituitary surgery. DHEAS remains suppressed for months or years after plasma cortisol has normalized [310]. The action of ACTH on adrenal mineralocorticoids is more complex. In the zona glomerulosa. ACTH acutely stimulates aldosterone release [312]. Yet this action is only transient since increased concentrations of cortisol in the adrenal cortex inactivates cytochrome 450P 11-bcorticosterone methyl oxidase. In contrast, in the zona fasciculata and reticularis the stimulatory action of ACTH is permanent. Thus 11-deoxycorticosterone (DOC), corticosterone (B), and often 18-OH-DOC are elevated whereas aldosterone and 18-OH-B are normal or slightly

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suppressed in parallel with low plasma renin activity. The concentration of plasma zona fasciculata mineralocorticoids (DOC) is directly correlated to that of ACTH and participates as one determinant in the mechanism of high blood pressure [312,313]. Various physiologic agents have recently gained a new interest as possible regulators of ACTH action at the adrenal level or even as regulators themselves. Angiotensin II, serotonin [314], interleukins and as yet unidentified monocyte products [315] have shown some apparent stimulatory actions. Atrial natriuretic factor inhibits the action of ACTH both on the zona glomerulosa and the zona fasciculata [316]. Peptides with anti-ACTH action (corticostatins) have been isolated from rabbit lung and peritoneal neutrophils which are unrelated to POMC [317]. Although the pathophysiologic relevance of these observations remains elusive they may offer some speculative thoughts on new therapeutic approaches. Effects of Non-ACTH POMC Peptides on Corticosteroid Secretions

N-terminal fragment, g3-MSH, b- and g-LPH, b-MSH, aMSH, and b-endorphin have all been shown to exert some effect on adrenal secretions [318–324]. In comparison with ACTH much higher concentrations were required, raising some doubt on their real significance and on a possible minor contamination (less than 0.1%) of purified preparations [318]. An aldosterone-stimulating activity of the Nterminal fragment [24,323], b-LPH [320], b-endorphin [322], b-MSH [321], a-MSH [319], and g3-MSH [324] has been reported. Specific receptors to Lys-g3-MSH have been described in the rat adrenal [325] where it would act essentially as a synergic molecule with ACTH. The clinical relevance of these results remains somewhat uncertain, primarily because of the weak intrinsic action of the peptides, and also because peptides like g3-MSH and b-MSH are not normally found within normal or tumoral human pituitaries [150,326]. Besides in patients with Cushing’s disease, increased plasma immunoreactive Lys-g3-MSH has been occasionally reported in some patients with idiopathic hyperaldosteronism [327], a finding which could not be confirmed by others in the same type of patients nor in other patients with dexamethasone-suppressible hyperaldosteronism. As to the somewhat elusive pituitary aldosterone stimulating factor (ASF), it appears to be unrelated to POMC [328]. Although often suggested, the definite demonstration that some abnormal fragments of POMC processing, preferentially generated in nonpituitary tumors responsible for the ectopic ACTH syndrome, somehow enhance the secretion of mineralocorticoids by the adrenals still remains to be made. Similarly, that cortical adrenal androgen stimulating hormone (CASH)—or joining peptide1–12—is a specific regulator of adrenocortical androgens has not been confirmed [329]. ACTH7–38 or corticotrophin inhibiting peptide (CIP) exerts an anti-ACTH action [330]. Although occasionally

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described in some pituitary extracts it is not a significant product of POMC in the human normal or tumoral pituitary. Effects of ACTH on Adrenocortical Growth

Hypophysectomy results in adrenal cortex atrophy that is restored by the sole administration of ACTH [294]. Thus, in vivo, ACTH is the predominant if not the exclusive trophic factor for the adrenals. Prolonged in vivo stimulation with chronic ACTH administration or oversecretion eventually leads to an increase in total adrenal protein and RNA synthesis. Cell proliferation is indicated by an increase in total DNA [294]; the resulting adrenocortical hyperplasia participates in the amplified response of the chronically stimulated gland, and the weight of each gland can be greatly increased. The exact mechanism whereby ACTH promotes adrenocortical growth still remains somewhat mysterious, since in vitro studies show a paradoxical negative effect of ACTH on adrenocortical cell proliferation [295]. As already mentioned, the growth-stimulatory effect of ACTH in vivo most likely proceeds through the activation of a local and complex network of autocrine growth factors and their own receptors which appear to trigger the expression of early cellular protooncogenes such as c-fos [331]. Although a number of other substances, including POMC-peptides such as g3-MSH [332], have been shown to exert some adrenocortical growth effect they do not appear to be sufficiently potent to exert a direct effect in vivo.

Extraadrenal Effects of ACTH and POMC Peptides ACTH, b- and g-LPH all contain a common heptapeptide (Met-Glu-His-Phe-Arg-Trp-Gly) which bears the melanocyte-stimulating activity present within POMC [17]. As measured in the frog skin bioassay the three molecules have essentially the same intrinsic bioactivity [333]. The more potent peptides (¥100) a-MSH and b-MSH5–22 are not formed in normal and tumoral anterior pituitaries in humans. They may be generated in some nonpituitary tumors responsible for the ectopic ACTH syndrome [326]. Thus in Cushing’s disease and in Nelson’s syndrome high plasma levels of ACTH, b-LPH and g-LPH all participate, for essentially the same part, in the hyerpigmentation. The same core heptapeptide is responsible for the lipolytic activity of the LPHs and ACTH. This effect is speciesspecific and observed predominantly in the rabbit. Human (and rat) adipocytes are essentially not responsive. Because a small, but definite, amount of b-endorphin is formed in the anterior pituitary the question has arisen of the potential effect of this highly powerful analgesic. Very high levels of authentic nonacetylated, presumably fully bioactive, b-endorphin have been measured and chemically identified in some patients with Nelson’s syndrome. These patients showed no evidence of analgesia and had no

response after naloxone administration [334]. This observation emphasizes the total lack of analgesic action of circulating b-endorphin which cannot cross the blood–brain barrier to act on its CNS receptors. CSF b-endorphin levels were low or normal in patients with Cushing’s disease and even in Nelson’s patients with highly elevated plasma levels [335]. PATHOLOGY OF THE ADRENAL IN CUSHING’S DISEASE

Simple Diffuse Hyperplasia The most common adrenocortical lesion of Cushing’s disease is bilateral simple diffuse hyperplasia [4]. The two glands are symmetrically (and generally moderately) enlarged, weighing between 5 and 12 g each at operation. The glands are yellow or brown and the cortex appears regularly widened on section. At the light microscope examination a wide inner zone of compact zona reticularis cells separated from an outer zone of clear cells is observed. The zona glomerulosa is not changed. The cells themselves usually appear normal. Already in this form of hyperplasia small nodular lesions are found which emphasize the essential continuity of this condition with the nodular hyperplastic form with large, macroscopic nodules [336].

Multinodular Hyperplasia Although this definition is somewhat arbitrary, it is generally used whenever one or several macroscopic (visible to the naked eye) yellow nodules are present [4,6]. Such glands, in general, have a greater weight than in simple diffuse hyperplasia. The size of the nodules displays an extremely wide range of variation from a few millimeters to several centimeters. Although as a rule they occur in both glands, marked asymmetry is occasionally seen, which may falsely indicate an autonomous adenoma-like lesion. In contrast to the autonomous adenomas, a constant feature that must be thoroughly searched, is that the attached cortex which lies in between the nodules is always hyperplastic [4]. At the light microscope, nodular cells show features not dissimilar with that of the hyperplastic regions with alternate collections of compact and clear cells. Controversy still exists on the mechanism leading to nodular formation, its possible implication as a transient state leading to the formation of autonomous adenomas, and even adrenal carcinomas [337–342]. A large body of evidence suggests that in most cases multinodular hyperplasia is an anatomical variant that has kept its normal ACTH dependency: (i) unilateral adrenalectomy of a highly predominant and asymmetrical gland fails to cure the hypercortisolism [343]; (ii) in many cases a fine hormonal evaluation is consistent with a pituitary source of ACTH as the responsible drive of cortisol oversecretion [341]; and (iii) finally the finding and removal of a pituitary

Chapter 13

microadenoma has convincingly been shown to cure such patients [344]. It is assumed that multinodular hyperplasia results from longstanding ACTH stimulation of the adrenal cortex [345]. In other cases the situation is less clear particularly because the ACTH-dependency of the hypercortisolism is in question [346–348]: plasma ACTH is undetectable, the 17-hydroxycorticosteroids not stimulated by the metyrapone test, and cortisol secretion poorly or not at all suppressed by the classic high-dose dexamethasone test. None of these data is by itself sufficient to prove that ACTH secretion is suppressed. A nondetectable plasma ACTH level simply may be under the lower limit of the assay and still be present in sufficient amount to stimulate a large mass of adrenal cells [349,350] that have been shown to be even more sensitive to ACTH than simple hyperplastic cells [351]. Some patients who did not respond to the classic high-dose (8 mg/day) dexamethasone suppression test subsequently responded to a higher dose of 16 or 32 mg [352]. It thus appears that the “autonomy” of cortisol secretion may be only apparent and not actual in many cases; and hormonal tests must be interpreted with the view that a large mass of highly ACTH-sensitive adrenocortical cells may somehow modify the classic limits of their responses [349,350,352]. Yet there remain some cases of authentic multinodular hyperplasia where the most thorough investigations have failed to detect the slightest indication of basal or stimulated (CRH) ACTH activity, including inferior petrosal sinus [353] or after bilateral adrenalectomy [354]. In these cases an ACTH-independent bilateral macronodular adrenal hyperplasia must be diagnosed [354]. The cause of this syndrome remains elusive. Privileged observations have suggested that “transition from pituitary-dependent to adrenal dependent Cushing’s syndrome” [342,355,356] may occur, providing a tentative explanation if not a definite proof. An alternate hypothesis is that some as yet unidentified non-ACTH factors exert a stimulatory action on normal—or more likely adenomatous—adrenocortical cells [353,354].

Cushing’s Disease and Adrenocortical Carcinoma The development of an adrenocortical carcinoma has been reported in exceptional patients with long-lasting Cushing’s disease and the multinodular hyperplasia [340,357]. In one case the patient had evidence of a 5 mm pituitary cystic basophil adenoma found at autopsy [358]. Similar, and exceptional, observations of occasional malignant adrenocortical lesions have been made in patients with poorly controlled congenital adrenal hyperplasia [357]. They raise the question of the possible role of ACTH on the generation or, more likely, the growth promotion of a concurrent adrenocortical adenoma. Convincing evidence that chronic ACTH stimulation may eventually generate an autonomous adrenocortical lesion is still lacking.

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Adrenal Rests Accessory adrenocortical tissue is often found in ectopic sites [357]. Classically it contains only the cortical component of the gland. The most usual sites include the celiac plexus, the kidney, the gonads, the broad ligaments, the epididymis, and the spermatic cord. They may also occur beneath the liver capsule. Capsular extrusions are collections of adrenocortical cells just outside the capsule of the adrenal glands. They are thus distinct from adrenal nodules. Histologically they appear to contain only zona fasciculata cells. They are ACTHsensitive and may develop concomitantly with diffuse adrenocortical hyperplasia. These accessory adrenocortical tissues probably explain why persistent cortisol secretion is not exceptional after an apparent total bilateral adrenalectomy [359]. They may be reactivated by the chronic stimulatory effect of highly elevated ACTH plasma levels and even become the source of excess steroid secretion in Nelson’s syndrome. OTHER CAUSES OF CUSHING’S SYNDROME Understanding the pathophysiologic mechanisms of these conditions is essential to the principles of the differential diagnosis of Cushing’s syndrome.

ACTH-dependent Spontaneous Cushing’s Syndromes CRH-secreting Tumors

CRH-secreting tumors have recently been recognized as a cause of chronic pituitary ACTH oversecretion, and hence Cushing’s syndrome [259]. Rare hypothalamic tumors have been described such as gangliocytomas [257]. More patients have presented with the ectopic CRH syndrome. The most frequent nonhypothalamic tumors responsible for CRH secretion have been the prostate, small cell lung cancers colon carcinomas, nephroblastoma, thyroid medullar carcinomas, and bronchial carcinoids [259,360]. Pituitary tissue obtained in such patients exhibited the expected corticotroph cell hyperplasia [257–259]. In general the patients presented with mild clinical features of hypercortisolism. Although, theoretically, chronic CRH hypersecretion by a nonhypothalamic tumor might induce pituitary ACTH oversecretion, some pathophysiologic aspects of the syndrome remain ambiguous. First, CRH is only weak ACTH stimulator [361], CRH infusion in normal volunteers for three consecutive days inducing only a slight ACTH and cortisol rise although plasma CRH values were extraordinarily high, up to 10 000 pg/ml [362]. Moreover, the placenta, which is a “physiologic” source of ectopic CRH, induces very high plasma CRH values (up to 1000 pg/ml) during the last trimester of pregnancy [264], yet plasma free cortisol again is only slightly elevated [363,364]. The poor stimulatory action of circulating CRH on ACTH secretion

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in these two conditions is tentatively explained by two reasons: (in the down-regulation of CRH receptors at the pituitary level by glucocorticoids [365–367]; and (ii) the buffering effect of large amounts of circulating CRHbinding protein similar in males and females, and independent of estrogen action [368,369]. Second, most patients with Cushing’s syndrome due to ectopic CRH production had much lower plasma CRH values [259,264,370,371] than those observed in pregnant women. Third, when the CRH-secreting tumors could be examined in most cases they were found to contain ACTH and/or other POMC products as well [360,371,372]. Thus, except for a single case where a metastasis located at the median eminence [259] might have been the source of excess CRH acting directly at the pituitary level (suprisingly, in this patient, cortisol was not suppressed by dexamethasone), skipping the buffering effect of the CRH-binding protein [369], there is still some question as to whether moderately elevated plasma CRH levels originating from an ectopic source can ultimately induce a state of chronic ACTH over-secretion. The definitive proof should be accepted when removal of a tumor harboring only CRH (and not ACTH) eliminates the Cushing’s syndrome. Probably because of the limited number of reported cases and the pending questions regarding its pathophysiologic mechanism, the ectopic CRH syndrome has not been ascribed a clear basal or dynamic specific hormonal pattern. Besides CRH, ectopic secretion of bombesin has been claimed to induce pituitary ACTH oversecretion leading to another cause of ectopic Cushing’s syndrome with a somewhat analogous mechanism [373]. This proposal remains to be confirmed. The Ectopic ACTH Syndrome

Probably first reported by Brown in 1928 [374], the existence of the ectopic ACTH syndrome was definitively estab-

lished by Liddle’s group in the 1960s [375]. Since that time a number of reviews have documented its prevalence as a cause of Cushing’s syndrome, its various clinical presentations, and its specific hormonal pattern [376–378]. Recent advances in the molecular aspects of ACTH biosynthesis and POMC gene expression have shed new light on its pathophysiologic mechanism [379]. POMC gene expression is a ubiquitous phenomenon which normally takes place in many nonpituitary tissues [41–48]; a highly dominant mode of POMC gene expression proceeds through a transcription initiation starting at the 5¢ end of the third exon generating a short, truncated, POMC RNA that contains the coding region for ACTH but lacks that for a signal peptide of the precursor and which therefore is nonfunctional [44,46,47]. For a nonpituitary tissue, or tumor, to produce the ectopic ACTH syndrome several essential qualitative and quantitative conditions must be met. 1. A shift in POMC gene transcription initiation must occur which directs the generation of a pituitarylike POMC mRNA, the translation product of which may enter the secretory pathway. 2. A maturation process must occur which releases at least some ACTH1–39. 3. Ultimately, if some genuine ACTH1–39 happens to be properly formed it must be secreted in excess, a quantitative aspect which depends on the rate of gene transcription on the one hand, on the amount of functional tumor mass on the other. The molecular mechanisms of ACTH oversecretion in pituitary and nonpituitary tumors are schematically shown in Fig. 13.12. In pituitary tumors the overall process of POMC gene expression appears qualitatively unaltered, yet exaggerated; in nonpituitary tumors various types of POMC transcripts are formed and different maturation processes operate that are appropriate for the resident hormone pre-

FIGURE 13.12. Schematic presentation of the molecular mechanisms of pro-opiomelanocortin (POMC) gene expression and adrenocorticotropic hormone (ACTH) oversecretion in a pituitary tumor (left panel) and a nonpituitary tumor (right panel).

Chapter 13

cursor of the given tissue (e.g., procalcitonin in a medullary thyroid carcinoma, progastrin-releasing peptide in a bronchial tumor) and more or less efficient for the ectopic POMC. Hence an abnormal maturation pattern of POMC is a classic, although inconstant, feature of the ectopic ACTH syndrome. POMC may be poorly processed [51,380,381] or abnormal fragments such as CLIP and hb-MSH5–22 may be generated [50,326,382,383]. These processing abnormalities diminish the tissue’s ability to secrete authentic ACTH—the sole bioactive peptide in terms of steroidogenesis—and somehow protect the patients from the consequences of the tumor production. They also provide the investigator with subtle molecular clues that an ACTH-dependent Cushing’s syndrome may originate from a nonpituitary source. The V3 vasopressin receptor is abundantly expressed on carcinoid tumors also producing ACTH [387], in contrast to small cell lung carcinomas. In these latter tumors with ectopic ACTH secretion, aberrant transcription of POMC maybe directly related to the neoplastic phenotype [388]. Another hallmark of the ectopic ACTH syndrome is its production being totally unresponsive to glucocorticoid feedback, providing the basis for hormonal investigation. Apparently this lack of glucocorticoid sensitivity is not due to a lack of glucocorticoid receptor within the tumor [384]. Apart from exceptional cases [370,385,386], these tumors are also unresponsive to CRH. Because the longstanding hypercortisolic state has appropriately suppressed the pituitary ACTH, the patients do not respond to the CRH test in vivo, in contrast with patients with Cushing’s disease [196]. Although the classic sources of the ectopic ACTH syndrome are tumors derived from endocrine tissues [377] recent observations imply mononuclear cells as possible alternate sources. These data should be analyzed in view of the recent report that POMC gene expression and ACTH production occur normally in some circulating mononuclear cells [48,389]. The Cortisol Hyperreactive Syndrome

The case was recently described of a patient who exhibited some clinical features of Cushing’ syndrome but had low levels of plasma and urinary cortisol [390]. Cellular studies revealed that his tissues were abnormally sensitive to the action of glucocorticoids; higher affinity and higher response of aromatase to glucocorticoids were found in isolated adipocytes. Although ACTH was low and poorly reactive to the CRH test it is not clear whether the small amount of secreted cortisol is still under the control of inappropriately (?) secreted pituitary ACTH.

ACTH-independent Spontaneous Cushing’s Syndromes Primary Adrenocortical Tumors

Primary adrenocortical tumors cause approximately 20% of the cases of spontaneous Cushing’s syndromes in adults [2].

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Benign adenomas and adrenocortical carcinomas distribute evenly. As for Cushing’s disease a female preponderance is noted (Table 13.2). Chronic glucocorticoid excess induces an appropriate suppression of pituitary ACTH. The contralateral and the nontumorous ipsilateral adrenals both are atrophic [4,357]. Cortisol secretion is autonomous and unresponsive to either glucocorticoid deprivation or administration. Most benign adrenocortical adenomas respond to exogenously administered ACTH, and most adrenocortical carcinomas do not [14]. Whereas benign tumors are usually small and secrete exclusively cortisol, malignant tumors are much larger, and secrete a whole array of steroid precursors and androgens. Removal of a benign adrenal adenoma induces an immediate and definitive cure with often transient, sometimes long-lasting, hypocorticotropism. Malignant adrenocortical tumors are highly aggressive; in most series the survival rate is only 20% 5 years after diagnosis [14,15]. Other Adrenocortical Disorders

Primary Pigmented Nodular Adrenal Disease (PPNAD) This rare condition occurs primarily in childhood [391]. Cortisol oversecretion is autonomous with hormone dynamics essentially similar to those encountered in cases of adrenocortical adenomas. Pituitary ACTH is suppressed, unresponsive to the CRH test or to cortisol deprivation (metyrapone test), and cortisol secretion is unresponsive to the dexamethasone suppression tests. However, this primary adrenal disorder is driven by bilateral adrenocortical lesions: the two glands harbor numerous nodular lesions that appear typically brown or black. The adrenal’s size is classically not increased. Histologically, the nodules consist of typical compact adrenocortical cells with eosinophilic cytoplasm containing brown pigment. The adrenocortical tissue which lies in between the nodules has been variously described as normal or more often atrophic; the latter aspect separates this condition from the more usual and ACTH-dependent multinodular hyperplasia. Other features add to the concept that adrenocortical nodular dysplasia is a separate entity. It may be part of a more complex clinical spectrum called the Carney complex which associates myxomas of the heart, skin or breast, pigmented skin lesions, endocrine tumors, and peripheral nerve tumors (schwannomas), and which is often a hereditary condition transmitted as a Mendelian autosomal dominant trait [392,393]. It was recently shown that germline mutations of the regulatory subunit R1-a of the protein kinase 4 (PKA) was present in a majority of such patients [394,395]. ACTH-independent Bilateral Macronodular Adrenal Hyperplasia Already mentioned, this condition suggests that non-ACTH factors may induce cortisol hypersecretion by nodular and hyperplastic adrenocortical glands [353,354]. Exceptional familial cases have been reported [396]. A recent report convincingly demonstrates that such adrenocortical lesions had acquired an inappropriate sensitivity to gastric inhibitory polypeptide that stimulated cortisol release

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in vivo and in vitro, also explaining why the patient had high plasma cortisol increases after meals [397,398]. This led to the concept of various “illegitimate” receptor expressions on some adrenal tumors: b-adrenergic-, vasopressin-, LHreceptors inducing cariable clinical phenotypes and pharmacologic responses [398a]. In the McCune–Albright syndrome, nodular hyperfunction may occur in different endocrine tissues including the adrenal glands where it can lead to hypercortisolism. It has been demonstrated that this syndrome is caused by a somatic mutation of the a-subunit of the Gs protein, which activates adenylyl cyclase [399]; thus cAMP production is constitutively activated and cortisol overproduction is genuinely autonomous in the affected areas of the gland. Gonadal Tumors

Exceptional cases of cortisol-secreting testicular and ovarian tumors have been described [400,401]. Whether these originated from ectopic adrenocortical cells is of speculative interest.

Iatrogenic Cushing’s Syndromes

tion of this condition is attributed to the pioneering work of his most famous student Harvey Cushing, who published the case of Minnie G. first in 1912 [409]; and later again in his classical monograph of 1932 [88] with eleven more cases. Minnie G. was “a young (16 y) woman . . . of most extraordinary appearance. Her round face was dusky and cyanosed, and there was an abnormal growth of hair, particularly noticeable on the sides of the forehead, upper lip, and chin. The mucous membranes were of bright colour despite her history of frequent bleeding. Her abdominous body had the appearance of a full-term pregnancy . . . numerous purplish striae were present over the stretched skin of the lower abdomen . . . the peculiar tense and painful adiposity affecting face, neck and trunk was in marked contrast to her comparatively spare extremities . . . [the] . . . most striking feature was the rapidly acquired adiposity of peculiar distribution in an amenorrheic young woman. . . .” DESCRIPTION OF THE CONDITION

CLINICAL FEATURES

Centripetal fat deposition is the most common manifestation of glucocorticoid excess and often the initial symptoms of the patient [2,3,410]. Although weight gain is classic it may be minimal and the peculiar distribution of adipose tissue readily distinguishes it from simple obesity. Fat accumulates in the face and the supraclavicular and dorsocervical fat pads, leading to the typical moon facies and buffalo-hump, most often accompanied by facial plethora. It may exhibit inflammatory features with hot and reddish skin and may be slightly painful [88]. This acquired habitus change is best evidenced by comparison with anterior photographs. Fat also accumulates over the thorax and the abdomen, which becomes protuberant. Development of lipomatosis in various situations has been occasionally described and may induce a reversible widening of mediastinum on chest X-ray [411]. Abnormal fat distribution is of variable degree; it is probably the most sensitive symptom of Cushing’s disease, being exceptionally absent [412,413]. It disappears rapidly and totally after cortisol hypersecretion is reduced. The fine pathophysiologic mechanism that determines fat redistribution probably lies in the differential sensitivity of central and peripheral adipocytes to the opposite lipolytic and lipogenic actions of cortisol excess on the one hand, and secondary hyperinsulinism on the other [2]. Less frequent, but certainly crucial, are the clinical features that pertain to the protein-wasting effect of cortisol. Absent in simple obesity they have a high diagnostic value and must be thoroughly searched at examination.

On a historical note, it has been proposed that the first published case of Cushing’s disease be “a near miss” mistakenly described by Osler in 1899 as having “an acute myxoedematous condition . . .” [407,408]. The unequivocal descrip-

1. Skin thinning due to the atrophy of the epidermis and the underlying connective tissue may be mild and is best appreciated by running the skin gently over the tibial crest. In some patients the skin is so

Exogenous Glucocorticoids

By far the most frequent cause of Cushing’s syndrome is iatrogenic [402]. Patients given high doses of glucocorticoids invariably develop the clinical features of Cushing’s syndrome, the severity of which depends on many variables, including the intrinsic glucocorticoid activity of the given drug, its in vivo bioavailability, the dose and duration of treatment, the mode of administration, and the personal sensitivity of each individual [403]. Drug administration may be facticious [404,405] and raise serious difficulties in the differential diagnosis, particularly with the recently described cortisol hyperreactive syndrome [390]. The syndrome may also result from large-dose administration of progestins, which possess a glucocorticoid action [406]. In all these situations pituitary ACTH is suppressed and the adrenals are atrophic. Exogenous Cortrosyn

Cortrosyn may be administered chronically in patients as an antiinflammatory or antiedematous agent. It will invariably induce the clinical features of Cushing’s syndrome with highly elevated cortisol, adrenal androgens, and DOC. In a way similar to that which occurs in the ectopic ACTH syndrome, pituitary ACTH (and other POMC-peptides) will be suppressed.

Chapter 13

fragile that it can be scratched simply by removing a strip of adhesive tape. Skin thinning and tension over accumulated fat both account for the plethoric appearance of the face and the purple aspect of striae due to the streaks of capillaries, which almost become visible. Striae are indeed present in many patients and are most commonly located on the abdomen and flanks, but also on the breasts, hips, and axillae. In contrast with the usually whitish and small striae often seen after pregnancy or rapid weight gain, the striae of Cushing’s disease are typically purple to red, and wide (>1 cm). Almost 62% of patients complain of easy bruisability whereas it is relatively uncommon in simple obesity [413]. The minimal trauma generate multiple ecchymotic lesions or purpura especially on the forearm; blood collection often results in large ecchymotic lesions. Minor wounds heal slowly and are the source of postoperative complications at the incision site. The most superficial wounds, especially frequent on the lower extremities, may lead to indolent infection and ulceration that take months to disappear. Lower-limb edema is frequent and does not always result from congestive heart failure but rather from increased capillary permeability. Protein wasting is responsible for a generalized tissue fragility. Surgeons usually find the tissues to tear easily. Spontaneous ruptures occur, mainly of tendons. 2. Muscle wasting is frequent and characteristically proximal leading to fatiguability, muscle atrophy occurring mostly in the lower limbs [414]. It is found on formal testing in about 60% of patients [413]. Disappearance of muscle mass may become apparent and measurable; it contrasts with the truncal obesity. The weakness may be so severe as to prevent the patient from getting up from a chair without help. 3. Bone wasting results in general osteoporosis. Particularly vulnerable is the vertebral body; loss of bone density is almost invariably present when searched by sophisticated means such as dualphoton-absorptiometry. Compression fractures of the spine are evident on plain X-rays in about 20% of the patients and almost half of the patients complain of backache [413]. Neurologic complications almost never happen. In contrast, kyphosis and loss of height, sometimes dramatic (up to 20 cm), are frequent. Pathologic fractures can occur elsewhere, particularly in the ribs and pelvis. Demineralization is readily visible on skull X-rays and shading of the dorsum sellae is quite common, indicating cortisol action, rather than an expanding pituitary adenoma. Renal stones, as a consequence of hypercalciuria are present in 15% of cases [413].

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4. The patient with chronic hypercortisolism has impaired defense mechanisms against infections. Banal bronchopulmonary infections may take a most aggressive, life-threatening course. Superficial mucocutaneous infections are extremely frequent, such as tinea versicolor and ungueal mycosis, which will only subside with the control of hypercortisolism. 5. A majority of patients have high blood pressure. It may occasionally be severe, inducing cardiac hypertrophy and eventually congestive heart failure. The pathophysiologic mechanism of hypertension in Cushing’s disease is complex and multifactioral due to both the glucocorticoid effect of cortisol [415,416] and to the mineralocorticoid effect of cortisol and DOC [417]. Increased susceptibility to both arterial and venous thrombosis is also present due to lipid [418] and coagulation [419] disturbances. Cardiovascular complication are the major threats of the disease and contribute greatly to its morbidity and mortality rate [3]. Successful removal of the pituitary microadenoma reduces high blood pressure [420]. 6. Hirsutism due to a slight excess of adrenocortical androgens is extremely frequent in women. Moderate hair growth is visible on the face (upper lips, chin, sideburns), and less often on the chest, breasts, abdomen, and upper thighs. A dorsal lanugo is often observed; some degree of acne and seborrhea are frequent. Frank virilism (temporal hair loss, coarsening of the voice, clitoral hypertrophy) occasionally occurs and would rather point to another cause of Cushing’s syndrome, especially an adrenocortical carcinoma. Excess adrenal androgens and cortisol both suppress the gonadotroph function resulting in an array of gonadal dysfunctions. Most female patients have oligomenorrhea or amenorrhea, and infertility is frequent. Rare patients may also have concomitant hyperprolactinemia [421,422]. In male patients the curtailed gonadotroph function [423] induces a dramatic fall in testosterone which is not compensated by the increased adrenocortical androgens. It results in loss of libido and diminished sexual performance. Loss of sexual hair and reduced testis size is observed. Gynecomastia does not usually develop. 7. Psychic disturbances are extremely common. They are highly variable both in their expression and severity and do not correlate with the intensity of the hypercortisolism. They are most often mild, limited to anxiety, increased emotional lability, and irritability of unwarranted euphoria. Sleep disorders are also frequent. Severe psychotic symptoms may occur such as depression, manic disorders, delusions and/or hallucinations, and may ultimately lead to

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suicide. No clean link is found between the premorbid psychologic status and the type of morbid psychologic manifestations [424]. In many cases controlling the hypercortisolism results in dramatic improvement with complete disappearance of the psychic manifestations. The skin, as already mentioned, is often plethoric, especially on the face. Hyperpigmentation is almost never observed in the usual, uncomplicated forms of Cushing’s disease where ACTH and LPH plasma levels are only moderately elevated. In contrast it is a frequent symptom of patients whose treatment is directed primarily at the adrenals, especially after total bilateral adrenalectomy. Miscellaneous clinical features have been claimed to be associated with Cushing’s disease and reported as classic manifestations, although they now appear rare and not obviously related to glucocorticoid excess. These include thirst and polyuria in absence of glycosuria or severe hypokalemia, and a tendency to exophthalmos which might result from orbital fat accumulation. Cataract is rarely present unless as a secondary consequence of diabetes mellitus [413]. Although exceptional, symptoms related to the mass effect of a pituitary tumor (headache, visual defect, pituitary insufficiency) should be looked for systematically. DIAGNOSIS OF CUSHING’S DISEASE

Routine Laboratory Tests Routine laboratory tests may provide some clue to the diagnosis, their major interest being to measure the severity of the disease which is not only related to the rate of cortisol secretion but also, for each individual, to its personal sensitivity to glucocorticoids. They will be most useful for the follow-up of treated patients. Altered counts of circulating leukocytes are frequent, showing increased neutrophils and decreased lymphocytes and eosinophils [410]. Significantly increased hemoglobin, although classically reported, is actually rare. Serum electrolytes are usually normal. In severe cases hypokalemia, alkalosis, and hypernatremia develop in response to high levels of cortisol and DOC. Although some degree of glucose intolerance is observed in most patients, frank fasting hyperglycemia occurs in a minority of patients (13%) [413,425]. Rarely, patients develop ketosis and may require transient insulin treatment. The mechanisms of the diabetogenic effect of cortisol are well known and increased insulin plasma levels reflect the state of insulin resistance. Plasma calcium and phosphate are usually normal and a mild hypercalciuria is reported in up to 40% of cases [410]. Lipid abnormalities are encountered in a minority of patients [418]. These are most often mild, showing a slight increase in triglycerides or combined hyperlipoproteinemia, especially in patients with impaired glucose tolerance.

Chest X-ray, and electrocardiogram are normal except in case of rib fractures and cardiac enlargement due to high blood pressure. Kidney function and liver tests are normal. Serum immunoglobulin G (IgG) have been reported to be slightly depressed. Bone mass is reduced in most patients, as are biochemical markers of bone formation like osteocalcin [426].

Clues to Clinical Diagnosis of Chronic Hypercortisolism The clinical features of hypercortisolism cover a wide spectrum of symptoms and signs. Many, such as obesity, high blood pressure, and psychologic disturbances, are extremely common and yet Cushing’s disease is rarely their cause. Thus several authors have attempted to characterize each sign and/or symptom according to its sensitivity and specificity by comparing its prevalence in patients and in suspected (obese) subjects [410,412,413], the sensitivity of a sign or symptom being the percentage of patients with Cushing’s syndrome who present it; the specificity of a sign or symptom being the percentage of subjects without Cushing’s syndrome who do not present it. As shown in Table 13.3 [412] abnormal fat distribution (central obesity) is the most sensitive sign, and evidence of protein wasting (osteoporosis, myopathy) is highly specific. In the absence of fat redistribution, the likelihood of Cushing’s disease is slim; in the presence of protein wasting, weight gain is highly suggestive of Cushing’s syndrome. This scheme provides a most useful guide that will prove highly fruitful for the clinical approach of many suspected cases.

Particular Clinical Presentations Difficulties for Diagnosis

Many patients with Cushing’s disease present with a highly suggestive combination of symptoms and signs, as just described, while in other cases, the clinical picture is less clear and often misleading for several reasons. 1. In some patients, the clinical features are less complete and sometimes one symptom may predominate. An occasional patient has been misdirected for months or even years to rheumatologic, or psychiatric clinics before it is realized Cushing’s syndrome is responsible for the symptomatology. 2. At both extremes, the intensity of the disease generates diagnostic difficulties. Mild forms may be mistaken for many ill-defined conditions, including polycystic ovary syndrome, essential hypertension, idiopathic cyclic edema [427], and idiopathic hirsutism. Alternatively, a rare case of authentic Cushing’s disease may present with symptoms so severe (including profound myopathy and

Chapter 13 Table 13.3. Prevalences of clinical features of Cushing’s syndrome among 211 patients in whom the syndrome was suspected. From Nugent et al. [412]

Clinical feature

Patients with Cushing’s syndrome

Patients without Cushing’s syndrome

Osteoporosis* Central obesity* Generalized obesity* Weakness* Plethora* WBC
11 000/mm3* Acne* Striae (red or purple)* Diastolic blood pressure
105 mmHg* Edema (pitting)* Hirsutism* Ecchymoses* Serum K+  3.6 mEq/L* Oligomenorrhea Headaches VPRC
49 Females Abnormal GTT Age  35 years

0.64 0.90 0.03 0.65 0.82 0.58 0.52 0.46 0.39 0.38 0.50 0.53 0.25 0.72 0.41 0.37 0.65 0.88 0.55

0.03 0.29 0.62 0.07 0.31 0.30 0.24 0.22 0.17 0.17 0.29 0.06 0.04 0.51 0.37 0.32 0.77 0.77 0.52

WBC, white blood cells; VPRC, volume of packed red cells; GTT, glucose tolerance test. * Prevalences differed significantly (P < 0.05) in the two groups.

hypokalemia) that will irresistibly suggest the ectopic ACTH syndrome. 3. Most patients with Cushing’s disease exhibit some fluctuation of cortisol secretion, others display a truly cyclic pattern [254,428–432] (Fig. 13.13). Episodes of active hypercortisolism are separated by periods of normal pituitary–adrenal activity of varying lengths. Some exhibit a fairly regular pattern of episodic hypercortisolism, and complain of “swelling” from time to time [427]. A slight delay in obtaining the necessary blood, salivary, or urine samples to establish the hypercortisolism may allow the diagnosis to be missed. The simplest way to make this diagnosis is to educate the patient to collect a 24-hour or overnight [254] urine sample or bedtime [433,434] saliva sample at the time when they feel that symptoms have recurred. 4. In the mild forms of Cushing’s disease, the diagnosis is often less apparent in men than in women. It is claimed that some persistent testicular androgens offer a better protection against the protein-wasting effect of cortisol. 5. In rare instances the first presenting symptoms will be those of a pituitary tumor. Careful evaluation of

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a macroadenoma might clearly indicate a state of ACTH hypersecretion in a patient who had no evident feature of chronic hypercortisolism. These findings may even be secondarily encountered during the careful monitoring of what was primarily diagnosed as a nonfunctional pituitary adenoma, stressing the need for prolonged follow-up of such patients [230–232]. Quite exceptionally, Cushing’s disease may be recognized in the systematic workup of a patient with MEN I [236]. Cushing’s Disease in Children

In children, Cushing’s disease almost invariably provokes growth retardation, if not growth arrest [435]. A decrease in growth rate may be the sole symptom in mild forms of the disease where the final diagnosis is often delayed. Weight gain with centripetal obesity, like in adults, is present in most cases however. Hormonal and imaging data have no particular aspect at this age. The occurrence of highly aggressive pituitary tumors has been reported [436,437]. The most usual treatment is the selective adenomectomy by the transsphenoidal route with a high immediate success rate [438]. Cushing’s Disease in Pregnant Women

Pregnancy occurs rarely in a hypercortisolic woman because of the hypofertility associated with this condition. To date less than 100 well-documented cases have been reported with Cushing’s syndromes of all causes [439,440]. It should be outlined that an abnormal preponderance of adrenocortical tumors is found in most series during pregnancy. In mild cases of Cushing’s disease the clinical diagnosis may be obscured by features frequently present in pregnancy such as weight gain, high blood pressure, abdominal striae, and impaired glucose tolerance. However, the presence of exaggerated morphological changes, virilism, and especially catabolic features should raise the suspicion. The physiologic modifications of pituitary–adrenal homeostasis in normal pregnancy also hamper the biologic diagnosis. The normal and slight hypercortisolic state of late pregnancy may be difficult to distinguish from that of a genuine Cushing’s disease. Probably the best indicators would be the indices of free plasma cortisol (24-hour urinary cortisol excretion and salivary cortisol) showing a definite increase—in comparison with standard values at the same stage of pregnancy—and a lack of circadian rhythm [363,441]. Increased free testosterone may also be of help. Dexamethasone suppression tests are of no value and the response to CRH is controversial. The finding of a pituitary adenoma on MRI would be helpful. Hypercortisolism during the course of pregnancy is associated with a high rate of maternal and fetal complications. Symptomatic treatment of diabetes and high blood pressure is always necessary. Most anticortisolic drugs are contraindicated: metyrapone has been rarely used [442]. Transsphenoidal surgery should be a relatively safe procedure during

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FIGURE 13.13. A case of cyclic Cushing’s disease. Summary of the patient’s daily morning plasma cortisol levels and daily 24-h urinary excretion of 17hydroxycorticosteroids (17-OHCS) and 17ketogenic steroid (17-KS) over a 100-day study period. From Brown et al. [428].

pregnancy but until now it has only been reported once [443]. A case of spontaneous resolution after delivery has been reported [444].

Course of Cushing’s Disease Until recently Cushing’s disease was a most severe condition with high morbidity and mortality rates. As reported in older series, Cushing’s disease ultimately led to death in a majority of untreated patients. Cardiovascular complications [3] were the predominant causes followed by infections and suicide. Today, cardiovascular and psychiatric complications still remain the major life-threatening complications. The ultimate prognosis of Cushing’s disease depends upon the severity of the hypercortisolic state and the aggressiveness of the pituitary tumor. Several factors determine the severity of the hypercortisolic state in a given patient: the level of cortisol overproduction, the duration of hypercortisolism, and above all, some intrinsic and so far not fully identified factors that establish a different set-point of peripheral glucocorticoid sensitivity for each individual, and in the same individual in different target tissues. This explains that variable clinical features are observed in patients with similar indices of hypercortisolism, and that in the same individual a defined target tissue seems to suffer more than the others. Because most, if not all, patients can now be cured from their disease (or at least hypercortisolism may be controlled) the practical question has become whether the clinical manifestations of Cushing’s disease are reversible after successful treatment. Some patients truly are rejuvenated. As a rule younger patients have more benefit from a cure than older patients. In the latter group skin changes, muscle wasting, and osteoporosis improve less obviously. Only recently have studies

with dual-photon absorptiometry shown that suppression of hypercortisolism seemed to induce a rise in bone mass [445]. Therefore, because some effects of chronic hypercortisolism, especially in older adults, induces changes that are not easily reversible, not only should these patients be treated aggressively, they should also be treated rapidly. The growth potential of the pituitary tumor may be another determinant of the final prognosis. Rare cases of spontaneous cure of Cushing’s disease have been reported. They are thought to result from infarction and/or calcification of a pituitary adenoma [446,447]. In a minority of patients tumor growth seems to be boosted by bilateral total adrenalectomy, eventually leading to Nelson’s syndrome. This rare occurrence is unpredictable. It is another argument that pinpoints the pituitary as the more logical and first target of therapeutic strategies. DIAGNOSTIC PROCEDURES Two steps should be used in the diagnostic approach. Firstly, establish that chronic hypercortisolism or Cushing’s syndrome is present; secondly, identify its cause with its specific prognostic and therapeutic implications. It is essential that the investigative work-up be done in a coordinated, and somewhat compulsive, fashion with the clear assumption that a diagnostic certainty is the best assurance of an appropriate treatment. The greatest difficulties are encountered when therapeutic procedures have been prematurely initiated in patients who subsequently turn out to have been misdiagnosed. Assessment of the pituitary–adrenal axis at that time may present insuperable obstacles. Only then is it regretted that sufficient time had not been allocated to perform the initial work-up. This approach requires a skilled nursing staff, well

Chapter 13

trained to perform basal and dynamic hormonal evaluations, as well as indisputable steroid and peptide assays. Sophisticated imaging techniques must also be capable of identifying inconspicuous anatomic lesions that can be as small as a few millimeters in diameter. HORMONAL EVALUATION

Establishing the Hypercortisolic State The numerous and nonspecific clinical features of chronic hypercortisolism explain that a Cushing’s syndrome is often considered; the low incidence of this syndrome explains that it is exceptionally confirmed. It was thus essential to develop the means to assess the cortisolic state and to identify, for a given individual, whether it is inappropriately high. An ideal parameter would be that which shows no overlap between normal subjects, including obese, and patients with a hypercortisolic state, whatever the etiology. Baseline Measurements

Plasma Cortisol Plasma cortisol is easily measured by competitive protein binding assay or currently, by more specific immunoassays [448]. As a group, patients with Cushing’s syndrome have higher morning plasma cortisol values, yet around 50% fall within the normal range [449,450]. Because patients with Cushing’s syndrome typically lack a normal circadian rhythm this overlap progressively disappears during the day (Fig. 13.14). Studies obtained from multiple series showed that normal values were found in 17% of 182 patients between 4.00 and 9.00 p.m. but in only 3.4% of 147 patients at 11.00 p.m. [448]. Late evening plasma cortisol has a good sensitivity but suffers from two drawbacks: (i) normal subjects show frequent fluctuations of plasma cortisol and so do patients with

FIGURE 13.14. Plasma cortisol of the same 125 patients with Cushing’s disease (CD) were obtained at 8.00 a.m. (a) and 8.00 p.m. (b) They are compared with those of normal subjects (N) at the same times.

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Cushing’s syndrome [100–102]; thus a trough value in a patient may overlap with an occasional burst of cortisol in a normal subject, including in the evening; and (ii) plasma cortisol measures the total (free + bound) circulating hormone; it will therefore be altered whenever corticosteroid binding globulin (CBG) concentration varies. Repeat plasma cortisol measurements are used to assess the lack of circadian rhythm in patients with Cushing’s syndrome. Various sampling frequencies—at least six per day— and mathematical paradigms have been proposed to define a normal, and an abnormal, circadian pattern [450,451]. They do not help so much to establish the diagnosis as to appreciate the ultimate quality of a therapeutic regimen. In theory, an ideal treatment should not only control the hypercortisolism but also restore a qualitatively normal pituitary–adrenal homeostasis, including a normal circadian rhythm. Plasma cortisol may be used as the end point of the various suppression tests (see below); it is inescapable in patients with chronic renal failure [452]. Some authors have used continuous blood withdrawal with a peristaltic pump to measure the integrated concentration of plasma cortisol over different lengths of time. It was found that the 24-hour integrative plasma cortisol reliably separated normal subjects from patients with the Cushing’s syndrome [97,98]; then a shortened collecting period over 6 hours proved equally efficient, provided that it was performed between 8.00 p.m. and 2.00 a.m. [453]. This approach is probably more interesting as a research tool than as a routine laboratory procedure; further curtailing the time of withdrawal would ultimately end up at the equally efficient and certainly less cumbersome single blood collection at 11.00 p.m. Plasma free cortisol is the best indicator of the cortisolic state. Not only is it biologically relevant, but it is also a highly sensitive parameter. Since plasma CBG is not totally saturated at normal plasma cortisol values a further elevation increases the ratio of free/bound cortisol. Whenever cortisol production increases, variations of free plasma cortisol are amplified in comparison with those of total plasma cortisol [454,455]. Measurement of plasma free cortisol requires sophisticated techniques which cannot be easily performed. Salivary Cortisol Salivary cortisol concentration is a reliable indicator of plasma free cortisol [456]. It offers a convenient, non-stressful way of sample collection, even in outpatients (Fig. 13.15) and a special device has been developed to measure its integrated concentration over time [457]. Although many studies would suggest that it can readily substitute for plasma cortisol with an at least equal performance [433,458], the applicability of this parameter in the diagnostic tests of Cushing’s syndrome has not yet been widely evaluated. Urinary Corticosteroids Basal urinary collections have long provided the sole index of adrenocortical activity of a

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FIGURE 13.15. Two year follow-up of 10.00 p.m. salivary cortisol in a patient with Cushing’s disease. Spontaneous fluctuations of the disease and the response to various therapeutic regimens are observed. R¥ , pituitary radiotherapy; KTC, ketoconazole. The horizontal black bar indicates the normal range of 10.00 p.m. salivary cortisol.

given individual. The 17-hydroxycorticosteroids measured by the Porter and Silber reaction and/or the 17-ketogenic steroids secondarily measured by the Zimmerman reaction have been extensively used. They suffer from several limitations. First, as many as 25% of obese subjects overlap with patients with Cushing’s syndrome [448]. This overlap is reduced when the excretion of 17-hydroxycorticosteroids is expressed in mg/day and mg per g of urinary creatinine [449]. Second, situations of increased (obesity, hyperthyroidism) or decreased (hypothyroidism) cortisol metabolism induce parallel variations in urinary 17hydroxycorticosteroids which do not correspond to a hyper- or hypocortisolic state but simply to adaptive changes in cortisol production rate [459–461]. Drugs that accelerate or derive cortisol metabolism in the liver (phenylhydantoin, barbiturates, 1,1-dichloro-2-(o-chlorophenyl)-2(p-chlorophenyl)-ethane (op¢DDD) alter the measured urinary 17-hydroxycorticosteroids without (or before for op¢DDD) altering the production rate and the plasma levels of cortisol [462,463]. For these reasons the baseline urinary 17-hydroxycorticosteroids should no longer be used to diagnose Cushing’s syndrome. In contrast with cortisol metabolites, 24-hour urinary cortisol excretion is an almost ideal marker of the cortisolic state. Urinary cortisol is measured by competitive protein binding assay after extraction, or by immunoassay. Because it is correlated with the levels of plasma free cortisol, urinary cortisol excretion has several invaluable qualities: (i) it is biologically relevant, being a reflection of how much biologically active, i.e., free, cortisol has been circulating over the last 24-hour period [464]; (ii) it is a highly sensitive marker, since whenever the cortisol production rate increases twofold, urinary cortisol excretion increases fourfold, whereas the 17-hydroxycorticosteroids

and plasma cortisol increase only twofold (Fig. 13.16); and (iii) it is not altered in obese patients, in estrogentreated females, or by drugs or conditions that modify cortisol metabolism [449,465]. A number of studies have verified that the theoretical advantages of urinary cortisol excretion actually offer a practical gain for the diagnosis of Cushing’s syndrome [448]. An almost perfect distinction is obtained between patients with Cushing’s syndrome and normal subjects, provided that the urine collection is well done, and that the laboratory has validated its normal values in a large population of normal subjects (Fig. 13.17). This single basal measurement has a diagnostic accuracy comparable to the reference low-dose dexamethasone suppression tests [450,466,467]. Variations on the theme have been developed that measure urinary cortisol excretion over short (and different) periods of time to obtain a circadian pattern. Unsurprisingly, urinary cortisol excretion shows the same variations as plasma cortisol [468]. Vesperal (20–24-hour) [469] or overnight [254] urinary cortisol excretion have proved excellent diagnostic tools; they offer an obvious gain in convenience for the work-up or the follow-up of outpatients. Cortisol Production Rate Daily cortisol production rate has an excellent sensitivity, since all patients with Cushing’s syndrome have, as expected, increased cortisol production rates [448]. It has several disadvantages: (i) it is a difficult and cumbersome procedure requiring the administration of labeled isotopes; and (ii) it has a poor specificity since cortisol production rate appropriately rises whenever cortisol metabolism is increased [449]. This adaptive reaction simply maintains the eucortisolic state. The recent development of a more practical analytic procedure using a stable isotope may renew this approach [470].

Chapter 13

FIGURE 13.16. Correlation between the relative variations of urinary cortisol and 17-hydroxycorticosteroids in response to the stimulatory action of RU 486 in patients with Cushing’s disease.

FIGURE 13.17. Baseline urinary 17-hydroxycorticosteroids and cortisol in the same 61 patients with Cushing’s disease (CD) are compared with the values obtained in normal subjects (N).

Suppression Tests

These tests were established in the late 1950s and early 1960s at a time when the sole measurement of baseline urinary 17-hydroxycorticosteroids offered a poor predictive value to separate normal subjects from patients with Cushing’s syndrome. The Classic Low-dose Dexamethasone Suppression Test The scientific knowledge on pituitary adrenal regu-

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lation had led Liddle to surmise that “. . . the fact that in Cushing’s syndrome cortisol secretion is manifestly excessive implies that the normal restraint on pituitary or adrenal function is not operating properly. . . .” To test this hypothesis it was “. . . desirable that the steroid selected for the purpose of suppressing ACTH be one which did not itself contribute appreciably to the level of 17 hydroxycorticoids in the urine . . .” [105]. Thus synthetic steroid analogs were selected because of their high glucocorticoid potency. It was anticipated that they would suppress ACTH when given in minute amounts as compared to the daily amount of normally secreted cortisol. It was established that 0.5 mg dexamethasone, given every 6 hours for eight doses (2 mg/day) induced almost complete suppression of urinary 17hydroxycorticosteroid excretion on the second day of administration in normal subjects (<2.5 mg/g urinary creatinine). In contrast, almost all patients with Cushing’s syndrome, whatever the etiology, maintained relatively high levels (>2.5 mg/g urinary creatinine) indicating that their feedback mechanism indeed was “. . . not operating properly . . .” Thus this low dose of dexamethasone allowed a convenient and efficient means to separate patients with, and subjects without, Cushing’s syndrome [105,448,449,461]. Initially appreciated through measurement of the urinary 17-hydroxycorticosteroids, the suppressive effect of the lowdose dexamethasone test has been subsequently evaluated by measuring urinary cortisol excretion or morning plasma or salivary cortisol collected, precisely 2 hours after the last oral dose of dexamethasone, with an equal diagnostic accuracy [467,471,472]. Analysis of multiseries gathering several hundred cases showed that less than 5% of patients with Cushing’s syndrome had normal suppression, and only an exceptional subject without the syndrome failed to suppress normally. Some authors have proposed to improve the test by tailoring the dose of dexamethasone according to body weight and administering 20 mg/kg each day rather than a fixed dose of 2 mg/day [449]. In children, it is certainly essential to adjust the dexamethasone dose [473], usually to body surface area at 2 mg/day per 1.73 m2 for the classic low-dose dexamethasone suppression test. Since it was designed, the classic low-dose dexamethasone suppression test has been considered the most reliable means to confirm or rule out the diagnosis of Cushing’s syndrome. It remains the preferred reference test [448]. The Overnight 1-mg Dexamethasone Suppression Test Based on the same theoretical grounds, numerous alternate suppression tests have been proposed which attempted to offer some practical advantage over the classic approach. Probably the most popular is the overnight 1-mg dexamethasone suppression test [474]. Dexamethasone (1 mg) is administered orally between 11.00 and 12.00 p.m. and plasma cortisol is measured the next morning at 8.00 a.m. In normal subjects plasma cortisol values will be suppressed below a definite limit (established by each labora-

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tory, and depending on the assay method), usually less than 20 ng/ml with most immunoassays. A number of series have established the high sensitivity of the test, since only an exceptional patient with Cushing’s syndrome will suppress normally [448]. Unfortunately the test’s specificity is not good, since it has been found positive (lack of normal suppression) in as many as 13% of obese subjects and in 23% of hospitalized or chronically ill patients [448]. It may also be falsely positive in women taking estrogen. Thus, although it does not show the same diagnostic accuracy as the classic low-dose dexamethasone test it is still highly useful, and convenient, to eliminate diagnosis of Cushing’s syndrome in outpatients. As an alternative to blood collection, salivary cortisol has been used to assess the suppressive effect of the overnight 1-mg dexamethasone test with essentially similar results [433]. Further studies are needed to establish if it will improve the specificity of the test. Different authors have used different criteria to establish the cut-off point for normal suppression; it may be chosen as the upper limit of the normal range, the mean plus 1, 2, or 3 standard deviations, or even arbitrarily. These manipulations have implications, since raising the cut-off point increases the test specificity (less false-positive), but at the same time decreases the sensitivity (more falsenegative). A sound philosophy [475] is probably to use stringent cut-off points that tend to lower the specificity since it is more acceptable to restudy a subject with suspected Cushing’s syndrome than to miss the diagnosis. These limitations apply to the interpretation of other tests. A reasonable approach to diagnosis sometimes necessitates repeating tests, which must always be correlated with the clinical observation. Other Suppression Tests Some have proposed to suppress cortisol by intravenous dexamethasone infusion in order to avoid (hypothetical) variations due to interindividual differences in the rate of dexamethasone absorption. Various dosages and times of administration have been used that all successfully achieved the desired separation between patients with Cushing’s syndrome and normal (or obese) subjects [476–478]. In the field of dexamethasone suppression the ingenuity of many investigators has led to the development of many different tests. The result is extraordinarily reassuring since, even if some tests are better, all work essentially in the same manner and therefore offer an effective confirmation to the hypothesis that initiated this approach. The trick really is to use a potent glucocorticoid agonist and to titer its dosage of administration so that it will be sufficient to totally suppress cortisol production of all normal subjects (including obese), yet is insufficient to totally suppress cortisol production in all patients with Cushing’s disease and, of course, in those with the other causes of Cushing’s syndrome.

Establishing the ACTH-driven Hypercortisolic State When the diagnosis of Cushing’s syndrome has been unequivocally obtained, its etiological investigation relies, above all, upon the appreciation of the corticotroph function. Plasma ACTH

The first successful approach was that of Liddle’s group in 1961 [90] who used the Lipscomb and Nelson [89] ACTH bioassay “. . . in search of a definitive answer to the question of whether the pituitary secretes abnormal quantities of corticotropin (ACTH) in Cushing’s disease. . . .”The answer was positive, and was rapidly confirmed by others. A few years later Berson and Yalow chose the ACTH assay as one of their first RIAs developed in humans and immediately applied this new method to the investigation of the pituitary–adrenal axis [52]. Until recently ACTH RIA has been the method of choice to assess the corticotroph function because of its sensitivity, and specificity [479]. ACTH is rapidly destroyed in blood by enzymes. Special care is necessary to obtain adequate plasma samples for RIA. The RIA itself presents difficulties that pertain to the low plasma concentrations, the strong affinity of ACTH for absorption to glassware, a tendency for the labeled tracer to undergo incubation damage and interference of plasma with a given antiserum. There is therefore an absolute need that both blood collection and ACTH RIA be performed expertly. The diagnostic implications of plasma ACTH determination are too important to allow uncertainty of sampling and testing. Because various antisera will be directed against various epitopes of the molecule, some discrepancies have been observed between different RIAs, and between a given RIA and the bioassay [479,480]. Over the years many reliable RIAs have been developed using either extracted or unextracted plasma [479]. Other means to measure plasma ACTH have been developed. Radioreceptor assays [481] and the cytochemical or redox bioassay [482] have the advantage of measuring bioactive ACTH. The redox bioassay offers extraordinary sensitivity that is at least 100 times better than that of most RIAs. However, these two theoretical advantages are not really needed for diagnostic investigation of Cushing’s syndrome and thus cannot compete with the ease of RIAs. IRMAs, in contrast, offer theoretical and practical advantages as well over classical RIAs [153,483,484]: the sensitivity is somewhat better than that of most RIAs, although in the same order of magnitude (1 pg/ml at best). The specificity is improved by definition since only intact ACTH1–39 is measured. Although ACTH fragments are not measured by the IRMAs they may interfere with the assay system at high concentrations by saturating the first antibody. Failure to recognize this may lead to erroneous interpretation [485]. Most important is the convenience of the IRMAs, which can be performed on unextracted plasma, with results

Chapter 13

obtained rapidly—within 24 hours—on a wide range of plasma values. Blood manipulations require fewer precautions than with RIAs since the “sandwich” effect protects the ACTH molecule during the incubation. Recent studies have largely confirmed the validity and efficacy of ACTH IRMAs which yield results which correlate almost perfectly with those obtained by the best RIAs in the same plasma samples [484]. Thus, because of their unique practical convenience it is anticipated that ACTH IRMAs will become the method of choice for evaluating plasma ACTH. In normal subjects, morning plasma ACTH constantly ranges between <10 and 80 pg/ml in most laboratories. Numerous series have shown that patients with Cushing’s disease have morning plasma ACTH levels that tend to be slightly elevated; ACTH is almost always measurable, between half and two-thirds of the patients have values within the normal range, and the values of the others usually do not exceed 200 pg/ml [94,95,448] (Fig. 13.18). Thus, morning plasma ACTH does not fully separate patients with Cushing’s disease from normal, just like morning plasma cortisol. This overlap disappears when ACTH is measured later in the day [486]. At this stage of the diagnostic procedure this overlap really is not troublesome since the goal is to separate the different causes of Cushing’s syndrome. In that prospect the information is invaluable; that ACTH plasma level is merely measurable is totally inappropriate and unquestionably indicates that the hypercortisolic state is ACTH driven. It eliminates the patients whose Cushing’s syndrome is secondary to an autonomously secreting adrenocortical tumor. In this latter situation pituitary ACTH secretion is appropriately suppressed and ACTH plasma levels are invariably undetectable [448], that is, under the lower sensitivity limit of the RIAs. It does not eliminate the patient with the ectopic ACTH syndrome. Plasma Non-ACTH POMC Peptides

Almost all natural POMC peptides have been measured in human blood: the N-terminal fragment [150,487,488],

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joining peptide [27,489], b-LPH and g-LPH [95,490–492], and b-endorphin [493,494]. Since they are secreted concomitantly with ACTH by the pituitary corticotrophs the plasma levels of any of them constantly shows almost perfect correlations with all the others (Fig. 13.19). The molar plasma ratio of two POMC fragments is usually close to one, with slight differences related to different metabolic clearance rates. Thus it is not surprising that plasma determination of any non-ACTH POMC fragment provides the investigator with essentially the same diagnostic accuracy as that of ACTH itself (see Fig. 13.18). On a practical basis LPH RIAs have been the most popular non-ACTH POMC fragments studied. They were the first available but also offer several practical advantages. In contrast with ACTH, both b-LPH and g-LPH are extremely stable in blood; immunoreactive plasma LPH values will remain unchanged in blood kept at room temperature for 24 hours [99], so that handling of blood collection is much less troublesome. Because there are large species differences in the common amino terminal region of the b- and g-LPHs, these molecules are highly antigenic and antibodies with high affinity may be easily raised. Hence direct LPH RIA in a small volume (50 ml) of unextracted plasma is readily feasible [99]. Like ACTH, plasma immunoreactive LPH tends to be slightly elevated in Cushing’s disease, and its value completely discriminates patients with Cushing’s disease and patients with autonomous cortisol-secreting adrenocortical tumors who always have undetectable plasma values [95]. Other reports have shown essentially identical results using the Nterminal fragment, the joining peptide, or the b-endorphin RIAs. Plasma Adrenocortical Androgens

The pattern of adrenocortical steroid secretion provides some clues in the etiologic work-up [2]. Because ACTH also regulates adrenocortical androgen secretion the latter tend to be elevated in Cushing’s disease (and the ectopic

FIGURE 13.18. Morning plasma values for cortisol, adrenocorticotropic hormone (ACTH), and lipotropin (LPH) in the same blood sample obtained from normal subjects (N), patients with Cushing’s disease (CD), patients with a cortisol-secreting adrenocortical tumor (AT), and patients with the ectopic ACTH syndrome (E).

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Plasma ACTH Levels The ACTH plasma level by itself provides a first clue to the source of ACTH oversecretion. Patients with the ectopic ACTH syndrome tend to have higher levels than patients with Cushing’s disease. Yet the overlap between the two groups is wide [95,448] and further investigations are needed for a clear separation (Fig. 13.18).

FIGURE 13.19. Correlation between plasma immunoreactive lipotropin (LPH) and adrenocorticotropic hormone (ACTH) baseline values in patients with Cushing’s disease and Nelson’s syndrome.

ACTH syndrome) whereas they are decreased in benign adrenocortical adenoma since this tumor typically produces only glucocorticoids that suppress pituitary ACTH secretion [310,311,495]. These notions are most helpful for the diagnosis of female patients: low plasma testosterone, DHEAS, and D-4-androstenedione will be suggestive of a benign adrenocortical adenoma. Slightly elevated androgens will point to Cushing’s disease but will not rule out the ectopic ACTH syndrome. Highly increased androgens will suggest an adrenocortical carcinoma [14].

Establishing the Pituitary Origin of the ACTHdriven Hypercortisolic State At this point it becomes necessary to discriminate between patients whose ACTH oversecretion is of pituitary (Cushing’s disease) or nonpituitary (ectopic ACTH syndrome) origin. Over the years various approaches have been developed to find the source of ACTH oversecretion in Cushing’s syndrome. Essential clues are provided by sophisticated measurement of corticotroph function that, besides the quantitative and qualitative assessment of its baseline levels, will also require dynamic manipulations, and sometimes invasive tracking investigations. Because many of these procedures were primarily set to eliminate an adrenocortical tumor as well, this aspect will also be discussed briefly when necessary.

Plasma non-ACTH POMC Peptides Altered POMC maturation is common in nonpituitary tumors, and decidedly unusual in pituitary corticotroph adenomas [49,51]. This subtle mechanism may be useful in detecting abnormal POMC fragments in blood that would pinpoint, although not identify, a nonpituitary origin of the ACTH oversecretion. Partial degradation of ACTH into CLIP is fairly common in nonpituitary tumors [50] (see Fig. 13.8). CLIP escapes detection by most (sufficiently specific) ACTH RIAs as well as by ACTH IRMAs. Since the LPHs are unaffected by the altered POMC processing the plasma LPH/ACTH ratio is increased [95]. Gel filtration chromatography and/or high-pressure liquid chromatography (HPLC) of plasma samples or extracts will also detect abnormal molecular forms of ACTH, or unusual molecules like b-MSH5–22 [326]. Elegant multitargeted IRMA systems have been developed that can recognize by simple direct plasma assays the occurrence of an abnormal POMC processing at a given location on the precursor molecule [496,497]. These approaches have their limitations, however. Besides being only available to highly specialized laboratories, their sensitivity is low, and their specificity also is not perfect. Rare cases of pituitary macroadenoma have been described which convincingly did not process POMC normally [154,155]. Dynamics of the Corticotroph Function

The Classic High-dose Dexamethasone Suppression Test The purpose here is to test the pituitary-dependency of the hypercortisolic state. In the classic [105] test dexamethasone is given orally at the dose of 2 mg every 6 hours (8 mg/day) for 2 days. Urinary corticosteroids are measured on the second day of dexamethasone administration and compared with their pretreatment (control) value. In the original paper of Liddle, all patients with Cushing’s disease decreased their urinary 17-hydroxycorticosteroid to less then 50% of control values, whereas all those with adrenocortical tumors failed to reach this level of suppression [105]. Since this report it has been abusively stated by many authors that all patients with Cushing’s disease should suppress to less than 50% of their control values on the highdose dexamethasone suppression test. Actually “. . . the degree of suppression is not crucial, as long as it is beyond the day-to-day fluctuations observed

Chapter 13

during control periods. In response to large doses of dexamethasone . . . most [patients with Cushing’s disease] exhibit decreases to less than 50% of their control values. A few, however, have been known merely to exhibit decreases to 70 to 80% of their control values” [461]. Numerous series have confirmed that whereas some 90% of patients with Cushing’s disease suppress to less than 60% of their control values on the high-dose dexamethasone test, no rigid cut-off level should be given that rules out the diagnosis of Cushing’s disease [448]. In some patients with authentic Cushing’s disease this level of suppression (50–60% of baseline) could be obtained only by administering much higher doses of dexamethasone, sometimes up to 32 mg/day [352,448]. Recent data suggest that these patients have a more severe disease as judged by baseline plasma and urinary cortisol [498]. If this test has a great specificity to eliminate autonomous secreting adrenocortical tumors, it is somewhat less powerful to eliminate the ectopic ACTH syndrome where an apparent suppression is not rarely observed [386,448,499]. Comparing previous and current dexamethasone urinary corticosteroid values does not only evaluate the effect of dexamethasone, but also the effect of time. Many tumors have spontaneously cycling or fluctuating activities that may induce large variations over a 2-day period. Thus an ACTH-secreting nonpituitary tumor that would spontaneously decrease its activity at the time when the test is performed could be erroneously interpreted as being suppressed by dexamethasone [500]. Alternatively a paradoxical increase in cortisol secretion has been occasionally observed in patients with authentic Cushing’s disease, a phenomenon best explained by spontaneous fluctuations of the disease [428,429,501]. The only way to avoid this flaw for a single individual would be to obtain repeated urinary values to establish the degree of spontaneous variations, and/or to repeat the test itself to evaluate whether it is reproducible. The high-dose dexamethasone test often confirms information already available from the classic low-dose dexamethasone test. Many patients with Cushing’s disease who, by definition, fail to completely suppress on the low-dose test, however exhibit a definite decrease in their urinary corticosteroids. Thus at the same time these patients exhibit an abnormal degree of resistance to the suppressive effect of glucocorticoids, which is the hallmark of Cushing’s disease. Some variations have been brought to the classic test which measure urinary cortisol instead of 17hydroxycorticosteroid, or morning plasma cortisol before and after the 2 days of dexamethasone administration, with essentially the same diagnostic accuracy. The Overnight 8-mg Dexamethasone Suppression Test In this test 8 mg of dexamethasone is given orally as

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a single dose at 11.00 p.m. and the 8.00 a.m. plasma cortisol the next morning is compared with that of the previous (control) day. The proposed cut-off point for a positive response (suppressibility) is a plasma cortisol decrease to 50% or less of its control value [502]. With this arbitrary criterion, two studies gathering 73 patients with Cushing’s disease, eight with adrenocortical tumors and 12 with ectopic ACTH syndromes compared this overnight test directly with the classic high-dose dexamethasone suppression test performed in the same patients. The new test appeared at least as efficient if not better, with 89% sensitivity and 100% specificity for the diagnosis of Cushing’s disease [503]. That this overnight suppression test reaches higher diagnostic accuracy than the classic test may be explained by the simple fact that it is a stronger one since the 8-mg dose is given as a single administration. In the same manner as for the classic test, there is no theoretical reason to fix a rigid cut-off at 50% decrease. Others have studied the acute variations of plasma cortisol during dexamethasone infusion [504] to discriminate pituitary-dependent Cushing’s disease. The Metyrapone Test The purpose of this test is not dissimilar to that of the high-dose dexamethasone suppression test since it also evaluates the pituitary-dependency of the adrenocortical hyperfunction. The approach is just the inverse, i.e., to observe the corticotroph response to cortisol deprivation. In the classic test [505] 750 mg of metyrapone are given every 4 hours for six doses. Urinary (24-hour) 17hydroxycorticosteroids are measured the day before, the day on, and the day after metyrapone administration. Normal subjects usually show at least a two-fold rise in urinary 17hydroxycorticosteroids on the treatment day or on the day after, compared with the day before, reaching values above 10 mg/day [505,506]. Results obtained from more than 100 patients with Cushing’s disease from different studies showed that virtually all patients responded to metyrapone with an increase in urinary 17-hydroxycorticosteroids. The sensitivity of the test reaches almost 98% [448]. In many patients an explosive response is obtained (up to 100 mg/24 h). Thus failure to respond to metyrapone essentially excludes the diagnosis of Cushing’s disease. If this test has a great specificity to eliminate adrenocortical tumors it is less powerful to eliminate the ectopic ACTH syndrome [499]. When the diagnostic accuracies of the metyrapone and the classic high-dose dexamethasone suppression tests are compared, similar figures are obtained, indicating that they merely address the same question as to whether the pituitary is involved. Alternate methods have been proposed including the use of single-dose metyrapone tests [448,507]. Measuring plasma 11-deoxycortisol to assess the response to metyrapone in Cushing’s syndrome requires special precautions. In Cushing’s disease spontaneous and short fluctuations in ACTH activity may blunt the plasma 11-

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deoxycortisol increase. Whatever the cause of Cushing’s syndrome, blockade of the 11-b-hydroxylase will automatically, and inevitably, increase plasma 11-deoxycortisol whether or not an ACTH rise is triggered. In case of an adrenocortical tumor, the plasma 11-deoxycortisol increase will remain much lower than that observed in Cushing’s disease. However, in patients with the ectopic ACTH syndrome, especially if ACTH plasma levels are high, plasma 11deoxycortisol will rise to levels identical with those reached in Cushing’s disease, even though the ACTH levels do not change [508]. These flaws are avoided in the classic metyrapone test evaluated on the urinary 17hydroxycorticosteroids; because they are the sum of cortisol and 11-deoxycortisol metabolites they will only rise if ACTH secretion increases. Thus it is highly recommended that the metyrapone test be performed in its classic setting with the total urinary 17-hydroxycorticosteroids as the best parameter. The LPH plasma levels rise in response to metyrapone in patients with Cushing’s disease and could help to discriminate them from those with the ectopic ACTH syndrome where no response is observed [508]. The true diagnostic value of this approach is not well established. Direct Assessment of Pituitary ACTH Reserve Several secretagogs that act specifically on the corticotroph cell in the normal subject have been used in Cushing’s syndrome with the assumption that they would only trigger further ACTH secretion if the latter were of pituitary origin. The LVP Test LVP is a synthetic peptide analog of AVP that exhibits the same agonistic activity on the pituitary V1 receptors. It is administered as a bolus intramuscular injection of 10 IU. Plasma cortisol and ACTH are measured before, and up to 60 minutes after injection [93]. LVP has long been the sole ACTH secretagog with a direct pituitary action. Its use has been limited because of its low stimulatory activity in comparison with its effects on smooth muscle V1 receptors which generate gastrointestinal symptoms, general pallor, and high blood pressure. These unwanted effects contraindicate its use in older subjects or patients at risk for coronary heart disease or glaucoma. In the diagnostic work-up its major interest is to achieve a complete separation between patients with adrenocortical tumors, where ACTH levels remain undetectable, and the rare patients with Cushing’s disease who have low-toundetectable baseline ACTH and in whom LVP invariably restores measurable plasma ACTH [95]. The use of LVP to discriminate between Cushing’s disease and the ectopic ACTH syndrome has not been established. More recently the desmopressin (which is a V2 and V3 agonist) has been used as a more potent ACTH secretagog in Cushing’s disease, with less side effects. As normal subjects rarely respond to the test (10 mg i.v.) it is useful to predict recurrence after pituitary surgery [509].

The CRH Test A major breakthrough was achieved with the isolation, characterization, and synthesis of ovine CRH in 1981 [59]. This discovery opened up new avenues to investigators of corticotroph function in humans [264,509,510]. Thorough studies in normal subjects rapidly showed that the ovine peptide was active in humans, eliciting an ACTH response that was definitively higher than that elicited by LVP, but still lower than that obtained after insulin-induced hypoglycemia [361,511]. Dose–response studies indicated that administration of 10 mg/kg body weight maximally stimulated cortisol release, while larger amounts could induce still higher ACTH responses [361,512]. Most investigators use an optimal clinical testing dose of 1 mg/kg; others use a fixed dose of 100 mg. The peptide is administered as a bolus intravenous injection and ACTH and cortisol are measured before and up to 120 minutes thereafter. The test is well tolerated; the few side-effects are mild facial flushing and neck tightness. In contrast with normal subjects, the time of day when the test is performed has no particular implication in Cushing’s syndrome, but for convenience it may be performed in the morning. Recent data comparing the ovine and human CRH peptides in the same patients confirm that the former has a higher potency and provides a better diagnostic accuracy, largely outweighing the theoretical advantage of using a homologous peptide, at least for a single-dose testing [513]. The theoretical promise of the CRH test relies on it being a potent and specific stimulator of pituitary ACTH, thus allowing a better separation between patients with Cushing’s disease, adrenocortical tumors, and, especially, the ectopic ACTH syndrome [196] (Fig. 13.20). As with many tests confusion arises with the various ways different authors not only administer CRH but also appreciate an “exaggerated” or a “flat” response [509]. Criteria for a positive or a negative response are seldom defined. In a survey of 10 published series [196,514–522] Kaye and Crapo [503] developed their own criteria from these combined data: a positive response would be a relative increase of more than 50% in ACTH or of more than 20% in cortisol; a negative response would be a relative increase of less than 50% in ACTH or of less than 20% in cortisol. With these criteria, the sensitivity and specificity of the CRH test for the diagnosis of Cushing’s disease would be 80 and 95% using the ACTH response, and 91 and 95% using the cortisol response. There is a general agreement that the test has a high diagnostic accuracy which compares favorably with that of the classic high-dose dexamethasone suppression test [523]. In evaluating 100 patients with Cushing’s disease and 16 patients with ectopic ACTH secretion, a single a.m. CRH stimulation was performed. Seven percent of patients with ACTH-dependent Cushing’s did not respond, while no patient with ectopic ACTH secretion responded to CRH [527]. In the series where both tests were applied to the same patients, similar diagnostic accuracies were found [515,518,524]. In some cases however, the two tests did not agree, leading some authors to advocate a combined-test

Chapter 13

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FIGURE 13.20. Responses of plasma immunoreactive (IR) adrenocorticotropic hormone (ACTH) and cortisol to corticotropinreleasing hormone (means ± SEM) in eight untreated patients with Cushing’s disease (a), six patients with Cushing’s syndrome due to ectopic ACTH secretion (b) and 10 controls. From Chrousos et al. [196].

strategy to achieve the correct diagnosis. Authentic cases of Cushing’s disease that did not respond to CRH have been reported by several authors and account for the 86% sensitivity of the test [503]. The stimulatory action of CRH can be strengthened by the synergistic effect of AVP or its V1 analogs [525]. Recent data obtained with a combined CRH/AVP test showed that all patients with Cushing’s disease responded positively [526]. Occasional patients with the ectopic ACTH syndrome exhibited an apparent positive response [386,515]. In some cases it may be questioned whether the ACTH increase originated from the tumor or the normal pituitary. Diagnostic difficulty is particularly important in the exceptional cases of bronchial carcinoid tumors that also respond to the high-dose dexamethasone suppression test and metyrapone [386]. Whether these responses are apparent or real is not proved, although in vitro studies tend to indicate that an occasional nonpituitary tumor may be authentically CRHresponsive [370]. These rare cases may lead to unwarranted pituitary surgery for a mistakenly proposed diagnosis of Cushing’s disease. They are the ones which would justify systematic bilateral inferior petrosal sinus sampling. That the pituitary tumor responsible for Cushing’s disease further increases its ACTH secretion in response to CRH is further evidence of its intrinsic relative resistance to glucocorticoids. Indeed, the state of chronic hypercortisolism should normally suppress CRH action on the corticotrophs. Thus it is not surprising to observe that the CRH and the

high-dose dexamethasone suppression tests each provide essentially the same diagnostic accuracy [523] since both assess the relative insensitivity to glucocorticoids of the pituitary tumor. Tracking the ACTH Source: Bilateral Inferior Petrosal Sinus Sampling

The availability of reliable plasma ACTH RIAs—and more recently IRMAs—has prompted the development of invasive sampling procedures aimed at collecting blood draining immediately from the pituitary gland. The goal of this approach is twofold: firstly to establish whether ACTH oversecretion is of pituitary or nonpituitary origin; and secondly, and in the case of Cushing’s disease, to lateralize the pituitary location of a microadenoma. A reliable technique requires that blood sampling be done close enough to the pituitary, that is, within the inferior petrosal sinus. Because a pituitary adenoma will lateralize its secretion in the ipsilateral inferior petrosal sinus it is essential that both sinuses be catheterized. Both sinuses and peripheral blood must be sampled simultaneously [509]. A central-to-peripheral ACTH gradient is calculated by the ratio of ACTH plasma levels in the inferior petrosal sinus with the highest level over ACTH in the peripheral blood. In patients with Cushing’s disease this gradient is almost always over 2, with a mean of 15. In patients with the ectopic ACTH syndrome this gradient is almost always lower than 1.7. Analysis of different series and individual

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case reports all confirm the great diagnostic power of the procedure to discriminate between Cushing’s disease and the ectopic ACTH syndrome [528–535]. Although somewhat invasive, particularly considering the general vascular fragility of patients with Cushing’s syndrome, there are no serious side-effects reported. The slight discomfort of the technique [536] is largely overcome by its diagnostic accuracy. In the case of Cushing’s disease this procedure also helps to localize the pituitary microadenoma by evaluating the sinus-to-sinus ACTH gradient [537–539]. A gradient over 1.5 lateralizes the adenoma to the pituitary half draining in the ipsilateral sinus with the highest ACTH level. Some have reported that the test can be improved by simultaneous CRH stimulation which increases the gradient [530,540]. Variable efficacy of this approach has been reported, often with a high success rate [503]. In fact this technique is not diagnosis-directed; its goal is to help the neurosurgeon remove a pituitary microadenoma that would not be readily picked up by imaging techniques and possibly not seen at surgery. Successful blind hemihypophysectomies directed by sampling lateralization have been claimed [530,539]. Obvious difficulties are anticipated in previously operated patients, and with macroadenomas and microadenomas situated centrally. Incorrect lateralizations have been reported [529,531,541] in patients with Cushing’s disease. Several authors have recently reported that other pituitary hormones (PRL, GH, a-subunit) colateralize with ACTH on the ipsilateral sinus draining the microadenoma [537,542–544]. Since these non-ACTH peptides were not detected by immunohistologic studies in the removed adenomas they raise the question of a nonspecific effect of the adenoma on pituitary blood flow, or of an as yet undemonstrated local, and general, paracrine effect of the tumor. A single group recently proposed the direct catheterization of both cavernous sinuses [545].

gland. With coronal images and an adequate method of injection, CT can achieve a sensitivity no higher than 50% [112,116,503,547–549]. The microadenoma will appear as a hypodense round lesion; a mass effect on the pituitary stalk and diaphragma will depend on the size of the lesion. The specificity of CT is not perfect since abnormal images are not infrequent and may provide false-positive results in patients with other causes of Cushing’s syndrome [550,551]. CT scanning also easily recognizes the exceptional initial macroadenoma (Fig. 13.21). MRI

This technique has significantly improved our ability to detect pituitary microadenomas in Cushing’s disease. Several studies have shown that many patients with a negative CT have a positive MRI [552–554]. T1-weighted MRI images should be obtained in the coronal plane without and with gadolinium enhancement. Typical of a microadenoma is a hypointense signal better delimited after enhancement (Fig. 13.22). Although the number of patients examined with this technique is still low a definite increased sensitivity is obtained with more than 70% [503,552,553] of positive cases. Because no patient was reported to have a negative MRI and a positive CT scan, MRI should be considered the test of choice for pituitary imaging in Cushing’s disease. Gadolinium-enhanced images also seem superior to CT in establishing cavernous sinus invasion.

The Adrenals The main, and crucial, goal of adrenal imaging in Cushing’s syndrome is to rule out an adrenal tumor. Standard X-ray, tomography, ultrasonography, and retroperitoneal pneumography have all been outrated by the highly effective and noninvasive techniques using MRI and especially CT scanning.

IMAGING TECHNIQUES

The Pituitary Skull X-ray and Tomograms

Because most pituitary corticotroph adenomas are small, gross deformation of the pituitary sella are rarely encountered [546] in untreated Cushing’s disease. They may be demonstrated in patients who develop Nelson’s syndrome, and in the rare patients with an initial macroadenoma. Skull X-rays will often show evidence of osteopenia of the dorsum sellae, and provide the neurosurgeon with useful indications on the bone landmarks and state of pneumatization of the sphenoidal sinus. CT Scanning

With the development of pituitary surgery as the treatment of choice for Cushing’s disease, preoperative localization of a pituitary adenoma is more important. CT has been for a long time the only imaging technique for the pituitary

FIGURE 13.21. A huge corticotroph macroadenoma detected by computed tomography scan in a patient with mild clinical features of Cushing’s disease and a cyclic evolution.

Chapter 13

(a)

(b)

(c)

(d)

(e)

(f)

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FIGURE 13.22. Pituitary magnetic resonance image in Cushing’s disease. T1-weighted images obtained in the coronal plane with gadolinium enhancement. Adenomas of increasing size are depicted from (a) to (f).

As a result of chronic stimulation by excess ACTH the two adrenal glands develop hyperplasia exhibiting CT features that will be essentially the same in Cushing’s disease and the ectopic ACTH syndrome. As a rule both glands are moderately enlarged; there is no reliable measure of the adrenals but a loss of normal concavity of their borders is considered pathologic. Occasional nodules may be present, probably more frequently in Cushing’s disease than in the ectopic ACTH syndrome. Macronodular hyperplasia develops in up to 15% of patients with Cushing’s disease [343]. In cases where it is highly asymmetrical with a predominant macronodule on one side, an erroneous diagnosis of adrenocortical adenoma may be made that possibly leads to an unwarranted and unsuccessful unilateral adrenalectomy. Great care should be exerted to analyze the contralateral gland which, in contrast with a benign adrenocortical adenoma, will not show the characteristic features of adrenal atrophy [343]. This is also the rare situation where adrenal scintigraphy with iodocholesterol [555] will be of help in definitively proving the bilateral, although asymmetrical, functional lesions in the case of macronodular hyperplasia, in contrast with the strictly unilateral isotope uptake by a benign adrenocortical adenoma [556,557]. No adrenocortical tumor large enough to cause Cushing’s syndrome, i.e., >1.5 cm, should escape detection by CT. A benign adrenocortical adenoma is readily visible in the fat-filled perirenal area of these patients and it is essential to appreciate the atrophic aspect of the contralateral gland by comparing its thickness with that of the diaphragma crus [353]. Adrenocortical carcinomas, as a rule,

are characteristically large and partly necrotic tumors. They may contain calcifications or hemorrhagic areas. At this stage MRI can be used as the most sensitive method in the preoperative assessment of vascular patency of the inferior vena cava and of locoregional invasion (liver, kidney, and pancreas) using sagittal and coronal planes.

PITFALLS IN DIAGNOSIS

Drug Interactions A more extensive description of drug interactions is provided in Chapter 9. Inducers of High CBG Plasma Levels

High estrogen states, as encountered in pregnancy and in oral contraceptive treatment, induce increased plasma CBG levels. This modification is accompanied by parallel increase in plasma cortisol [558]. Persistence of a normal pituitary–adrenal axis is easily demonstrated by other indices; free plasma cortisol and salivary cortisol are normal and have normal circadian variations, while 24-hour urinary cortisol excretion is normal. Although false-positive responses to the overnight 1 mg dexamethasone suppression test are occasionally observed, the classic low-dose dexamethasone test is normal [448,449]. In late pregnancy the situation is more complex due to additional factors that profoundly modify the pituitary–adrenal homeostasis (see below). op¢DDD and/or some of its metabolites have been shown to have estrogen-like actions [559]. In some indi-

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viduals highly elevated plasma CBG levels may obscure a proper evaluation of the drug’s action on cortisol production. Urinary and/or salivary measurements bypass this potential pitfall. Liver Enzyme Inducers

Several drugs have the common property to induce liver enzyme activations that accelerate the metabolism of endogenous and/or exogenous steroids and of some pharmacologic agents [404]. op¢DDD [463], rifampicin [560], phenytoin [561], and barbiturates [562] divert cortisol metabolism toward 6bhydroxycortisol. This highly polar compound escapes the extraction usually performed on urine samples, artifactually lowering the result of the Porter and Silber assay. This explains why the urinary 17-hydroxycorticosteroids drop within a few days after the onset of op¢DDD treatment whereas plasma cortisol remains unchanged until the delayed adrenolytic action of the drug begins its effect, generally only after a few weeks. Anticonvulsants like phenytoin and barbiturates also accelerate dexamethasone metabolism [462]. Patients on these drugs have false-positive low-dose dexamethasone suppression tests [448]. In some patients with suspected Cushing’s syndrome it may be difficult to interrupt their anticonvulsant treatment. It has been proposed to monitor the test with concomitant measurement of plasma dexamethasone [563]; alternatively, because cortisol metabolism is less accelerated a suppression test has been calibrated where plasma corticosterone suppressibility is assessed after oral administration of 50 mg cortisol at midnight [564]. In such patients, however, basal urinary cortisol excretion is normal. Antiglucocorticoids (RU 486)

Although this newly developed drug is used primarily as an antiprogesterone it also exerts an antiglucocorticoid action that is readily observed within a few hours after single oral administration [565,566]. As expected, plasma and urinary cortisol are elevated and suppressibility by dexamethasone is altered. Because of the long duration of action of the drug this state of general glucocorticoid resistance is still noticeable up to 3 days after single dose administration [567]. Pilot studies have been performed where patients received longterm therapy with RU 486 (200–400 mg/day) up to several months, for breast cancer. A two- to threefold plasma cortisol increase was observed after 2 weeks of treatment which plateaued thereafter and was not modified by the 1-mg overnight dexamethasone suppression test [568]. This increased pituitary–adrenocortical activity is an adaptive, and appropriate, response to the state of druginduced glucocorticoid resistance. As expected, no clinical feature of hypercortisolism is observed. Glucocorticoids

A rare patient may present with clinical features of glucocorticoid excess while on glucocorticoid treatment for an

inflammatory disease, and also have an endogenous cause of Cushing’s syndrome. The diagnosis may be easily made in the case of an autonomously secreting adrenocortical tumor. It is theoretically much more difficult in the rare case where Cushing’s disease is suspected, since the abnormal pituitary ACTH secretion may have been somewhat sensitive to the suppressive effect of exogenous steroids. Glycyrrhetinic Acid

Glycyrrhetinic acid, a hydrolytic product of glycyrrhizic acid, has long been recognized as a causative agent of a pseudohyperaldosteronism syndrome. Its mechanism of action has been unraveled [569]. The compound inhibits the enzyme 11b-hydroxysteroid dehydrogenase which mainly converts cortisol to the inactive cortisone. Because this enzyme activity is present in the kidney, its inhibition induces a local excess of cortisol which will act, in a spill-over mechanism, on the kidney mineralocorticoid (or glucocorticoid type I) receptor and exert a mineralocorticoid-like effect [570]. As a consequence of the blockade of cortisol metabolism in the kidney urinary cortisol is increased; plasma cortisol is unchanged. Thus urinary cortisol is a false indicator of the cortisolic state in subjects under liquorice abuse [571].

Intercurrent Pathologic States Simple obesity has long been a major diagnostic problem when urinary 17-hydroxycorticosteroids were the usual markers of the adrenocortical activity [458]. Obesity per se induces an increased metabolic clearance rate of cortisol [459,460]. As an adaptive and appropriate response the cortisol production rate is increased with increased urinary cortisol metabolites. It has now been clearly demonstrated that the more appropriate parameters of baseline cortisol homeostasis (plasma and salivary cortisol, circadian rhythm, and urinary cortisol excretion), and the classic low-dose dexamethasone suppression test are all normal in simple obesity [448]. Hyperthyroidism also accelerates cortisol metabolism with the same consequences as simple obesity, with urinary 17-hydroxycorticosteroids being elevated. Other parameters of cortisol homeostasis remain normal. Hypothyroidism induces the opposite abnormalities, i.e., low urinary 17hydroxycorticosteroids [572]. Chronic renal failure has been mistakenly associated with abnormal glucocorticoid regulation, including diminished suppressibility by dexamethasone [573]: Because urinary measurements are evidently useless special caution must be applied to the sole possible plasma measurements. Polar metabolites of cortisol accumulate in blood to such high levels that they may significantly interfere in some cortisol assays that are not sufficiently specific. With the necessary precautions, including plasma extraction or highly specific immunoassay, plasma cortisol is normal and normally suppressible by the classic low-dose dexamethasone test

Chapter 13

[452,575]. Correct assessment of the pituitary–adrenal axis may be further hampered by the finding of increased plasma LPH levels [157,452], especially in hemodialysis patients, due solely to a decreased plasma clearance of LPH [576]. Plasma ACTH remains normal [452]. Patients with HIV infection, especially if treated with protease inhibitors, may exhibit features of pseudo-Cushing’s syndrome, including fat pads and central obesity. Appropriate ACTH/cortisol suppression after dexamethasone excludes the diagnosis of Cushing’s disease [574]. An exceptional patient has been reported who had both Addison’s and Cushing’s diseases [577]. The diagnosis was achieved by demonstrating the lack of normal circadian ACTH rhythm (which is normally preserved in Addison’s disease) under precise conditions of cortisol administration.

Hypercortisolic States Without Cushing’s Syndrome Various pathologic or physiologic conditions may be associated with biochemical, and sometimes clinical, evidences of endogenous glucocorticoid excess (Table 13.4). In these situations, increased cortisol production is thought to be driven by pituitary ACTH oversecretion secondary to CNS disorder or to an appropriate adaptive reaction. This functional hypercortisolic state is usually mild and transient and regresses with its cause. Hence it is not classically regarded as a cause of genuine Cushing’s syndrome, but has long been recognized and best studied in depressed patients. Depression

Patients with severe endogenous depression often exhibit biochemical stigmata of hypercortisolism [265]. Plasma cortisol and urinary steroids excretion are increased, and are not suppressed normally on the classic low-dose dexamethasone test. Activation of the pituitary–adrenal axis is fairly specific of depression among other conditions of primary affective disorders and may be observed in as many as Table 13.4. syndrome

Hypercortisolic states without Cushing’s

Functional hypothalamic CRH oversecretion Depression Anorexia nervosa Alcoholism Chronic stress Strenuous exercice Nonhypothalamic CRH oversecretion Pregnancy General insensitivity of glucocorticoids Familial resistance to glucocorticoids Pregnancy RU 486 CRH, corticotropin-releasing hormone.

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40–60% of patients in some series [264]. These observations eventually led to the routine use of differently designed and debated dexamethasone suppression tests as a biologic means for both the diagnosis and the follow-up of such patients. Normal or slightly increased plasma ACTH levels indicate that the disorder is pituitary driven. A fine evaluation of the hypothalamic–pituitary–adrenal axis of depressed patients has recently shed new light on the pathophysiologic mechanism leading to the hypercortisolic state of this disorder [578]. Depressed patients have an attenuated plasma ACTH response to CRH in comparison with normal controls, yet their basal plasma cortisol levels are elevated, and respond normally to CRH. These results indicate that the pituitary corticotroph is intrinsically normal, the attenuated ACTH response to CRH showing that they are sensitive to the negative feedback of increased cortisol levels ( just the reverse happens in Cushing’s disease). The normal cortisol response to CRH, in spite of blunted ACTH rise, is compatible with hyperplasia and hyperresponsiveness of the adrenal cortex, as has been independently reported by others in depressed patients [579]. The dynamics of ACTH are similar to those observed in normal subjects administered long-term CRH infusion [362] and therefore point to the hypothalamus or suprahypothalamic regions as the primary cause of ACTH oversecretion. Although the source and significance of CSF CRH is debated [264], the finding that depressed patients have increased CSF CRH levels [266], which eventually appear to correlate positively with the degree of pituitary–adrenocortical overactivity [267], has been taken as a further indication that this condition is due to a hypothalamic dysfunction with CRH overproduction. Whatever the exact pathophysiologic mechanism, the hypercortisolic state that accompanies depression often creates a serious diagnostic problem. A depressed patient may present with obesity, mild hirsutism, slight hypertension, and moderate glucose intolerance. Although none of them is by itself absolutely conclusive, several features may more or less distinguish between transient functional hypercortisolism and true Cushing’s syndrome with secondary depression. Classically in depression: 1. the hypercortisolic state is clinically and biologically mild. Urinary cortisol excretion almost never exceeds three times the upper limit of normal [580]; 2. the circadian pattern of plasma cortisol levels is less disrupted and sometimes a phase-shift phenomenon is merely observed [581,582]; 3. cortisol response to insulin-induced hypoglycemia is present in depressed patients in contrast to patients with Cushing’s syndrome of any cause, including Cushing’s disease [103,104,448]; 4. ACTH response to CRH is attenuated in contrast to the exaggerated response of Cushing’s disease; a wide overlap, nevertheless is observed [578];

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5. finally, imaging investigations should find no evidence of adrenocortical or pituitary tumor. Cases have been reported where depression preceded the occurrence of a true Cushing’s disease, raising the question of a possible pathophysiologic role for CRH, and further complicating the diagnostic issue. Anorexia Nervosa

Anorexia nervosa is associated with an array of neuroendocrine disorders among which sustained hypercortisolism is frequent [265] (see Chapter 18). Increased urinary cortisol and lack of normal suppression by the classic low-dose dexamethasone test may be found. Clinical features of hypercortisolism are absent probably because of the mild hypercortisolic state and the lack of sufficient substrates, more likely than because of a hypothetic downregulation of glucocorticoid receptors. The fine evaluation of ACTH and cortisol response to CRH in underweight patients with anorexia nervosa reveals patterns very similar to those observed in depressed patients [583]. Together with the finding of an increased CSF CRH level in anorexia nervosa [584,585] these data point to a hypothalamic or suprahypothalamic origin of the pituitary–adrenocortical overactivity in anorexia nervosa. An exceptional case has been reported where authentic Cushing’s disease with a pituitary adenoma found at surgery occurred 2 years after the onset of anorexia nervosa [586]. In contrast with depressed patients there is generally no clinical hesitation for the diagnosis. Abnormal corticotroph dynamics are corrected with weight restoration, and they might simply represent a nonspecific manifestation of inanition [587]. Alcoholism

Patients with chronic alcoholism may present with clinical and biochemical features of glucocorticoid excess creating a pseudo-Cushing’s syndrome [588–590]. General fatigue, diminished muscle strength, plethoric facies, truncal obesity, and abdominal striae may be encountered which all mimic the typical clinical features of Cushing’s syndrome [346]. A diagnosis which is further supported by the finding of increased plasma cortisol and urinary steroid excretion, a disrupted circadian rhythm, and lack of normal response to the classic low-dose dexamethasone suppression test. Alterations of the hypothalamic–pituitary–adrenal axis consistent with a hypothalamic origin are found in patients under chronic alcohol abuse, yet they are mild and present only in a minority of patients. Thus, it remains to be determined whether these functional abnormalities are associated with the propensity for alcohol abuse, are caused by ethanol intake possibly through a decrease of 11b hydroxysteroid dehydrogenase activity [591,592], or simply related to a common CNS disorder also responsible for depression. Whatever the mechanism involved, alcoholic pseudo Cushing’s syndrome is a real diagnostic challenge. The simplest and most effective way to avoid a false diagnosis is to

think of alcoholism and to observe the nice parallel decrease and normalization of cortisol indices and liver function tests during alcohol withdrawal in hospitalized patients [588–590,593]. Stress

Transient states of glucocorticoid excess without clinical stigmata commonly accompany an array of stressful conditions. They are thought to represent normal adaptive activation of the hypothalamic–pituitary–adrenal axis. Many such situations are encountered, including surgery, testtaking, various acute and chronic illnesses, terminal illnesses, extended burns, and diabetes mellitus [448,594,595]. The simple stress of hospitalization has been claimed to increase glucocorticoid secretion. These observations emphasize the absolute need to await the resolution of any stressful intercurrent condition before initiating a proper diagnostic evaluation. Strenuous Exercise

Slight alterations of the pituitary–adrenal axis may be encountered in response to physical exercise [596]. In a recent study, moderate elevation in baseline plasma cortisol and a blunted ACTH and cortisol response to CRH were observed in normal men running more than 45 miles per week [509]. Pregnancy

Normal pregnancy is associated with a profound hormonal turmoil that significantly alters glucocorticoid homeostasis (see also Chapter 17). In the first months of pregnancy increased estrogens induce a two- to threefold rise in plasma CBG that reaches a maximum at about 3 months and plateaus thereafter [558]. This generates a parallel rise in plasma cortisol but, in a similar manner to that observed in women on estrogen contraception, it does not induce a true hypercortisolic state since plasma free cortisol, and salivary and urinary cortisol remain within the normal range. With time more significant alterations develop that culminate in the last trimester when unequivocal features of a hypercortisolic state are found, at least from a biochemical viewpoint. Mean unbound and salivary cortisol and urinary cortisol excretion show a two- to threefold increase [363,364,441]. Thirty percent of women have 24-hour urinary cortisol excretion above the upper limit of normal, nonpregnant women, and most have an abnormal response to the classic low-dose dexamethasone suppression test [597]. The mechanism, and consequences, of this slight state of authentic hypercortisolism is not totally understood. Yet, major advances have been made in recent years which illuminate this intriguing problem. The normal placenta has been discovered as a large and physiologic site for CRH gene expression [598], depositing enormous quantities of the peptide into the maternal blood

Chapter 13

flow. Plasma CRH levels in late pregnancy may attain peaks of several thousand picograms per milliliter in comparison with the picograms per milliliter range in normal, nonpregnant women [368]. Although a large proportion of circulating CRH is bound to a carrier protein [599,600], strikingly elevated levels of free and bioactive CRH circulate at this time. Under such conditions and because plasma ACTH levels in pregnant women show a moderate but significant rise of about two- to threefold [597], it first seemed logical to charge placental CRH as a natural culprit. The situation however is not as clear; no correlation has been found between plasma CRH and pituitary–adrenal parameters [363]. Conservation of a perfectly normal, although slightly shifted upward, circadian rhythm of salivary cortisol is in sharp contrast with the steady state of high plasma CRH levels [363]. It points to an unrestrained hypothalamic drive that continues to operate and which overcomes both peripheral CRH and the expected negative feedback of increased plasma free cortisol. Whether it is related to a direct action of hypothalamic CRH at the pituitary, to AVP, or to an as yet unidentified factor, is unknown. Progesterone exerts an antiglucocorticoid action on rat pituitary corticotroph cells [601]; it has been hypothesized that prolonged and highly elevated progesterone levels induce a state of relative and general glucocorticoid resistance [363]. This would explain the slight shift in plasma free cortisol with conserved normal circadian rhythm, the abnormal dexamethasone suppressibility, and also the absence of peripheral clinical features of hypercortisolism. This hypothesis is reinforced by the recent finding that the change in salivary cortisol after delivery correlated with the increase in serum progesterone concentration in late prenancy [363]. Some have suggested that increased plasma ACTH in pregnancy might result from placental secretion [597] and/or a reviviscent intermediate lobe of the pituitary [602,603]. Familial Resistance to Glucocorticoids

This newly recognized syndrome was first identified in a patient with hypertension and hypokalemia [604]. Fine hormonal evaluation showed no evidence of aldosterone oversecretion or adrenocortical enzyme blockade. Instead evidence of glucocorticoid excess was found; plasma cortisol and urinary cortisol were elevated. Suppression of plasma cortisol by increasing doses of dexamethasone was abnormal with a shift to the right of the dose–response curve demonstrating the relative resistance of the pituitary to the negative glucocorticoid feedback in a manner similar to that observed in Cushing’s disease [605]. Two features were different; there was a normal circadian rhythm of plasma cortisol, and a total absence of clinical features of hypercortisolism. These observations suggested that the state of glucocorticoid resistance was not restricted to the pituitary, but was general.This hypothesis was reinforced by the finding of decreased glucocorticoid binding affinity of the patient’s

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fibroblasts [605], and recently established by the cloning of the glucocorticoid receptor in an affected patient. A single base substitution (A Æ T) at position 2054 changed Asp641 to Val within a highly conserved and hitherto supposedly functional region of the ligand-binding domain of the receptor, explaining the loss of affinity [170]. This rare familial syndrome has now been identified in several families, amounting to about 20 such patients. The clinical and biochemical features severely affect the patients with homozygous defects. Increased activity of the pituitary–adrenal axis is an adaptive, and thus appropriate, reaction. The hypertension and hypokalemia are explained by the increased mineralocorticoid activity due to excess DOC and cortisol acting on the normally sensitive mineralocorticoid receptor.

Normal Suppression with the Classic Low-dose Dexamethasone Test in Authentic Cushing’s Disease It has been estimated that a minority of patients (5%) with authentic Cushing’s disease suppress normally with the classic low-dose dexamethasone test, and thus are falsenegatives [448]. Returning to the original data provides a simple explanation [105]. The first trials to titer the daily amount of synthetic glucocorticoid necessary to suppress urinary 17-hydroxycorticosteroids used two different molecules with different potencies, namely D1-9a-fluorocortisol and D1-16a-methyl-9a-fluorocortisol (or dexamethasone). Titration curves readily show that complete suppression requires 2 mg/day of the first compound, but only £1 mg/day of dexamethasone. Curiously, in the original paper both drugs are used under the same generic name “DFF” leading the author to anticipate that “. . . although these two compounds were used interchangeably in the present study, it is possible that smaller doses of dexamethasone would be appropriate, in view of the apparent greater potency of this agent” [105]. In occasional patients with Cushing’s disease, normal suppressibility by the classic low-dose dexamethasone test has been attributed to a decreased metabolic clearance rate for dexamethasone [606,607]. Simultaneous measurements of plasma endogenous cortisol and dexamethasone provide a means whereby to evaluate suppressibility in comparison with the dose–response curve obtained in normals [564,607]. Other causes of apparently normal suppression in Cushing’s disease are encountered in the rare patients with true cyclical episodes of hypercortisolism whenever the test is performed during a quiescent phase.

Etiologic Pitfalls Cushing’s Disease Mimicking an Autonomous Adrenocortical Tumor

The classic situation is that of a patient with Cushing’s syndrome with apparent autonomous cortisol oversecretion

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[346]: urinary 17-hydroxycorticosteroids fail to suppress with the classic high-dose dexamethasone test, basal ACTH is low or undetectable, and adrenal imaging reveals a unilateral adrenal mass. When a unilateral adrenalectomy is performed, although transiently ameliorated, the hypercortisolism inevitably recurs allowing a correct and a posteriori diagnosis of Cushing’s disease in its macronodular hyperplastic form. This situation is not uncommon and the diagnosis would be correctly established if strict criteria were used. 1. Establishing autonomous cortisol production requires indisputable proof. It has previously been noted how the high-dose dexamethasone test should be interpreted with more subtlety and how it must be sometimes strengthened [352]. The ACTH RIA may be insensitive and undetectable basal plasma ACTH levels may become detectable with a better assay or after LVP or CRH stimulation [95]. A metyrapone test may also be of help showing a rise in urinary 17-hydroxycorticosteroids. Thus in many cases what appears as an autonomous adrenocortical activity does not resist a closer, and stronger, examination. 2. The second aspect that needs thorough evaluation is adrenal imaging. Although it may be highly asymmetrical to the point of mimicking a unilateral adrenocortical tumor, the macronodular hyperplasia of Cushing’s disease is not accompanied by contralateral atrophy, as is the case in a true autonomous adrenocortical adenoma [343]. Thus careful examination of the contralateral gland on CT scan almost invariably confirms the diagnosis. It may be in this rare situation where iodocholesterol scanning may be helpful, showing asymmetrical but bilateral isotope uptake [556,557]. Severe Cushing’s Disease Mimicking the Classic Ectopic ACTH Syndrome

The clinical presentation of a genuine Cushing’s disease may be severe enough as to mimic the classic form of the ectopic ACTH syndrome, with rapid onset, profound myopathy, severe hypokalemia, and definite hyperpigmentation [156,608]. Although the dynamic exploration of the corticotroph function may be concordant with Cushing’s disease, in some cases the correct diagnosis is obscured by some unexpected responses, such as a lack of suppressibility on the classic high-dose dexamethasone tests and sometimes lack of response to the CRH test [503]. In most cases however, pituitary imaging will point to the source of ACTH often showing a large macroadenoma on CT scan or MRI. If necessary, and if possible, bilateral inferior petrosal sinus sampling should ultimately provide the unequivocal solution. Mild Ectopic ACTH Syndrome Mimicking the Classic Cushing’s Disease

It has become increasingly recognized that some nonpituitary tumors provoke a Cushing’s syndrome with both clin-

ical and biochemical features similar to those of the classic Cushing’s disease [499]. Mild and slowly progressive symptoms are found together with dynamic tests strictly compatible with a nonautonomous, glucocorticoid responsive, cortisol overproduction [346]. In a minority of such cases a positive response to the CRH test is another pitfall for diagnosis [370,386,515]. Because most of these patients have had small and rather indolent bronchial carcinoid tumors [609] that until recently had escaped the usual means of detection by standard Xray, many have undergone unsuccessful pituitary surgery [610]. In some patients the correct diagnosis was made up to 10 years later [346]. The rare but classic occult carcinoid tumor which can be suspected by the detection of abnormal circulating POMC fragments and successfully detected by chest CT scan or MRI should always be borne in mind. The clear evidence of a pituitary microadenoma on MRI helps to eliminate this possibility. If it is not detectable, the slight risk of an unwarranted pituitary surgery should be weighed against the mild risk and discomfort of bilateral inferior petrosal sinus sampling which, at this stage, offers the sole and highly efficient means to separate the two conditions. STRATEGY Because there are different causes of Cushing’s syndrome and many different tests to distinguish between them the final diagnosis can theoretically be obtained through many different paths. Thus a general strategy is needed, the aim of which is to obtain a certain diagnosis with the minimum patient risk and discomfort for the patient at the maximum benefit–cost ratio. It should always be guided by the clinical features of the given patient and proceed in a stepwise fashion.

A Clinically Driven Strategy The diagnosis of Cushing’s syndrome requires a clinical presentation compatible with that originally described by Harvey Cushing [88]. Indeed, it may be wise to recall that in its absence no such investigation should be undertaken. In patients with obvious pathologic conditions known to be accompanied by functional hypercortisolic states (anorexia nervosa, alcoholism), the fine exploration of glucocorticoid homeostasis should cautiously await the disappearance of the primary disorder. The same attitude applies to patients under severe stressful conditions. A patient with authentic Cushing’s syndrome may have such severe complications of disease that some tests which could further compromise the condition may be contraindicated. Thus, the diagnostic approach may be modulated by some particular clinical presentations. There may be cases where it is important to delay testing, and others where it is urgent to treat and bypass tests. In the vast majority of

Chapter 13

cases however a defined and coordinated procedure can be applied.

A Stepwise Strategy A two-step diagnostic approach should first establish the hypercortisolic state and subsequently its cause. The Hypercortisolic State

Urinary cortisol excretion in a 24-hour collection is the most useful test. It has a better specificity than the overnight 1-mg dexamethasone suppression test and escapes various pitfalls pertaining to dexamethasone metabolism and drug interference. This simple baseline urinary collection achieves a diagnostic accuracy comparable to that of the reference classic low-dose dexamethasone suppression test. The Cause of the Hypercortisolic State

Hypercortisolic states without Cushing’s syndrome are usually easily recognized if not anticipated in the context of

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the primary disorder. The final diagnosis of Cushing’s syndrome will invariably rely on the combination of several diagnostic procedures using both hormonal and imaging tests that are summarized in Fig. 13.23. Several of these tests appear to readily distinguish patients with Cushing’s disease from the two other principal causes of spontaneous Cushing’s syndrome and the diagnosis of one of them should, theoretically, be sufficient. However, as mentioned previously their sensitivity and specificity are not high enough to always permit a certain diagnosis of each individual patient, particularly with the ectopic ACTH syndrome. Considering only the result of the classic high-dose dexamethasone suppression test, or the metyrapone test, or basal and/or CRH-stimulated plasma ACTH may not offer the ultimate diagnostic certainty. On these grounds a reasonable and classic strategy has been to perform all three tests in a coordinated fashion assuming that obtaining concordant results of all tests eliminates the risk of misinterpreting data that would have resulted from spontaneous fluctuations of cortisol or ACTH secretion. Although

FIGURE 13.23. Pathways to the diagnosis of Cushing’s syndrome. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; CT, computed tomography; MRI, magnetic resonance imaging.

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obtaining a serum cortisol level at midnight may often be inconvenient, this measurement was shown to effectively distinguish 240 patients with Cushing’s syndrome from 23 patients with pseudo-Cushing’s states in 96% of patients [652]. The CRH test has advantages over the two other classics. It is a rapid and harmless test that suffers almost no contraindication. It also distinguishes between the ectopic ACTH syndrome and an autonomous adrenal tumor. In proper hands and with a reliable ACTH assay (now provided by ACTH IRMA) it offers practical advantages. Bilateral inferior petrosal sinus sampling is being increasingly performed with a high diagnostic accuracy to separate pituitary and nonpituitary sources of ACTH. It has led some groups to propose its systematic use as the main if not sole diagnostic procedure for the etiologic work-up. Yet, because it represents an invasive technique, particularly considering the vascular fragility of these patients, and because its performance may rely above all on the skill of one particular investigator, others are reluctant to consider this test as a primary, systematic and routine diagnostic procedure for etiology. Pituitary imaging with MRI now detects microadenomas in up to 70% of patients with Cushing’s disease. A reasonable strategy therefore establishes the diagnosis of Cushing’s disease on the basis of concordant dynamic testing of the pituitary corticotroph function and the simultaneous presence of a pituitary microadenoma by MRI. In case of a negative pituitary imaging a thorough and systematic search for a nonpituitary tumor should be undertaken. Bilateral inferior petrosal sinus sampling may be considered with the expectation that it will avoid unwarranted transsphenoidal surgery in the rare case of an occult ectopic ACTH syndrome mimicking Cushing’s disease, and that it will provide useful information on the lateralization of the pituitary microadenoma for the surgeon in cases where the disease is confirmed. Adrenal imaging is essential in the workup of Cushing’s syndrome, especially to eliminate an autonomous adrenocortical tumor. In Cushing’s disease iodocholesterol scanning may be of help to evaluate asymmetrical macronodular lesions. However, in these cases the evaluation of pituitary corticotroph function remains the cornerstone of the etiologic investigation. TREATMENT In identifying the goals of treatment for Cushing’s disease, the morbidity and mortality of untreated chronic hypercortisolism dictate that the condition be treated rapidly and actively in most patients. Such goals are to correct adrenocortical oversecretion, ablate or destroy the primary tumoral lesion, respect anterior pituitary functions possibly restoring a normal pituitary–adrenal axis, and eventually reverse the peripheral manifestations of steroid excess.

These ideal goals cannot always be achieved and in many cases the treatment will only permit a patient to be controlled but not cured. Correction of adrenocortical oversecretion may be accompanied by persistent abnormality of the circadian rhythm (on op¢DDD), a need for life-long (bilateral adrenal surgery) or transient (selective pituitary adenomectomy) steroid coverage, or progressive development of pituitary insufficiency (radiotherapy). Over the years various strategies have been developed directed at either the adrenals or the pituitary and using surgical, radiation, and pharmacologic approaches either alone or in various combinations. Today, surgical removal of a pituitary microadenoma by the transsphenoidal route appears as the only therapeutic means capable of curing a patient. Yet, it is not always feasible nor always successful.

PITUITARY-DIRECTED THERAPIES

Surgery Pituitary surgery emerged as a major therapeutic approach in the late 1970s. Two groups [109,110] who performed it systematically in patients who had no evidence of sellar enlargement on skull X-ray demonstrated that most patients harbored a microadenoma in their pituitary and were cured by its selective removal. The rationale that guided this systematic approach was based on the prevalence of such microadenomas at autopsy [3,88], the reported successes in occasional patients who had been operated [611–613], and the convenience and safety of a novel neurosurgical procedure, namely the transsphenoidal route [612,614]. Over the last 10 years transsphenoidal pituitary exploration has become widespread in many centers and more than a thousand operated patients have been reported in published series. Prior to surgery, patients should be prepared so that severe hypertension and hyperglycemia be controlled, and infected areas eradicated. Depending on the severity of the hypercortisolic state some patients may need a course of anticortisolic treatment for several months before surgery. In all cases patients should receive glucocorticoid coverage during surgery and the operation should be performed only by experienced neurosurgeons, preferably in referral centers. Under these strict conditions the transsphenoidal approach is considered a safe procedure [531]. Mortality is exceptionally reported as a consequence of meningitis [111], bleeding [615], or delayed myocardial infarction [551], accounting for five operation-related deaths in about 550 published patients [616]. CSF leak occurs in 3–8% of cases. Mild and transient complications such as diabetes insipidus and facial and periorbital hematomas are more frequent. A successful surgical outcome of a selective adenomectomy characteristically induces a state of usually transient, although sometimes lasting up to several years, corticotroph deficiency during which steroid coverage is necessary. In

Chapter 13

most patients a progressive return to a completely normal pituitary–adrenal axis is observed. All baseline measurements, all dynamics tests and the circadian rhythm of cortisol are normal [111,116,140–142,145,616] (Fig. 13.24). Thus pituitary surgery has the potential to cure patients. Estimating the cure rate of pituitary surgery is difficult when comparing the results of different series. There are variable criteria for cure [617,618,711–713], variable durations of follow-up after surgery, and even variable surgical techniques and strategies. If an immediate success (or initial cure) is defined as the patient with normal or a low cortisolic state in the first 1–3 months after surgery, there is a general agreement for a high early success rate. Screening the results of more than 800 operated patients reported in 14 series from 14 different centers published between 1979 and 1989 shows that the early success rates varied between 66 and 88% [619]. In the seven largest series which report between 60 and 216 cases, this number varies between 70 and 92% [111–117]. These encouraging figures must be tempered by the fact that some patients who were early successes by the best criteria [289] eventually relapse. The rate of recurrences is difficult to analyze in the various series for lack of uniformity and because the valid figure, i.e., relapse rate (patients ¥ years of follow-up) is only rarely reported. It has been estimated at about 8% [616], although it can be as high as 15% [111,619] in some series. The postoperative work-up shows

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that, as a group, patients who ultimately recur have higher cortisol responses to CRH and higher baseline urinary cortisol excretion than other early cured patients who will not recur [111,619]. Yet, there is a large overlap. Because true recurrences may occur as late as 8 years [113] postoperatively, it is recommended that all initially cured patients be regularly – and indefinitely – followed. The reason for relapses remains obscure. It has been interpreted by some as the manifestation of a persistent hypothalamic drive that would have been primarily responsible for the development of a pituitary adenoma; alternatively a partial adenomectomy could spare a small population of tumoral cells that subsequently regrow [290,291]. A crucial question is to understand the reasons for the early surgical failures. Some circumstances provide an obvious explanation: (i) profuse local bleeding, often due to dural venous sinus, may prevent exposure of the gland [112]; (ii) a pituitary adenoma may be located above the sella (Fig. 13.25) or even in the sphenoid sinus [120,121]; or (iii) a patient with an occult ectopic ACTH syndrome may have been misdiagnosed [499,610]. Excluding these causes there are still patients who are unexpected surgical failures, either because the exploration cannot detect the adenoma or because removal of an apparent adenoma does not control the hypercortisolism. A thorough search for an indicator that would predict a favorable or unfavorable surgical outcome has not clearly distin-

FIGURE 13.24. Long-term follow-up of pituitary–adrenal function after successful pituitary surgery (S). (a) Circadian variation of plasma cortisol. (b, c) Plasma cortisol and adrenocorticotropic hormone (ACTH) responses to the lysine vasopressin (LVP) test. From Guilhaume et al. [111].

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FIGURE 13.25. Pituitary magnetic resonance image exhibiting a corticotroph adenoma situated above the sella turcica.

guished a convincing predictive biochemical parameter [111]. It has been proposed that the cure rate was lower in patients with large macroadenomas [112] with paradoxical responses to TRH and/or LHRH [619], with circulating autoantibodies against pituitary ACTH-producing cells [620], and in those with evidence of intermediate lobe involvement [245]. These suggestions remain controversial [616]. It will be interesting to observe if results of presurgical MRI pituitary imaging will correlate with the surgical success rate. Better correlations have emerged from studies systematically comparing the surgical outcome and histologic characteristics of the removed pituitary fragments [111,112,616,621]. One study reported that tumoral cells in the excised tissue were more prevalent in early successes (72%) than in surgical failures (24%, P < 0.01) [111]. The fact that adenomatous cells were not identified in most surgical failures suggested that either a pituitary adenoma was present which had been missed; or that there was no adenoma in the pituitary. The latter, which would favor a hypothalamic hypothesis for some Cushing’s diseases [134], actually is hardly tenable since no evidence of corticotroph cell hyperplasia was found histologically in this same study [111,621]. A much more likely explanation is that most of the time surgical failure occurs because a microadenoma was indeed present but missed. The fact that pre- and postoperative urinary cortisol excretion and plasma ACTH remained absolutely unchanged in patients who failed surgery despite removal of a significant portion (ca. 50%) of their anterior pituitary can be taken as an indication that only suppressed corticotroph cells had been removed, leaving the adenoma in situ [111]. Some patients have finally been cured when a microadenoma was found at a second operation [117,291]. There is no theoretical reason why it should be easy to explore a solid organ and discover inconspicuous lesions a few millimeters in size under a microscopic view that is often blurred by hemorrhages, and

at the same time ignore the lures of small microcystic structures lying close to the posterior lobe. Thus, technical difficulties should not be minimized as an evident cause of surgical failure. The surgical outcome does not always correlate with the histological data when some patients are cured after a mere exploration of the pituitary [112] or when no adenomatous cells were apparently removed [111,621], and others being surgical failures although such cells were found [111]. In a large series reporting 216 cases the primary predictor of failure to surgery was the existence of lateral extrasellar extension of the tumor [112]. Some groups have advocated that total hypophysectomy be performed systematically in order to diminish the risk of failure [623]. Others find no improved early success with this strategy [616]. Although total hypophysectomy appears to lower the risk of relapses it certainly augments the risks of hypopituitarism, and many recommend it in particular patients—usually postmenopausal women—and only if the surgeon fails to identify the adenoma [112]. In an attempt to improve the efficacy of pituitary surgery several groups have tried to develop new approaches to help the neurosurgeon find the microadenoma, or at least locate the pituitary half which harbors the lesion. Preoperative histologic examinations and ACTH determinations in peripituitary blood [624] have been claimed to be of help. But the most popular approach has been the bilateral inferior petrosal sinus sampling. A ratio of the ACTH level on one side to the other greater than 1.5 indicates that the adenoma lies in that same half of the pituitary gland [530,539]. Because some patients have been cured by hemihypophysectomy guided on the sole results of this test it may be indicated in the patients with no MRI evidence of microadenoma. It might avoid the total hypophysectomy, with its life-long hormone replacement, proposed by some if the surgical exploration were negative. Yet this technique should probably be reserved to experienced teams and its real diagnostic accuracy is variably appreciated [529,541]. Pituitary surgery has reemerged as a most fruitful treatment of Cushing’s disease. It essentially provides a rapid and easily assessable result with a high rate of success in expert hands. It has been successfully performed in a patient with an empty sella [626]. Its major causes of failure are anatomic due to the lateral extension, the small size, or the inaccessibility of the tumor. It is the sole treatment that results in a complete restitution ad integrum of the pituitary–adrenal axis. After successful pituitary surgery in 161 patients treated for Cushing’s Disease, long-term (mean of 8.7 years) survival was similar to that expected from an age- and sex-matched control population [625]. In case of failure of a selective adenomectomy or partial hypophysectomy all other therapeutic strategies remain open, including a second attempt at transsphenoidal exploration. It is ideally performed and evaluated by an integrated team with an endocrinologist, a radiologist, a neurosurgeon, and a histol-

Chapter 13

ogist. Transsphenoidal pituitary surgery for ACTH-secreting pituitary tumors is associated with a higher complication rate than that observed after similar surgery for other pituitary tumor cell types. About 13% of patients undergoing tumor resection in an experienced center develop complications, especially deep vein thrombosis [531].

Radiation Conventional radiotherapy

Probably the first patient to receive pituitary irradiation for Cushing’s disease was patient E.G.F. (or case 11 of Cushing’s monograph) who was almost dying from his condition when “. . . he was given . . . four X-ray treatments. During their course, he felt particularly miserable, but, his downward progression for the preceding month was unmistakenly checked. The improvement in his general condition was so striking it must have been something more than coincidence . . .” [88]. Subsequently conventional megavoltage pituitary irradiation has been proposed as a first-line treatment of Cushing’s disease. Success rates vary between groups depending on the proposed criteria to define cure. Because this treatment usually does not restore a normal circadian rhythm nor a normal response to the classic low-dose dexamethasone suppression test, the criteria for “cured” or “improved” patients are most often set arbitrarily according to some plasma cortisol or urinary steroid values. In a series of 51 irradiated patients, of 44 who had been followed-up for more than 1 year, 10 were judged cured (urinary 17-hydroxycorticosteroids <7 mg/g creatinine) for periods up to 14 years and 13 others were judged improved (urinary 17-hydroxycorticosteroids <10 mg/g creatinine) [627]. Subsequent reevaluation of this group showed that the success rate was especially high in the children (<20 years old) with 80% being cured, and suggesting that only about 15% of adults would be cured with an additional 30% improved [628]. Other groups have reported success rates somewhat higher, in the 50% range [629,630]. Most groups have delivered between 35 and 52 Gy with a daily fractional dose of ca. 200 cGy. Lower doses (20 Gy) have a high relapse rate [631]. The response to radiotherapy is slow, taking months or years for a full effect. Significant complications of modern radiotherapy are rare provided that the total and fractional doses remain within established limits. The most frequent is the late occurrence of hypopituitarism [631,632]. Serious complications such as injury to optic nerve or chiasma, radiation-induced carcinogenesis, and brain necrosis have been also reported in occasional patients with Cushing’s disease. However, they are truly exceptional for total doses of less than 50 Gy [633]. Because of its limitations as the sole treatment of Cushing’s disease, pituitary radiotherapy has been combined

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with various other therapeutic regimens [634]. Its combination with unilateral adrenalectomy does not seem justified in view of the poor success rate [635]. More logically and more efficiently, pituitary irradiation is associated with transient adrenocortical-directed medical treatment such as metyrapone or op¢DDD [637,638] until it has achieved its full effect. Twenty-five of 30 patients with persistent or recurrent Cushing’s disease after pituitary surgery who underwent radiation were in remission for a median followup of 42 months [636]. No recurrences occurred, and most patients were controlled within 2 years, especially when receiving concomitant ketoconozole therapy. Pituitary irradiation is probably undisputed in large macroadenomas that are either inoperable or only partially removed by surgery because of local extension [630]. Some controversy still exists on its prophylactic action for Nelson’s syndrome in patients subjected to bilateral adrenalectomy. Stereotactic Radiosurgery with the g-knife

An original device called g-knife has been developed and efficiently used for the last 20 years at the Karolinska Institute of Stockholm. A hemispheric instrument (collimator helmet) allows a cerebral target to be placed at a constant and exact intersection of 201 beams of 60Co radiation that simultaneously crossfire to the lesion. This technique achieves high precision and can deliver a fixed dose of radiation to areas ranging in size from 4 cm to a few millimeters without major side effects. The complete treatment is achieved in a single painless session of 5–30 minutes. The g-knife has been widely used to destroy pituitary adenomas with a high success rate, reaching 76% in Cushing’s disease with no relapses [639]. This rate is even improved when the pituitary lesion is precisely identified by MRI. It would be desirable that this radiation procedure be extended to several other centers, allowing a wider and more significant evaluation of what appears as a highly promising therapeutic means for its convenience and, hopefully, its high success rate.

Heavy Particle Radiotherapy The use of heavy particles (a-particle irradiation or protonbeam therapy) allows the delivery of a higher dose of radiation on a smaller volume target. Reported success rates appear somewhat higher than with conventional radiotherapy, between 65 and 80% [640,641]. This gain in efficacy is offset by an increased incidence of side effects such as optic nerve alteration, oculomotor palsies, and hypopituitarism. These methods are not applicable to large tumors with suprasellar or sinus extension, and they are only available in a limited number of specialized centers with a cyclotron. Radioactive Implants

Direct implantation of radioactive seeds within the sella has been claimed a safe and efficient treatment in the limited centers that perform this specialized stereotactic approach

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[642,643]. Local interstitial irradiation is delivered by 198Au or 90Y. In the largest and recently reported series of 86 patients, 77% had achieved remission after 1 year [644]. The authors emphasize the lack of recurrence of their cured patients as a major advantage over pituitary surgery. Yet interstitial irradiation is associated with a 50% incidence of hypopituitarism which compares quite unfavorably with conventional radiotherapy, and especially with surgery.

Medical Treatments Various drugs have been tentatively used to try to suppress oversecretion of ACTH in Cushing’s disease. Whatever the promises of the initial studies it is fair to say that in the long range none has gained a level of credibility that could favorably compare with that of the other therapeutic means [645].

Bromocriptine

The dopaminergic agent bromocriptine has initially been reported to cause an acute suppression of ACTH in a subset of patients with Cushing’s disease or Nelson’s syndrome [652–654]. Long-term remissions have been subsequently reported in occasional patients with Cushing’s disease. It has been suggested that bromocriptine-responsive patients harbored a distinctive type of pituitary adenoma that would originate from intermediate-lobe remnants [245]. This hypothesis has been debated [246,251]. A single controlled study established that bromocriptine was no more effective than placebo to acutely lower cortisol in most, if not all, patients with Cushing’s disease [245]. It remains possible however that an occasional tumor acquires some unexpected sensitivity to the dopaminergic drug, yet it remains exceptional [249,655]. Somatostatin

Cyproheptadine

In the mid-1970s the first cases of cyproheptadine-induced remissions were reported in three patients with Cushing’s disease [646]. Clinical and laboratory improvement manifested after 2–3 months of treatment at a dose of 24 mg/day. The drug subsequently proved also to be efficient in cases with Nelson’s syndrome [647]. The course of treated patients soon appeared highly variable. Some remained in remission long after (up to 3 years) the drug was discontinued, a majority relapsed either immediately after drug cessation or even while still under therapy [118]. Cyproheptadine possesses an array of pharmacologic actions since it is simultaneously antiserotonergic, antihistaminergic, anticholinergic, and antidopaminergic [118]. It is usually claimed that cyproheptadine blocks ACTH secretion in humans at the hypothalamic level through its antiserotonin action and its supposed beneficial therapeutic effect in Cushing’s disease has been taken as an indication that an intrinsic hypothalamic abnormality was at the origin of the disease [118]. Yet in vitro studies have also shown a direct inhibitory effect of cyproheptadine on ACTH release from cultured human pituitary adenoma cells [183]. Cyproheptadine administration constantly induces undesirable side-effects such as hyperphagia, weight gain, and sedation. Today it seems quite clear that antiserotonin drugs have a questionable therapeutic efficacy, through an unclear mechanism of action, and at the price of constant undesirable side effects. Sodium Valproate

Sodium valproate, another CNS-directed drug, has been reported to induce clinical remissions in some patients with Cushing’s disease or Nelson’s syndrome [648,649]. This indirect GABA-ergic drug, which acts by inhibiting GABA transaminase, could theoretically lower CRH production [118]. The promises of its action have not been confirmed by longterm studies [650,651].

Since the initial report showing that somatostatin infusion induced a partial decrease of plasma ACTH in five patients with Nelson’s syndrome [656] there have been a few studies of its action in Cushing’s disease and Nelson’s syndrome using the analog SMS 201-995 (octreotide). The clearest conclusion of these various anecdotal reports is that the somatostatin analog is ineffective in treating Cushing’s disease [657], in contrast to what is observed in some, but not all, patients with the ectopic ACTH syndrome [658]. Other Drug Treatments

CRH does not induce a state of pituitary corticotroph desensitization on tumor cells in vitro [162]. There is no theoretical reason to believe that chronic administration of a powerful CRH analog would inhibit ACTH secretion by a pituitary tumor. Although various peptides (corticostatins) and ACTH analogs [330] with anti-ACTH activity have been described, none has been used for pharmacologic or therapeutic trials in humans not adapted to treatment of Cushing’s disease. At the present time there is no effective means to pharmacologically control ACTH secretion or counteract its peripheral action in Cushing’s disease. The promises of the first trials with various CNS-directed compounds have not been confirmed in the long term. The proven efficacy of a drug should be unequivocally established only on the basis of well-designed and well-controlled trials [249,659]. Elegant studies have shown that many patients with Cushing’s disease have spontaneous fluctuations of their disease activity. It was nicely demonstrated that various CNS-directed drugs had a variable efficacy in the same patient that simply correlated with phases of spontaneous remissions [254]. These considerations are not trivial. It is not exceptional that a patient is referred to a specialized center after several months, or years, of a totally inefficient treatment trustfully administered on the basis of its alleged but not proven benefit.

Chapter 13

ADRENAL-DIRECTED THERAPIES

Surgery Total Bilateral Adrenalectomy

The recognition that adrenocortical overactivity was the common denominator of all spontaneous Cushing’s syndromes and the availability of steroid replacement therapy both boosted the indication of total bilateral adrenalectomy as a radical treatment of Cushing’s disease in the early 1950s [660,661]. The obvious and major advantage of this surgical option is its unequaled efficacy to control the hypercortisolic state that is constant and immediate. The first series reported a high operative mortality rate in the range of 5 to 10% [661]. A high incidence of postoperative complications was also a major concern in those fragile patients. Wound infections, poor healing, pancreatic injury, acute cholecystitis, pulmonary infections, and thromboembolism were the most frequent causes of a high morbidity rate. Some teams have advocated the posterior approach to the adrenals simultaneously by two surgical teams to expedite the procedure and minimize the postoperative morbidity of the more classic transabdominal approach [660]. In reality, the important dogma is to operate on patients who have been prepared, that is after a significant period of eucortisolic state, most often obtained by pharmacologic means. Although it remains a difficult surgical procedure, its mortality is now almost negligible and morbidity is greatly reduced with these precautions, provided that it is performed by a skilled and experienced surgical team. Adrenalectomized patients will require life-long steroid coverage by gluco- and mineralocorticoids with its unavoidable constraints, need for adaptation, education, and the risk of acute adrenal insufficiency. Unexpectedly, some patients resume endogenous cortisol secretion that may even lead to recurrence of their hypercortisolism, years after a total bilateral adrenalectomy. This occurrence is not exceptional, being reported in as many as 10% of cases [211,359,662]. It is due to the presence of some adrenal rests that have escaped the surgeon’s knife or to accessory glands located in various sites and which have regrown under the stimulatory action of chronically and highly elevated ACTH plasma levels. In some patients, the drastic cortisol deprivation induced by adrenal surgery seems to trigger a definite boost in the growth and secretory activity of the pituitary tumor which was at the origin of the disease. Sellar deformations and clinical hyperpigmentation occur, with increased plasma ACTH levels, defining the Nelson’s syndrome [663,664]. These tumors often grow aggressively, which may bear a significant morbidity and even mortality [211]. Thus the high efficacy of adrenal surgery is counterbalanced by several disadvantages [665]. It is reasonable to propose such an approach only when pituitary-directed treatments have failed or are contraindicated.

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Other Surgical Approaches

Subtotal resection of the adrenals had been initially proposed as the theoretically ideal surgical option. Retrospective analysis of various series shows that it actually fails in its object of restoring normal adrenocortical function in almost 90% of patients: most become adrenal-insufficient requiring steroid coverage, and almost 20–25% relapse [211]. Others have proposed total bilateral adrenalectomy and adrenal autotransplantation, either by inserting slices of the gland within and under the rectus muscle [666], or by transplanting one-third of a gland by vascular connection between the adrenal and the saphenous veins [667,668]. It seems that an occasional success may occur where the transplanted tissue remains active, eventually visualized by iodocholesterol scanning, and capable of delivering a reasonable amount of endogenous steroids up to 11 years after surgery [667]. The fine-tuning of cortisol homeostasis in such conditions is hardly predictable. Long-term follow-up of eight adrenal autotransplants gave rather unfavorable results [669].

Medical Treatments op¢DDD: An Adrenolytic Drug

In the late 1940s it was found by serendipity that the insecticide DDD provoked a selective necrosis of the dog adrenal cortex that predominated in the zona fasciculata and reticularis [670]. A contaminant of the crude DDD preparation exhibited the effective adrenolytic action: 1,1-dichloro-2-(ochlorophenyl)-2-(p-chlorophenyl)-ethane or op¢DDD. This compound was first used in humans for the chemotherapy of adrenocortical carcinomas where it exhibited a clear adrenolytic action [671]. Its therapeutic use was soon extended to the treatment of Cushing’s disease [638,672–674]. op¢DDD is a highly lipophilic compound with particular kinetics. Its absorption rate is very variable depending on the vehicle [675]. Compared with the commercially available tablets it is better absorbed when given in milk or chocolate, and poorly absorbed when micronized with the gastroresistant cellulose acetylphthalate. In this case much higher doses must be given (up to 12 g/day), in comparison with a usual dose of 3 g/day in its tablet form, but gastrointestinal side effects are minimized. The drug is stored in the adrenals and in the fat [676] and has been detected in the blood as long as 20 months after treatment cessation [677]. The most common side-effects of op¢DDD are digestive and neurologic [638]. Nausea and anorexia have been recorded in about 30% of patients; dizziness, apathy, and general weakness are often encountered transiently. All these side effects are generally minor; they disappear spontaneously or after lowering the dose. It is quite exceptional that they require more than a few days of drug interruption. More severe neurologic symptoms such as ataxia and tremor are extremely rare.

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Similar symptoms may result from adrenal insufficiency and before attributing them to a toxic effect of the drug vigorous glucocorticoid administration should be attempted. Adrenal insufficiency may occur in hydrocortisone-supplemented patients because through its effect on liver enzymes the drug accelerates the metabolism of exogenously administered steroids [463]. In some cases much higher doses of hydrocortisone are needed than usually required to supplement an Addisonian patient [678,679]. op¢DDD almost constantly provokes a series of biochemical alterations that reflect its being a major inducer of liver microsomal enzymes [678]. Plasma g-glutamyl transferase and alkaline phosphatase are increased but hepatitis never occurs. Blood cholesterol also invariably rises to a mean value of 3.6 g/L [638]. Caution should be exerted to adjust any intercurrent treatment involving liver metabolism (such as anti-vitamin K), and estrogen-containing birth control pills may be inefficient. Many patients on op¢DDD treatment show features of an estrogen-like effect: gynecomastia occurs in as many as 50% of male patients [638], and large increases in plasma CBG, sex-binding globulin, and thyroxine-binding globulin (up to six times baseline) have been reported. These actions are to be related to that of chlorinated insecticides such as op¢DDT [569]. Although not demonstrated directly for op¢DDD it is conceivable that the compound or one of its metabolites is also a potent estrogen-like agent. These effects, coupled with the rise in plasma cholesterol, obviously raise serious questions on a possible deleterious vascular effect, yet curiously there has been no systematic study on the general effect of op¢DDD on the vascular risk and on coagulation homeostasis. No renal or hematologic toxicity has been described. Allergic reactions (skin rash) are rare and transient. Diminished total and free T4 has been reported and may be related to a competition between op¢DDD and T4 on thyroxine-binding globulin [680]. Interestingly the gonads are not a target of op¢DDD action, which does not interfere with gonadal steroidogenesis [681]. Because of its presumed teratogenic

effect contraception should be insured in treated females and pregnancy only allowed after at least 2 years of interruption of the treatment; babies born from such patients have shown no abnormalities. Patients with Cushing’s disease almost invariably reduce their cortisol production on op¢DDD [638]. As already mentioned the response should not be assessed only on plasma cortisol or on urinary 17-hydroxycorticosteroids, which may be artifactually altered. Direct indicators of plasma free cortisol such as salivary or urinary cortisol are the best parameters. Decreased cortisol production is a slow phenomenon that is manifest after 1 or 2 months of treatment. Because the action of the drug is somewhat predominant on the zona fasciculata and reticularis the mineralocorticoid secretion has been claimed to be more preserved [673]. In many cases however it can also be fully suppressed [638]. op¢DDD provokes mitochondrial degeneration in adrenal cortical cells [673] and evidence for an altered activity of 11b-hydroxylase has been observed in patients with Cushing’s disease with a slight increase in plasma DOC and 11-deoxycortisol levels and in the ratios of DOC/ corticosterone and 11-deoxycortisol/cortisol [682]. Yet the particular and invaluable property of op¢DDD is that it is not merely an enzyme inhibitor, but truly an adrenolytic drug. The decreased cortisol production results from a loss of adrenocortical cells. This mechanism of action is different from that of the classic enzyme inhibitors which only block, more or less completely, the steroidogenesis pathway; hence the enormous advantage of op¢DDD. In contrast with the pure enzyme inhibitors its efficacy is not compromised by an escape phenomenon. It is nicely corroborated by the rise in ACTH and LPH which invariably is triggered in response to the relative cortisol deprivation (Fig. 13.26). Because the treatment with op¢DDD had been so efficient many patients refused adrenal surgery that had initially been planned after a medical preparation with the drug! Thus it became possible to observe the long-term effect of

FIGURE 13.26. Values (mean + SEM) of morning plasma lipotropin (LPH), adrenocorticotropic hormone (ACTH), and cortisol in patients with Cushing’s disease before therapy (stippled bars) and on op¢DDD (clear bars). From Kuhn et al. [95].

Chapter 13

op¢DDD as the sole treatment of Cushing’s disease [638]. Whereas about 80% of patients responded to treatment, it appeared that hypercortisolism recurred in most after cessation of the drug; 60% relapses were observed within 2 to 69 months. Although op¢DDD is a highly effective adrenolytic drug with unique properties, its use as sole therapy in Cushing’s disease has several limitations. Because of its numerous and serious side effects, its particular kinetics, and its highly variable bioavailability it necessitates close and repeated monitoring. The drug cannot pretend to cure a patient, but merely to control the hypercortisolism to a variable extent, and this has to be regularly evaluated. Many patients will develop adrenal insufficiency. Although its efficacy may last for years in a given patient, its effect is most often only transient. A better indication of op¢DDD is probably when transient control of hypercortisolism is needed, for example, waiting for the full effect of pituitary irradiation to become manifest [637,638], or to prepare a severely ill patient for pituitary or adrenal surgery. In the latter situation, the close observation of ACTH variations under prolonged reduction of plasma cortisol may be a predictive value of the aggressiveness of the pituitary tumor. Inhibitors of Cortisol Synthesis

Various pharmacologic agents that inhibit cortisol synthesis have been tentatively proposed for the treatment of Cushing’s disease. Metyrapone Metyrapone inhibits 11b-hydroxylase activity, blocking the last step of adrenal steroid biosynthesis, the conversion of the biologically inactive 11-deoxycortisol to cortisol. As expected, patients with Cushing’s disease respond to the cortisol-lowering effect of metyrapone by an overshoot of ACTH secretion that is anticipated to override the partial enzyme blockade [508]. Few reports describe its effectiveness in occasional patients [683,684]. A single group has systematically studied its long-term (up to 66 months) effect in patients with Cushing’s disease. Although ACTH did rise in response to the drug (750–4000 mg/day) it apparently was not sufficient to overcome the metyrapone blockade [685]. As noted elsewhere the patients of this study had also received pituitary radiotherapy, which may explain why the anticipated escape phenomenon was not reported in these very patients [686]. Furthermore, metyrapone often results in some general side effects including nausea and dizziness; it increases the secretion of adrenocortical androgens and may result in intolerable worsening of hirsuties in female patients [685]. Thus the beneficial effect of metyrapone as sole treatment of Cushing’s disease appears far from evident. It may be useful as an adjunct treatment while awaiting the full effect of pituitary irradiation. It may gain in power if administered concomitantly with other cortisol-lowering drugs [687,688] and may be useful for its rapid onset of action.

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Aminoglutethimide Aminoglutethimide blocks the first step in adrenal steroid biosynthesis. Its use in patients with Cushing’s disease has provided inconsistent results that are out weighed by its frequent side effects [689] which include somnolence, dizziness, and skin rash. Its use has been proposed in association with metyrapone [688]. Imidazole Derivatives: Ketoconazole and Etomidate The anticortisolic drug of the imidazole family, ketoconazole, inhibits various steps of adrenal and testicular steroidogenesis [690]. Cortisol synthesis is inhibited at the levels of the 20–22 desmolase and 11b-hydroxylase. Several studies initiated in the late 1980s have shown its rapid cortisollowering action in patients with Cushing’s disease [691,692] and its prolonged beneficial effect as the sole treatment in some series [693–695]. The ACTH response to long-term ketoconazole administration is somewhat variable, although it was increased in some patients, with an exaggerated response to CRH [696]. The successful action of long-term ketoconazole administration may be restricted, as for metyrapone, to patients who were concomitantly subjected to pituitary irradiation [693]. Patients have been reported who progressively escaped from the beneficial effect of ketoconazole [697]. Thus the real efficacy of the drug as the sole treatment of Cushing’s disease should await further evaluation. It has few side effects besides the rare toxic hepatitis. Another imidazole derivative, the anesthetic drug etomidate, also inhibits cortisol synthesis. It was recently shown that it can be safely administered intravenously at a nonhypnotic dose with a dramatic and immediate cortisollowering effect [698]. It is proposed as an alternative for the rapid control of severe hypercortisolic states. RU 486: Hopes and Limitations

The potent antiglucocorticoid action of RU 486 in humans raised the hope of a potential new pharmacologic approach in the treatment of patients with chronic hypercortisolism. The first reported case indeed showed a dramatic beneficial effect of the drug in a patient with ectopic ACTH syndrome [699]. The situation in Cushing’s disease is completely different. Based on the known pathophysiologic mechanism of the disease it was anticipated that RU 486 would antagonize cortisol action not only at the periphery but also at the pituitary and immediately trigger a brisk ACTH and cortisol rise. A single study performed in five patients with Cushing’s disease given the drug (400 mg/day) for three consecutive days confirmed this fear [700]. All indices of corticotroph and adrenocortical activities showed a major rise (Fig. 13.27). Urinary free cortisol increased 10-fold in some patients! Thus this short-term study demonstrated that RU 486 administration in Cushing’s disease will inevitably provoke an immediate pituitary retort. What will be the final balance at the peripheral target organ between the action of RU 486 and the increased endogenous cortisol is

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FIGURE 13.27. Pituitary–adrenal response to RU 486 (400 mg/day for 3 days) in a patient with Cushing’s disease. LPH, lipotropin; 17-OH, 17-hydroxycorticosteroids; UFC, urinary free cortisol.

unknown. At the present time a sensitive and convenient way of evaluating this peripheral balance that would allow the drug to be administered safely is lacking, especially in view of its long duration of action. Although it is possible that RU 486 may help to control hypercortisolism in some urgent situations [701], it should not be considered as a routine alternative for treating patients with Cushing’s disease. NELSON’S SYNDROME Don H. Nelson reported in 1958 the case of “. . . a patient who, three years after bilateral adrenalectomy for hyperadrenocorticisim, was found to have a chromophobe tumor of the pituitary gland that was secreting large quantities of ACTH” [663]. At that time the fine pathophysiologic mechanism of “Cushing’s syndrome due to bilateral adrenal hyperplasia” was undecided and even the role of the pituitary was debated, essentially because the lack of a sensitive ACTH assay did not allow measurement of the hormone in such patients. There was something prophetic in Nelson’s paper where he described the first 10 patients bearing his syndrome: “Ten patients, previously adrenalectomized for

Cushing’s syndrome, who have subsequently developed evidence of a disturbance of the pituitary gland, have been studied.”The recognition of this new entity was indeed illuminating; it pointed at the pituitary as the genuine cause of “Cushing’s syndrome due to bilateral adrenal hyperplasia” [664]. The evidence of “a disturbance of the pituitary gland” relied on an array of variously associated and more or less sensitive indicators such as hyperpigmentation, enlarged pituitary gland by roentgenologic examination or visual field defect, and increased plasma ACTH [209,664]. Because much more sophisticated and sensitive means have been designed to analyze the corticotroph function and pituitary morphology it is now known that both are disturbed in these patients, since the beginning of the disease and long before adrenal surgery. Nelson’s syndrome today should be reassessed. At the least it should refer not to the appearance but to the progression of a pituitary disturbance that follows, or is boosted by, adrenal surgery. Precisely because the definition of Nelson’s syndrome is variously appreciated, its incidence after adrenal surgery has been variably estimated as ranging from 5 to 78% in some series [2]. Judged on plasma ACTH increase as well as on hyperpigmentation, evidence of pituitary disease progress after adrenal surgery is almost constant [95,665]. The diagnosis of Nelson’s syndrome is based upon classic criteria, i.e., the occurrence of both hyperpigmentation and roentgenographic evidence of sellar enlargement. Although poorly sensitive, these criteria have two major advantages: (i) they have always been available allowing retrospective studies on large series of patients; and (ii) the occurrence of a sellar enlargement most often corresponds to a pituitary tumor the size of which is relevant for a significant morbidity. On the basis of these criteria, the prevalence of Nelson’s syndrome is lower, but still highly variable ranging from 8 to 38% [2,209,702–704]. Some authors report that pituitary tumors may occur as late as 16 years after surgery [703,704] although it is not known whether the patients were all regularly followed. In our series where patients were examined at least once a year we have found that pituitary tumor growth is an early event that was detected by skull X-ray at a mean of 2.7 years postsurgery (range 1–4.8 years). It is concordant with the finding that the ACTH rise within the year after adrenal surgery discriminates between the patients who will subsequently develop Nelson’s syndrome and those who will not [705,706]. In 76 patients who did not receive pituitary irradiation, 12 showed roentgenologic evidence of tumor growth, the actuarial curve indicating a risk of 29 ± 7% at 5 years postsurgery (95% confidence interval). Children seem to be more prone to develop Nelson’s syndrome [707]. No parameter has been found that could predict the behavior of the pituitary adenoma in response to the adrenal surgery. Recent data suggest that the ACTH rise in response to op¢DDD-induced cortisol long-term deprivation discriminated between patients at risk and the others, the former showing a definitely higher ACTH retort. Whether

Chapter 13

pituitary irradiation offers a prophylactic means against Nelson’s syndrome has been debated [627,703–705]. In our own series, none of 18 patients who received pituitary irradiation before or within 3 years after adrenal surgery developed Nelson’s syndrome. Corticotroph tumors of Nelson’s syndrome are among the most aggressive pituitary tumors. They can be rapidly growing, they usually have an infiltrative pattern and often show extrasellar extension, and/or cavernous sinus invasion [708]. True pituitary cancers with extracranial metastases have been described [207,209,703]. Plasma ACTH is usually above 1000 pg/ml and can reach the very high values of 100 000 pg/ml. Hyperpigmentation is invariable present. Stimulation of adrenal rests may lead to recurrent hypercortisolism with concomitant androgen and DOC oversecretion [359,709,710]. Treatment of such tumors is of utmost difficulty; surgery is almost always incomplete and irradiation therapy has limited efficacy [95,629]. An occasional tumor may spontaneously infarct [446]. These tumors may ultimately cause the death of a patient whose hypercortisolism is perfectly controlled [211]. A suggested mechanism is that total bilateral adrenalectomy provokes a dramatic cortisol deprivation state that triggers not only an overshoot of ACTH secretion but also a burst of tumor growth. Adrenalectomized patients receive steroid coverage in a total dosage that may surpass the physiologic substitution. However, on a daily basis the pituitary tumor is totally deprived of cortisol for several hours during the night. This is probably the major difference with the patient who still has two adrenals and a permanent production of cortisol during 24 hours. Although it has been amply demonstrated and finely explained how cortisol deprivation stimulates ACTH production it still remains to be shown if, and how, cortisol also acts on the growth of corticotroph cells. As already suggested, restored hypothalamic CRH activity may participate in the pathophysiologic mechanism of the tumor growth. So far there has been no means to evaluate the growth potential of a pituitary corticotroph adenoma. Because it remains an unpredictable event which somehow appears to be triggered by cortisol lowering it adds another reason why all efforts should be made to choose as a first-line treatment the therapeutic means which at the same time ablates this threat.

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pling if there is no obvious extrasellar lateral extension. It can be chosen as a first-line treatment in the moderately severe patient who does not require a prior preparation with anticortisolic drugs. If a microadenoma is found at exploration it is selectively removed by partial hypophysectomy. Most patients will be immediately cured. Long-term follow-up is necessary since late recurrences may occur. If the surgical exploration fails to identify an adenomatous lesion some have advocated immediate total hypophysectomy. It seems fair however to suggest only a partial hypophysectomy at a first operation. In some cases a small microadenoma will be excised and the patient will be cured. With the hope of increasing the odds of a successful blind partial hypophysectomy in case of a negative transsphenoidal exploration some groups perform a systematic bilateral inferior petrosal sinus sampling procedure prior to surgery. If a clear lateralization of ACTH is found it pinpoints the side of the gland which should be removed since it presumably harbors the inconspicuous corticotroph adenoma too small to be seen by the surgeon. It may be fair however to restrict this invasive procedure only to the patients who have no visible lesion on pituitary MRI. Failure of Pituitary Surgery

In case of initial surgical failure the partial hypophysectomy option has three advantages: (i) the overall pituitary function is not compromised; (ii) histologic examination of the obtained pituitary tissue provides information to explain the failure; and (iii) all therapeutic options remain open, including a second surgical attempt at the pituitary [711,712]. The excised pituitary tissue may show no tumoral tissue but only “normal” pituitary fragments with few corticotroph cells, some of them exhibiting Crooke’s hyaline features. The first consideration should be that of a diagnostic error, especially a missed occult ectopic ACTH syndrome. A complete reevaluation of the patient should be undertaken. If Cushing’s disease is ultimately confirmed the surgical failure may be best explained by the fact that a microadenoma does exist, but was missed. Alternatively histologic examination of the removed tissue may reveal the presence of tumoral cells within fragments of normal pituitary. In that situation it is highly likely that only part of an adenoma has been excised.

STRATEGY

Pituitary Surgery as the First-line Treatment The Transsphenoidal Approach

Pituitary surgery offers the success rate, and the quality of cure that undoubtedly designate it as the best therapeutic option. A systematic approach by the transsphenoidal route is indicated whenever the dynamic hormonal tests are all concordant with the diagnosis of Cushing’s disease, if the evidence for a pituitary adenoma has been obtained by MRI or, for certain groups, by bilateral inferior petrosal sinus sam-

A Second Trial of Pituitary Surgery?

This option can be envisaged only after the diagnosis of Cushing’s disease has been thoroughly reassessed, and the presence of a pituitary microadenoma clearly demonstrated either by bilateral inferior petrosal sinus sampling or after repeat MRI in the patient treated by anticortisolic drugs. It should not be performed if evidence of extrasellar lateral extension has been obtained. Secondary successes are reported in about 73% of patients [291]. In selected patients a total hypophysectomy may be planned in the prospect

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of increasing the odds of definitive success. Whatever the option the risk of compromising the overall pituitary function is maximized [291]. This strategy applies also to patients in whom the disease recurs.

When Pituitary Surgery is Questionable as a First-line Treatment Some situations raise serious doubt on the probability that first-line pituitary surgery will be successful and may command a different strategy. The classic situation is when the diagnosis between Cushing’s disease and the ectopic ACTH syndrome is unclear. The hormonal dynamics are consistent with Cushing’s disease but the pituitary MRI is negative, or the hormonal dynamics are not strictly concordant with Cushing’s disease. The bilateral inferior petrosal sinus sampling offers the theoretical means to resolve this ambiguity and has proved its efficacy in some groups. However it is not a widely accepted procedure because of its invasiveness, the need of an experienced radiologic team, and its diagnostic limitations [625]. A safe and practical alternative is to administer adrenaldirected therapy with drugs such as op¢DDD or ketoconazole. At the same time the hypercortisolism will be treated and close surveillance of the corticotroph function, of pituitary MRI, and other potential sources of nonpituitary ACTH should be conducted. Although this approach precludes the further use of dynamic hormonal testing it is a strategy that often provides time to secondarily detect an emerging small pituitary adenoma or sometimes a small bronchial carcinoid tumor. It is acceptable in view of the usually low agressiveness of these tumors and allows subsequent surgical treatment of these lesions in well-prepared patients. Rare pituitary tumors present with evidence of lateral extrasellar extension in the cavernous sinus are better detected by MRI. These potentially aggressive tumors should best be treated with combined radiotherapy and op¢DDD. The severity of the hypercortisolism may be severe enough to preclude immediate pituitary surgery. The patient may be prepared for surgery by a course of anticortisolic treatment for several months. Alternatively, a mild or cyclic form of Cushing’s disease may first require further close surveillance and repeat hormonal evaluation before a radical treatment option is undertaken.

After Pituitary Surgery has Failed At that time it is most often necessary to control the hypercortisolism with an adrenal-directed treatment. It is our experience that op¢DDD has the highest efficacy. Depending on the aggressiveness of the pituitary tumor simultaneous radiotherapy is often indicated and op¢DDD may be

discontinued later. This approach is effective, and use of less toxic ketoconazole may in fact be more beneficial. In rare cases of failure, total bilateral adrenalectomy may eventually be necessary, with its low, although unpredictable, risk of Nelson’s syndrome and the debated prophylactic role of pituitary radiation therapy. PERSPECTIVES Great promise has arisen from the early successes of pituitary surgery. These patients should be followed regularly and for a long time. The recurrence rates that will be observed in the years to come will permit a sound judgment on the efficacy of this therapeutic approach. In some cases, a small adenoma lying deep in a small pituitary gland remains a challenge for the therapist. It may not be totally unrealistic to envisage the development of more sensitive techniques that will detect and destroy these inconspicuous lesions. CRH analogs may be designed to target the appropriate isotopes or drugs specifically on the tumor cells eventually providing a convenient, elegant, and, hopefully, efficient new therapeutic approach. What is also needed is a practical and sensitive biochemical marker of the peripheral action of glucocorticoids. It would be a most useful aid to evaluate the real efficacy of all therapeutic means. It would also help to better evaluate those frequent patients who look somewhat hypercortisolic but have “normal” hormonal investigations. There may well be a large fringe of ill-defined pathologic states that potentially result from a slight disruption of cortisol homeostasis and cannot be detected by present modes of investigation uniformly directed toward the sole assessment of cortisol production rather than toward its action. ACKNOWLEDGMENTS The authors are greatly indebted to Professor P. Thomopoulos and Dr H. Escourolle for their comments and participation in obtaining hormonal data; to Professor L. Olivier and Dr E. Vila-Porcile for fruitful discussions and for the histologic illustrations; to Dr J.P. Abecassis and Professor A. Bonnin for their comments and the imaging illustrations; to MM J.F. Massias and F. Lenne for their contribution to the art work. They express their deep gratitude to Dr C. Bertagna for her benevolent and tolerant review of the text. This work would not have been possible without the invaluable secretarial expertise of Mrs M. Le Scouarnec. REFERENCES 1 Huff TA. Clinical syndromes related to disorders of adrenocorticotrophic hormone. In: Allen MB, Makesh VB, eds. The Pituitary: a Current Review. New York: Academic Press, 1977:153–168. 2 Baxter JD, Tyrrell JB. The adrenal cortex. In: Felig P, Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and Metabolism. New York: McGraw-Hill, 1981:385–510.

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284 Pepin MC, Pothier F, Barden N. Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene. Nature 1992;355:725–728. 285 Stenzel-Poore MP, Cameron VA, Vaughan J, Sawchenko PE, Vale W. Development of Cushing’s syndrome in corticotropin-releasing factor transgenic mice. Endocrinology 1992;130:3378–3386. 286 Sano T, Asa SL, Kovacs K. Growth hormone-releasing hormone-producing tumors: clinical, biochemical, and morphological manifestations. Endocr Rev 1988;9:357–373. 287 Sonino N, Fava GA, Grandi S, Mantero F, Boscaro M. Stressful life events in the pathogenesis of Cushing’s syndrome. Clin Endocrinol 1988;29:617–623. 288 Sonino N, Fava GA, Boscaro M. A role for life events in the pathogenesis of Cushing’s disease. Clin Endocrinol 1993;3:261–264. 289 Lamberts SWJ, Klijn JGM, de Jong FH. The definition of true recurrence of pituitary-dependent Cushing’s syndrome after transsphenoidal operation. Clin Endocrinol 1987;26:707–712. 290 Kuwayama A. Long-term results of pituitary surgery in Cushing’s disease. In: Ludecke DL, Chrousos GP, Tolis G, eds. ACTH, Cushing’s Syndrome, and other Hypercortisolemic States. New York: Raven Press, 1990:289–295. 291 Friedman RB, Oldfield EH, Nieman LK et al. Repeat trans-sphenoidal surgery for Cushing’s disease. J Neurosurg 1989;71:520–527. 292 Hammer GD, Mueller G, Lin B, Petrides JS, Roos BA, Low MJ. Ectopic corticotropin-releasing hormone produced by a transfected cell line chronically activates the pituitary–adrenal axis in transkaryotic rats. Endocrinology 1992;130:1975–1985. 293 Jones MT. Control of adrenocortical hormone secretion. In: James VHT, ed. The Adrenal Gland. New York: Raven Press, 1979:93–130. 294 Gill GN. ACTH regulation of the adrenal cortex. In: Gill GN, ed. Pharmacology of Adrenal Cortical Hormones. New York: Pergamon, 1979:35–66. 295 Hornsby PJ. The mechanism of action of ACTH in the adrenal cortex. In: Cooke BA, King RJB, Van Der Molen HJ, eds. Hormones and their Actions, Part II. Elsevier Science Publishers BV (Biomedical Division), 1988:193–210. 296 Mertz LM, Pedersen RC. The kinetics of steroidogenesis activator polypeptide in the rat adrenal cortex. Effects of adrenocorticotropin, cyclic adenosine 3¢ : 5¢ monophosphate cycloheximide and circadian rhythm. J Biol Chem 1989;264:15274–15279. 297 Waterman MR, Simpson ER. Regulation of the biosynthesis of cytochromes P-450 involved in steroid hormone synthesis. Mol Cell Endocrinol 1985;39:81–89. 298 John ME, John MC, Boggaram V, Simpson ER, Waterman MR. Transcriptional regulation of steroid hydroxylase genes by corticotropin. Proc Natl Acad Sci USA 1986;83:4715–4719. 299 Liddle GW. Regulation of adrenocortical function in man. In: Christy NP, ed. The Human Adrenal Cortex. New York: Harper and Row, 1971:41–68. 300 Penhoat A, Jaillard C, Saez JM. Corticotropin positively regulates its own receptors and cAMP response in cultured bovine adrenal cells. Proc Natl Acad Sci USA 1989;86:4978–4981. 301 Begeot M, Langlois D, Penhoat A, Saez JM. Variations in guanine-binding proteins (Gs, Gi) in cultured bovine adrenal cells. Consequences on the effects of phorbol and cholera-toxin-induced cAMP production. Eur J Biochem 1988;174:317–321. 302 Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science 1992;257:1248–1251. 303 Lebrethon MC, Penhoat A, Naville D, Jaillard C, Saez JM. Regulation of ACTH-receptor mRNA level by ACTH and angiotensin II in human (HAC) and bovine (BAC) cultured fasciculata-reticularis cells. 75th meeting of the American Endo. Soc. Las Vegas, June 1993 abstract 1680. 304 Penhoat A, Naville D, Jaillard C, Chatelain PG, Saez JM. Hormonal regulation of insulin-like growth factor I secretion by bovine adrenal cells. J Biol Chem 1989;264:6858–6862. 305 Louveau I, Penhoat A, Saez JM. Regulation of IGF-1 receptors by corticotropin and angiotensin-II in cultured bovine adrenocortical cells. Biochem Biophys Res Commun 1989;163:32–36. 306 Penhoat A, Chatelain PG, Jaillard C, Saez JM. Characterization of somatomedin-C/insulin-like growth factor I and insulin receptors on cultured bovine adrenal fasciculata cells. Role of these peptides on adrenal cell function. Endocrinology 1988;122:2518–2526. 307 Rainey WE, Viard I, Mason JI, Cochet C, Chambaz EM, Saez JM. Effects of transforming growth factor beta on ovine adrenocortical cells. Mol Cell Endocrinol 1988;60:189–198. 308 Kolanowski J, Crabbe J. Le mécanisme de l’hyperreactivité corticosurrénale à la corticotropine (ACTH) dans la maladie de Cushing. Horm Res 1980;13:337 (Abstract). 309 West CD, Dolman LI. Plasma ACTH radioimmunoassays in the diagnosis of pituitary–adrenal dysfunction. Ann NY Acad Sci 1977;297:205–219.

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362 Schulte HM, Chrousos GP, Gold PW et al. Continuous administration of synthetic ovine CRF in man. J Clin Invest 1985;75:1781–1785. 363 Allolio B, Hoffmann J, Linton EA, Winkelmann W, Kusche M, Schulte HM. Diurnal salivary cortisol patterns during pregnancy and after delivery: relationship to plasma corticotrophin-releasing-hormone. Clin Endocrinol 1990;33:279–289. 364 Abou-Samra AB, Pugeat M, Dechaud H et al. Increased plasma concentration of N-terminal lipotrophin and unbound cortisol during pregnancy. Clin Endocrinol 1984;20:221–228. 365 Schwartz J, Billestrup N, Perrin M, Rivier J, Vale W. Identification of corticotropin-releasing factor (CRF) target cells and effects of dexamethasone on binding in anterior pituitary using a fluorescent analog of CRF. Endocrinology 1986;119:2376–2382. 366 Childs GV, Moreil JL, Niendorf A, Aguilera G. Cytochemical studies of corticotropin-releasing factor (CRF) receptors in anterior lobe corticotropes: binding, glucocorticoid regulation, and endocytosis of [Biotiny1-Ser1] CRF. Endocrinology 1986;119:2129–2142. 367 Huager RL, Millan MA, Catt KJ, Aguilera G. Differential regulation of brain and pituitary corticotropin-releasing factor receptors by corticosterone. Endocrinology 1987;120:1527–1533. 368 Linton EA, Wolfe CDA, Behan DP, Lowry PJ. A specific carrier substance for human corticotrophin releasing factor in late gestational maternal plasma which could mask the ACTH-releasing activity. Clin Endocrinol 1988;28:315–324. 369 Linton EA, Behan DP, Saphier PW, Lowry PJ. Corticotropin-releasing hormone (CRH)-binding protein: reduction in the adrenocorticotropinreleasing activity of placental but not hypothalamic CRF. J Clin Endocrinol Metab 1990;70:1574–1580. 370 Suda T, Kondo M, Totani R et al. Ectopic ACTH syndrome caused by lung cancer that responded to corticotropin-releasing hormone. J Clin Endocrinol Metab 1986;63:1047–1051. 371 Raux-Demay MC, Proeschel MF, de Keyzer Y, Bertagna X, Luton JP, Girard F. Characterization of human corticotrophin releasing hormone and proopiomelanocortin related peptides in a thymic carcinoid tumor responsible for Cushing’s syndrome. Clin Endocrinol 1988;29:649–657. 372 Upton GV, Amatruda TT. Evidence for the presence of tumor peptides with corticotropin-releasing factor like activity in the ectopic ACTH syndrome. N Engl J Med 1971;285:419–424. 373 Howlett TA, Price J, Hale AC et al. Pituitary ACTH dependent Cushing’s syndrome due to ectopic production of a bombesin-like peptide by a medullary carcinoma of the thyroid. Clin Endocrinol 1985;22:91–101. 374 Brown WH. A case of pluriglandular syndrome: “Diabetes of bearded women”. Lancet 1928;ii:1022–1023. 375 Meador CK, Liddle GW, Island DP et al. Cause of Cushing’s syndrome in patients with tumors arising from “nonendocrine” tissue. J Clin Endocrinol Metab 1962;22:6893–703. 376 Liddle GW, Nicholson WE, Island DP, Orth DN, Abe L, Lowder SC. Clinical and laboratory studies of ectopic humoral syndromes. Recent Prog Horm Res 1969;25:283–314. 377 Orth DN. Ectopic hormone production. In: Felig P, Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and Metabolism. New York: McGraw-Hill, 1981;191–217. 378 Rees LH, Ratcliffe JG. Ectopic hormone production by nonendocrine tumours. Clin Endocrinol 1974;3:263–299. 379 White A, Clark AJL. The cellular and molecular basis of the ectopic ACTH syndrome. Clin Endocrinol 1993;39:131–142. 380 Yalow RS, Berson SA. Size heterogeneity of immunoreactive human ACTH in plasma and in extracts of pituitary glands and ACTH-producing thymoma. Biochem Biophys Res Commun 1971;44:439–445. 381 Bertagna XY, Nicholson WE, Sorenson GD, Pettengill OS, Mount CD, Orth DN. Corticotropin, lipotropin, and b-endorphin production by a human nonpituitary tumor in tissue culture: evidence for a common precursor. Proc Natl Acad Sci USA 1978;75:5160–5164. 382 Orth DN, Nicholson WE, Mitchell WM, Island DP, Liddle GW. Biologic and immunologic characterization and physical separation of ACTH and ACTH fragments in the ectopic ACTH syndrome. J Clin Invest 1973;52: 1756–1769. 383 Ratcliffe JG, Scott AP, Bennett HPJ et al. Production of a corticotrophin-like intermediate lobe peptide and of corticotrophin by a bronchial carcinoid tumour. Clin Endocrinol 1973;2:51–55. 384 Clark AJL, Stewart MF, Lavender PM et al. Defective glucocorticoid regulation of proopiomelanocortin gene expression and peptide secretion in a small cell lung cancer cell line. J Clin Endocrinol Metab 1990;70:485–490. 385 Oosterom R, Verleun T, Bruining HA, Hackeng WHL, Lamberts SWJ.

Secretion of adrenocorticotropin, b-endorphin and calcitonin by cultured medullary thyroid carcinoma cells. Effects of synthetic corticotropin-releasing factor and lysine vasopressin. Acta Endocrinol 1986;113:65–72. 386 Malchoff CD, Orth DN, Abboud C, Carney JA, Pairolero PC, Carey RM. Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone, metyrapone, and corticotropin-releasing factor. Am J Med 1988;84:760–764. 387 de Keyzer Y, Lenne F, Auzan C et al. The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome. J Clin Invest 1996;97:1311–1318. 388 Raffin-Sanson ML, de Keyzer Y, Bertagna X. Syndromes of ectopic ACTH secretion: recent pathophysiological progresses and their clinical implications. The Endocrinologist 2000;10:97–106. 389 Meyer WJ III, Smith EM, Richards GE, Cavallo A, Morrill AC, Blalock JE. In vivo immunoreactive adrenocorticotropin (ACTH) production by human mononuclear leukocytes from normal and ACTH-deficient individuals. J Clin Endocrinol Metab 1987;64:98–105. 390 Iida S, Nakamura Y, Fujii H et al. A patient with hypocortisolism and Cushing’s syndrome-like manifestations: cortisol hyperreactive syndrome. J Clin Endocrinol Metab 1990;70:729–737. 391 Meador CK, Bowdoin B, Owen WC, Farmer TA. Primary adrenocortical nodular dysplasia: a rare cause of Cushing’s syndrome. J Clin Endocrinol Metab 1967;27:1255–1263. 392 Carney JA, Hruska LS, Beauchamp GD, Gordon H. Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Mayo Clin Proc 1986;61:165–172. 393 Young WF, Carney JA, Musa BU, Wulffraat NM, Lens JW, Drexhage HA. Familial Cushing’s syndrome due to primary pigmented nodular adrenocortical disease. N Engl J Med 1989;321:1659–1664. 394 Kirschner LS, Sandrini F, Monbo J, Lin JP, Carney JA, Stratakis CA. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex. Hum Mol Genet 2000;9:3037–3046. 395 Casey M, Vaughan CJ, He J et al. Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest 2001;107:235. 396 Findlay JL, Sheeler LR, Engeland WC, Aron DC. Familial adrenocorticotropinindependent Cushing’s syndrome with bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 1993;76:189–191. 397 Lacroix A, Bolte E, Tremblay J et al. Gastric inhibitory polypeptide-dependent cortisol hypersecretion – a new cause of Cushing’s syndrome. N Engl J Med 1992;327:974–980. 398 Reznik Y, Allali-Zerah V, Chayvialle JA et al. Food dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med 1992;327:981–986. 398aLacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocr Rev 2001;22:75–110. 399 Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N Engl Med 1991;325:1688–1695. 400 Knyrim K, Higi M, Hossfeld DL, Seeber S, Schmidt CG. Autonomous cortisol secretion by a metastatic Leydig cell carcinoma associated with Klinefelter’s syndrome. J Cancer Res Clin Oncol 1981;100:85–93. 401 Marieb NJ, Splangler S, Kashgarian M, Heimann A, Schwartz ML, Schwartz PE. Cushing’s syndrome secondary to ectopic cortisol production by ovarian carcinoma. J Clin Endocrinol Metab 1983;57:737–740. 402 Christy NP. Iatrogenic Cushing’s syndrome. In: Christy NP, ed. The Human Adrenal Cortex. New York: Harper and Row, 1971:395–425. 403 Tyrrell JB, Baxter JD. Endocrinology and metabolism. In: Felig P, Baxter JD, Broadus AE, Frohman AL, eds. Glucocorticoid Therapy. New York: McGraw-Hill, 1981:599–623. 404 O’Hare JP, Vale JA, Wood S, Corrall RJ. Factitious Cushing’s syndrome. Acta Endocrinol 1986;111:165–167. 405 Cook DM, Meikle AW. Factitious Cushing’s syndrome. J Clin Endocrinol Metab 1985;61:385–387. 406 Siminoski K, Goss P, Drucker DJ. The Cushing’s syndrome induced by medroxyprogesterone acetate. Ann Intern Med 1989;111:758–760. 407 Altschule MD. A near miss. Osler’s early description of Cushing’s syndrome with, regrettably, no post-mortem examination. N Engl J Med 1980;302:1153–1155. 408 Osler W. An actue myxoedematous condition, with tachycardia, glycosuria, melaena, mania, and death. J Nerv Ment Dis 1899;26:65–71. 409 Cushing H. The Pituitary Body and its Disorders, Philadelphia: Lippincott, 1912. 410 Ross EJ, Marshall-Jones P, Friedman M. Cushing’s syndrome: diagnostic criteria. Q J Med 1966;35:149–192.

Chapter 13 411 Santini LC, Williams JL. Mediastinal widening (presumable lipomatosis) in Cushing’s syndrome. N Engl J Med 1971;284:1357–1359. 412 Nugent CA, Warner HR, Dunn JT, Tyler FH. Probability theory in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 1964;24:621–627. 413 Ross EJ, Linch DC. Cushing’s syndrome-killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet 1982;ii:646–649. 414 Luton JP, Valcke JC, Turpin G, Forest M, Bricaire H. Muscle et syndrome de Cushing. Ann Endocrinol 1970;31:157–169. 415 Bricaire H, Thibonnier M, Hautecouverture M, Corvol P, Luton JP. Variations du système rénine angiotensine aldostérone dans la maladie de Cushing. Nouv Presse Med 1980;9:1007–1009. 416 Ritchie CM, Sheridan B, Fraser R et al. Studies on the pathogenesis of hypertension in Cushing’s disease and acromegaly. Q J Med 1990;280:855–867. 417 Saruta T, Suzuki H, Handa M, Igarash Y, Kondo K, Senba S. Multiple factors contribute to the pathogenesis of hypertension in Cushing’s syndrome. J Clin Endocrinol Metab 1986;62:275–279. 418 Luton JP, Richard CH, Laudat MH, Pinon JC, Bricaire H. Manifestations cardiovasculaires et anomalies lipidiques au cours du syndrome de Cushing. Nouv Presse Med 1982;11:2693–2698. 419 Patrassi GM, Dal Bo Zanon R, Boscaro M, Martinelli S, Girolami A. Further studies on the hypercoagulable state of patients with Cushing’s syndrome. Thromb Haemost 1985;518–520. 420 Ludecke DK, Niedworok G. Results of microsurgery in Cushing’s disease and effect on hypertension. Cardiology 1985;72:91–94. 421 Jurney TH, De Ruyter H, Vigersky RA. Cushing’s disease presenting as amenorrhoea with hyperprolactinaemia: report of two cases. Clin Endocrinol 1981;14:539–545. 422 Yamaji T, Ishibashi M, Teramoto A, Fukushima T. Hyperprolactinemia in Cushing’s disease and Nelson’s syndrome. J Clin Endocrinol Metab 1984;58:790–795. 423 Luton JP, Thieblot P, Valcke JC, Mahoudeau J, Bricaire H. Reversible gonadotropin deficiency in male Cushing’s disease. J Clin Endocrinol Metab 1977;45:488–495. 424 Mazet PH, Simon D, Luton JP, Bricaire H. Syndrome de Cushing: symptomatologie psychique et personnalité de 50 malades. Nouv Presse Med 1981;10:2565–2570. 425 Luton JP, Strauch G, Salmon D, Linard M, Bricaire H. Etude de la glycorégulation au cours des syndromes de Cushing avant et après thérapeutique. Journées endocrinologiques de Langue Française, Paris. La Revue Française d’Endocrinologie Clinique, Nutrition et Métabolisme 1973;4:315–320. 426 Sartorio A, Ambrosi B, Colombo P, Morabito F, Faglia G. Osteocalcin levels in Cushing’s disease before and after treatment. Horm Metab Res 1998;20:70. 427 Kuchel O, Bolte E, Chretien M et al. Cyclical edema and hypokalemia due to occult episodic hypercorticism. J Clin Endocrinol Metab 1987;64:170–174. 428 Brown RD, Van Loon GR, Orth DN, Liddle GW. Cushing’s disease with periodic hormonogenesis: one explanation for paradoxical response to dexamethasone. J Clin Endocrinol Metab 1973;36:445–451. 429 Liberman B, Wajchenberg BL, Tambascia MA, Mesquita CH. Periodic remission in Cushing’s disease with paradoxical dexamethasone response: an expression of periodic hormonogenesis. J Clin Endocrinol Metab 1976;43:913–918. 430 Schteingart DE, McKenzie AL. Twelve-hour cycles of adrenocorticotropin and cortisol secretion in Cushing’s disease. J Clin Endocrinol Metab 1980;51: 1195–1198. 431 Vagnucci AH, Evans E. Cushing’s disease with intermittent hypercortisolism. Am J Med 1986;80;83–88. 432 Schweikert HU, Fehm HL, Fahlbusch R et al. Cyclic Cushing’s syndrome combined with cortisol suppressible, dexamethasone non-suppressible ACTH secretion: a new variant of Cushing’s syndrome. Acta Endocrinol 1985; 110:289–295. 433 Laudat MH, Cerdas S, Fournier C, Guiban D, Guilhaume B, Luton JP. Salivary cortisol measurement: a practical approach to assess pituitary–adrenal function. J Clin Endocrinol Metab 1988;66:343–348. 434 Hermus AR, Pieters GF, Borm GF et al. Unpredictable hypersecretion of cortisol in Cushing’s disease: detection by daily salivary cortisol measurements. Acta Endocrinol 1993;5:428–432. 435 Raux-Demay MC, Girard F. Hyperfonctionnement corticosurrénalien. In: Bertrand J, Rappaport R, Sizonenko PC, eds. Endocrinologie Pédiatrique. Lausanne: Payot, 1982:471–481. 436 Miller WL, Townsend JJ, Grumbach MM, Kaplan AL. An infant with Cushing’s disease due to an adrenocorticotropin-producing pituitary adenoma. J Clin Endocrinol Metab 1979;48:1017–1025.

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465 Beardwell CG, Burke CW, Cope CL. Urinary free cortisol measured by competitive protein binding. J Endocrinol 1968;43:79–89. 466 Murphy BEP. Clinical evaluation of urinary cortisol determinations by competitive protein-binding radioassay. J Clin Endocrinol Metab 1968;28:343–348. 467 Vidal-Trecan G, Laudat MH, Thomopoulos P, Luton JP, Bricaire H. Urinary free corticoids: an evaluation of their usefulness in the diagnosis of Cushing’s syndrome. Acta Endocrinol 1983;103:110–115. 468 Kobberling J, Von Zur Muhlen A. The circadian rhythm of free cortisol determined by urine sampling at two-hour intervals in normal subjects and in patients with severe obesity or Cushing’s syndrome. J Clin Endocrinol Metab 1973;38:313–319. 469 Laudat MH, Billaud L, Thomopoulos P, Vera O, Yllia A, Luton JP. Evening urinary free corticoids: a screening test in Cushing’s syndrome and incidentally discovered adrenal tumours. Acta Endocrinol 1988;119:459–464. 470 Esteban NV, Loughlin T, Yergey AL et al. Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab 1991;71:39–45. 471 Kennedy L, Atkinson AB, Johnston H, Sheridan B, Hadden DR. Serum cortisol concentrations during low dose dexamethasone suppression test to screen for Cushing’s syndrome. Br Med J 1984;289:1188–1191. 472 Luthold WW, Marcondes JA, Wajchenberg BL. Salivary cortisol for the evaluation of Cushing’s syndrome. Clin Chim Acta 1985;151:33–39. 473 Hindmarsh PC, Brook CG. Single dose dexamethasone suppression test in children: dose relationship to body size. Clin Endocrinol 1985;23:67–70. 474 Nugent CA, Nichols T, Tyler FH. Diagnosis of Cushing’s syndrome—single dose dexamethasone suppression test. Arch Intern Med 1965;116:172–176. 475 Cronin C, Igoe D, Duffy MJ, Cunningham SK, McKenna TJ. The overnight dexamethasone test is a worthwhile screening procedure. Clin Endocrinol 1990;33:27–33. 476 James VHT, Landon J, Wynn V. Oral and intravenous suppression tests in the diagnosis of Cushing’s syndrome. J Endocrinol 1965;33:515–524. 477 Abou-Samra AB, Dechaud H, Estom B et al. b-Lipotropin and cortisol responses to an intravenous infusion of dexamethasone suppression test in Cushing’s syndrome and obesity. J Clin Endocrinol Metab 1985;61:116–119. 478 Atkinson AB, McAteer EJ, Hadden DR, Kennedy L, Sheridan B, Traub AI. A weight-related intravenous dexamethasone suppression test distinguishes obese controls from patients with Cushing’s syndrome. Acta Endocrinol 1989;120:753–759. 479 Orth DN. Adrenocortictropic hormone (ACTH). In: Jaffe BM, Behrman HR, eds. Methods of Hormone Radioimmunoassay. New York: Academic Press, 1979:245–284. 480 Besser GM, Orth DN, Nicholson WE, Bynny RL, Abe K, Woodham JP. Dissociation of disappearance of bioactive and radioimmunoreactive ACTH from plasma in man. J Clin Endocrinol Metab 1971;32:595–603. 481 Lefkowtiz RJ, Roth J, Pastan I. Radio-receptor assay of adrenocorticotropic hormone: new approach to assay of polypeptide hormone in plasma. Science 1970;170:633–635. 482 Chayen J, Loveridge N, Daly JR. A sensitive bioassay for adrenocorticotrophic hormone in human plasma. Clin Endocrinol 1972;1:219-233. 483 Hodgkinson SC, Allolio B, Landon J, Lowry PJ. Development of a nonextracted “two-site” immunoradiometric assay for corticotropin utilizing extreme amino- and carboxy- terminally directed antibodies. Biochem J 1984;218:703–711. 484 Findling JW, Engeland WC, Raff H. The use of immunoradiometricassay for the measurement of ACTH in human plasma. Trends Endocrinol Metab 1990;1:283–287. 485 Raff H, Findling JW, Wong J. Short loop adrenocorticotropin feedback after ACTH 1–24 in injection in man is an artifact of the immunoradiometric assay. J Clin Endocrinol Metab 1989;69:678–680. 486 Horrock PM, London DR. Diagnostic value of 9 am plasma adrenocorticotrophic hormone concentrations in Cushing’s disease. Br Med J 1982;285:1302–1303. 487 Hope J, Ratter SJ, Estivariz FE, McLoughlin L, Lowry PJ. Development of a radioimmunoassay for an amino-terminal peptide of pro-opiocortin containing the gamma-MSH region: measurement and characterization in human plasma. Clin Endocrinol 1981;15:221–227. 488 Chan JSD, Seidah NG, Chretien M. Measurement of N-terminal (1–76) of human proopiomelanocortin in human plasma: correlation with adrenocorticotropin. J Clin Endocrinol Metab 1983;56:791–796. 489 Phlipponneau M, Lenne F, Proeschel MF, Girard F, Luton JP, Bertagna X. Plasma immunoreactive joining peptide in man: a new marker of proopiomelanocortin processing and corticotroph function. J Clin Endocrinol Metab 1993;76:325–329.

490 Gilkes JJH, Rees LH, Besser GM. Plasma immunoreactive corticotrophin and lipotrophin in Cushing’s syndrome and Addison’s disease. Br Med J 1977;1:996–998. 491 Wiedemann E, Saito T, Linfoot JA, Li CH. Radio-immunoassay for human blipotropin in unextracted plasma. J Clin Endocrinol Metab 1977;45:1108–1111. 492 Krieger DT, Liotta AS, Suda T, Goodgold A, London E. Human plasma immunoreactive lipotropin and adrenocorticotropin in normal subjects and in patients with pituitary–adrenal disease. J Clin Endocrinol Metab 1979;48:566–571. 493 Wiedemann E, Saito T, Linfoot JA, Li CH. Specific radioimmunoassay of human b-endorphin in unextracted plasma. J Clin Endocrinol Metab 1979;49:478–480. 494 Smith R, Grossman A, Gaillard R et al. Studies on circulating metenkephalin and b-endorphin: normal subjects and patients with renal and adrenal disease. Clin Endocrinol 1981;15:291–300. 495 Halpin DM, Burrin JM, Joplin GF. Serum testosterone levels in women with Cushing’s disease. Acta Endocrinol 1990;122:71–75. 496 Crosby SR, Stewart MF, Ratcliffe JG, White A. Direct measurement of the precursors of adrenocorticotropin in human plasma by two-site immunoradiometric assay. J Clin Endocrinol Metab 1988;67:1272–1277. 497 Lowry PJ, Linton EA, Hodgkinson SC. Analysis of peptide hormones of the hypothalamic pituitary adrenal axis using “two-site” immunoradiometric assays. Horm Res 1989;32:25–29. 498 Odagiri E, Demura R, Demura H et al. The changes in plasma cortisol and urinary free cortisol by an overnight dexamethasone suppression test in patients with Cushing’s disease. Endocrinol Jpn 1988;35:795–802. 499 Howlett TA, Drury PL, Perry L, Doniach I, Ress LH, Besser GM. Diagnosis and management of ACTH-dependent Cushing’s syndrome: comparison of the features in ectopic and pituitary ACTH production. Clin Endocrinol 1986;24:699-713. 500 Bailey RE. Periodic hormonogenesis—a new phenomenon. Periodicity in function of a hormone-producing tumor in man. J Clin Endocrinol Metab 1971;32:317–327. 501 Liberman B, Wajchenberg BL, Tambascia MA, Mesquita CH. Periodic remission in Cushing’s disease with paradoxical dexamethasone response: an expression of periodic hormonogenesis. J Clin Endocrinol Metab 1976;43:913–918. 502 Tyrrell JB, Findling JW, Aron DC, Fitzgerald PA, Forsham PH. An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing’s syndrome. Ann Intern Med 1986;104:180–186. 503 Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med 1990;112:434–444. 504 Croughs RJM, Docter R, DeJong FH. Comparison of oral and intravenous dexamethasone suppression tests in the differential diagnosis of Cushing’s syndrome. Acta Endocrinol 1973;72:54–62. 505 Liddle GW, Estet HL, Kendall JW, Williams WC, Townes AW. Clinical application of a new test of pituitary reserve. J Clin Endocrinol Metab 1959;19:875–894. 506 Streeten DHP, Anderson GH, Dalakos TG et al. Normal and abnormal function of the hypothalamic–pituitary–adrenocortical system in man. Endocr Rev 1984;5:371–394. 507 Spiger M, Jubiz W, Meikle AW, West CD, Tyler FH. Single-dose metyrapone test: review of a four-year experience. Arch Intern Med 1975;135:698–700. 508 Abou-Samra AB, Fevre-Montange M, Pugeat M et al. The value of blipotrophin measurement during the short metyrapone test in patients with pituitary diseases and in Cushing’s syndrome. Acta Endocrinol 1984;105:441–448. 509 Colombo P, Dall’Asta C, Barbetta L et al. Usefulness of the desmopressin test in the post-operative evaluation of patients with Cushing’s disease. Eur J Endocrinol 2000;143:227–234. 510 Orth DN. Corticotropin-releasing hormone in humans. Endocr Rev 1992;13:164–191. 511 Grossman A, Nieuwenhuyzen Kruseman AC, Perry L et al. New hypothalamic hormone, corticotropin releasing factor, specifically stimulates the release of adrenocorticotrophic hormone and cortisol in men. Lancet 1982;i:921–922. 512 Watson SJ, Lopez JF, Young EA, Vale W, Rivier J, Knazek RA. Effects of low dose oCRH in humans: endocrine relationships and beta-endorphin-beta lipotropin responses. J Clin Endocrinol Metab 1988;66:10–15. 513 Nieman LK, Cutler GB, Oldfield EH, Loriaux DL, Chrousos GP. The ovine corticotropin-releasing hormone (CRH) stimulation test is superior to the human CRF stimulation test for the diagnosis of Cushing’s disease. J Clin Endocrinol Metab 1989;69:165–169. 514 Chrousos GP, Nieman L, Nisula B et al. Corticotropin-releasing factor stimulation test. N Engl J Med 1984;311:471–473.

Chapter 13 515 Nieman LK, Chrousos GP, Oldfield EH, Avgerinos PC, Cutler GB, Loraux DL. The ovine corticotropin-releasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing’s syndrome. Ann Intern Med 1986;105:862–867. 516 Newell-Price J, Grossman A. Diagnosis and management of Cushing’s syndrome. Lancet 1999;353:2087-2088. 517 Boscaro M, Rampazzo A, Sonino N, Merola G, Scanarini M, Mantero F. Corticotropin releasing hormone stimulation test: diagnostic aspects in Cushing’s syndrome. J Endocrinol Invest 1987;10:297–302. 518 Hermus AR, Pieters GF, Pesman GJ, Smals AG, Benraad TJ, Kloppenborg PW. The corticotropin-releasing-hormone test versus the high dose dexamethasone test in the differential diagnosis of Cushing’s syndrome. Lancet 1986;ii:540–544. 519 Jorgensen H, Skare S, Frey H, Hanssen KF, Norman N. Effects of synthetic corticotropin-releasing factor in normal individuals and in patients with hypothalamic–pituitary–adrenocortical disorders. Acta Med Scand 1985;218:79–84. 520 Muller OA, Stalla GK, Von Werder K. Corticotropin-releasing-factor: a new tool for the differential diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 1983;57:227–229. 521 Schrell V, Fahlbusch R, Bushfelder M, Riedi S, Stall GK, Muller OA. Corticotropin-releasing hormone stimulation test before and after transsphenoidal selective microadenomectomy in 30 patients with Cushing’s disease. J Clin Endocrinol Metab 1987;64:1150–1159. 522 Muller OA, Stalla GK, Von Werder K. CRH in Cushing’s syndrome. Horm Metab Res 1987;16:51–58. 523 Orth DN. Cushing’s syndrome. N Engl J Med 1995;332:791–803. 524 Grossman AB, Howlett TA, Perry L et al. CRF in the differential diagnosis of Cushing’s syndrome: a comparison with the dexamethasone suppression test. Clin Endocrinol 1988;29:167–178. 525 Favrod-Coune C, Raux-Demay MC, Proeschel MF, Bertagna X, Girard F, Luton JP. Potentiation of the classic ovine corticotrophin-releasing hormone stimulation test by the combined administration of small doses of lysine vasopressin. Clin Endocrinol 1993;28:405–410. 526 Dickstein G, DeBold CR, Gaitan D et al. Plasma ACTH and cortisol responses to ovine corticotropin-releasing hormone (CRF), arginine vasopressin (AVP), CRH plus AVP, and CRH plus metyrapone in patients with Cushing’s disease. J Clin Endocrinol Metab 1996;81:2934 –2941. 527 Nieman LK, Oldfield EH, Wesley R et al. A simplified morning ovine corticotropin-releasing hormone stimulation test for the differential diagnosis of ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab 1993;77:308–312. 528 Landolt AM, Valavanis A, Girard J, Eberle AN. Corticotrophin-releasing factortest used with bilateral, simutaneous inferior petrosal sinus blood-sampling for the diagnosis of pituitary-dependent Cushing’s disease. Clin Endocrinol 1986;25:687–696. 529 Bonelli FS, Huston III J, Carpenter PC et al. Adrenocorticotropic hormonedependent Cushing’s syndrome: sensitivity and specificity of inferior petrosal sinus sampling. Am J Neuroradiol 2000;21:690–696. 530 Schulte HM, Allolio B, Gunther RW et al. Bilateral and simultaneous sinus petrosus inferior catheterization in patients with Cushing’s syndrome: plasmaimmunoreactive-ACTH-concentrations before and after administration of CRF. Horm Metab Res 1987;16:66–67. 531 Semple PL, Laws ER. Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing’s disease. J Neurosurg 1999;91:175–179. 532 Oldfield EH, Doppman JL, Nieman LK et al. Petrosal sinus sampling with and without corticotrophin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 1991;325:897–905. 533 Findling JW, Kehoe ME, Shaker JL, Raff H. Routine inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin (ACTH)dependent Cushing’s syndrome: early recognition of the occult ectopic ACTH syndrome. J Clin Endocrinol Metab 1991;73:408–413. 534 Bessac L, Bachelot I, Vasdev A et al. Le cathétérisme des sinus pétreux inférieurs. Sa place dans le diagnostic du syndrome de Cushing. Expérience de 23 explorations. Ann Endocrinol 1992;53:16–27. 535 Tabarin A, Greselle JF, San-Galli F et al. Usefulness of the corticotropinreleasing hormone test during bilateral inferior petrosal sinus sampling for the diagnosis of Cushing’s disease. J Clin Endocrinol Metab 1991;75:53–59. 536 Aron DC, Findling JW, Tyrrell JB. Cushing’s disease. Endocrinol Metab Clin North Am 1987;16:705–730. 537 Wiggam MI, Heaney AP, McIlrath EM et al. Bilateral inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome: a comparison with other diagnostic tests. J Clin Endocrinol Metab 2000;85:1525–1532.

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564 Meikle AW, Stanchfield JB, West CD, Tyler FH. Hydrocortisone suppression test for Cushing’s syndrome. Arch Intern Med 1974;134:1068–1071. 565 Gaillard RC, Riondel A, Muller MF, Hermann W, Baulieu EE. RU 486: a steroid with antiglucocorticoid activity that only disinhibits the human pituitary–adrenal system at a specific time of the day. Proc Natl Acad Sci USA 1984;81:3879–3882. 566 Bertagna X, Bertagna C, Luton JP, Husson JM, Girard F. The new steroid analog RU 486 inhibits glucocorticoid action in man. J Clin Endocrinol Metab 1984;59:25–28. 567 Raux-Demay MC, Pierret T, Bouvier d’Yvoire M, Bertagna X, Girard F. Transient inhibition of RU 486 antiglucocorticoid action by dexamethasone. J Clin Endocrinol Metab 1990;70:230–233. 568 Klijn JGM, de Jong FH, Bakker GH, Lamberts SWJ, Rodenburg CJ, AlexievaFigush J. Antiprogestins, a new form of endocrine therapy for human breast cancer. Cancer Res 1989;49:2851–2856. 569 Stewart PM, Wallace AM, Valentino R, Burt D, Shackleton CHL, Edwards CRW. Mineralocorticoid activity of liquorice: 11b-hydroxysteroid dehydrogenase deficiency comes of age. Lancet 1987;ii:821–824. 570 Stewart PM, Corrie JET, Shackleton CHL, Edwards CRW. Syndrome of apparent mineralocorticoid excess: a defect in the cortisol–cortisone shuttle. J Clin Invest 1988;82:340–349. 571 MacKenzie MA, Hoefnagels WHL, Jansen RWMM, Benraad TJ, Kloppenborg PWC. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers. J Clin Endocrinol Metab 1990;70:1637-1643. 572 Cohen KL. Metabolic, endocrine, and drug induced interference with pituitary function tests: a review. Metabolism 1977;26:1165–1177. 573 Wallace EZ, Rosman P, Toshav N, Sacerdote A, Balthazar A. Pituitary–adrenocortical function in chronic renal failure: studies of episodic secretion of cortisol and dexamethasone suppressibility. J Clin Endocrinol Metab 1979;50:46–51. 574 Miller KK, Dally PA, Sentochnik D et al. Pseudo-Cushing’s syndrome in human immunodeficiency virus-infected patients. Clin Infec Diseases 1998;27:68–72. 575 Workman RJ, Vaughn WK, Stone WJ. Dexamethasone suppression testing in chronic renal failure: pharmacokinetics of dexamethasone and demonstration of a normal hypothalamic–pituitary–adrenal axis. J Clin Endocrinol Metab 1986;63:741–746. 576 Aronin N, Liotta AS, Shickmanter B, Schussler GC, Krieger DT. Impaired clearance of b-lipotropin in uremia. J Clin Endocrinol Metab 1981;53:797–800. 577 Dexter RN, Orth DN, Abe K, Nicholson WE, Liddle GW. Cushing’s disease without hypercortisolism. J Clin Endocrinol Metab 1970;30:573–579. 578 Gold PW, Loriaux L, Roy A et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. N Engl J Med 1986;314:1329–1335. 579 Amsterdam JD, Winocur A, Abelman E, Lucki I, Rickels K. Cosyntropin (ACTH 1–24) stimulation test in depressed patients and healthy subjects. Am J Psychiatry 1983;140:907–909. 580 Carroll BJ, Curtis GC, Davies BM, Mendels J, Sugarman AA. Urinary free cortisol excretion in depression. Psychol Med 1976;6:43–50. 581 Sachar EJ, Hellman L, Roffwarg HP, Halpern FS, Fukushima DK, Gallagher TF. Disrupted 24-hr patterns of cortisol secretion in psychotic depression. Arch Gen Psychiatry 1973;28:19–26. 582 Schlechte JA, Sherman B, Pfohl B. A comparison of adrenal cortical function in patients with depressive illness and Cushing’s disease. Horm Res 1986;23:1–8. 583 Gold PW, Gwirtsman H, Avgerinos PC et al. Abnormal hypothalamic–pituitary–adrenal function in anorexia nervosa. N Engl J Med 1986;314:1335–1342. 584 Hotta M, Shibasaki T, Masuda A et al. The responses of plasma adrenocorticotropin and cortisol to corticotropin-releasing hormone (CRH) and cerebrospinal fluid immunoreactive CRH in anorexia nervosa patients. J Clin Endocrinol Metab 1986;62:319–324. 585 Kaye WH, Gwirtsman J, George DT et al. Elevated cerebrospinal fluid levels of immunoreactive corticotropin releasing hormone in anorexia nervosa: relationship to state of nutrition, adrenal function, and intensity of depression. J Clin Endocrinol Metab 1987;64:203–208. 586 Katz JL, Weiner J, Kream J, Zumoff B. Cushing’s disease in a young woman with anorexia nervosa: pathophysiological implications. Can J Psychiatry 1986;31:861–864. 587 Fichter MM, Pirke KM, Holsboer F. Weight loss causes neuroendocrine distrubances: experimental study in healthy starving subjects. Psychiatry Res 1986;17:61–72. 588 Smals AG, Kloppenborg PW, Njo KT, Knoben JM, Ruland CM. Alcoholinduced Cushingoid syndrome. Br Med J 1976;2:1298.

589 Rees LH, Besser GM, Jeffcoate WJ, Goldie DJ, Marks W. Alcohol-induced pseudo-Cushing’s syndrome. Lancet 1977;i:726–728. 590 Kirkman S, Nelson DH. Alcohol-induced pseudo-Cushing’s disease: a study of prevalence with review of the literature. Metabolism 1988;37:390–394. 591 Berman JD, Cook DM, Buchman M, Keith LD. Diminished adrenocorticotropin response to insulin-induced hypoglycemia in nondepressed, actively drinking male alcoholics. J Clin Endocrinol Metab 1990;71:712–717. 592 Stewart PM, Burra P, Shackleton CHL, Sheppard MC, Elias E. 11 Betahydroxysteroid dehydrogenase deficiency and glucocorticoid status in patients with alcoholic and non alcoholic chronic liver disease. J Clin Endocrinol Metab 1993;76:748–751. 593 Lamberts SWJ, Klijn JGM, de Jong FH, Birkenhager JC. Hormone secretion in alcohol-induced pseudo-Cushing’s syndrome. JAMA 1979;242:1640–1643. 594 Sawin CT. Measurement of plasma cortisol in the diagnosis of Cushing’s syndrome. Ann Intern Med 1968;68:624–631. 595 Gold EM. The Cushing syndromes: changing views of diagnosis and treatment. Ann Intern Med 1979;90:829–844. 596 Petraglia F, Barletta C, Facchinetti F et al. Response of circulating adrenocorticotropin beta-endorphin, beta-lipotropin and cortisol to athletic competition. Acta Endocrinol 1988;118:332–336. 597 Rees LH, Burke CW, Chard T, Evans SW, Letchworth AT. Possible placental origin of ACTH in normal human pregnancy. Nature 1975;234:620–622. 598 Grino M, Chrousos GP, Margioris AN. The corticotropin releasing hormone gene is expressed in human placenta. Biochem Biophys Res Commun 1987;148:1208–1214. 599 Orth DN, Mount CD. Specific high affinity binding protein for human corticotrophin releasing hormone in normal human plasma. Biochem Biophys Res Commun 1987;143:411–417. 600 Linton EA, Lowry PJ. A large molecular weight carrier substance for CRF-41 in human plasma. J Endocrinol 1986;111:150. 601 Abou Samra AB, Loras B, Pugeat M, Tourniaire J, Bertrand J. Demonstration of an antiglucocorticoid action of progesterone on the corticosterone inhibition of b-endorphin release by rat anterior pituitary in primary culture. Endocrinology 1984;115:1471–1475. 602 Abou Samra AB, Pugeat M, Dechaux H, Nachury L, Tourniaire J. Acute dopaminergic blockade by sulpiride stimulates b-endorphin secretion in pregnant women. Clin Endocrinol 1984;21:583–588. 603 Pieters GFFM, Smals AGH, Goverde HJM, Kloppenborg PWC. Paradoxical responsiveness of adrenocorticotropin and cortisol to thyrotropin releasing hormone (TRH) in pregnant women. Evidence for intermediate lobe activity? J Clin endocrinol Metab 1981;55:387–389. 604 Vingerhoeds ACM, Thijssen JHH, Schwarz F. Spontaneous hypercortisolism without Cushing’s syndrome. J Clin Endocrinol Metab 1975;43:1128–1133. 605 Chrousos GP, Vingerhoeds A, Brandon D et al. Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease. J Clin Invest 1982;69:1261–1269. 606 Caro JF, Meikle AW, Check JH, Cohen SN. “Normal suppression” to dexamethasone in Cushing’s disease: an expression of decreased metabolic clearance for dexamethasone. J Clin Endocrinol Metab 1978;47:667–670. 607 Meikle AW, Lagerquist LG, Tyler FH. Apparently normal pituitary–adrenal suppressibility in Cushing’s syndrome: dexamethasone metabolism and plasma levels. J Lab Clin Med 1975;86:472–478. 608 Fachnie JD, Zafar MS, Melinger RC, Chason JL, Kahkonen DM. Pituitary carcinoma mimics the ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 1980;50:1062–1065. 609 Mason AMS, Ratcliffe JG, Buckle RM, Mason AS. ACTH secretion by bronchial carcinoid tumours. Clin Endocrinol 1972;1:3–25. 610 Federman DF, Mark EJ. Persistance of Cushing’s syndrome after hypophysectomy. N Engl J Med 1981;305:1637–1643. 611 Lagerquist LG, Meikle AW, West CD, Tyler FH. Cushing’s disease with cure by resection of a pituitary adenoma: evidence against a primary hypothalamic defect. Am J Med 1974;57:826–830. 612 Hardy J. Transsphenoidal microsurgery of the normal and pathological pituitary. Clin Neurosurg 1969;16:185–217. 613 Bigos ST, Robert F, Pelletier G, Hardy J. Cure of Cushing’s disease by trans-spheoidal removal of a microadenoma from a pituitary gland despite a radiographically normal sella turcica. J Clin Endocrinol Metab 1977;45:1251–1260. 614 Guiot G, Bouche J, Opriou A. Les indications de l’abord sphenoidal dans les adénomes hypophysaires. Nouv Presse Med 1967;75:1563–1568. 615 Bigos ST, Somma M, Rasio E et al. Cushing’s disease: management by transsphenoidal pituitary microsurgery. J Clin Endocrinol Metab 1980;50:348–354.

Chapter 13 616 Burke CE, Adams CBT, Esiri MM, Morris C, Bevan JS. Transsphenoidal surgery for Cushing’s disease: does what is removed determine the endocrine outcome? Clin Endocrinol 1990;33:525–537. 617 McCance DR, Gordon DS, Fannin TF et al. Assessment of endocrine function after transsphenoidal surgery for Cushing’s disease. Clin Endocrinol 1993;38:79–86. 618 Trainer PJ, Lawrie HS, Verhelst J et al. Transsphenoidal resection in Cushing’s disease: undetectable serum cortisol as the definition of successful treatment. Clin Endocrinol 1983;38:73–78. 619 Pieters GFFM, Hermus ARMM, Meijer E, Smals AGH, Kloppenborg PWC. Predictive factors for initial cure and relapse rate after pituitary surgery for Cushing’s disease. J Clin Endocrinol Metab 1989;69:1122–1126. 620 Scherbaum WA, Schrell U, Gluck M, Fahlbusch R, Pfeiffer EF. Autoantibodies to pituitary corticotropin-producing cells: possible marker for unfavourable outcome after pituitary microsurgery for Cushing’s disease. Lancet 1987;i:1394–1396. 621 Olivier L, Vali-Porcile E. Pituitary pathology in Cushing’s disease. Histology and morphometry of pituitary tissues removed through microsurgery. Pathol Res Pract 1988;183:587-591. 622 Taylor HC, Velasco ME, Brodkey JS. Remission of pituitary-dependent Cushing’s disease after removal of nonneoplastic pituitary gland. Arch Intern Med 1980;140:1366–1368. 623 Thomas JP, Richards SH. Long term results of radical hypophysectomy for Cushing’s disease. Clin Endocrinol 1983;19:629–636. 624 Ludecke DK. Intraoperative measurement of adrenocorticotropic hormone in peripituitary blood in Cushing’s disease. Neurosurgery 1989;24:201–205. 625 Swearingen B, Biller BMK, Barker II FG et al. Long-term mortality after transsphenoidal surgery for Cushing disease. Ann Int Med 1999;130:821–824. 626 Ganguly A, Stanchfield JB, Roberts TS, West CD, Tyler FH. Cushing’s syndrome in a patient with an empty selle turcica and a microadenoma of the adenohypophysis. Am J Med 1976;60:306–309. 627 Orth DN, Liddle GW. Results of treatment in 108 patients with Cushing’s syndrome. N Engl J Med 1971;285:243–247. 628 Jennings AS, Liddle GW, Orth DN. Results of treating childhood Cushing’s disease with pituitary irradiation. N Engl J Med 1977;297:957–962. 629 Howlett TA, Plowman PN, Wass JAH, Rees LH, Jones AE, Besser GM. Megavoltage pituitary irradiation in the management of Cushing’s disease and Nelson’s syndrome: long-term follow-up. Clin Endocrinol 1989;31:309-323. 630 Helberg FE, Sheline GE. Radiotherapy of pituitary tumors. Endocrinol Metab Clin North Am 1987;667–684. 631 Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Sutton ML. Long-term follow-up of low-dose external pituitary irradiation for Cushing’s disease. Clin Endocrinol 1990;33:445–455. 632 Sharpe GF, Kendall-Taylor P, Prescott RWG et al. Pituitary function following megavoltage therapy for Cushing’s disease: long term follow up. Clin Endocrinol 1985;22:169–177. 633 Aristizabal S, Caldwell WL, Avila J, Mayer EG. Relationship of time dose factors to tumour control and complications in the treatment of Cushing’s disease. Int J Radiat Oncol Biol Phys 1977;2:47–54. 634 Murayama M, Yasuda K, Minamori Y, Mercado-Asis L, Yamakita N, Miura K. Long-term follow-up of Cushing’s disease treated with reserpine and pituitary irradiation. J Clin Endocrinol Metab 1992;75:935–942. 635 Lamberts SWJ, de Jong FH, Birkenhager JC. Evaluation of a therapeutic regimen in Cushing’s disease. The predictability of the result of unilateral adrenalectomy followed by external pituitary irradiation. Acta Endocrinol 1977;86:146–155. 636 Estrada J, Boronat M, Mielgo M et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med 1997;336:172–177. 637 Schteingart DE, Tsao HS, Taylor CI, McKenzie A, Victoria R, Therrien BA. Sustained remission of Cushing’s disease with mitotane and pituitary irradiation. Ann Intern Med 1980;5:613–619. 638 Luton JP, Mahoudeau JA, Bouchard PH et al. Treatment of Cushing’s disease by op’DDD. Survey of 62 cases. N Engl J Med 1979;300:459– 464. 639 Degerblad M, Rahn T, Bergstrand G, Thoren M. Long-term results of stereotactic radiosurgery to the pituitary gland in Cushing’s disease. Acta Endocrinol 1986;112:310–314. 640 Linfoot JA. Heavy ion therapy: alpha particle therapy of pituitary tumors. In: Linfoot JA, ed. Recent Advances in the Diagnosis and Treatment of Pituitary Tumors. New York: Raven Press, 1979:245–267. 641 Kjelberg RN, Kliman B. Lifetime effectiveness—a system of therapy for pituitary adenomas, emphasizing Bragg peak proton hypophysectomy. In: Linfoot JA, ed. Recent Advances in the Diagnosis and Treatment of Pituitary Tumors. New York: Raven Press, 1979:269–288.

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642 Burke CW, Doyle FH, Joplin GF, Arnot RN, MacErlean DP, Russel Fraser T. Cushing’s disease: treatment by pituitary implantation of radioactive gold or yttrium seeds. Q J Med 1973;168:693–714. 643 Cassar J, Doyle FH, Lewis PD, Mashiter K, Van Noorden SV, Joplin GF. Treatment of Nelson’s syndrome by pituitary implantation of yttrium-90 or gold-198. Br Med J 1976;2:269–272. 644 Sandler LM, Richards NT, Carr DH, Mashiter K, Joplin GF. Long term follow-up of patients with Cushing’s disease treated by interstitial irradiation. J Clin Endocrinol Metab 1987;65:441–447. 645 Miller JW, Crapo L. The medical treatment of Cushing’s syndrome. Endocr Rev 1993;14:443–458. 646 Krieger DT, Amorosa L, Linick F. Cyproheptadine-induced remission of Cushing’s disease. N Engl J Med 1975;293:893–896. 647 Aronin N, Krieger DT. Persistent remission of Nelson’s syndrome following discontinuance of cyproheptadine treatment. N Engl J Med 1980;302:453. 648 Elias AN, Gwinup G, Valenta LJ. Effects of valproic acid, naloxone and hydrocortisone in Nelson’s syndrome and Cushing’s disease. Clin Endocrinol 1981;15:151–154. 649 Jones MT, Gillham B, Beckford U et al. Effect of treatment with sodium valproate and diazepam on plasma corticotropin in Nelson’s syndrome. Lancet 1981;i:1179–1181. 650 Kelly W, Adams JE, Laing I, Longson D, Davies D. Long-term treatment of Nelson’s syndrome with sodium valproate. Clin Endocrinol 1988;28:195–204. 651 Allolio B, Winkelmann W, Kaulen D, Hipp F, Mies R. Valproate in Cushing’s disease. Lancet 1982;i:171. 652 Papanicolaou DA, Yahovski JA, Cutler GB, Chrousos GP, Nieman LK. A single midnight serum cortisol measurement distinguishes Cushing’s syndrome from pseudo-Cushing states. J Clin Endocrinol Metab 1998;83:1163–1167. 653 Lamberts SWJ, Klijin JGM, De Quijada M et al. The mechanism of the suppressive action of bromocriptine on adrenocorticotropin secretion in patients with Cushing’s disease and Nelson’s syndrome. J Clin Endocrinol Metab 1980;51:307–311. 654 Kennedy AL, Sheridan B, Montgomery DAD. ACTH and cortisol response to bromocriptine, and results of long-term therapy in Cushing’s disease. Acta Endocrinol 1978;89:461–468. 655 Atkinson AB, Kennedy AL, Sheridon B. Six year remission of ACTHdependent Cushing’s syndrome using bromocriptine. Postgrad Med J 1985;61:239–242. 656 Tyrrell JB, Lorenzi M, Gerich JE, Forsham PH. Inhibition by somatostatin of ACTH secretion in Nelson’s syndrome. J Clin Endocrinol Metab 1975;40:1125–1127. 657 Lamberts SWJ. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev 1988;9:417–436. 658 Bertagna X, Favrod-Coune C, Escourolle H et al. Suppression of ectopic ACTH secretion by the long-acting somatostatin analog SMS 201-995. J Clin Endocrinol Metab 1989;68:988–991. 659 Kopperschaar HP, Croughs RJ, Thijssen JH, Schwarz F. Response to neurotransmitter modulating drugs in patients with Cushing’s disease. Clin Endocrinol 1986;25:661–667. 660 Scott HW, Liddle GW, Mulherin JL, McKenna TJ, Stroup SL, Rhamy RK. Surgical experience with Cushing’s disease. Ann Surg 1977;185:524–534. 661 Welbourn RB, Montgomery DAD, Kennedy TL. The natural history of treated Cushing’s syndrome. Br J Surg 1971;58:1–17. 662 Kemink L, Hermus A, Pieters G, Benraad TH, Smals A, Kloppenborg P. Residual adrenocortical function after bilateral adrenalectomy for pituitarydependent Cushing’s syndrome. J Clin Endocrinol Metab 1992;75:1211–1214. 663 Nelson DH, Meakin JW, Dealy JB, Matson DD, Emerson K, Thorn GW. ACTH-producing tumor of the pituitary gland. N Engl J Med 1958;259:161–164. 664 Nelson DH, Meakin JW, Thorn GW. ACTH-producing pituitary tumors following adrenalectomy for Cushing’s syndrome. Ann Intern Med 1960;52:560–569. 665 Kelly WF, MacFarlane IA, Longson D, Davis D, Sutcliffe H. Cushing’s disease treated by total adrenalectomy: long term observation in 43 patients. Q J Med 1983;52:224–231. 666 Urban MD, Lee PA, Danisk RK, Migeon CJ. Treatment of Cushing’s disease with bilateral adrenalectomy and autotransplantation. Horm Res 1980;13:81–89. 667 Barzilai D, Dickstein G, Kanter Y, Plavnick Y, Schramek A. Complete remission of Cushing’s disease by total bilateral adrenalectomy and adrenal autotransplantation. J Clin Endocrinol Metab 1980;50:853–856. 668 Xu YM, Qiao Y, Wu P, Chen ZD, Jin NT. Adrenal autotransplantation with attached blood vessels for treatment of Cushing’s disease. J Urol 1989;141:6–8.

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669 Hardy JD, Moore DO, Langford HG. Cushing’s disease today. Late follow-up of 17 adrenalectomy patients with emphasis on eight with adrenal autotransplants. Ann Surg 1985;201:595–603. 670 Nelson AA, Woodard G. Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2,2 bis (parachorophenyl)-1,1 dichloroethane (DDD or TDE). Arch Path 1949;48:387–394. 671 Bergenstal DM, Lipsett MB, Moy RH, Hertz R. Regression of adrenal cancer and suppression of adrenal function in man by op’DDD. Trans Assoc Am Physicians 1959;72:341–350. 672 Southren AL, Tochimoto S, Strom L, Ratuschni A, Ross H, Gordon G. Remission in Cushing’s syndrome with op’DDD. J Clin Endocrinol Metab 1966;26:268–278. 673 Temple TE, Jones DJ, Liddle GW, Dexter RN. Treatment of Cushing’s disease. Correction of hypercortisolism by op’DDD without induction of aldosterone deficiency. N Engl J Med 1969;281:801–805. 674 Bricaire H, Luton JP. Douze ans de traitement médical de la maladie de Cushing: usage prolongé de l’op’DDD dans quarante six cas. Nouv Presse Med 1976;5:325–329. 675 Moolenaar AJ, Van Slooten H, Van Seters AP, Smeenk D. Blood levels of op’DDD following administration in various vehicles after a single dose and during long-term treatment. Cancer Chemother Pharmacol 1981;7:51-54. 676 Touitou Y, Moolenaar AJ, Bogdan A, Auzeby A, Luton JP. op’DDD (mitotane) treatment for Cushing’s syndrome: adrenal drug concentration and inhibition in vitro of steroid synthesis. Eur J Clin Pharmacol 1985;29:483–487. 677 Leiba S, Weinstein R, Shindel B et al. The protracted effect of op’DDD in Cushing’s disease and its impact on adrenal morphogenesis of young human embryo. Ann Endocrinol 1989;50:49–53. 678 Hague RV, May W, Cullen DR. Hepatic microsomal enzyme induction and adrenal crisis due to op’DDD therapy for metastatic adrenocortical carcinoma. Clin Endocrinol 1989;31:51–57. 679 Robinson GB, Hales IB, Henniker AJ et al. The effect of op’DDD on adrenal steroid replacement therapy requirements. Clin Endocrinol 1987;27: 437–444. 680 Marshall JS, Tomkins LS. Effect of op’DDD and similar compounds on thyroxine binding globulin. J Clin Endocrinol Metab 1968;28:386–392. 681 Ojima M, Hashimoto S, Itoh N et al. Effects of op’DDD on pituitary-gonadal function in patients with Cushing’s disease. Nippon Naibunpi Gakkai Zasshi 1988;64:451–462. 682 Brown RD, Nicholson WE, Chick WT, Stroott CA. Effect of op’DDD on human adrenal steroid 11b-hydroxylation activity. J Clin Endocrinol Metab 1973;36:730–733. 683 Donckier J, Burrin JM, Ramsay ID, Joplin GF. Successful control of Cushing’s disease in the elderly with long term metyrapone. Postgrad Med J 1986;62:727–730. 684 Dickstein G, Lahav M, Shen-Orr Z, Edoute Y, Barzilai D. Primary therapy for Cushing’s disease with metyrapone. JAMA 1986;255:1167–1169. 685 Jeffcoate WJ, Rees LH, Tomlin S, Jones AE, Edwards CRW, Besser GM. Metyrapone in long-term management of Cushing’s disease. Br Med J 1977;2:215–217. 686 Orth DN. Metyrapone is useful only as adjunctive therapy in Cushing’s disease. Ann Intern Med 1978;89:128–130. 687 Child DF, Burke CW, Burley DM, Rees LH, Fraser TR. Drug control of Cushing’s syndrome. Combined aminoglutethimide and metyrapone therapy. Acta Endocrinol 1976;82:330–341. 688 Thoren M, Adamson U, Sjöberg HE. Aminoglutethimide and metyrapone in the management of Cushing’s syndrome. Acta Endocrinol 1985;109:451–457. 689 Schteingart DE, Conn JW. Effects of aminoglutethimide upon adrenal function and cortisol metabolism in Cushing’s syndrome. J Clin Endocrinol Metab 1967;27:1657–1666. 690 Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987;317:812–818. 691 Cerdas S, Billaud L, Guilhaume B, Laudat MH, Bertagna X, Luton JP. Effets à

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court terme du ketoconazole dans les syndromes de Cushing. Ann Endocrinol 1989;50:489–496. McCance DR, Hadden DR, Kennedy L, Sheridan B, Atkinson AB. Clinical experience with ketoconazole as a therapy for patients with Cushing’s syndrome. Clin Endocrinol 1987;27:593–599. Loli P, Berselli ME, Tagliafferri M. The use of ketoconazole in the treatment of Cushing’s syndrome. J Clin Endocrinol Metab 1986;63:1365–1371. Sonino M, Boscaro M, Merola G, Mantero F. Prolonged treatment of Cushing’s disease by ketoconazole. J Clin Endocrinol Metab 1985;61:718–722. Angeli A, Frairia R. Ketoconazole therapy in Cushing’s disease. Lancet 1985;i:821. Boscaro M, Sonino N, Rampazzo A, Mantero F. Response of pituitaryadrenal axis to corticotrophin releasing hormone in patients with Cushing’s disease before and after ketoconazole treatment. Clin Endocrinol 1987;27: 461–467. Tsigos C, Papanicolaou DA, Chrousos GP. Advances in the diagnosis and treatment of Cushing’s syndrome in Bailliere’s. Clin Endocrinol and Metab 1995;9:315–336. Schulte HM, Benker G, Reinwein D, Sippell WG, Allolio B. Infusion of low dose etomidate: correction of hypercortisolemia in patients with Cushing’s syndrome and dose–response relationship in normal subjects. J Clin Endocrinol Metab 1990;70:1426–1430. Nieman LK, Chrousos GP, Kellner C et al. Successful treatment of Cushing’s syndrome with the glucocorticoid antagonist RU 486. J Clin Endocrinol Metab 1985;61:536–540. Bertagna X, Bertagna C, Laudat MH, Husson JM, Girard F, Luton JP. Pituitary–adrenal response to the antigulcocorticoid action of RU 486 in Cushing’s syndrome. J Clin Endocrinol Metab 1986;63:639–643. Van der Lely AJ, Fockin K, Van der Mast RC, Lamberts SWJ. Rapid reversal of acute psychosis in the Cushing’s syndrome with the cortisol receptor antagonist mifepristone (RU 486). Ann Int Med 1991;114:143–144. Kasperlik-Zaluska AA, Nielubowicz J, Wislawski J et al. Nelson’s syndrome: incidence and prognosis. Clin Endocrinol 1983;19:693–698. Kemink SAG, Smals AGH, Hermus ARMM et al. Nelson’s syndrome: a review. The Endocrinologist 1997;7:5–9. Cohen KL, Noth RH, Pechinski T. Incidence of pituitary tumors following adrenalectomy. Arch Intern Med 1978;138:575–579. Barnett AH, Livesey JH, Friday K, Donald RA, Espiner EA. Comparison of preoperative and postoperative ACTH concentrations after bilateral adrenalectomy in Cushing’s disease. Clin Endocrinol 1983;18:301–305. Moreira AC, Castro M, Machado HR. Longitudinal evaluation of adrenocorticotrophin and beta-lipotrophin plasma levels following bilateral adrenalectomy in patients with Cushing’s syndrome. Clin Endocrinol 1993;39:91–96. Hopwood NJ, Kenny FM. Incidence of Nelson’s syndrome after adrenalectomy for Cushing’s disease in children. Am J Dis Child 1977;131:1353–1356. Bonner RA, Mukai K, Oppenheimer JH. Two unusual variants of Nelson’s syndrome. J Clin Endocrinol Metab 1979;49:23–29. Verdonk C, Guerin C, Lufkin E, Hodgson SF. Activation of virilizing adrenal rest tissues by excessive ACTH production. Am J Med 1982;73:455–459. Baranetsky NG, Zipser RD, Goebelmann U et al. Adrenocorticotropindependent virilizing paraovarian tumors in Nelson’s syndrome. J Clin Endocrinol Metab 1979;49:381–386. Bochicchio D, Losa M, Buchfelder M. Factors influencing the intermediate and late outcome of Cushing’s disease treated by transsphenoidal surgery: a retrospective study by the European Cushing’s disease survey group. J Clin Endocrinol Metab 1995;80:3114–3120. McCane DR, Besser M, Atkinson AB. Assessment of cure after transsphenoidal surgery for Cushing’s disease. Clin Endocrinol 1996;44:1–6. Blevins Jr LS, Christy JH. Cushing’s disease due to ACTH-secreting macroadenomas: management issues. The Endocrinologist 1999;9:257–262.

C h a p t e r

14 Thyrotropin-secreting Pituitary Tumors Yona Greenman Shlomo Melmed

Thyrotropin (thyroid-stimulating hormone, TSH) secreting adenomas are the rarest type of functional pituitary tumor [1–6]. The coexistence of hyperthyroidism, a pituitary mass and excessive thyrotropin production demonstrated using a TSH bioassay was first described in 1960 and subsequently revisited in 1969 [7,8]. With the development of a radioimmunoassay (RIA) for TSH [9,10] the disease became increasingly recognized [11,12]. The introduction of sensitive TSH immunoassays [13,14], capable of distinguishing normal from frankly suppressed TSH levels, further improved our ability to diagnose these tumors. In fact, the reported prevalence of TSH secreting tumors has almost tripled in the last decade [15], and they represented 2.8% of operated tumors in a large surgical series [16]. In patients with primary thyroid disease, by far the most common cause of hyperthyroidism, TSH levels are suppressed by the elevated peripheral thyroid hormones, and are undetectable. When TSH itself is responsible for thyroid hyperstimulation, it is readily detected, being either inappropriately in the normal range or frankly elevated. The previous unavailability of sensitive TSH RIAs, and a reluctance to use this diagnostic tool routinely in hyperthyroidism, had led in the past to delayed diagnosis of TSH-secreting adenomas. Therefore, treatment was inappropriately directed to the thyroid gland and consequently tumors were only detected when they were already large and locally invasive, with resulting high morbidity [17]. Now, patients can be correctly diagnosed in an earlier stage, thus hopefully improving the therapeutic outcome. This chapter reviews the pathophysiology, clinical characteristics, and therapeutic approach to these tumors. The discussion reflects the documented experience with these patients in the literature.

PATHOGENESIS TSH is a glycoprotein hormone with a molecular mass of 28 kDa which is secreted by the thyrotroph cells in the anterior pituitary gland. It is composed of a- and b-subunits, linked by a noncovalent bond [18]. The a-subunit is common to the other glycoprotein hormones—luteinizing hormone (LH), follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG), being encoded by a gene on chromosome 6. The human b-TSH gene is situated on chromosome I and is unique, conferring immunologic and biologic specificity to the molecule. Each subunit alone is devoid of receptor binding and biologic activity. b-subunits appear to be limiting in the biosynthesis of the complete hormone [19]. The b-TSH gene is under transcriptional control of Pit-1, a transcription factor restricted to the anterior pituitary gland, and specifically expressed only in thyrotrophs, lactotrophs and somatotrophs [20]. It has a critical role in the development of caudomedial thyrotophs in rats and activation of b-TSH gene expression in these cells. In humans, a similar functional role is supported by the demonstration that mutations in the Pit-1 gene cause a syndrome of congenital hypothyroidism, dwarfism and prolactin deficiency [21,22]. Pit-1 is also critical for the survival and proliferation of thyrotrophs, as well as lactotrophs and somatotrophs [23]. In addition to its developmental role, it seems that Pit-1 is also involved in the transient regulation of gene expression, as Pit-1 binding sites in the b-TSH gene mediate thyrotropin-releasing hormone (TRH) responsiveness [24]. TSH secretion is controlled by the integrated thyrotroph response to humoral and central signals. TRH secreted by the hypothalamus is the major stimulator of TSH secretion. Upon binding to its receptor, activation of the phosphatidyl-inositol bisphosphate pathway and prompt rise 561

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in cytoplasmic ionized calcium is coupled to the initiation of TSH secretion [25]. TRH also controls posttranslational glycosylation of TSH, which is important for its biologic activity [26]. Thyroid hormones are the dominant hormones responsible for inhibiting TSH secretion. Thyroxine (T4) is converted to triiodothyronine (T3) by an intrapituitary type II 5¢-deiodinase. T3 then binds to its nuclear receptor, inhibiting the rate of transcription of the two subunit genes and subsequently decreasing their messenger ribonucleic acid (mRNA) levels [27]. Thyroid hormones also reduce TRH precursor mRNA synthesis in the hypothalamus [28] and reduce the number of TRH receptors on the thyrotroph [29]. Other hormones and hypothalamic factors have a role in regulating TSH secretion. Dopamine (DA) and its agonists inhibit TSH secretion, while DA-receptor blocking agents such as metoclopramide and domperidone increase TSH concentration both in euthyroid and hypothyroid subjects [30]. Somatostatin lowers serum TSH concentrations in normal and hypothyroid patients, and also reduces the serum TSH response to TRH [18]. Both DA and somatostatin inhibitory actions are mediated at the thyrotroph level, as shown in cultured human pituitary cells [31]. Glucocorticoids decrease serum TSH in a dose-related manner [32] while estrogens enhance and androgens inhibit the TSH response to TRH. The role of disordered hypothalamic or peripheral endocrine function vs. the presence of intrinsic lesions in the pituicyte in the pathogenesis of pituitary cell transformation has been the focus of intense investigation [33,34]. Enlargement of the pituitary gland due to long-standing hypothyroidism is a well-recognized disorder [35]. TSH hypersecretion and pituitary hyperplasia develop as a consequence of chronic attenuated negative feedback by thyroid hormone. Recognition of this entity has important clinical implications, as thyroxine replacement therapy fully resolves these “pseudotumors” of the pituitary, avoiding inadvertent surgery [36,37]. In some instances, though, true TSHsecreting adenomas may arise in these patients [38,39], being found in 8% of pituitary glands derived from hypothyroid subjects examined in a pathologic study [40]. Pituitary tumors may be produced experimentally in animals by inducing hypothyroidism either by utilizing antithyroid drugs or by thyroid ablation [11]. Most TSH adenomas are, however, primary pituitary lesions that are not associated with thyroid failure; on the contrary, they usually cause a hyperthyroid state. Furthermore, in patients with selective pituitary thyroid hormone resistance, the pituitary gland is morphologically normal, without resultant adenoma formation despite longstanding TSH hypersecretion. A case of a TSH-secreting microadenoma apparently coexisting with the syndrome of pituitary resistance to thyroid hormone has been reported [41]. The role of excessive TRH secretion in causing thyrotroph proliferation and adenoma formation is not well established. Urinary excretion of TRH was reported to be

in the normal range in one patient [42] and serum TRH was detectable in another [43], both being hyperthyroid when tested. Exogenous TRH failed to further increase serum TSH in both patients, as occurs in most patients harboring TSH-secreting adenomas who have been studied dynamically with TRH [11]. TRH binding sites were not detectable in membranes derived from two thyrotropic tumors, in accordance with their unresponsiveness to in vivo TRH stimulation [44]. The absence of TRH binding sites could be a primary pituitary defect, or alternatively could be due to downregulation by the increased serum thyroid hormone concentrations [45]. The later possibility is supported by the observation that the majority of tumors studied in vitro were responsive to TRH stimulation in contrast to the absent TSH responsiveness to TRH observed in most tumors studied in vivo. The absence of pituitary tissue hyperplasia surrounding TSH-secreting adenomas argue against a role for TRH hypersecretion in tumor formation. Mutations leading to constitutive activation of the TRH receptor or components of its signal transduction pathway could also be potentially involved in TSH-omas pathogenesis. Nevertheless, no mutations on the TRH receptor, G alpha q, G alpha 11 or G alpha s were detected in the tumors screened [46,47]. Alternatively, defective suppression of TSH secretion by somatostatin, DA or thyroid hormones could be involved in the pathogenesis of these tumors. In the majority of patients harboring TSH-secreting tumors, there is no response of TSH secretion to DA or dopaminergic drugs [11]. DA receptors were not detectable in tumoral membranes of two patients who failed to suppress their TSH levels after DA or bromocriptine administration [48]. An unusual patient exhibiting a paradoxical TSH increase after L-dopa administration was shown to possess tumor dopaminergic receptors [49]. The description of TSH secreting tumors in two patients receiving long-term phenothiazine treatment raised the possibility of a facilitating effect of this DA receptor-blocking drug in the development of these tumors [50]. It should be noted, however, that long-term phenothiazine treatment does not enhance plasma TSH levels. Although TSH-secreting tumors may be associated with impaired DA receptor function, the role of defective DA binding in the pathogenesis of these tumors remains unclear [51]. Furthermore, no mutations on the dopamine type 2 receptor gene were detected in 3 TSH-omas tested [52]. In contrast to DA, most thyrotropinomas respond to somatostatin and its analogs by decreasing TSH and asubunit secretion [53]. Tumors studied so far demonstrated specific radioiodinated-Tyr-DTrps-SRIH binding sites, measured either on membrane preparations or on frozen tumor sections by autoradiography [54,55]. Somatostatin induced cell membrane hyperpolarization causes a decrease in intracellular ionized calcium concentration and inhibition of TSH secretion [56]. Thus, the somatostatin inhibitory pathway appears intact in these tumors. Defective negative feedback of thyroid hormone on TSH secretion could also be involved in the pathogenesis of

Chapter 14

TSH-secreting tumors. Most patients harboring TSH-omas do not suppress TSH after administration of T3 or T4. Studies on the expression and structure of thyroid hormone receptors (TR) have been reported. Sequencing of TRa1 and TRb1 from six tumors has been reported as normal [15]. Absence of TRa1, TRa2 and TRb1 mRNA expression has been reported [57]. In another study, normal expression levels of TRa and TRb mRNA were detected in two TSH secreting tumors, but the nuclear proteins were undetectable, suggesting a posttranscriptional defect in RNA processing [58]. Clearly, more studies are required to assess the potential role of abnormal thyroid hormone receptors in the formation or progression of these tumors. The monoclonal origin of growth hormone (GH), adrenocorticotropic hormone (ACTH) and prolactin (PRL) secreting tumors as well as nonfunctioning tumors was determined by X-chromosome inactivation analysis [59–61]. Three TSH-secreting adenomas studied were also found to be monoclonal in origin [62]. Molecular studies on possible amplified, mutated or overexpressed oncogenes, or inactivated tumor suppressor genes are scarce, probably due to the rarity of these tumors. 11q13 deletions [63], c-myc, c-fos and c-myb overexpression [64], and p53 inactivation [65] were not found in the few tumors tested. Finally, the pituitary specific transcription factor Pit-1 has been the focus of intense investigation, but collectively the data suggests that pituitary tumorigenesis is not associated with altered expression of these gene [66]. Pit-1 transcripts of normal size and sequence were found in GH-, PRL- and TSH-secreting tumors [67]. There is no evidence for marked gene overexpression [68], nor there is any correlation between the degree of Pit-1 expression and tumor behavior [69]. PATHOLOGY Thyrotroph cell adenomas are chromophobic, containing a few small cytoplasmic granules, mainly at the cell periphery, that stain for periodic acid–Schiff (PAS), aldehyde fuchsin, and aldehyde thionin [70]. The cells usually immunostain positively for TSH, although occasionally no TSH immunopositivity is found, suggesting that the synthesized hormone is immediately released and is not stored in sufficient amounts to be demonstrable. Alternatively, the molecule could be antigenically altered in the tumor [3, 71–73]. On electron microscopy, thyrotroph cell adenomas consist of elongated angular cells with long cytoplasmic processes containing small sparse, spherical secretory granules (50– 200 nm), usually lining up along the cell membrane [70]. An interesting feature of TSH-secreting tumors is that many are plurihormonal, producing a-subunits, PRL, GH, LH, and FSH, in different combinations in addition to TSH [74]. Most frequently GH and PRL are cosecreted with TSH, in line with the common transcription regulation by Pit-1 shared by these hormones. These tumors are monomor-

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563

phous, consisting of one morphologically distinct cell type that produces two or more hormones [6,75,76], or plurimorphous, being composed of two or more morphologically distinct cell types [77] each producing different hormones, sometimes in the same secretory granule [78–80]. Despite positive immunostaining in the cell cytoplasm, hormone production may not always be manifest clinically, or by increased serum TSH levels. Similarly, positive GH immunostaining is sometimes associated with normal serum GH levels without evidence of clinical acromegaly [6,48,73,81]. Positive TSH immunostaining without clinical evidence of hyperthyroidism is present in up to 33% of silent pituitary adenomas studied in different pathologic series [82,83]. This discrepancy could be due to synthesis of TSH molecules that either are not being secreted or are not detected by routine assay methods. Secretion of uncombined a- and b-subunits that are biologically inactive could explain the lack of clinical expression of these tumors. It is unclear whether plurihormonal adenomas arise from early poorly differentiated stem cells which undergo multidirectional differentiation, or from cells that are normally capable of producing more than one hormone, the transformed cells retaining the ability to express multiple hormones [84]. Alternatively, a mature fully differentiated cell could dedifferentiate to a more primitive form after neoplastic transformation [85,86]. TSH-secreting tumors tend to have very fibrous consistency. Interestingly, basic fibroblastic growth factor (bFGF) was found to be increased in the blood of two patients harboring mixed PRL/TSH secreting adenomas, and the tumoral tissue also exhibited elevated bFGF mRNA expression [87]. The characteristics and clinico-pathological correlation of 121 TSH-secreting tumors are reviewed in Table 14.1. Thus far, only one TSH-secreting carcinoma has been described [132]. Besides being locally invasive, there was also evidence of tumor metastasis to lung, liver, bone, and the abdominal cavity. Interestingly, initially the tumor stained positively for PRL and a-subunit but not for TSH. Five years later the patient developed clinical hyperthyroidism and the resected tumor subsequently also stained positively for TSH. CLINICAL FEATURES The clinical features of patients with TSH-secreting tumors are summarized in Table 14.2. Most patients with TSHsecreting tumors present with classic symptoms and signs of hyperthyroidism, indistinguishable from those caused by primary thyroid disease. Unlike Graves’ disease, however, ophthalmopathy, pretibial myxedema, and acropachy are absent and the female preponderance characteristic of autoimmune thyroid disease is not apparent. In the majority of these patients thyroid antibodies and thyroid receptor antibodies are undetectable. In a few patients, low titers of antithyroid antibodies were found [42,43,97,101], compatible with the incidence of positive testing in the

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Table 14.1. characteristics

Pituitary Tumors

Secretory characteristics of TSH-secreting tumors of 121 patients by immunocytochemical staining and clinical

Immunostaining Number of patients

a-subunit

[References]

TSH

[79,73]

-

23

[5,6,43,44,53,59,88–96]

+

-

11

[3,6,37,81,94,97–99]

+

+

8

[48,73,75,76,79,100,101]

+

+

6

[49,54,73,79,80,102]

+

+

7

[5,53,77,89,103,104]

+

5

[5,73,78,105]

+

+

2

[6,106]

+

+

3

[54,107,108]

+

+

1

[109]

+

+

1

[53]

+

1

[72]

-

1

[3]

-

-

-

1

[3]

-

+

+

[44,53,54,97,98,110–122]

ND

ND

ND

ND

2

23

GH

+

PRL

FSH

LH

ACTH

Clinical features

-

Both patients clinically and biochemically hyperthyroid, 1 patient [48] with increased PRL and A/G

-

7 patients [6,36,37,40,63,64] with increased PRL, 4 of which with A/G and 1 with decreased libido 1 patient without clinical acromegaly [58] 1 patient euthyroid [6]

-

1 patient euthyroid [75], 1 patient increased PRL [53], 3 patients no acromegaly [38,50]

-

1 patient [39] with increased PRL and A/G

+

All patients with clinical hyperprolactinemia except 1 [78] with normal PRL

+

3 patients without acromegaly or increased PRL [50,80] +

Elevated FSH, no acromegaly [81] normal serum FSH with acromegaly [6]

+

Normal serum FSH

+ +

+

+

-

+

Euthyroid with increased FSH and increased PRL ND

+

Euthyroid, increased serum LH, ACTH + in 2% of cells, no clinical Cushing Hyperthyroid, with clinical acromegaly

ND

ND

ND

Patients with hyperthyroidism and increased TSH

1

[122]

-

ND

+

9

[3,5,17,50,54,122–124]

ND

ND

ND

ND

ND

ND

ND

Clinical acromegaly and hyperthyroidism, 1 patient [99] with increased PRL

[5,17,125–129]

ND

ND

ND

ND

ND

ND

ND

Prolactin hypersecretion, 1 patient with A/G [100]

2

[17,130]

ND

ND

ND

ND

ND

ND

ND

Increased LH, increased FSH

1

[131]

ND

ND

ND

ND

ND

ND

ND

Increased FSH

1

[17]

ND

ND

ND

ND

ND

ND

ND

Increased PRL, increased FSH

12

Clinical acromegaly

A/G, amenorrhea/galactorrhea; TSH, thyrotropin; GH, growth hormone; PRL, prolactin; FSH, follicle-stimulating hormone; LH, luteinizing hormone; ACTH, adrenocorticotropic hormone; ND, not done; +, positive immunostaining; -, negative immunostaining.

Chapter 14 Table 14.2. Clinical characteristics of patients with TSHsecreting pituitary tumors* Age (mean ± SEM) (years) Sex (female %) Goiter Clinical acromegaly Amenorrhea and galactorrhea Impotence or decreased libido (male) Euthyroid Visual field defects Headaches

41.5 ± 14 (range 11–84) 54% 88–94% 17–24% 14–30% 7% 5–12% 38–64% 12–40%

* Data derived from [15,133,134].

general population [135,136]. These levels do not imply a causal relationship of the tumor with antithyroid damage. Not all patients present with hyperthyroidism. Some were euthyroid, and presented with acromegaly [6,100], amenorrhea [88], decreased libido [6], and visual field defects [72]. Few patients, despite the presence of hyperthyroidism, come to the attention of their physicians for symptoms related to GH hypersecretion [78,122,123], hypogonadism [17], delayed puberty and tall stature [91], amenorrhea [88,125], or mass effects of the tumor causing blurred vision [72,110,115]. The unusual presentation of periodic paralysis related to hyperthyroidism has also been reported [92,137]. TSH-secreting tumors occurring in the context of multiple endocrine neoplasia syndrome type 1 [73,138] and in McCune–Albright syndrome [139] have also been described. In about 90% of the patients, the thyroid gland was diffusely enlarged as assessed by physical examination, or by thyroid scan. Multinodular glands are less frequent, with the thyroid mass being the presenting symptom in only one patient [80]. Differentiated thyroid carcinoma has been reported in two patients [140,141]. Rapidly growing goiter causing dyspnea and stridor, with tracheal compression leading to tracheomalacia has also been reported [104]. Regrowth of the thyroid gland after near total thyroidectomy in patients inappropriately treated for primary thyroid disease may alert the physician to the presence of excess TSH production. In fact, about one-third of the patients have previously undergone thyroidectomy or radioiodine treatment for mistakenly diagnosed primary hyperthyroidism. In this group, TSH levels are higher and the pituitary tumors seem to be larger and more invasive than in untreated patients, underscoring the importance of accurate diagnosis [15]. Radioiodine uptake by the thyroid gland is virtually always elevated. Unilateral exophthalmos due to orbital invasion by the pituitary tumor was reported in three cases [7,111,117]. Cosecretion of GH occurs commonly, being reported in one-fourth of the patients. Hyperprolactinemia has been

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565

reported in over one-third of patients, with most manifesting amenorrhea, galactorrhea, impotence, or decreased libido (Table 14.2). In many of these patients stalk compression by the large TSH-secreting tumor probably accounts for the hyperprolactinemia. Cosecretion of FSH was found in nine patients, seven of whom had elevated serum FSH levels, while LH hypersecretion was found in four patients, one of whom also had elevated androgen levels [3]. Positive immunostaining for ACTH has been reported in only one tumor, with no clinical evidence of hypercortisolism [3]. As these tumors are usually large at the time of diagnosis, local intracranial mass effects are frequently encountered. Visual field defects and complaints of headaches are common. Detailed studies of anterior pituitary hormone function are not available in most documented cases, making it difficult to accurately assess the prevalence of hypopituitarism.

DIAGNOSIS

Laboratory Studies The presence of elevated, inappropriately normal, or just detectable TSH levels, measured by a reliable and sensitive assay, concurrently with elevated peripheral thyroid hormones is essential for the diagnosis of a TSH-secreting tumor. In the past, TSH RIAs were incapable of distinguishing between normal and suppressed TSH levels occurring in primary hyperthyroidism. This lack of assay sensitivity led to a delay in the identification of many patients with TSH-secreting tumors, who were initially diagnosed and treated for primary hyperthyroidism. Many of these patients were rendered euthyroid or hypothyroid by thyroid ablation and were no longer hyperthyroid at the time of diagnosis. The mean delay between documentation of hyperthyroidism and diagnosis of a TSH adenoma was 6 ± 2 years in patients with intact thyroid, as opposed to 12 ± 3 years in those with previously treated thyroids [134]. Some patients were misdiagnosed for over 20 years [17,89]. The new sensitive TSH immunometric assays employ labeled antibody in sandwich formation, as opposed to labeled antigen used in the classical RIAs. The third generation immunometric assays have a sensitivity of 0.01– 0.02 mU/I as opposed to earlier RIAs which had a sensitivity limit of 1–2 mU/I [14]. A fourth generation TSH immunochemiluminometric assay has been described, with a functional sensitivity of 0.001 mU/I [142]. These assays clearly distinguish the markedly suppressed TSH levels found in primary hyperthyroidism from conditions in which the thyrotroph is not suppressed to such a degree. TSH levels should therefore be interpreted in the light of the assay employed. The importance of early diagnosis should be emphasized, as it increases the chances of identifying smaller tumors with a more favorable outcome [15,17]. TSH levels vary widely, ranging from 0.5 [89] to 780 mU/L [17]. Importantly, mean

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TSH levels are several fold higher in patients previously treated by thyroid ablation, despite peripheral thyroid hormone levels still in the hyperthyroid range [15,134]. About 20% of patients had normal TSH levels. Serum TSH levels do not appear to correlate with the severity of clinical hyperthyroidism, suggesting the existence of TSH molecules with variable biologic activity [143]. TSH molecules secreted by these tumors are immunologically identical to native TSH [48,71,76,79,101,121]. The biologic/ immunologic (B/I) ratio of serum or tumor derived TSH from patients with thyrotropinomas is usually increased [17,48,71,119]; in one patient the molecule was shown to be smaller than native TSH [71]. In another patient with a decreased B/I ratio, the TSH molecule was increased in size [48]. Variant or aberrant glycosylation of the TSH glycoprotein may explain the altered B/I ratio found in the molecule secreted by these tumors [144]. There appears to be a poor correlation between pituitary tumor size, overall prognosis, and serum TSH levels [17]. The TSH a-subunit is elevated in the majority of patients due to its excessive and uncoordinated production by the tumor [97]. The mean a-subunit level documented is 16 ± 28 mg/L (n = 72) ranging from 0.1 [5] to 150 mg/L [17]. Marked elevation of serum a-subunits may portend a poor prognosis [17]. In a few patients, normal a-subunit levels were reported [5,73]. The a-subunit/TSH molar ratio is almost invariably greater than 1, ranging from 0.1 [5] to 296 [53]. This ratio is helpful in the differential diagnosis between thyrotropinomas and nontumorous TSH hypersecretion, where the ratio is usually less than unity. This may be especially helpful in patients with small microadenomas, which may be difficult to visualize by imaging techniques [108]. Caution should be exercised when evaluating a-subunit levels in menopausal women or in men with primary hypogonadism, as elevated gonadotropins could contribute to the observed elevated a-subunit level, which is common to the glycoprotein hormones [112,145]. In these patients, different normal criteria have been suggested [145].

Dynamic Tests Absence of a TSH response to exogenous TRH stimulation was initially believed to be a universal finding in these patients, implying autonomous TSH hypersecretion by the tumor. Although this is true for most patients, over 20% do in fact respond normally to TRH, with a poststimulatory doubling of the basal TSH levels [11,133,134]. Thus, a blunt TSH response to TRH stimulation supports the presence of a thyrotropinoma, but a normal test by no means excludes the diagnosis. The a-subunit and the TSH responses to TRH were usually parallel, but in some instances, a TRH-induced rise in a-subunit values occurred despite an absent TSH response [76,97]. This could indicate the presence of two distinct cell populations possessing different receptor expression.

Patients harboring TSH-secreting tumors do not suppress TSH levels normally after exogenous administration of T3 or T4. In only 17% of tested patients a slight reduction of TSH levels was observed after T3 administration for 10 days [133]. Conversely, reduction of circulating T4 or T3 by antithyroid drugs results in elevation of TSH levels in the majority of patients. This suggests that endogenous elevated thyroid hormone levels have some inhibitory effect on tumor thyrotroph function. Intravenous DA, L-dopa, or bromocriptine reduced TSH levels in only 25% of patients tested. In a single patient, a paradoxical rise of TSH following L-dopa administration was observed [49]. In a few patients, the DA agonist may in fact reduce a-subunit levels, without altering TSH levels [5,76,102]. DA antagonists fail to increase TSH levels in most patients tested. Glucocorticoids appear to maintain their ability to suppress TSH secretion in most of these patients. In nine of 11 patients receiving exogenous steroids, a decrease in TSH levels was observed, normalizing thyroid hormone levels in four cases [5,42,43,97,112,117,118,121]. Somatostatin infusion or octreotide administration reduced TSH levels in the majority of patients tested [15]. a-Subunit levels were also reduced by octreotide administration in 10 of 12 patients documented. Circadian and pulsatile TSH secretion is absent in most patients [5,78,146]. TSH pulsatility was detected in three patients [80,102,147], but the physiologic circadian TSH variation was absent. Several tumors were also tested by the same stimulatory and inhibiting agents in vitro. A striking contrast to the data obtained from in vivo tests was the observation that six of nine tumors responded to in vitro TRH administration by increasing TSH secretion [133]. Gonadotropin-releasing hormone [GNRH] and GHreleasing hormone (GHRH) also increased TSH secretion in a few tumors [79,124]. In about 40% of tumors tested, both T3 and DA agonists reduced in vitro TSH secretion by tumor cells [133]. Furthermore, T4 treatment of mice bearing thyrotropic tumors (TtT97) caused a 30% reduction in tumor size and an increase in TRb1 mRNA [148]. Glucocorticoids increased TSH secretion in one tumor by 213% [81], while in two other, TSH secretion [124] or the TSH response to TRH administration was decreased [79]. Although surprisingly somatostatin caused a 121% increase in TSH secretion in one tumor [81], in all others studied both somatostatin and its analog octreotide caused a decrease in in vitro TSH secretion [54,78,99].

Pituitary Imaging Most reported thyrotropinomas are large macroadenomas. Delayed diagnosis and previous inadvertent ablative therapy to the thyroid gland, thereby reducing endogenous negative feedback on the thyrotroph, have been implicated as possible causes for this relatively aggressive tumor proliferation [17]. In support of this hypothesis is the recent report of an increased incidence of invasive macroadenomas in patients

Chapter 14

who had previously undergone thyroid ablation, in comparison with patients with intact thyroid [15]. Furthermore, intrasellar tumors were more frequent in patients with untreated thyroid [15]. Whether these tumors, in addition, display an inherently more invasive growth behavior is speculative. About 10% of cases are microadenomas, that are diagnosed mainly by computed tomography (CT) and/or magnetic resonance imaging (MRI), although in isolated cases explorative transsphenoidal surgery [17] or inferior petrosal sinus sampling [108] were necessary for tumor localization. About one-fourth of patients harboring macroadenomas had minimal or no suprasellar extension, while the remainder had either marked suprasellar extension or invasion of sphenoidal and cavernous sinuses. Collectively, about 30% of the patients harbor either microadenomas or small enclosed macroadenomas with better clinical prognosis, whereas in 70%, larger tumors are evident. Some of these tumors are highly invasive, extending to the hypothalamus, brain stem [17] or orbit [117]. Curiously, two cases of highly calcified tumors (“pituitary stones”) have been reported [149]. Thyrotropinomas have been successfully imaged by means of Indium-111 pentetreotide single-photon emission tomography, thus further confirming the presence of somatostatin receptors in these tumors in vivo [150]. There was a trend for a direct correlation between the degree of TSH inhibition after acute octreotide administration and the degree of radioisotope uptake by the tumor, but larger series are necessary to confirm these findings. This imaging modality may also play a role in the identification of ectopic tumors, although so far only one case of ectopic TSHsecreting pituitary tumor has been reported in the nasopharinx [151]. The presence of tumoral dopamine receptors have been demonstrated in vivo by iodine-123 iodobenzamine scanning in one patient [152] but not in another [153]. DIFFERENTIAL DIAGNOSIS Faced with a patient with elevated thyroid hormone levels and detectable circulating TSH, two important clinical diagnoses should be considered. These include inappropriate TSH secretion [154] and euthyroid hyperthyroxinemia. The syndrome of inappropriate TSH secretion comprises two entities: (i) neoplastic TSH secretion; and (ii) nonneoplastic pituitary hypersecretion of TSH due to thyroid hormone resistance. Generalized thyroid hormone resistance, as first described by Refetoff in 1967 [155], is manifest with patients being metabolically euthyroid or hypothyroid. A defect in the ligand binding domain of the b-gene form of the thyroid hormone receptor, caused by point mutations in the gene, has been indentified as the etiology of the disorder [156]. When thyroid hormone resistance is predominant in the pituitary gland, patients are clinically hyperthyroid. In contrast to patients harboring TSH-secreting adenomas, pituitary imaging in these patients is normal. Biochemically, they have normal a-subunit levels

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and a-subunit/TSH molar ratios are less than 1 [97]. When dynamically tested, they usually display an exaggerated TSH stimulation by TRH, and often TSH levels are suppressible by thyroid hormones and DA agonists [73], in contrast to patients harboring thyrotropinomas. Peripheral markers of thyroid hormone action may also assist in the differential diagnosis of these two entities. Circulating sex hormonebinding globulin (SHBG) is elevated in over 90% of TSHoma patients, reflecting clinical hyperthyroidism, whereas levels are usually normal in thyroid hormone resistance [157]. Similarly, markers of bone turnover such as carboxyterminal cross-linked telopeptide of type I collagen (ICTP) are elevated in the hyperthyroid state caused by TSH-secreting tumors and are in the normal range in thyroid resistance syndrome [158]. An occasional patient with a TSH-secreting microadenoma not demonstrable by imaging techniques may be difficult to distinguish from patients with selective pituitary resistance to thyroid hormones. In these cases screening family members for thyroid function abnormalities may be helpful, pointing to the diagnosis of thyroid hormone resistance syndrome, as familial cases of TSH-secreting tumors have not been reported. Alternatively, direct screening for TRb1 mutations may be required. Several disorders cause euthyroid hyperthyroxinemia [159]. They are not uncommon and should be excluded before considering an extensive workup for inappropriate TSH secretion. 1. Artifactual high thyroxine levels can be caused by thyroxine-binding antibodies, seldom encountered in autoimmune thyroid disease. Free thyroxine levels are usually normal. 2. TSH levels are also spuriously elevated in patients with anti-TSH antibodies or human antimouse immunoglobulins [160] in some TSH assays. 3. Abnormalities in circulating thyroid-binding proteins (globulins; TBG) may also cause elevated total thyroxine levels with normal TSH levels. Increased TBG levels, either congenital or secondary to estrogen, drugs or liver disease are not uncommon. In these patients the free thyroid hormone levels are also normal. Similarly, increased binding to prealbumin or albumin as occurs in familial dysalbuminemic hyperthyroxinemia [95] may cause a similar biochemical profile. 4. Situations in which there is inhibition of T4 to T3 conversion including drugs that inhibit 5¢-deiodinase activity, 5¢-deiodinase deficiency, or the sickeuthyroid syndrome can lead to elevated thyroxine levels. T3 levels are usually normal and reverse (r)T3 levels elevated in these patients. Clinically, when exogenous thyroxine treatment is given, there is a period of approximately 6 weeks for TSH to be effectively lowered and achieve steady-state levels. In this “disequilibrium” situation, that also occurs physiologically

568

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Table 14.3.

Pituitary Tumors

Differential diagnosis of TSH-secreting tumors

Condition

Metablic status

Inappropriate TSH secretion TSH-cell adenoma Thyroid hormone resistance Generalized Pituitary Euthyroid hyperthyroxinemia Interference of antibodies in assays for T4 and TSH Increase in thyroxine binding proteins Inhibition of T4 to T3 conversion Thyroid hormone-TSH disequilibrium

Hyperthyroid Eurthyroid of hypothyroid Hyperthyroid Euthyroid Euthyroid Euthyroid Euthyroid

during the neonatal period, elevated thyroxine levels may occur in the presence of detectable TSH levels [160]. The conditions to be considered when evaluating a patient for a TSH-secreting tumor are summarized in Table 14.3. TREATMENT Therapy directed at the thyroid gland level was previously used in a large number of patients either because they were initially diagnosed as having primary thyroid disease, or as an attempt to control hyperthyroidism until the pituitary tumor could be targeted. Antithyroid drugs reduced thyroid hormone levels, at least temporarily, in most patients, but sometimes it was ineffective [117]. About one-third of patients underwent partial or total thyroidectomy, or radioactive iodine ablation, sometimes in multiple occasions [6,81,89,118,126] because of recurrence of goiter and hyperthyroidism. In some instances, ablative thyroid therapy was used after unsuccessful pituitary surgery in an attempt to control the hyperthyroidism [42,79,106,117]. Importantly, all therapies directed to the thyroid gland result in increased TSH secretion by the pituitary gland, and in the long-term carry the potential risk of causing tumor expansion [15,161]. As such, direct antithyroid treatment should be avoided, reserving the use of antithyroid drugs for short-term preparation for pituitary surgery. b-adrenergic blocking agents such as propranolol provide temporary symptomatic relief and can be used as adjunct therapy. Selective transsphenoidal pituitary surgery is the preferred initial approach to these patients as it provides the chance of complete removal of neoplastic tissue and definitive cure, thus controlling hyperthyroidism, while preserving anterior pituitary function [161]. Surgical “cure,” defined as normalization of thyroid hormone and TSH levels, and absence of residual mass on pituitary imaging has been documented in approximately 30% of patients after surgery [15]. Not surprisingly, patients cured by surgery harbor either microadenomas or

macroadenomas with minimal or no extrasellar expansion, emphasizing the importance of early diagnosis and treatment. An additional third of patients normalize thyroid function despite the presence of residual tumor on imaging studies. The value of pituitary surgery in patients with larger tumors where total excision is not feasible should be underscored. Debulking of tumor mass often provides improvement in visual field defects, CNS symptoms, and hyperthyroidism. The complications of transsphenoidal surgery, including diabetes insipidus, rhinorrhea, and pituitary failure are more fully described in Chapter 10. Radiation therapy has been used as an adjuvant to surgery in about 50 patients. In some patients, tumor growth was stabilized and patients became euthyroid, despite persistently elevated TSH levels. The actual cure rate for radiotherapy is probably underestimated due to lack of longterm follow-up studies. Nevertheless, the use of radiotherapy with its well known long term side effects (see Chapter 11) should be carefully weighted in light of the current availability of efficacious medical treatment such as somatostatin analogs. Dexamethasone, and DA agonists which could theoretically suppress TSH secretion, are of little clinical value. Dexamethasone is not recommended for long-term treatment because of unacceptable side effects. The DA agonist bromocriptine is usually ineffective, but successfully normalized thyroid function tests in two patients, reducing but not normalizing their TSH levels [118,127]. In two other patients a modest decrease in TSH levels was obtained [79,129] and in one of them a 28% reduction in tumor size was reported [129]. The somatostatin analog octreotide is the main medical modality available for treatment of TSH-secreting tumors [162], and acute and long-term effects have been reviewed [15,163]. Normalization of thyroid hormone and TSH levels was achieved in 78% and 72%, respectively, of 33 patients treated with octreotide for up to 2 weeks. All patients exhibited a reduction in thyroid hormone levels [163]. The TSH response after 1 or 2 weeks of treatment improved, including five patients who did not respond to acute administration of octreotide [163]. In long-term studies thyroid hormone and TSH normalization occurred in 95% and 79% respectively. A decrease in TSH of at least 50% from baseline was reported in over 90% of patients [15]. With cessation of therapy, the biochemical profile returns to pretreatment levels. In about 20% of patients on octreotide an escape of TSH hypersecretion without increased thyroid hormone levels was observed [5,15,99, 120,163]. The tachyphylaxis was successfully reversed by increasing the dose of octreotide. In a smaller fraction of patients, “true escape” occurred, with increasing thyroid hormone levels which did not respond to increasing doses of octreotide [15,163]. Impressive improvement in visual field defects is apparent [120,126], and change in visual fields can be noted as soon as 3 hours after initiation of treatment, while tumor

Chapter 14

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FIGURE 14.1. (a) TI-weighted magnetic resonance image of pituitary adenoma (straight arrows) before octreotide treatment of patient with thyrotropin-secreting pituitary adenoma. The tumor displaces the optic chiasm upwards (curved arrows) and obliterates the suprasellar cistern. (b) Postgadolinium magnetic resonance image shows marked enhancement of the suprasellar tumor. From Sy et al. [130]

FIGURE 14.2. (a) Magnetic resonance image shows marked reduction of thyrotropin-secreting pituitary adenoma size 13 weeks after octreotide therapy. The left side of the pituitary gland is enhanced (black arrow) and the pituitary stalk can be visualized tilted towards the left (white arrow). (b) Postgadolinium T1-weighted magnetic resonance image shows enhanced pituitary gland (arrows) and normal optic chiasm (curved arrow). From Sy et al. [130]

mass shrinkage is apparent after 3 months [120]. Despite improvement in visual fields tumor size may not change [126]. Visual improvement is observed in 75% of patients. Reduction in tumor size is observed in about half of patients receiving long-term therapy with octreotide [15,162,163], ranging up to 70% reduction in volume. Figs 14.1–14.3 exemplify the response obtained in one patient [130]. Tumor size does not increase while under octreotide therapy. Side effects of octreotide are fully discussed in Chapter 11.

The long-acting somatostatin analog lanreotide has been successfully employed in the treatment of patients with TSH secreting tumors. TSH levels decrease and thyroid hormone levels normalize during a 6-month treatment period [164]. CRITERIA OF CURE AND FOLLOW-UP No single criteria is sufficient to define cure of patients harboring a TSH-secreting tumor. Normalization of thyroid hormone and TSH levels, albeit a clinical goal, does not

SECTION 3

Pituitary Tumors

350

20

300 250 200

TSH (mU/L)

Octreotide acetate (µg/day)

570

150 100

15 10 5

50 0

0

0 3 6 9 15 21 27 33 39 45 51

0 369

15 21 27 33 39 45 51

Weeks

Weeks 5

250

T3RIA (nmol/L)

T4RIA (nmol/L)

300 200 150 100 50 0

0 369

15 21 27 33 39 45 51

4 3 2 1 0

0 369

15 21 27 33 39 45 51

Weeks

Weeks

FIGURE 14.3. Effect of octreotide on thyrotropin (TSH), T4, and T3 levels in a patient with a TSH-secreting adenoma. RIA, radioimmunoassay. From Sy et al. [130]

FIGURE 14.4. T3 suppression after pituitary surgery in 14 apparently cured patients either untreated or treated with thyroid ablation before pituitary tumor resection. Horizontal dashed lines indicate the upper and lower limits of TSH levels. Only five of nine untreated patients and two of five previously thyroid-ablated patients are truly cured, with complete serum TSH suppression. From Beck-Peccoz et al. [15]

necessarily reflect cure, as it may occur despite the presence of significant residual tumor mass. Apparent complete tumor surgical excision evidenced by postoperative MRI imaging cannot be accepted as cure either, as recurrence may occur, especially in patients in whom dynamic stimulatory and suppressive tests of TSH secretion remain abnormal. Undetectable TSH levels in the early postoperative period in patients who were hyperthyroid before surgery are a good indication of complete tumor removal, as recently reported [165]. The most sensitive and specific index of cure seems to be basal and TRH stimulated suppression of TSH levels during T3 administration (T3 suppression test, Fig. 14.4), [15,165].

Because of the relative rarity of these tumors and the lack of homogeneous large treatment series, recurrence and follow-up data are lacking. Thus, careful long term monitoring of these patients is indicated. CONCLUSIONS With improved diagnostic techniques and increased awareness of the disease, TSH-secreting tumors are being more readily detected. It appears that diagnosis of the disease in an earlier stage of tumor growth may improve prognosis. As there are essentially few unique aspects of the clinical presentation of these hyperthyroid patients, their initial distinc-

Chapter 14

tion from patients with primary thyroid disease is difficult. It therefore appears justifiable to recommend routine TSH measurements in the basal evaluation of hyperthyroid patients, especially those with symmetric goiter and absence of ophthalmopathy. Antithyroid drugs and b-blockers should be used initially for short-term control of hyperthyroidism. Pituitary microsurgery is the cornerstone of treatment, providing a good chance of remission for small tumors or improvement of symptoms by debulking larger tumors. Radiotherapy initiated after unsuccessful surgery may control tumor growth, but its use should be weighed against the promising effects of somatostatin analogs that successfully control tumoral hypersecretion in the majority of patients, often also controlling tumor growth. Hopefully the availability of improved diagnostic and therapeutic tools will control the aggressive behavior usually associated with these rare pituitary tumors. REFERENCES 1 Wilson CB. A decade of pituitary microsurgery. The Herbert Olivecrona Lecture. J Neurosurg 1984;61:814–833. 2 Mukai K. Pituitary adenomas immunocytochemical study of 150 tumors with clinicopathologic correlation. Cancer 1983;52:648–653. 3 Saeger W, Lüdecke DK. Pituitary adenomas with hyperfunction of, TSH. Virchows Arch [Pathol Anat] 1982;394:255–261. 4 Ilse G, Ryan N, Kovacs K, Ilse D. Calcium deposition in human pituitary adenomas studied by histology, electron microscopy, electron diffraction and Xray spectometry. Exp Pathol 1982;18:377–388. 5 Beckers A, Abs R, Mahler C et al. Thyrotropin-secreting pituitary adenomas: report of seven cases. J Clin Endocrinol Metab 1991;72:477–483. 6 Trouillas J, Girod C, Loras B et al. The TSH secretion in the human pituitary adenomas. Path Res Pract 1988;183:596–600. 7 Jailer JW, Holub DA. Remission of Graves’ disease following radiotherapy of a pituitary neoplasm. Am J Med 1960;28:497–500. 8 Lamberg PA, Ripatti J, Gordin A et al. Chromophobe pituitary adenoma with acromegaly and TSH-induced hyperthyroidism associated with parathyroid adenoma. Acta Endocrinol 1969;60:157–172. 9 Utiger RD. Radioimmunoassay of human plasma thyrotropin. J Clin Invest 1965;49:1277–1286. 10 Odell WD, Wilber JF, Paul WE. Radioimmunoassay of thyrotropin in human serum. J Clin Endocrinol Metab 1965;25:1179–1188. 11 Smallridge RC. Thyrotropin-secreting pituitary tumors. Endocrinol Metab Clin North Am 1987;16:765–792. 12 Faglia G, Beck-Peccoz P, Piscitelli G, Medri G. Inappropriate secretion of thyrotropin by the pituitary. Hormone Res 1987;26:79–99. 13 Van Heyningen V, Abbot SR, Daniel SG et al. Development and utility of a monoclonal antibody-based, highly sensitive immunoradiometric assay of thyrotropin. Clin Chem 1987;33:1387–1390. 14 Spencer CA, LoPresti JS, Patel A et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990;70:453–460. 15 Beck-Peccoz P, Brucker-Davis F, Persani L et al. Thyrotropin-secreting pituitary tumors. Endocr Rev 1996;17:610–638. 16 Minderman T, Wilson C. Thyrotropin-producing pituitary adenomas. J Neurosurg 1993;79:521–527. 17 Gesundheit N, Petrick PA, Nissim M et al. Thyrotropin-secreting pituitary adenomas: clinical and biochemical heterogeneity. Ann Intern Med 1989; 111:827–835. 18 Stockigt JR. Serum thyrotropin and thyroid hormone measurements and assessment of thyroid hormone transport. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the thyroid, a fundamental and clinical text, 8th ed. Philadelphia: JB Lippincott, 2000:376–392. 19 Weintraub BD, Gershengorn MC, Kourides I, Fein H. Inappropriate secretion of thyroid-stimulating hormone. Ann Intern Med 1981;95:339– 351.

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72 Koide Y, Kugai N, Kimura S et al. A case of pituitary adenoma with possible simultaneous secretion of thyrotropin and follicle-stimulating hormone. J Clin Endocrinol Metab 1982;54:397–403. 73 Wynne AG, Gharib IT, Scheithauer B et al. Hyperthyroidism due to inappropriate secretion of thyrotropin in 10 patients. Am J Med 1992; 92:15–24. 74 Scheithauer BW, Horvath E, Kovacs K et al. Plurihormonal pituitary adenomas. Semin Diagn Pathol 1986;3:69–82. 75 Clore JN, Sharpe AR, Sahni KS et al. Thyrotropin-induced hyperthyroidism: evidence for a common progenitor stem cell. Am J Med Sci 1988;295:3–5. 76 Beck-Peccoz P, Piscitelli G, Amr S et al. Endocrine, biochemical, and morphological studies of a pituitary adenoma secreting growth hormone, thyrotropin (TSH), and alpha-subunit: evidence for secretion of TSH with increased bioactivity. J Clin Endocrinol Metab 1986;62:704–710. 77 Duello TM, Halmi NS. Pituitary adenoma producing thyrotropin and prolactin—an immunocytochemical and electron microscopic study. Virchows Arch [A] 1977;376:255–265. 78 Malarkey WB, Kovacs K, O’Dorisio TM. Response of a GH and TSHsecreting pituitary adenoma to a somatostatin analogue (SMS 201–995): evidence that GH and TSH coexist in the same cell and secretory granules. Neuroendocrinology 1989;49:267–274. 79 Kuzuya M, Inoue K, Ishibashi M et al. Endocrine and immunohistochemical studies on thyrotropin (TSH)-secreting pituitary adenomas: Responses of TSH, alpha-subunit and growth hormone to hypothalamic releasing hormones and their distribution in adenoma cells. J Clin Endocrinol Metab 1990;71: 1103–1111. 80 Terzolo M, Orlandi F, Basseti M et al. Hyperthyroidism due to a pituitary adenoma composed of two different cell types, one secreting alpha-subunit alone and another cosecreting alpha-subunit and thyrotropin. J Clin Endocrinol Metab 1991;72:415–421. 81 Simard M, Mirrell CJ, Pekary AE et al. Hormonal control of thyrotropin and growth hormone secretion in a human thyrotrope pituitary adenoma studied in vitro. Acta Endocrinol 1988;119:283–290. 82 Black PM, Hsu DW, Klibanski A et al. Hormone production in clinically nonfunctioning pituitary adenomas. J Neurosurg 1987;66:244–250. 83 Heshmati HM, Turpin G, Kujas M et al. The immunocytochemical heterogeneity of silent pituitary adenomas. Acta Endocrinol 1988;118:533– 537. 84 Sanno N, Teramoto A, Matsuno A et al. GH and PRL gene expression by nonradioisotopic in situ hybridization in TSH-secreting pituitary adenomas. J Clin Endocrinol Metab 1995;80:2518–2522. 85 Kovacs K, Stefaneanu L. Histochemical analysis of pituitary adenomas. In: Melmed S, Robbins RT, eds. Molecular and Clinical Advances in Pituitary Disorders. Boston: Blackwell Scientific Publications, 1991:229–237. 86 Sano T. Plurihormonality in neuroendocrine tumors. Endocr Pathol 1990;1: 193–195. 87 Ezzat S, Horvath E, Kovacs K et al. Basic fibroblast growth factor expression in two prolactin and thyrotropin-producing pituitary adenomas. Endocr Pathol 1995;6:125–134. 88 Scanlon ME, Howells S, Peters JR et al. Hyperprolactinaemia, amenorrhoea and galactorrhoea due to a pituitary thyrotroph adenoma. Clin Endocrinol 1985;23:35–42. 89 Grisoli F, Leclercg T, Winteler JP et al. Thyroid-stimulating hormone pituitary adenomas and hyperthyroidism. Surg Neurol 1986;25:361–368. 90 Kellet HA, Wyllie AH, Dale BAB et al. Hyperthyroidism due to a thyrotrophin-secreting microadenoma. Clin Endocrinol 1983;19:57–65. 91 Takano K, Kogawa M, Tsushima T, Shizume K. A TSH secreting pituitary tumor accompanied by high stature: presentation of a case and review of the literature. Endocrinol Jpn 1981;28:215–223. 92 Kiso Y, Yoshida K, Kaise K et al. A case of thyrotropin (TSH)-secreting tumor complicated by periodic paralysis. Jpn J Med 1990;29:399–404. 93 Mashiter K, Van Noorden SV, Fahlbusch R et al. Hyperthyroidism due to a TSH secreting pituitary adenoma: case report, treatment and evidence for adenoma TSH by morphological and cell culture studies. Clin Endocrinol 1983;18:473–483. 94 Duty B, Mollard P, Dufy-Barbe L et al. The electrophysiological effects of thyrotropin-releasing hormone are similar in human TSH and prolactinsecreting pituitary cells. J Clin Endocrinol Metab 1988;67:1178–1185. 95 Jackson JA, Verdonk CA, Spiekerman M. Euthyroid hyperthyroxinemia and inappropriate secretion of thyrotropin. Recognition and diagnosis. Arch Intern Med 1987;147:1311–1313. 96 Girod C, Trouillas J, Claustrat B. The human thyrotropic adenoma: pathologic diagnosis in five cases and critical review of the literature. Semin Diagn Pathol 1986;3:58–68.

Chapter 14 97 Kourides IA, Ridgway EC, Weintraub BD et al. Thyrotropin-induced hyperthyroidism: use of alpha and beta subunit levels to identify patients with pituitary tumors. J Clin Endocrinol Metab 1977;45:534–543. 98 Beck-Peccoz P, Mariotti S, Guillausseau PJ et al. Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with the somatostatin analog SMS 201–995. J Clin Endocrinol Metab 1989;68:208–214. 99 Wemeau JL, Dewailly D, Leroy R et al. Long-term treatment with the somatostatin analog SMS 201-995 in a patient with a thyrotropin and growth hormone-secreting pituitary adenoma. J Clin Endocrinol Metab 1988;66: 636–639. 100 Kovacs K, Horvath E, Ezrin C, Weiss MH. Adenoma of the human pituitary producing growth hormone and thyrotropin. Virchows Arch [Pathol Anat] 1982;395:59–68. 101 Carlson HE, Linfoot JA, Braunstein GD et al. Hyperthyroidism and acromegaly due to a thyrotropin and growth hormone secreting pituitary tumor—lack of hormonal response to bromocriptine. Am J Med 1983; 74:915–923. 102 Samuels MH, Wood WM, Gordon DE et al. Clinical and molecular studies of a thyrotropin secreting pituitary adenoma. J Clin Endocrinol Metab 1989;68: 1211–1215. 103 Tolis G, Bird C, Bertrand G et al. Pituitary hyperthyroidism case report and review of the literature. Am J Med 1978;64:177–181. 104 Horn K, Erhardt F, Fahlbusch R et al. Recurrent goiter, hyperthyroidism, galactorrhea and amenorrhea due to a thyrotropin and prolactin-producing pituitary tumor. J Clin Endocrinol Metab 1976;43:137–143. 105 Gharib H, Carpenter PC, Scheithauer BW, Service EJ. The spectrum of inappropriate pituitary thyrotropin secretion associated with hyperthyroidism. Mayo Clin Proc 1982;57:556–563. 106 Hirasawa R, Hashimoto K, Makino S et al. Effect of a long-acting somatostatin analogue (SMS 201-995) on a growth hormone and thyroid stimulating hormone-producing pituitary tumor. Acta Med Okayama 1991;45:107–115. 107 Jaquet P, Hassoun J, Delori P et al. A human pituitary adenoma secreting thyrotropin and prolactin: immunohistochemical, biochemical and cell culture studies. J Clin Endocrinol Metab 1984;59:817–824. 108 Frank SI, Gesundheit N, Doppman JL et al. Preoperative lateralization of pituitary microadenomas by petrosal sinus sampling: utility in two patients with non-ACTH-secreting tumors. Am J Med 1989;87:679–682. 109 Tindall GT, Barrow DE, eds. Disorders of the Pituitary. St Louis: CV Mosby, 1986:301–320. 110 Hamilton CR Jr, Adams EC, Maloof F. Hyperthyroidism due to thyrotropinproducing pituitary chromophobe adenoma. N Engl J Med 1970;283: 1077–1080. 111 Suntarnlohanakul S, MoSuwan L, Vasiknanont P et al. TSH secreting pituitary adenoma in children: a case report. J Med Assoc Thai 1990;73:175–179. 112 Smith CE, Smallridge RC, Dimond RC, Wartofski L. Hyperthyroidism due to a thyrotropin-secreting pituitary adenoma. Arch Intern Med 1982;174: 1709–1711. 113 Salti IS, Nuwayri-Salti N, Bergman RA et al. Thyrotropin secreting pituitary tumors: a cause of hyperthyroidism. J Neurol Neurosurg Psychiatry 1980;43: 1141–1145. 114 Orme SM, Lamb JT, Nelson M, Belchez PE. Shrinkage of thyrotropin secreting pituitary adenoma treated with octreotide. Postgrad Med J 1991; 67:466–468. 115 Afrasiabi A, Valenta L, Gwinup G. A TSH secreting pituitary tumor causing hyperthyroidism: presentation of a case and review of the literature. Acta Endocrinol 1979;92:448–454. 116 Anniko M, Tribukait B, Werner S, Wersäll J. TSH-secreting tumor—a case report. Arch Otorhinolaryngol 1983;238:135–142. 117 Yovos JG, Falko JM, O’Dorisio TM et al. Thyrotoxicosis and a thyrotropinsecreting pituitary tumor causing unilateral exophthalmos. J Clin Endocrinol Metab 1981;53:338–343. 118 McLellan AR, Connell JMC, Alexander WD, Davies ED. Clinical response of thyrotropin-secreting macroadenoma to bromocriptine and radiotherapy. Acta Endocrinol 1988;119:189–194. 119 Filetti S, Rapoport B, Aron DC et al. TSH and TSH subunit production by human thyrotrophic tumor cells in monolayer culture. Acta Endocrinol 1982; 99:224–231. 120 Warnet A, Lajeunie E, Gelbert F et al. Shrinkage of a primary thyrotropinsecreting pituitary adenoma treated with the long-acting somatostatin analogue octreotide (SMS 201-995). Acta Endocrinol 1991;124:487–491. 121 Mihailovic V, Feller MS, Kourides IA, Utiger RD. Hyperthyroidism due to excess thyrotropin secretion: follow-up studies. J Clin Endocrinol Metab 1980;50:1135–1138.

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122 Hill SA, Falko JM, Wilson CB, Hunt W. Thyrotropin producing pituitary adenomas. J Neurosurg 1982;57:515–519. 123 Coculescu M, Pop A, Constantinovici A et al. Mixed TSH and HGH-secreting pituitary adenoma. Endocrinologie 1982;20:209–216. 124 Lamberts SWJ, Oosterom R, Verleun T et al. Regulation of hormone release by cultured cells from a thyrotropin-growth hormone-secreting pituitary tumor. Direct inhibiting effects of 3,5,3¢-triiodothyronine and dexamethasone on thyrotropin secretion. J Endocrinol Invest 1984;7:313–317. 125 Benoit R, Pearson-Murphy BE, Rosert F et al. Hyperthyroidism due to a pituitary TSH secreting tumor with amenorrhoea-galactorrhoea. Clin Endocrinol 1980;12:11–19. 126 Guillausseau PJ, Chanson PH, Timsit J et al. Visual improvement with SMS 201-995 in a patient with a thyrotropin-secreting pituitary adenoma. N Engl J Med 1987;317:53–54. 127 Jap TS, Kwok CF, Ho LT. Thyrotropin and prolactin-secreting pituitary tumor—dissociated hormonal response to bromocriptine. Chin Med J 1990;45:191–195. 128 Barbarino A, De Marinis L, Anile C, Maira G. Normal pituitary function and reserve after selective transphenoidal removal of a thyrotropin-producing pituitary adenoma. Metabolism 1980;29:739–744. 129 Wollesen F, Andersen T, Karle A. Size reduction of extrasellar pituitary tumors during bromocriptine treatment. Ann Intern Med 1982;96:281– 286. 130 Sy RAG, Bernstein R, Chynn KY, Kourides IA. Reduction in size of a thyrotropin and gonadotropin secreting pituitary adenoma treated with octreotide acetate (somatostatin analog). J Clin Endocrinol Metab 1992;74: 690–694. 131 Bermingham J, Haenel EC. Hyperthyroidism with a FSH and TSH-secreting pituitary adenoma. J Am Osteopath Assoc 1989;89:1560–1566. 132 Mixson AJ, Friedman TC, Katz DA et al. Thyrotropin-secreting pituitary carcinoma. J Clin Endocrinol Metab 1993;76:529–533. 133 Greenman Y, Melmed S. Thyrotropin-secreting pituitary tumors. In: Melmed S ed. The pituitary, 1st edn Cambridge: Blackwell Science, 1995: 546–558. 134 Brucker-Davis F, Oldfield EH, Skarulis MC et al. Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab 1999;84:476–486. 135 Khangure MS, Dingle PR, Stephenson J et al. A long-term follow-up of patients with autoimmune thyroid disease. Clin Endocrinol 1977;6:41–48. 136 Hawkins BR, Chea PS, Dawkins RL et al. Diagnostic significance of thyroid microssomal antibodies in randomly selected population. Lancet 1980;ii: 1057–1059. 137 Alings AM, Fliers E, de Herder WW et al. A thyrotropin-secreting pituitary adenoma as a cause of thyrotoxic periodic paralysis. J Endocrinol Invest 1998;21:703–706. 138 Burgess JR, Shepherd JJ, Greenaway TM. Thyrotropinomas in multiple endocrine neoplasia type 1 (MEN-1). Aust NZ J Med 1994;24:740–741. 139 Gessl A, Freissmuth M, Czech T et al. Growth hormone–prolactin–thyrotropinsecreting pituitary adenoma in atypical McCune–Albright syndrome with functionally normal Gs alpha protein. J Clin Endocrinol Metab 1994;79: 1128–1134. 140 Calle-Pascual AL, Yuste E, Martin P et al. Association of a thyrotropin-secreting pituitary adenoma and a thyroid follicular carcinoma. J Endocrinol Invest 1991;14:499–502. 141 Gasparoni P, Rubello D, Persani L, Beck-Peccoz P. Unusual association between a thyrotropin-secreting pituitary adenoma and a papillary thyroid carcinoma. Thyroid 1998;8:181–183. 142 Spencer CA, Schwarzbein D, Guttler RB et al. Thyrotropin (TSH)-releasing hormone stimulation test responses employing third and fourth generation TSH assays. J Clin Endocrinol Metab 1993;76:494–498. 143 Beck-Peccoz P, Persani L. Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol 1994;131:331–340. 144 Magner JA, Klibanski A, Fein H et al. Ricin and lentil lectin affinity chromatography reveals oligosaccharide heterogeneity of thyrotropin secreted by 12 human pituitary tumors. Metabolism 1992;41:1009–1015. 145 Beck-Peccoz P, Persani L, Faglia G. Glycoprotein hormone a-subunit in pituitary adenomas. Trends Endocrinol Metab 1992;3:41–45. 146 Brabant G, Prank K, Ranft U et al. Circadian and pulsatile TSH secretion under physiological and pathophysiological conditions. Horm Metab Res 1990;23(suppl.):12–17. 147 Adriaanse R, Brabant G, Endert E et al. Pulsatile thyrotropin and prolactin secretion in a patient with a mixed thyrotropin- and prolactin-secreting pituitary adenoma. Eur J Endocrinol 1994;130:113–120.

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148 Sarapura VD, Wood WM, Gordon DF, Ridgway EC. Effect of thyroid hormone on T3-receptor mRNA levels and growth of thyrotropic tumors. Mol Cell Endocrinol 1993;91:75–81. 149 Webster J, Peters JR, John R et al. Pituitary stone: two cases of densely calcified thyrotropin-secreting pituitary adenomas. Clin Endocrinol 1994; 40:137–143. 150 Losa M, Magnani P, Mortini P et al. Indium-111 pentetreotide single-photon emission tomography in patients with TSH-secreting pituitary adenomas: correlation with the effect of a single administration of octreotide on serum TSL levels. Eur J Nucl Med 1997;24:728–731. 151 Cooper DS, Wening BM. Hyperthyroidism caused by an ectopic TSHsecreting pituitary tumor. Thyroid 1996;6:337–343. 152 Verhoeff NP, Bemelman FJ, Wiersinga WM, van-Royen EA. Imaging of dopamine D2 and somatostatin receptors in vivo using single-photon emission tomography in a patient with a TSH/PRL-producing pituitary macroadenoma. Eur J Nucl Med 1993;20:555–561. 153 deHerder WW, Reijs AE, Kwekkeboom DJ et al. In vivo imaging of pituitary tumors using a radiolabelled dopamine D2 receptor radioligand. Clin Endocrinol 1996;45:755–767. 154 Gershengorn MC, Weintraub BD. Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone. A new syndrome of “inappropriate secretion of TSH”. J Clin Invest 1975;56:633–642. 155 Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deafmutism, stippled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 1967; 27:279–294. 156 Beck-Peccoz P, Mannavola D, Persani L. Thyroid hormone receptor mutations. In: Beck-Peccoz P, ed. Regulation of pituitary hormone secretion. Philadelphia: Bioscientifica Ltd, 1999:45–59.

157 Beck Peccoz P, Roncoroni R, Mariotti S et al. Sex hormone-binding globulin measurement in patients with inappropriate secretion of thyrotropin (IST): evidence against selective pituitary thyroid hormone resistance in nonneoplastic IST. J Clin Endocrinol Metab 1990;71:19–25. 158 Persani L, Preziati D, Matthews CH et al. Serum levels of carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in the differential diagnosis of the syndrome of inappropriate secretion of TSH. Clin Endocrinol 1997; 47:207–214. 159 Borst GC, Eil C, Burman KD. Euthyroid hyperthyroxinemia. Ann Intern Med 1983;98:366–378. 160 Gesundheit N. Thyrotropin induced hyperthyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the thyroid, a fundamental and clinical text, 7th edn. Philadelphia: JB Lippincott, 2000:559–565. 161 McCutcheon IE, Weintraub BD, Oldfield EH. Surgical treatment of thyrotropin-secreting pituitary adenomas. J Neurosurg 1990;73:674–683. 162 Chanson P, Warnet A. Treatment of thyroid-stimulating hormone secreting adenomas with octreotide. Metabolism 1992;41(suppl. 2):62–65. 163 Chanson P, Weintraub B, Harris AG. Octreotide therapy for thyroidstimulating hormone-secreting pituitary adenomas. Ann Intern Med 1993;119: 236–240. 164 Gancel A, Vuillermet P, Legrand A et al. Effects of a slow-release formulation of the new somatostatin analogue lanreotide in TSH-secreting pituitary adenomas. Clin Endocrinol 1994;40:421–428. 165 Losa M, Giovanelli M, Persani L et al. Criteria for cure and follow-up of central hyperthyroidism due to thyrotropin-secreting pituitary adenomas. J Clin Endocrinol Metab 1996;81:3084–3096.

C h a p t e r

15 Gonadotroph Adenomas Peter J. Snyder

Adenomas that arise from the gonadotroph cells are among the most common adenomas of the pituitary gland, but they are the most difficult to recognize because they secrete inefficiently and the secreted products—intact gonadotropins and their subunits—usually do not produce a readily recognizable clinical syndrome. Consequently, these adenomas are often not recognized until they become so large as to cause neurologic symptoms. PATHOPHYSIOLOGY Gonadotroph adenomas usually synthesize and secrete the products of the normal gonadotroph cell, intact gonadotropins—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—and their subunits—a, FSHb, and LHb—but the secretion usually differs from that of other pituitary adenomas in two ways. First, gonadotroph adenomas secrete inefficiently compared to many other pituitary adenomas. Macroadenomas that arise from lactotroph cells, for example, typically produce serum prolactin concentrations 100–1000 times normal. Macroadenomas that arise from gonadotroph cells, in contrast, may produce serum concentrations of its secretory products up to 10 times normal, but often not above normal at all; in those cases the secretory nature of the adenomas can be recognized only by their response to stimulation and/or by their secretory behavior in vitro. Second, gonadotroph adenomas usually do not secrete intact gonadotropins and their subunits in the same proportions as do normal gonadotroph cells.

Secretion In Vivo Basal Secretion

Intact FSH and LH Gonadotroph adenomas often produce supranormal basal serum concentrations of intact

FSH but less commonly of intact LH. The degree of FSH elevation is minimal to 10 times normal. The first reported cases of gonadotroph adenomas all manifested supranormal serum concentrations of FSH [1–5], so in the first series of patients recognized to have gonadotroph adenomas a supranormal serum FSH concentration was used as identification [6]. Only later was it realized that the pituitary adenomas of some patients whose serum concentrations of FSH are normal secrete FSH in culture and therefore that they are also gonadotroph adenomas. The FSH secreted by gonadotroph adenomas is apparently normal, or nearly normal, qualitatively. The size of the FSH appears similar to that of intact FSH, not of the FSH subunits, a and FSHb, since on gel filtration of sera from patients who have gonadotroph adenomas and supranormal serum FSH concentrations, FSH immunoreactivity elutes in a position similar to that of a highly purified preparation of intact pituitary FSH rather than that of the subunits (Fig. 15.1) [7]. The pattern of charge on the FSH secreted by most of these adenomas also appears to be close to normal, since the chromatofocusing patterns of both FSH immunoreactivity [8] and biologic activity [9] are similar to those of FSH from nonadenomatous pituitary glands. FSH from patients with gonadotroph adenomas is biologically active in vitro; in fact, the ratio of biologic to immunologic activity in the sera of men with gonadotroph adenomas is even greater than that of age-matched normal men (Fig. 15.2) [9]. In vivo biologic activity, however, has not been tested and would not necessarily parallel the in vitro activity, since in vivo activity depends on the clearance of FSH as well as its intrinsic activity. The basal serum concentration of intact LH may be slightly supranormal but is rarely substantially supranormal in patients who have gonadotroph adenomas. When it is elevated and the patient a male, the serum testosterone 575

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FIGURE 15.1. Gel filtration pattern of immunoreactive FSH in the serum of a man with a gonadotroph adenoma and supranormal serum FSH. Elution of this man’s FSH in a pattern similar to that of purified intact pituitary FSH, shown by the arrow, rather than to FSHb or a subunits, is evidence that the FSH secreted by this gonadotroph adenoma is intact FSH. From Snyder et al. [7] FIGURE 15.2. The ratios of FSH biologic activity to immunoreactivity in the sera of 14 men with gonadotroph adenomas and supranormal serum FSH concentrations compared to the ratios in 11 age-matched normal men. From Galway et al. [9]

FIGURE 15.3. Serum concentrations of FSH, LH, and testosterone in a man who had a gonadotroph adenoma secreting both FSH and intact LH. Blood was sampled before and after each of two surgical procedures. Although secretion of FSH by gonadotroph adenomas is common, secretion of intact LH is not. That the supranormal serum LH is biologically effective is shown by the supranormal serum testosterone concentration. From Snyder et al. [1]

concentration, as one would predict, is also supranormal (Fig. 15.3) [1,10–13]. In most men with gonadotroph adenomas the serum LH concentration is within the normal range or slightly elevated and the testosterone concentration is normal or subnormal [14]. When the testosterone is subnormal, it increases rapidly to normal in response to administration of exogenous human chorionic gonadotropin [15], suggesting a secondary cause of the hypogonadism, presumably due to compression of the normal gonadotroph cells by the large but inefficient gonadotroph adenoma. Gonadotropin Subunits: a, FSHb, and LHb Gonadotroph adenomas may produce supranormal basal serum concentrations of a and FSHb and LHb subunits.

When gonadotroph adenomas are identified by a supranormal basal serum FSH concentration, many [6,7,16–18], perhaps one third [6] of the patients also exhibit a supranormal serum a subunit concentration. The degree of elevation of the a subunit concentration can be more or less than that of the FSH concentration. Those few gonadotroph adenomas recognized by their supranormal serum concentration of intact LH also may exhibit a supranormal serum a concentration [10,13]. Some pituitary adenomas produce supranormal serum concentrations of a subunit but not of intact FSH or LH [19,20], many of these are probably also gonadotroph adenomas, because they may secrete intact FSH, as well as a subunit, in culture [21]. Gonadotroph adenomas identified by supranormal basal serum FSH

Chapter 15

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the a subunit in these patients is secreted by the adenomatous somatotroph cells. Stimulated Secretion

FIGURE 15.4. Similarity of LHb subunit mRNA from two gonadotroph adenomas to that from normal pituitary, as demonstrated by S1-nuclease mapping. A 35-base, 32P-labelled oligonucleotide that overlaps with the transcriptional start site of the LHb gene was hybridized to RNA, digested with S1-nuclease, and analyzed by electrophoresis on a 20% polyacrylamide-urea gel followed by autoradiography. Oligonucleotides of known length (arrows) were used to determine the lengths of the labeled oligonucleotides protected from digestion by S1-nuclease. The protected oligonucleotides from two gonadotroph adenomas (lanes 4 and 5) were similar to those from normal pituitary (lane 3); lane 1 is oligonucleotide before digestion and lane 2 is no RNA. From Jameson et al. [22]

concentrations generally produce supranormal basal concentrations of serum FSHb as well [14]. The a, LHb, and FSHb genes in gonadotroph adenomas appear to be the same as those in the normal pituitary. The transcriptional start sites of the a and LHb subunit genes in gonadotroph adenomas have been shown to be identical to those in the normal pituitary by S-1 nuclease mapping [22]. Specific circular deoxyribonucleic acids (cDNAs) that overlap the 5¢ ends of the a and LHb subunit messenger ribonucleic acids (mRNAs) were hybridized to RNA from gonadotroph adenomas, protecting the RNAs from S-1 nuclease digestion. The lengths of the protected oligonucleotides were the same as those from normal pituitary (Fig. 15.4). By another technique adenoma FSHb mRNA also appeared to be similar to that of normal pituitary mRNA. Other Secretory Products Documented or presumed gonadotroph adenomas have occasionally been shown to secrete products other than gonadotropins and their subunits. One patient was found to have an adenoma that produced supranormal serum concentrations of FSH and TSH [23]. About one-third of patients with acromegaly have supranormal serum concentrations of a subunit [24], but both in vivo [25] and in vitro [26,27] evidence suggest that

Administration of thyrotropin-releasing hormone (TRH) to patients who have gonadotroph adenomas often produces an increase in their serum concentration of LHb subunit and less often intact FSH and LH. These responses are characteristic of gonadotroph adenomas, because normal men and women show no response of intact FSH and FSHb and no more than a 33% increase in intact LH and LHb [14,28,29]. In a study of 16 women who had pituitary macroadenomas that were clinically nonfunctioning, 11 could be identified as being of gonadotroph origin by their LHb subunit responses to TRH; four had responses of intact LH and three of intact FSH (Fig. 15.5) [29]. Of 38 men who had pituitary macroadenomas that were clinically nonfunctioning, 14 had responses of LHb, five of intact LH, and four intact FSH (Fig. 15.6) [14]. Administration of GnRH to patients who have gonadotroph adenomas results in greatly variable FSH and LH responses, from subnormal to inability to determine if the increase in FSH or LH is secreted by adenomatous or normal gonadotroph cells.

Synthesis and Secretion In Vitro Basal Secretion

When gonadotroph adenomas that are recognized in vivo by supranormal basal or stimulated serum concentrations of gonadotropins and/or their subunits are excised and studied in vitro, they usually synthesize and secrete large amounts of the same intact hormones and subunits they had in vivo, confirming the gonadotroph nature of the adenomas. These adenomas often synthesize and secrete large amounts of other gonadotroph cell products as well. For example, when adenomas that produce supranormal serum FSH concentrations in vivo are excised and established in dispersed cell culture, they usually secrete large amounts of FSH, but they often secrete intact LH also (Table 15.1) [21]. Similarly, adenomas that produce a supranormal serum concentration of a subunit but not of intact FSH may secrete as much FSH in culture as adenomas that produced supranormal serum FSH concentrations (Table 15.1) [21]. Not surprisingly, adenomas that produce supranormal serum FSH concentrations stain immunospecifically for FSH and LH [30]. When pituitary adenomas that are not associated in vivo with supranormal serum concentrations of any pituitary hormones, i.e., so called “nonsecreting” or “nonfunctional” adenomas, are studied in vitro, a majority have been shown to synthesize and secrete intact gonadotropins and/or their subunits in vitro, demonstrating that they are also gonadotroph adenomas. The results are similar whatever the in vitro technique: dispersed cell culture and assay of the culture medium [31–33], immunospecific staining of fixed adenoma tissue [31–34], or extraction of mRNA (Table 15.2) [22]. Using these techniques 70–100% of “nonsecret-

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FIGURE 15.5. Increases in the serum concentrations of intact FSH, LH, alpha subunit, and, mostly, LHb subunit to TRH in 16 women with adenomas that had been thought to be “nonsecreting” on the basis of basal serum hormone concentrations. The dashed lines show the ranges of serum concentrations in 16 age-matched healthy women. Eleven women with “nonsecreting” adenomas exhibited significant responses to TRH of LHb subunit, four of intact LH and a subunit, and three of FSH. From Daneshdoost et al. [14]

FIGURE 15.6. Increases in the serum concentrations of intact FSH, LH, alpha subunit, and, mostly, LHb subunit to TRH in 38 men with adenomas that had been thought to be “nonsecreting” on the basis of basal serum hormone concentrations. The dashed lines show the ranges of serum concentrations in age-matched healthy men. From Daneshdoost et al. [14]

ing” adenomas have been found to synthesize and/or secrete some combination of intact FSH and LH and a, FSHb, and LHb subunits. Up to 25% of these adenomas demonstrate intact TSH, TSHb, or a, but only sporadic adenomas show evidence of prolactin, growth hormone or ACTH. Stimulated Secretion

Gonadotroph adenomas, whether initially identified in vivo or only in vitro, may respond in culture to stimulation with

both GnRH and TRH. In one study gonadotropinreleasing hormone (GnRH) stimulated the secretion of LH in two of five adenomas and FSH in two of six [35]. Unlike the responses of gonadotropins to GnRH in vivo, which cannot be ascribed with certainty to normal or adenomatous gonadotroph cells, the locus of the responses of adenoma cells culture to GnRH seems clear. TRH stimulated the secretion of LH in three of five and FSH in two of six adenomas [35].

Gonadotroph Adenomas

Chapter 15 Table 15.1. adenoma cells Patient number

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Secretion of pituitary hormones from excised and cultured pituitary

a Subunit LHb (ng/24 h/0.5 ¥ 106 cells)

FSH

LH

TSH

GH

Supranormal serum FSH 1 5.4 2 5.1 3 27.0

1.8 5.3 1.6

0.5 0.3 1.0

Supranormal serum a subunit 4 12.7 5 17.0 6 2.7 7 0.6

0.2 7.7 7.2 0.7

Supranormal serum prolactin 8 < 0.1 9 0.9 10 0.7 11 0.8

0.2 – – 0.5

PRL

0.39 0.49 0.22

< 0.03 < 0.33 < 0.22

< 0.07 < 0.10 < 0.05

0.12 < 0.14 0.11

7.2 10.7 22.0 14.1

< 0.04 0.85 0.48 0.04

< 0.33 0.44 < 0.10 < 0.06

0.19 < 0.27 0.21 0.13

0.12 0.11 0.16 0.81

1.2 2.4 0.4 0.6

< 0.02 < 0.1 0.01 0.05

< 0.04 < 1.1 < 0.25 0.26

13.7 0.90 0.50 440

2730 3050 1200 235

Adenomas are grouped by in vivo hormonal secretory abnormalities. Not only did cells from adenomas associated with supranormal serum FSH concentrations secrete relatively large amounts of FSH in culture, so did some adenomas associated with supranormal serum concentrations of a subunit but not FSH, indicating that some “a subunit-secreting” adenomas are gonadotroph adenomas. From Snyder et al. [7]

Table 15.2. Synthesis and secretion in vitro of pituitary hormones by “nonsecreting” pituitary adenomas

Authors No. of patients FSHb, LHb, a TSHb, a Prolactin Growth hormone ACTH

Immunostaining (%)

Hormone secretion in culture (%)

Black et al. [34] 36 66.7 33.3 16.7 2.8 8.5

Asa et al. [32] 12 100 25 0 0 0

mRNA (%) Jameson et al. [22] 13 69.3 7.7 0 0 7.7

In each study the authors examined by an in vitro technique (immunospecific staining, hormone secretion in culture, or mRNA expression) surgically excised pituitary adenoma tissue that had been judged to “nonsecreting” by basal serum hormone concentrations in vivo.

PATHOLOGY Gonadotroph adenomas are not usually recognized until they become very large, but they differ little, if any, from other pituitary macroadenomas in gross pathologic appearance or by light or electron microscopy. Gonadotroph adenomas can be reliably distinguished pathologically from other pituitary adenomas only by detecting the expression of the FSHb, LHb, or a subunit genes by immunospecific staining for the subunits in adenoma tissue, extracting their mRNAs from adenoma tissue, or by secretion of

intact gonadotropins or the subunits by cultured adenoma cells.

Gross Pathology Because excessive secretion of gonadotropins and their subunits do not cause a recognizable clinical syndrome, gonadotroph adenomas are generally not recognized until they become so large that they cause neurological symptoms. Gonadotroph adenomas, however, do not differ in their gross pathologic characteristics from other pituitary

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adenomas of similar size. Like other pituitary macroadenomas, they may extend outside of the sella turcica in any direction. Superior extension may elevate and compress the optic chiasm and even compress the hypothalamus and third ventricle; lateral extension into the cavernous sinuses may encase the internal carotid arteries and compress the oculomotor nerves; inferior extension into the sphenoid sinus may cause CSF rhinorrhea. Focal areas of hemorrhage are often found within gonadotroph adenomas, but most are not associated with the clinical syndrome of pituitary apoplexy.

Light Microscopy By light microscopy gonadotroph adenomas often differ little from other pituitary adenomas when stained with hematoxylin and eosin. As in other pituitary adenomas, the cells are not arranged in the normal pituitary glandular pattern but instead are in cords [30,36], sometimes interspersed with varying amounts of fibrous tissue. In any one adenoma the cells are usually similar in size, but vary considerably among adenomas. The cytoplasm stains neither with hematoxylin nor eosin, so for many years gonadotroph adenomas were called “chromophobe adenomas.”This term, which implied that the cells were hormonally inactive, contributed to the erroneous impression that the adenomas were nonsecreting By light microscopy gonadotroph adenomas can often be recognized when stained specifically for gonadotropin subunits. Not only do adenomas associated with elevated serum gonadotropin concentrations stain for gonadotropin subunits (Fig. 15.7) [30,36], so do more than 70% of adenomas that are associated with no supranormal serum concentration of any pituitary hormone [31,32,34]. The percentage of cells that stain immunospecifically for gonadotropin subunits, however, is smaller than the percentage of somatotroph or

lactotroph adenoma cells that stain for growth hormone of prolactin. The intensity of staining of gonadotroph adenomas is also less than that of somatotroph and lactotroph adenomas. Some gonadotroph adenomas, however, can not be recognized at all by immunospecific staining. Many adenomas that do not stain immunospecifically for any pituitary hormone and are called “null cell” or “oncocytic” (because of densely packed mitochondria) secrete intact gonadotropins and/or their subunits in cell culture [32].

Electron Microscopy The electron microscopic appearance of gonadotroph adenomas is variable. Some adenomatous gonadotroph cells have numerous secretory granules of varying sizes and cytoplasmic organelles, and others have sparse secretory granules and few organelles [30,37]. Yet others have numerous mitochondria (“oncocytes”) and few secretory granules [31]. ETIOLOGY Gonadotroph adenomas appear to be true neoplasms, arising from a somatic mutation of a single progenitor cell that divides repetitively. The evidence for this view comes from studies that show that virtually all pituitary adenomas, including gonadotroph adenomas, are monoclonal, that is, arise from a somatic mutation of a single cell. These studies utilized the technique of restriction fragment length polymorphism to determine if pituitary adenomas in women whose other somatic cells are heterozygous for the enzymes hypoxanthine phosphoribosyltransferase (HPRT) and phosphoglycerate kinase (PGK) are homozygous or heterozygous. This technique relies on the fact that early in embryogenesis in females one X chromosome, either of maternal or paternal origin, is inactivated. Because the inactivation is random, normal somatic tissues from women who

FIGURE 15.7. Demonstration of FSH and LH in gonadotroph adenoma cells by immunoperoxidase staining. The left panel shows positive cytoplasmic staining (brown color) in several cells for FSH; staining for LH was similarly positive. The right panel shows no cytoplasmic staining for prolactin; staining for growth hormone was similarly negative.

Chapter 15

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FIGURE 15.8. Demonstration of the apparent monoclonality of five pituitary adenomas. The bands represent DNA fragments of the HPRT gene from the peripheral leukocytes (lanes a and b) and pituitary adenoma cells (lanes c and d) of five women. The leukocytes of each patient show both alleles of the gene (lane b), but the adenoma cells show only one allele (lane c), supporting the hypothesis that these adenomas arose from clonal expansion of a single cell. From Alexander et al. [57]

are heterozygous for a gene express approximately equal amounts of both alleles of that gene. In contrast, a neoplasm that occurs after embryogenesis in a heterozygous woman arises from a single progenitor cell and therefore expresses only one of the alleles. In one study of five women whose pituitary macroadenomas expressed some combination of FSHb, LHb, and a subunit and whose peripheral leukocytes were heterozygous for HPRT, the adenomas had predominantly one allele or the other (Fig. 15.8) [38]. This study suggests that gonadotroph adenomas arise from a somatic mutation of a single progenitor cell which then proliferates, but what mutation and what causes the transformation remain unknown. Specific mutations are known that appear to cause development of about 40% of somatotroph adenomas [39] and pituitary adenomas associated with multiple endocrine hyperplasia type I [40], but the mutations that cause other pituitary adenomas, including gonadotroph adenomas, are not known. Investigators have searched, directly or indirectly, for many other mutations that might be causally related to the development of other pituitary adenomas, including genes that express c-Myc, c-fos, c-myb [41], ras [42,43], retinoblastoma suppresser [44–46], IL-6 [47], pituitary adenylate cyclase activating peptides [48], protein kinase C [49], basic fibroblast growth factor [50], epidermal growth factor [51], transforming growth factor b [52], gonadotropin-releasing hormone [53], gonadotropinreleasing hormone receptor [54], pituitary tumor tranforming gene [55], activin [56,57], and follistatin

[57,58], but none has been clearly associated with the pathogenesis of any human pituitary adenomas. External hormonal stimulation from the hypothalamus now seems unlikely to be a primary cause of gonadotroph adenomas, but might have a secondary effect on adenoma growth and probably has an effect on adenoma secretion. The possibility that gonadotroph adenomas could arise from stimulation of the gonadotroph cells as a consequence of testosterone deficiency in long-standing primary hypogonadism was raised because of the observation that patients who have long-standing primary hypogonadism do develop some degree of pituitary enlargement [59]. Even before the recent demonstration that gonadotroph adenomas are monoclonal, however, a principal etiologic role of primary hypogonadism in the development of gonadotroph adenomas seemed unlikely, because the historical, clinical, and hormonal characteristics of patients with gonadotroph adenomas are quite distinct from those of patients with primary hypogonadism, as discussed under differential diagnosis. And yet, hormonal secretion by gonadotroph adenomas does seem to be dependent on endogenous GnRH, since administration of the GnRH antagonist Nal-Glu GnRH to patients with gonadotroph adenomas and supranormal serum FSH concentrations lowers the FSH to normal (Fig. 15.9) [60]. Histologic evidence also supports the view that gonadotroph adenomas are true neoplasms. Gonadotroph adenomas are composed of sheets of similar pituitary cells, rather than a mixture of various kinds of pituitary cells arranged in a sinusoidal pattern, as occurs in the

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Pituitary Tumors Table 15.3. adenomas

Clinical presentations of gonadotroph

Neurologic symptoms (most common) Visual impairment Headache Other (diplopia, seizures, CSF rhinorrhea, etc.) Incidental finding When magnetic resonance imaging is performed because of an unrelated symptom Hormonal symptoms (least common) Ovarian hyperstimulation when intact FSH is secreted in a premenopausal woman Premature puberty when intact LH is secreted in a prepubertal boy Symptoms resulting from anterior pituitary hormonal deficiencies (commonly occur but uncommonly are the presenting symptoms)

FIGURE 15.9. Suppression to normal of the initially supranormal serum FSH concentration in a man with a gonadotroph adenoma in response to the administration of the GnRH antagonist, Nal-Glu GnRH, 5 mg twice a day for 7 days. From Daneshdoost et al. [60]

normal pituitary. Hyperplasia of one kind of pituitary cell, in contrast, is manifest by an increase in that type of cell but not an effacement of the normal pituitary sinusoidal architecture or absence of other kinds of pituitary cell types. Gonadotroph adenomas usually come to clinical attention when they become so large as to cause neurologic symptoms, most commonly impaired vision (Table 15.3). The large size may also cause deficient hormonal secretion from the nonadenomatous pituitary, and these deficiencies may even be recognizable at the time of presentation, but they are usually not the impetus for the patient seeking medical attention. Gonadotroph adenomas are probably not recognized when they are microadenomas because excessive gonadotropin secretion usually does not cause a clinically recognizable syndrome, and also because these adenomas are usually so inefficient hormonally that when they are of “micro” size (less than 1 cm) they probably do not produce elevated serum gonadotropin or subunit concentrations.

Neurologic Symptoms Impaired vision is the symptom that most commonly leads a patient with a gonadotroph adenoma to seek medical attention, although another neurologic symptom may also do so. Visual impairment is caused by suprasellar extension of the adenoma that compresses the optic chiasm. If the extension is in the midline, the greatest compression occurs in the middle of the chiasm, the site of the fibers that cross and serve the nasal retinae and therefore receive visual

signals from the temporal fields. Vision from the temporal fields is thus compromised first, beginning with the superior quadrants. Suprasellar extension may also occur asymmetrically; if laterally, it could impair vision in one nasal field; if anteriorly, it could impair vision in all of one eye but not the other. When compression becomes more severe, central visual acuity is also affected. Some patients recognize the localized beginnings of their visual deficit, but others notice only that they cannot see what they once could. The onset of the deficit is usually so gradual that patients often do not seek ophthalmological consultation for months or even years. Even then the reason for the deficit may not be recognized, unless a visual field examination is performed, and the diagnosis delayed further. Other neurologic symptoms that may cause a patient with a gonadotroph adenoma to seek medical attention are headaches, caused presumably by expansion of the sella; diplopia, caused by oculomotor nerve compression due to lateral extension of the adenoma; CSF rhinorrhea, caused by inferior extension of the adenoma; and the excruciating headache and the diplopia caused by pituitary apoplexy, sudden hemorrhage into the adenoma.

Symptoms of Pituitary Hormonal Deficiencies At the time of initial presentation due to a neurologic symptom, many patients with gonadotroph adenomas, when questioned, admit to symptoms of pituitary hormonal deficiencies. Ironically, the most common pituitary hormonal deficiency is of LH, as a result of compression of the normal gonadotroph cells by the adenoma and lack of secretion of a substantial amount of intact LH by the adenomatous gonadotroph cells. The result in men is a subnormal serum testosterone concentration, which produces symptoms of decreased energy and libido. The result in premenopausal women is amenorrhea. Thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) deficiencies, leading to thyroxine and cortisol deficiencies, may also occur.

Chapter 15

Symptoms of Gonadotropin Excess There clinical syndromes that result from excessive gonadotropin secretion have been reported. In premenopausal women, excessive secretion of intact FSH causes ovarian hyperstimulation [61,62]. These women do not have cyclical ovarian function, and so do not have regular menses, but may have breakthrough bleeding. They have polycystic ovaries and thickened endometrium by ultrasound (Fig. 15.10) and supranormal serum concentrations of intact FSH, estradiol, and inhibin. In men, excessive secretion of intact FSH and LH may cause larger than normal testicular size [63]. In prepubertal boys, excessive secretion of intact LH causes premature puberty [64]. DIAGNOSIS The process of making the diagnosis of a gonadotroph adenoma usually proceeds first from recognizing that a patient’s visual abnormality or other symptom could represent a sellar mass, then to confirming the presence of a sellar mass by magnetic resonance imaging (MRI), and finally to finding secretory abnormalities of gonadotropins and their subunits characteristic of gonadotroph adenomas. Sometimes the sellar mass is found serendipitously when an MRI of the head is performed because of an unrelated symptom.

Visual and Other Abnormalities The visual abnormality most characteristic of a sellar mass is diminished vision in the temporal fields. Either or both eyes may be affected, and to variable degrees. Diminished visual acuity occurs when the optic chiasm is more severely

Gonadotroph Adenomas

583

compressed. Depending on the direction of suprasellar extension of the adenoma, other patterns of visual loss may also occur, so a sellar lesion should be suspected when any pattern of visual loss is unexplained. Other neurologic abnormalities that should raise the suspicion of a sellar mass are headaches, oculomotor nerve palsies, and CSF rhinorrhea. The quality of the headaches are not specific. Amenorrhea should also raise the suspicion of a sellar mass.

Imaging of the Pituitary MRI is more than sensitive enough to demonstrate any pituitary adenoma that has become so large as to impair vision or cause any other neurologic symptom. Because gonadotroph adenomas are generally hormonally inefficient, by the time that a gonadotroph adenoma produces supranormal serum concentrations of intact gonadotropins or their subunits, it is sufficiently large to be seen by MRI. MRI will not distinguish, however, adenomatous tissue from normal pituitary tissue; consequently, a clear distinction between an intrasellar mass lesion and the normal pituitary is evidence that the lesion is not a pituitary adenoma. MRI will also not distinguish a gonadotroph adenoma from other pituitary macroadenomas.

Hormonal Abnormalities Intrasellar mass lesions detected by MRI should be evaluated further by measurement of serum concentrations of pituitary hormones to determine if the lesion is of pituitary or nonpituitary origin, and if pituitary, the cell of origin. A pituitary adenoma of gonadotroph or thyrotroph cell origin should be suspected if the serum prolactin concentration is less than 100 ng/ml, the patient does not appear acromegalic and the serum IGF-1 concentration is not supranormal, and the patient does not have Cushing’s syndrome and does not have supranormal urine cortisol excretion. A lesion of nonpituitary origin could also account for these findings. Preoperative recognition that an intrasellar mass lesion is of gonadotroph origin depends on finding specific combinations of the serum concentrations of gonadotropins and their subunits (Table 15.4). The combinations differ somewhat in men and women. Men

FIGURE 15.10. Multiple ovarian cysts as seen by ultrasonography in a premenopausal woman who had a gonadotroph adenoma hypersecreting FSH and causing ovarian hyperstimulation syndrome. Arrows point to the cysts. From Djerassi et al. [61]

A supranormal serum FSH concentration in a man who has a sellar mass usually indicates that the lesion is a gonadotroph adenoma (Fig. 15.11).The diagnosis is strengthened if he also has other characteristic features of a gonadotroph adenoma, such as a supranormal basal serum concentration of a subunit or responses of intact FSH and LH or of LHb to TRH (Fig. 15.11). A supranormal serum LH accompanied by a supranormal serum testosterone, whether or not accompanied by a supranormal FSH, is strong evidence that the lesion is one of the unusual

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gonadotroph adenomas that secrete intact LH (Fig. 15.12). A supranormal serum a subunit as the sole basal serum abnormality indicates that the intrasellar lesion is of gonadotroph or thyrotroph origin. TRH stimulation of Table 15.4. In vivo hormonal criteria for the diagnosis of gonadotroph adenomas* (Any one or any combination of the following) Men

Women

Supranormal basal serum concentrations of FSH† a subunit LH and testosterone

FSH, but not LH a subunit relative to FSH and LH

Supranormal response to TRH of FSH LH LHb (most common)

FSH LH LHb (most common)

* Assuming the patient has a pituitary macroadenoma. † Assuming the patient does not have a history of primary hypogonadism.

intact FSH or LH or of LHb subunit would confirm a gonadotroph origin. If the basal serum concentrations of FSH, LH, and a subunit are supranormal, TRH stimulation of FSH, LH, or LHb subunit also would suggest that adenoma is of gonadotroph origin (Fig. 15.12). Women

Recognizing the gonadotroph origin of an intrasellar mass on the basis of basal serum hormone concentrations of intact FSH and LH is more difficult in women than in men. In a woman over 50 years old who has an intrasellar mass and elevated gonadotropins, distinguishing between the adenoma and normal postmenopausal gonadotroph cells as the source is usually not possible on the basis of the basal gonadotropins alone. Similarly, in a woman under 50 years old who has an intrasellar mass and elevated serum gonadotropins, distinguishing between the adenoma and premature ovarian failure as the source of the gonadotropins is also not usually possible on the basis of the FSH and LH values alone. A few combinations of basal FSH, LH, and a subunit values, however, do suggest strongly that an intrasellar mass is a gonadotroph adenoma. A markedly supranor-

FIGURE 15.11. Diagnosis of a gonadotroph adenoma in a 72-year-old man. He presented with visual impairment and was found to have an intrasellar mass lesion. The diagnosis of gonadotroph adenoma was made readily merely by finding supranormal basal serum concentrations of FSH (19.2 IU/L; normal range, 3–14) and a subunit (10.3 mg/L; normal range, 0.3–3.2). The responses to TRH of intact FSH and LH and of LHb subunit seen above are characteristic, although not necessary for the diagnosis in this patient.

FIGURE 15.12. Diagnosis of a gonadotroph adenoma in a 63-year-old man. Magnetic resonance imaging performed because of a motor vehicle accident showed an intra- and suprasellar mass lesion, which was asymptomatic. Although his basal serum concentrations of FSH (10.5 IU/L; normal, 3–14), LH (2.8 IU/L; normal, 3–18), and a subunit (1.5 mg/L; normal, 0.3–3.2) were all normal, the diagnosis of a gonadotroph adenoma was made by finding a threefold increase in the serum LHb subunit concentration in response to TRH.

Chapter 15

Gonadotroph Adenomas

585

FIGURE 15.13. Diagnosis of a gonadotroph adenoma in a 52-year-old woman. She had had regular menses until a hysterectomy (but not ovariectomy) at age 42 and was asymptomatic until the onset of blurred vision three months previously. Basal serum concentrations of FSH (19.5 IU/L), LH (5.2 IU/L), and a subunit (2.6 mg/L) were not diagnostic, but the two- and threefold responses of LH and FSH, respectively, to TRH and, most dramatically, the fivefold response of LHb subunit, indicate the gonadotroph nature of the adenoma.

mal FSH associated with a subnormal LH, for example, most likely indicates a gonadotroph adenoma, rather than the postmenopausal state or premature ovarian failure. A serum a subunit concentration that is supranormal when intact FSH and LH are not, or is supranormal out of proportion to the FSH and LH, also suggests a gonadotroph adenoma. More commonly, an intrasellar mass in a woman may be recognized as a gonadotroph adenoma by an increase in the FSH or LH, or even more frequently, the LHb subunit, in response to TRH (Fig. 15.13) [29].

Distinguishing a Gonadotroph Adenoma from Primary Hypogonadism The issue of distinguishing a gonadotroph adenoma from primary hypogonadism may be raised, because in both conditions serum concentrations of intact gonadotropins and their subunits may be supranormal and gonadal steroids may be subnormal. Furthermore, long-standing primary hypogonadism may cause some enlargement of the pituitary as a consequence of gonadotroph hyperplasia [59]. In practice, however, making this distinction is usually quite easy, because each exhibits a different clinical presentation and each a different set of hormonal secretory characteristics (Table 15.5). The major clinical distinction results from the observation that pituitary enlargement due to primary hypogonadism usually does not occur unless the hypogonadism is severe, untreated, and of many years duration. Consequently, such patients, both men and women, usually appear severely hypogonadal clinically. In contrast, men and women who have gonadotroph adenomas may be hypogonadal, but the hypogonadism is usually not severe or of long duration. Consequently, they do not appear hypogonadal clinically. The major difference in basal hormonal concentrations is the elevation of both FSH and LH in patients who have primary hypogonadism and the elevation of FSH but usually not LH, and sometimes by a greater elevation of a subunit, in patients who have gonadotroph adenomas.

Table 15.5. Comparison of characteristics of gonadotroph adenomas and primary hypogonadism in men

Puberty Fertility history Testicular size Serum testosterone Testosterone response to hCG (when basal value is subnormal) Serum FSH Serum LH a-subunit FSH response to TRH LHb response to TRH

Gonadotroph adenoma

Primary hypogonadism

Normal Normal Normal Low to high Marked, to well within normal range High Usually normal or sligtly high High to very high Common Very common

Often incomplete Subnormal Small Low to normal Subnormal

High High if testosterone is low High Absent Absent

The major difference in hormonal responses to TRH is that patients who have gonadotroph adenomas often exhibit responses of FSH, LH and, more commonly, LHb subunit [29], but patients who have primary hypogonadism do not [28]. Another clear difference is that men who have a subnormal serum testosterone on the basis of a gonadotroph adenoma exhibit an increase to well within the normal range when treated with hCG for 4 days [15], but men with primary hypogonadism do not.

Abnormal Secretion of Other Pituitary Hormones Pituitary adenomas that secrete intact gonadotropins and/or their subunits usually do not also secrete other pituitary hormones as well, but concomitant secretion of TSH and prolactin have been reported rarely. A serum prolactin concentration that is elevated but under 100 ng/ml,

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however, suggests not concomitant secretion by the adenoma but increased secretion by normal lactotroph cells that are less than normally inhibited because of stalk compression by the adenoma. Deficient secretion of other pituitary hormones often occurs due to the mass effect of the typically large gonadotroph adenomas and should always be investigated. Measurement of basal serum concentrations of T4, cortisol, and testosterone in men and estradiol in women and of ACTH reserve are usually necessary. TREATMENT Because gonadotroph adenomas are usually not detected until they become so large that they cause significant visual impairment, treatment must be directed at reducing adenoma mass and restoring vision as soon as possible. Surgery, usually transsphenoidal, is the only treatment that meets this criterion (Table 15.6). Gonadotroph adenomas are usually sensitive to radiation, which may be used to prevent regrowth if substantial adenoma tissue remains after surgery or to treat primarily if an adenoma is detected before it becomes so large as to cause neurologic symptoms. Several pharmacologic treatments have been tried, but none reduce adenoma size much.

Surgery Surgical Approaches

Transsphenoidal surgery via an operating microscope is usually the preferred treatment for gonadotroph adenomas

Table 15.6.

that impair vision significantly. Transsphenoidal surgery may also be performed because of severe headaches, diplopia, or other neurologic abnormalities, and elevation of the optic chiasm in the absence of visual impairment. The transsphenoidal approach is usually preferred over the transcranial as the initial procedure no matter how great the suprasellar extension, because pituitary adenomas are infradural and the risk of serious side effects is less. An endoscopic approach to sellar masses has been reported by some surgeons recently [65–67]. This approach, which appears to be evolving, employs an endoscope in a similar fashion to endoscopic surgery of the sinuses. Some patients with hormonally active pituitary adenomas appear to have been cured by this procedure and others have not been. Some of the same complications that occur from the microsurgical technique have been reported. Transcranial surgery may be performed when suprasellar adenoma tissue that remains after transsphenoidal surgery continues to cause clinically significant neurologic impairment. Neurologic side effects are somewhat more likely by this approach than by the transsphenoidal approach. Efficacy of Surgery

Transsphenoidal surgery almost always results in a decrease in adenoma size (Fig. 15.14) [68] and concomitantly an improvement in vision (Fig. 15.15) and decrease in hormone hypersecretion (Fig. 15.16) [68]. Seventy to eighty per cent of patients who have abnormal visual fields due to a gonadotroph adenoma in one series experienced improvement following transsphenoidal surgery [68]. This improvement is similar to that of all macroadenomas. In one series

Comparison of treatments for gonadotroph adenomas

Treatment

Indications

Complications

Transsphenoidal surgery

Intrasellar mass with suprasellar extension and severe visual impairment

Worsening of vision, oculor palsy, hematoma, CSF rhinorrhea, meningitis, diabetes insipidus, hypopituitarism

Transcranial surgery

Large, residual symptomatic extrasellar tissue following transsphenoidal surgery

Same as above, but more likely

Radiation

Primary treatment: intrasellar mass with only mild suprasellar extension

Transient: fatigue, nausea, hair loss, loss of taste and smell;

Adjuvant treatment: substantial residual adenoma tissue after visual

Permanent: hypopituitarism

Observation

Adenoma confined to sella; patient elderly or infirm

Visual impairment

Medications (dopamine agonists, somatostatin analogs, GnRH antagonists)

Experimental protocol

Generally ineffective

Chapter 15

Gonadotroph Adenomas

587

FIGURE 15.14. Reduction in gonadotroph adenoma size by transsphenoidal surgery as seen by magnetic resonance imaging in sagittal views. The left panel shows the large figure eight-shaped adenoma extending far above the sella and elevating the optic chiasm. The right panel shows that most of the adenoma has been excised and that the optic chiasm has been restored to its customary position. Improvement in his vision is shown in Figure 15.15.

FIGURE 15.15. Visual fields performed on an automated Humphrey instrument in a 42-year-old man with a gonadotroph adenoma before (upper pair) and 4 weeks after (lower pair) transsphenoidal excision of much of the adenoma. Before surgery he had a complete right temporal defect and a left superior temporal defect; afterwards visual fields were normal. Magnetic resonance imaging of his adenoma before and after surgery is shown in Figure 15.14. Courtesy of Dr. Peter J. Savino.

of 230 patients whose visual fields were abnormal before transsphenoidal surgery, the fields improved in 73%, remained the same in 23%, and worsened in 4% (Table 15.7) [69]. In another series of 113 pituitary adenomas that extended beyond the sella, 81% of those with visual field defects before surgery experienced improvement in fields

FIGURE 15.16. Serum FSH concentrations in 12 men with gonadotroph adenomas before and 4–6 weeks after transsphenoidal surgery. The decreases in FSH correlated with the decrease in size as determined by imaging. From Harris et al. [68].

after surgery, 19% remained the same, and none worsened [70]. Complications of Surgery

Serious complications of transsphenoidal surgery are uncommon, but appear to be greater when the adenoma is

588

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Table 15.7. Efficacy of transsphenoidal surgery for pituitary macroadenomas

Table 15.8. Complications of transsphenoidal surgery in relationship to the experience of the surgeon

Number of patients (%) whose vision was: Number of patients

Better

Unchanged

Worse

Acuity Normal before surgery Abnormal before surgery

181 104

NA 50

99 49

1 1

Fields Normal before surgery Abnormal before surgery

71 214

NA 76

99 20

1 4

Visual parameter

Adapted from [69].

very large and the surgeon has performed fewer transsphenoidal procedures. In a survey in which neurosurgeons were asked to report their own experience (Table 15.8), serious complications reported by the 958 respondents included carotid artery injury (1.1%), central nervous system injury (1.3%), loss of vision (1.8%), ophthalmoplegia (1.4%), hemorrhage or swelling of the residual tumor (2.9%), cerebrospinal fluid leak (3.9%), meningitis (1.5%), and death (0.9%) [71]. The chances of anterior pituitary insufficiencies (19.4%) and diabetes insipidus (17.8%) were higher. The incidence of each complication was higher among neurosurgeons who were less experienced. Among neurosurgeons who reported performing fewer than 200 transsphenoidal procedures, 1.2% of procedures resulted in death, but among neurosurgeons who reported performing more than 500 procedures, only 0.2% resulted in death. Although these results are based on retrospective self-reporting via questionnaire, they provide a broader assessment of complications of transsphenoidal surgery than that provided by the most experienced pituitary surgeons [72–74], whose complication rates are closer to those of the most experienced group above [71]. Complication rates are also greater in patients who have had prior pituitary surgery than in those who never had, and even greater in those whose prior surgery was via craniotomy than in those whose prior surgery was transsphenoidal [75]. Evaluation of the Results Surgery

The results of surgery should initially be evaluated 4–6 weeks afterwards. Residual adenoma tissue should be evaluated by MRI and by measurement of whatever hormones or subunits had been elevated before surgery. The functions of the nonadenomatous anterior pituitary should also be reevaluated postoperatively, as should vasopressin secretion. Neuroophthalmologic function should likewise be reevaluated.

Number of operations resulting in complication (%)

Complication

Number of previous operations

Carotid artery injury Central nervous system injury Hemorrhage into tumor bed Loss of vision Ophthalmoplegia Cerebrospinal fluid leak Meningitis Nasal septum perforation Anterior pituitary insufficiency Diabetes insipidus Death

<200

20–500

>500

1.4 1.6 2.8 2.4 1.9 4.2 1.9 7.6 20.6 19.0 1.2

0.6 0.9 4.0 0.8 0.8 2.8 0.8 4.6 14.9 NA 0.6

0.4 0.6 0.8 0.5 0.4 0.5 0.5 3.3 7.2 7.6 0.2

Data were collected from participating surgeons by questionnaire. Adapted from [71].

Table 15.9. pituitary

Techniques of radiation therapy to the

Technique

Radiation source

Portals

Conventional Conformal Sterotactic Radiosurgery Proton beam

Supervoltage Supervoltage

Three Multiple (computer generated)

Cyclotron Linear accelerator 60 Co

Multiple Multiple Multiple

Gamma knife

Radiation Techniques of Radiation

Radiation therapy has been used to treat pituitary adenomas for decades. The standard technique during this period has employed a supervoltage source to deliver a total of 45–50 Gy in daily two Gy doses via three external portals. Other techniques have recently been utilized which employ various radiation sources delivered stereotactically, to attempt to minimize the amount of radiation to which the brain is exposed (Table 15.9). One group of techniques, collectively called stereotactic radiosurgery, involves stereotactic administration of a large single dose of radiation from one of several possible sources, including protons from a cyclotron, high energy X-rays from a linear accelerator, or gamma radiation from a 60Co source (“gamma knife”). Another technique, called “conformal radiation”, involves administration of supervoltage radiation in fractionated doses, as in conventional radiotherapy, but from multiple portals and guided

Chapter 15

by a computer-generated model so that the radiation conforms to the boundaries of the lesion.

Gonadotroph Adenomas

589

performed one year after radiation and, if the mass is smaller, less frequently thereafter. Neuroophthalmologic evaluation should be repeated after radiation if it was abnormal before.

Efficacy of Radiation

When conventional radiation is administered following surgery for a pituitary macroadenoma, it is usually effective in preventing regrowth of the adenoma [76–78]. In one study of men who had conventional radiation therapy following surgery for clinically nonfunctioning pituitary macroadenomas, only 7% of the 63 patients who received radiation following surgery developed new visual impairment requiring additional treatment during the subsequent 15 years, but 66% of the 63 who did not receive radiation developed new visual impairment [78]. The efficacy of stereotactic methods of radiation delivery on preventing recurrence of pituitary adenomas and other sellar tumors remains to be determined. Complications of Radiation

There are both short-term and long-term side effects of conventional radiation. The short-term side effects include nausea, lethargy, loss of taste and smell, and loss of hair at the radiation portals. The first two remit within 2 months, and the latter two usually remit within 6 months but may be permanent. The long-term side effects include hypopituitarism and neurologic complications. Hypopituitarism may begin as soon as 1 month after completion of radiation, but usually not until a year or more. By 10 years afterwards, about 50% of patients have a deficiency of ACTH, TSH, or LH [78–81]. Neurologic side effects occur less commonly. Blindness occurring due to optic neuritis [82,83], brain tumors, and cerebrovascular accidents attributed to accelerated local atherosclerosis have been reported as case reports and in some series [84,85], but other series that have evaluated possible neurologic sequellae have found none [86]. Because the various stereotactic techniques for administering radiation to the sella area are designed to expose the structures surrounding the sella and the brain to less radiation than does the conventional technique, it is possible that some of these may not be as likely to cause neurologic sequellae as does the conventional technique, but it is too soon to know if this hope will be realized. The larger amount of radiation given per dose during stereotactic radiosurgery, however, poses a potentially greater risk of optic neuritis than does conventional radiation. In fact, radiation-induced optic neuritis has already been reported following this procedure [87]. Management of Patients after Radiation

Hormonal evaluation, both for excessive secretion of whichever intact gonadotropins and their subunits were secreted excessively by the adenoma prior to treatment and for deficient secretion by the nonadenomatous pituitary, should be performed 6 and 12 months after radiation and once a year thereafter. Evaluation of size by MRI should be

Pharmacologic Treatment Several drugs have been administered in attempts to treat gonadotroph adenomas, but so far none has been found that reduces their size consistently and substantially. Although dopamine does not decrease gonadotropin secretion to an appreciable degree in normal subjects, bromocriptine has been reported to reduce the secretion of intact gonadotropins and a subunit in a few patients and even to improve vision in one, but not to reduce adenoma size [88,89]. CV 205-504 has also been reported to reduce secretion and adenoma size in occasional patients [90]. The somatostatin analog, octreotide, has been used to treat gonadotroph adenomas because of the demonstration that somatostatin itself may decrease secretion by gonadotroph adenomas in vitro. Although there have been occasional reports of dramatic decreases in size of gonadotroph adenomas associated with octreotide administration [91,92] and some improvement in vision, the majority of patients have little if any improvement in adenoma size or vision [91–93]. Several agonist analogs of GnRH have been administered to patients with gonadotroph adenomas, based on the rationale that chronic administration of these agonists causes down-regulation of GnRH receptors on, and decreased secretion of FSH and LH from, normal gonadotroph cells. Administration of GnRH agonist analogs to patients with gonadotroph adenomas, however, generally produces either an agonist effect or no effect on secretion and no effect on adenoma size [94,95]. Potent antagonist analogs of GnRH have recently been developed. Administration for 1 week of the GnRH antagonist, Nal-Glu GnRH, to men with gonadotroph adenomas reduced their elevated FSH concentrations to normal [60]. However, when Nal-Glu administration was continued for 6 months, although FSH remained suppressed, adenoma size did not decrease [96]. REFERENCES 1 Snyder PJ, Sterling FH. Hypersecretion of LH and FSH by a pituitary adenoma. J Clin Endocrinol Metab 1976;42:544–550. 2 Friend JN, Judge DM, Sherman BM, Santen RJ. FSH-secreting pituitary adenomas: stimulation and suppression studies in two patients. J Clin Endocrinol Metab 1976;43:650–658. 3 Cunningham GR, Huckins C. An FSH and prolactin-secreting pituitary tumor: pituitary dynamics and testicular histology. J Clin Endocrinol Metab 1977;44: 248–253. 4 Demura R, Kubo O, Demura H, Shizume K. FSH and LH secreting pituitary adenoma. J Clin Endocrinol Metab 1977;45:653–657. 5 Kovacs K, Horvath E, Van Loon GR et al. Pituitary adenomas associated with elevated blood follicle-stimulating hormone levels: a histologic, immunocytologic, and electron microscopic study of two cases. Fertil Steril 1998;29:622–628. 6 Snyder PJ. Gonadotroph cell adenomas of the pituitary. Endocr Rev 1985; 6:552–563.

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7 Snyder PJ, Johnson J, Muzyka R. Abnormal secretion of glycoprotein-subunit and follicle-stimulating hormone (FSH) b-subunit in men with pituitary adenomas and FSH hypersecretion. J Clin Endocrinol Metab 1980;51: 579–584. 8 Chappel SC, Bashey HM, Snyder PJ. Similar isoelectric profiles of FSH from gonadotroph cell adenomas and non-adrenomatous pituitaries. Acta Endocrinol 1986;113:311–316. 9 Galway AB, Hsueh JW, Daneshdoost L et al. Gonadotroph adenomas in men produce biologically active follicle-stimulating hormone. J Clin Endocrinol Metab 1990;71:907–912. 10 Peterson RD, Kourides IA, Horwith M et al. Luteinizing hormone and subunit-secreting pituitary tumor: positive feedback of estrogen. J Clin Endocrinol Metab 1981;51:692–698. 11 Faggiano M, Criscuolo T, Perrone I et al. Sexual precocity in a boy due to hypersecretion of LH and prolactin by a pituitary adenoma. Acta Endocrinol 1983;102:167–172. 12 Whitaker MD, Prior JC, Scheithauer B et al. Gonadotrophin-secreting pituitary tumour: report and review. Clin Endocrinol 1985;22:43–48. 13 Klibanski A, Deutsch PJ, Jameson JL et al. Luteinizing hormone-secreting pituitary tumor: biosynthetic characterization and clinical studies. J Clin Endocrinol Metab 1987;64:536–542. 14 Daneshdoost L, Gennarelli TA, Bashey HM et al. Identification of gonadotroph adenomas in men with clinically nonfunctioning adenomas by the LHb subunit response to TRH. J Clin Endocrinol Metab 1993;77:1352–1355. 15 Snyder PJ, Bigdeli H, Gardner DF et al. Gonadal function in fifty men with untreated pituitary adenomas. J Clin Endocrinol Metab 1979;48:309–314. 16 Borges JL, Ridgway EC, Kovacs K et al. Follicle-stimulating hormone-secreting pituitary tumor with concomitant elevation of serum-subunit levels. J Clin Endocrinol Metab 1984;58:937–941. 17 Chapman AJ, MacFarlane A, Shalet SM et al. Discordant serum-subunit and FSH concentrations in a woman with a pituitary tumour. Clin Endocrinol 1984;21:123–129. 18 Demura R, Jibiki K, Kubo O et al. The significance of subunit as a tumor marker for gonadotropin-producing pituitary adenomas. J Clin Endocrinol Metab 1986;63:564–569. 19 Ridgway EC, Klibanski A, Ladenson PW et al. Pure alpha-secreting pituitary adenomas. N Engl J Med 1981;304:1254–1259. 20 Klibanski A, Ridgway EC, Zervas NT. Pure alpha subunit-secreting pituitary tumors. J Neurosurg 1983;59:585–589. 21 Snyder PJ, Bashey H, Phillips JL, Gennarelli TA. Comparison of hormonal behavior of gonadotroph cells adenomas in vivo and in culture. J Clin Endocrinol Metab 1985;61:1061–1065. 22 Jameson JL, Klibanski A, Black PM et al. Glycoprotein hormone genes are expressed in clinically nonfunctioning pituitary adenomas. J Clin Invest 1987; 80:1472–1478. 23 Konde Y, Kugal N, Kimura S et al. A case of pituitary adenoma with possible simultaneous secretion of thyrotropin and follicle-stimulating hormone. J Clin Endocrinol Metab 1982;54:397–403. 24 Oppenheim DS, Kana AR, Sangha JS, Klibanski A. Prevalence of alpha subunit hypersecretion in patients with pituitary tumors clinically nonfunctioning and somatotroph adenomas. J Clin Endocrinol Metab 1990;70:859–864. 25 Beck-Peccoz P, Bassetti M, Spada A et al. Glycoprotein hormone alpha subunit response to growth hormone (GH)-releasing hormone in patients with actrive acromegaly. Evidence for alpha subunit and GH co-existence in the same tumor cell. J Clin Endocrinol Metab 1985;61:541–546. 26 White MC, Newland P, Daniels M et al. Growth hormone secreting pituitary adenomas are heterogeneous in cell culture and commonly secrete glycoprotein hormone alpha subunit. Clin Endocrinol 1986;25:173–179. 27 Hofland LJ, Van Koetsveld PM, Verleun TM, Lamberts SWJ. Glycoprotein hormone alpha-subunit and prolactin release by cultured pituitary adenoma cells from acromegalic patients correlation with GH release. Clin Endocrinol 1989;30:601–611. 28 Snyder PJ, Muzyka R, Johnson J, Utiger RD. Thyrotropin-releasing hormone provokes abnormal follicle-stimulating hormone (FSH) and luteinizing hormone responses in men who have pituitary adenomas and FSH hypersecretion. J Clin Endocrinol Metab 1980;51:744–748. 29 Daneshdoost L, Gennarelli TA, Bashey HM et al. Recognition of gonadotroph adenomas in women. N Engl J Med 1991;324:589–594. 30 Trouillas J, Girod C, Sassolas G, Claustrat B. The human gonadotropic adenoma pathologic diagnosis and hormonal correlations in 26 tumors. Semin Diagnost Pathol 1986;3:42–57. 31 Mashiter K, Adams E, Van Noorden S. Secretion of LH, FSH and PRL shown by cell culture and immunocytochemistry of human functionless pituitary adenomas. Clin Endocrinol 1981;15:103–122.

32 Asa SL, Gerne BM, Singer W et al. Gonadotropin secretion in vitro by human pituitary null cell adenomas and oncocytomas. J Clin Endocrinol Metab 1986; 62:1011–1019. 33 Yamada S, Asa SL, Kovacs K et al. Analysis of hormone secretion by clinically nonfunctioning human pituitary adenomas using the reverse hemolytic plague assay. J Clin Endocrinol Metab 1989;68:73–80. 34 Black PM, Hsu DW, Klibanski A et al. Hormone production in clinically nonfunctioning pituitary adenoma. J Neurosurg 1987;66:244–250. 35 Kwekkeboom DJ, Dejong FH, Lamberts SWJ. Gonadotropin release by clinically nonfunctioning and gonadotroph pituitary adenomas in vivo and in vitro relation to sex and effects of thyrotropin-releasing hormone, gonadotropinreleasing hormone and bromocriptine. J Clin Endocrinol Metab 1989;68:1128–1135. 36 Horvath E, Kovacs K. Gonadotroph adenomas of the human pituitary sexrelated fine-structural dichotomy. Am J Pathol 1984;117:429–440. 37 Kovacs K, Horvath E. Tumors of the pituitary gland. Atlas of Tumor Pathology, Fascicle 21, 2nd Series, Washington Armed Forces Institute of Pathology 1986. 38 Alexander JM, Biller BMK, Bikkal H et al. Clinically nonfunctioning pituitary tumors are monoclonal in orgin. J Clin Invest 1990;86:336–340. 39 Landis CA, Masters SB, Spada A et al. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylate cyclase in human pituitary tumors. Nature 1989;340:692–696. 40 Chandrasekhapappa SC, Guru SC, Manickam P et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997;276:404–407. 41 Woloschak M, Roberts JL, Post K. c-Myc, c-fos, and c-myb gene expression in human pituitary adenomas. J Clin Endocrinol Metab 1994;79:253–257. 42 Cai WY, Alexander JM, Hedley-Whyte ET et al. Ras mutations in human prolactinomas and pituitary carcinomas. J Clin Endocrinol Metab 1994;78:89–93. 43 Pei L, Melmed S, Scheithauer B et al. H-ras mutations in human pituitary carcinoma metastases. J Clin Endocrinol Metab 1994;78:842–846. 44 Cryns VL, Alexander JM, Klibanski A, Arnold A. The retinoblastoma gene in human pituitary tumors. J Clin Endocrinol Metab 1993;77:644–646. 45 Zhu J, Leon SP, Beggs AH et al. Human pituitary adenomas show no loss of heterozygosity at the retinoblastoma gene locus. J Clin Endocrinol Metab 1994;78:922–927. 46 Ikeda H, Beauchamp RL, Yoshimoto T, Yandell DW. Detection of heterozygous mutation in the retinoblastoma gene in a human pituitary adenoma using pcrsscp analysis and direct sequencing. Endo Path 1995;6:189–196. 47 Jones TH, Daniels M, James RA et al. Production of bioactive and immunoreactive interleukin-6 (IL-6) and expression of IL-6 messenger ribonucleic acid by human pituitary adenomas. J Clin Endocrinol Metab 1994;78:180–187. 48 Robberecht P, Vertongen P, Velkeniers B et al. Receptors for pituitary adenylate cyclase activating peptides in human pituitary adenomas. J Clin Endocrinol Metab 1993;77:1235–1239. 49 Alvaro V, Levy L, Dubray C et al. Invasive human pituitary tumors express a point-mutated alpha-protein kinase-C. J Clin Endocrinol Metab 1993;77: 1125–1129. 50 Ezzat S, Smyth HS, Ramyar L, Asa SL. Heterogenous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas. J Clin Endocrinol Metab 1995;80:878–884. 51 LeRiche V, Asa SL, Ezzat S. Epidermal growth factor and its receptor (EGF-R) in human pituitary adenomas: EGF-R correlates with tumor aggressiveness. J Clin Endocrinol Metab 1996;81:656–662. 52 Ezzat S, Walpola IA, Ramyar L et al. Membrane-anchored expression of transforming growth factor alpha in human pituitary adenoma cells. J Clin Endocrinol Metab 1995;80:534–539. 53 Miller GM, Alexander JM, Klibanski A. Gonadotropin-releasing hormone messenger RNA expression in gonadotroph tumors and normal human pituitary. J Clin Endocrinol Metab 1996;81:80–83. 54 Alexander JM, Klibanski A. Gonadotropin-releasing hormone receptor mRNA expression by human pituitary tumors in vitro. J Clin Invest 1994;93: 2332–2339. 55 Zharg X, Horwitz GA, Heaney AP et al. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 1999;84:761–767. 56 Haddad G, Penabad JL, Bashey HM et al. Expression of activin/inhibin subunit messenger ribonucleic acids by gonadotroph adenomas. J Clin Endocrinol Metab 1994;79:1399–1403. 57 Alexander JM, Swearingen B, Tindall GT, Klibanski A. Human pituitary adenomas express endogenous inhibin subunit and follistatin messenger ribonucleic acids. J Clin Endocrinol Metab 1995;80:147–152. 58 Penabad JL, Bashey HM, Asa SL et al. Decreased follistatin gene expression in gonadotroph adenomas. J Clin Endocrinol Metab 1996;81:3397–3403.

Chapter 15 59 Samaan NA, Stephans AV, Danziger J, Trujillo J. Reactive pituitary abnormalities in patients with Klinefelter’s and Turner’s syndromes. Arch Intern Med 1979;139:198–201. 60 Daneshdoost L, Pavlou S, Molitch ME. Inhibition of follicle-stimulating hormone secretion from gonadotroph adenomas by repetitive administration of a gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 1990;71:92–97. 61 Djerassi A, Coutifaris C, West VA et al. Gonadotroph adenoma in premenopausal woman secreting follicle-stimulating hormone and causing ovarian hyperstimulation. J Clin Endocrinol Metab 1995;80:591–594. 62 Christin-Maitre S, Rongieres-Bertrand C, Kottler M-L et al. A spontaneous and severe hyperstimulation of the ovaries revealing a gonadotroph adenoma. J Clin Endocrinol Metab 1998;83:3450–3453. 63 Heseltine D, White MC, Kendall-Taylor P et al. Testicular enlargement and elevated serum inhibin concentrations occur in patients with pituitary macroadenomas secreting FSH. Clin Endocrinol 1998;31:411–423. 64 Ambrosi B, Basstti M, Ferrario R et al. Precocious puberty in a boy with a PRL, LH- and FSH-secreting pituitary tumour: hormonal and immunocytochemical studies. Acta Endocrinol 1990;122:569–576. 65 Sethi DS, Pillay PK. Endoscopic management of lesions of the sella turcica. J Laryngol Otol 1995;109:956–962. 66 Jho H-D, Carrau RL. Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. J Neurosurg 1997;87:44–51. 67 Yaniv E, Rappaport H. Endoscopic transseptal transsphenoidal surgery for pituitary tumors. Neurosurg 1997;40:944–946. 68 Harris RI, Schatz NJ, Gennarelli TA et al. Follicle-stimulating hormonesecreting pituitary adenomas: correlation of reduction of adenoma size with reduction of hormonal hypersecretion after transsphenoidal surgery. J Clin Endocrinol Metab 1983;56:1288–1293. 69 Trautmann JC, Laws ER Jr. Visual status after transsphenoidal surgery at the Mayo Clinic. Am J Ophthalmol 1983;96:200–208. 70 Black PM, Zervas NT, Candia G. Management of large pituitary adenomas by transsphenoidal surgery. Surg Neurol 1988;29:443–447. 71 Ciric I, Ragin A, Baumgartner C, Pierce D. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurg 1997;40:225–237. 72 Wilson CB. A decade of pituitary microsurgery. J Neurosurg 1984;61:814–833. 73 Black PM, Zervas NT, Candia GL. Incidence and management of complications of transsphenoidal operations for pituitary adenomas. Neurosurg 1987;20:920–924. 74 Barrow DL, Tindall GT. Loss of vision after transsphenoidal surgery. Neurosurg 1990;27:60–68. 75 Laws ER Jr, Fode NC, Redmond MJ. Transsphenoidal surgery following unsuccessful prior therapy. J Neurosurg 1985;63:823–829. 76 Zaugg M, Adamman O, Pescia R, Landolt AM. External irradiation of macroinvasive pituitary adenomas with telecobalt: a retrospective study with long-term follow-up in patients irradiated with doses mostly of between 4045 Gy. I J Radiation Oncology Biol Phys 1995;32:671–680. 77 McCord MW, Buatti JM, Fennel EM et al. Radiotherapy for pituitary adenoma: long-term outcome and sequellae. Int J Radiation Oncology 1997;39:437–444. 78 Gittoes NJL, Bates AS, Tse W et al. Radiotherapy for non-functioning pituitary adenomas. Clin Endocrinol 1998;48:331–337. 79 Snyder PJ, Fowble B, Schatz NJ et al. Hypopituitarism following radiation therapy of pituitary adenomas. Am J Med 1986;81:457–462.

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80 Littley MD, Shalet SM, Beardwell CG, Lillehei KO. Hypopituitarism following external radiotherapy for pituitary tumours in adults. Quart J Med 70;145:160. 81 Nelson P, Goodman M, Flickenger J et al. Endocrine function in patients with large pituitary tumors treated with operative decompression and radiation therapy. Neurosurg 1989;24:398–400. 82 Schatz NJ, Lichenstein S, Corbett JJ. Delayed radiation necrosis of the optic nerve and chiasm. In: Glaser MS, Smith JL, eds. Neuroophthalmopathy Symposium of the University of Miami and the Bascom Palmer Eye Institute, 8th ed. St. Louis: Mosby, 1978:131–139. 83 Millar JL, Spry NA, Lamb DS, Delahunt J. Blindness in patients after external beam irradiation for pituitary adenoma: two cases occurring after small daily fractional doses. Clin Oncology 1991;3:291–294. 84 Brada M, Ford D, Ashley S et al. Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. Brit Med J 1993;304:1343–1346. 85 Fisher BJ, Gaspar LE, Noone B. Radiation therapy of pituitary adenoma: delayed sequelae. Radiology 1993;187:843–846. 86 Dowsett RJ, Fowble B, Sergott RC et al. Results of radiotherapy in the treatment of acromegaly: lack of ophthalmologic complications. I J Radiation Oncology Biol Phys 1990;19:453–459. 87 Girkin CA, Comey CH, Lunsford LD et al. Radiation optic neuropathy after stereotactic radiosurgery. Ophthalmopathy 1997;104:1634–1643. 88 Berezin M, Olchovsky D, Pines A et al. Reduction of follicle-stimulating hormone (FSH) secretion in FSH-producing pituitary adenoma by bromocriptine. J Clin Endocrinol Metab 1984;59:1220–1222. 89 Vance ML, Ridgway EC, Thorner MO. Follicle-stimulating hormone and alpha subunit-secreting pituitary tumor treated with bromocriptine. J Clin Endocrinol Metab 1985;61:580–584. 90 Kwekkeboom DJ, Lamberts SJ. Long-term treatment with the dopamine agonist CV 205-502 of patients with a clinically non-functioning, gonadotroph, or a-subunit secreting pituitary adenoma. Clin Endocrinol 1992; 36:171–176. 91 Sy RAG, Bernstein R, Chynn KY, Kourides IA. Reduction in size of a thyrotropin- and gonadotropin-secreting pituitary adenoma treated with octreotide acetate (somatostatin analog). J Clin Endocrinol Metab 1992;74:690–694. 92 Warnet A, Harris AG, Renard E et al. A prospective multicenter trial of octreotide in 24 patients with visual defects caused by nonfunctioning and gonadotropin-secreting adenomas. Neurosurg 1997;41:786–797. 93 Katznelson L, Oppenheim DS, Coughlin F et al. Chronic somatostatin analog administration in patients with alpha subunit-secreting pituitary adenomas. J Clin Endocrinol Metab 1992;75:1318–1325. 94 Roman SH, Goldstein M, Kourides IA et al. The luteinizing hormone-releasing hormone (LHRH)agonist [D-TRP6-PRO9-NEt]LHRH increased rather than lowered LH and alpha subunit levels in a patient with an LH-secreting pituitary tumor. J Clin Endocrinol Metab 1984;58:313–319. 95 Klibanski A, Jameson JL, Biller BMK et al. Gonadotropin and alpha subunit responses to chronic gonadotropin-releasing hormone analog administration in patients with glycoprotein hormone-secreting pituitary tumors. J Clin Endocrinol Metab 1989;68:81–86. 96 McGrath GA, Goncalves RJ, Udupa JK et al. New technique for quantitation of pituitary adenoma size: use in evaluating treatment of gonadotroph adenomas with gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 1993;76:1363–1368.

C h a p t e r

16 Nonpituitary Tumors of the Sellar Region Steffen Albrecht Juan M. Bilbao Kalman Kovacs

The pituitary gland, sella turcica, and the parasellar region can be involved by a wide variety of nonneoplastic tumorlike lesions as well as by numerous benign and malignant neoplasms (Table 16.1). Exhaustive discussion of the clinical, radiological, pathological, and surgical aspects of all of these entities is obviously beyond the scope of this chapter. Detailed reviews of their pathology can be found elsewhere [1] and several extensive reviews of sellar imaging are also available [2–5]. In addition, there is a recent and well illustrated review of the various surgical approaches for sellar tumors [6].

ECTOPIAS

Pituitary Ectopy An ectopic pituitary gland can mimic a suprasellar tumor [7]. Adenohypophyseal ectopy has also been associated with cerebral malformations [8] and precocious puberty [9]. Ectopy of the neurohypophysis seems to be increasingly recognized since the advent of magnetic resonance (MR): MR yields more detailed images of the pituitary– hypothalamic axis than computed tomography (CT) and furthermore, the neurohypophysis produces a typical hyperintense “bright signal” on T1-weighted images in many (but not all) individuals [10]. Neurohypophysial ectopy is therefore easy to recognize: the normal bright spot in the posterior aspect of the pituitary gland is missing and appears instead elsewhere, usually in the region of the median eminence. Such extrasellar ectopia of the neurohypophysis was seen in only one of 1500 cranial MRs in patients without any evidence of sellar or parasellar disease [10]; instead, it is usually part of a triad that also includes absence of the pituitary stalk and hypoplasia of the adenohypophysis [11]. 592

Affected individuals have either severe isolated growth hormone deficiency or multiple anterior pituitary hormone insufficiencies [11]; diabetes insipidus, on the other hand, is not a feature, indicating that the ectopic posterior lobe is functioning normally. These patients have a greatly delayed and very low GH-response to GHRH infusion [12]. The triad was also seen in a pair of identical twins with a paracentric inversion of the short arm of chromosome 1; however, it is not certain whether the chromosomal alteration is causally related to the pituitary malformation [13]. Ectopia or hypoplasia/aplasia of the neurohypophysis with or without hypoplasia of the adenohypophysis can also be associated with septo-optic dysplasia (De Morsier syndrome), which combines uni- or bilateral optic nerve hypoplasia, midline cerebral malformations, and endocrine deficiencies [14–16].

Ectopic Salivary Gland Tissue Salivary gland rests can be found in virtually all autopsy pituitaries at any age if the glands are examined in serial section [17]. They are usually located in the posterior lobe and resemble serous acinar and duct cells of normal salivary glands [17]. In contrast to the almost universal presence of incidental salivary gland rests, symptomatic lesions are exceedingly rare, with only two reported cases [18,19]. Similarly, primary salivary gland-type tumors in the sellar region are also extremely rare: a few cases of sellar adenoid cystic carcinomas have been reported but are thought to have arisen in minor salivary gland tissue of the sphenoid sinus [20]; we are unaware of such tumors having occurred in the pituitary gland proper.

Chapter 16 Table 16.1. Sellar tumors and tumor-like lesions other than pituitary adenomas Ectopias Pituitary ectopy Neurohypophysial ectopy Salivary gland rests Hamartomas Hypothalamic hamartoma/hamartoblastoma Cysts Rathke’s cleft cyst Arachnoid cyst Epidermoid/dermoid cyst Inflammatory lesions Infection Sarcoidosis Lymphocytic hypohysitis Others Neoplasms Granular cell tumor Bone tumors Chordoma Cartilaginous tumors Others Craniopharyngioma Meningioma Glioma Of optic pathways (pilocytic astrocytoma) Of pituitary gland Chordoid glioma of third ventricle Gangliocytoma/gangliocytoma–adenoma Germ cell tumors Hematological proliferations Lymphoma Leukemia Plasmacytoma/multiple myeloma Langerhans cell histiocytosis Metastases Schwannoma Melanoma Vascular tumors

HAMARTOMAS

Hypothalamic Hamartoma Hypothalamic hamartomas are rare lesions that usually form a small pedunculated nodule attached to the floor of the third ventricle and projecting into the basal cistern; some are attached to the hypothalamus and project into the third ventricle. Histologically, they are composed of large, mature ganglion cells that resemble hypothalamic neurons; in addition, there is a highly differentiated glial stroma composed of astrocytes and oligodendrocytes. These lesions are quite “organoid” in appearance, including the presence of myelinated fiber tracts, and on a small, fragmented biposy

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specimen may be difficult to distinguish histologically from normal hypothalamus without the clinical history. Precocious puberty is one of the main manifestations of these lesions; in one large series, they accounted for 24 of 107 cases of precocious puberty of central origin [21]. They are also often associated with gelastic (laughing) seizures and behavioral problems, especially aggressive outbursts. Evidence has been presented that the hamartoma is the primary epileptogenic focus in these patients [22]. (For a more detailed discussion of the effects and therapy of hypothalamic hamartomas, the reader is referred to Chapter 8.) The constellation of hypothalamic hamartoma, pituitary insufficiency, postaxial polydactyly, cardiac and genito– urinary malformations, and imperforate anus constitutes the Pallister–Hall syndrome, which can be inherited as an autosomal dominant trait [23]. In the initial reports, the hypothalamic tumors were found to be composed of immature neuronal elements and therefore called “hamartoblastomas,” but in subsequent reports, lesions containing mature neurons similar to hypothalamic hamartomas were also seen [24–26], especially in older children, suggesting that the former constitute an immature stage of the latter [25,26]; this has led to the disappearance of the term “hamartoblastoma.” Recently, germline mutations of the GL13 zinc-finger transcription factor have been described in two affected families [23]. It remains to be seen whether sporadic hypothalamic hamartomas not associated with the syndrome carry somatic mutations of this gene.

CYSTS

Rathke’s Cleft Cyst Rathke’s cleft cysts are generally believed to originate from remnants of Rathke’s pouch, which is the Anlage of the adenohypophysis. During early embryogenesis, the anterior and posterior portions of the pouch give rise to the anterior and intermediate lobes of the pituitary gland, respectively. Later, the pouch may fail to obliterate completely, leaving behind cystic remnants at the interface between those lobes. Such cystic remnants can be found in up to one-fifth of autopsy pituitaries [27] as well as in pharyngeal pituitaries [28]. They are usually less than 5 mm in diameter [29]. Most are intrasellar with or without suprasellar extension, but some entirely suprasellar cases have been described [30,31] (Fig. 16.1). Even more rarely, they are located within the bones of the skull base [32]. Histologically, the cyst’s epithelium is composed of several cell types, including ciliated columnar cells similar to respiratory epithelium, and goblet cells. There may be focal squamous metaplasia. The cyst lumen is filled with mucus but can also contain cell debris and cholesterol crystals [33]. Some pituitary adenomas are intimately admixed with cysts indistinguishable from Rathke’s cleft cysts [33]. It is not clear whether these tumors represent true “transitional” neoplasms or a collision of two independent, relatively frequent lesions.

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MRI features are sufficiently distinctive to allow accurate preoperative diagnosis [31,34,35]. However, one group found that a T2-hypointense lesion causing anterior displacement of the pituitary stalk with a posterior ledge of the diaphragma sellae was highly suggestive of a Rathke’s cleft cyst [33]. Partial excision with drainage (with biopsy of the wall for histological conformation) is the treatment of choice; except for pituitary insufficiency and severe visual impairment, most deficits resolve at least partially and recurrence is unusual [31,34,35].

Epidermoid and Dermoid Cysts Most intracranial epidermoid and dermoid cysts arise in the cerebello–pontine angle, but sellar and parasellar examples also occur. Epidermoid cysts are lined by a keratinizing squamous epithelium similar to normal epidermis, hence the name. If the cyst wall also contains skin appendages, such as sebaceous glands and hair follicles, it is called a dermoid cyst. Symptoms usually arise from compression of adjacent structures [41]. Chemical meningitis secondary to spillage of keratinous debris [42] and the development of a squamous cell carcinoma in the cyst [42,43] are the two major complications. Other unusual presentations include subarachnoid hemorrhage [44], stroke [45], and rupture into the ventricular system [46]. Treatment is surgical. These cysts can coexist with arachnoid cysts [47]. F I G U R E 1 6 . 1 . Cyst of Rathke’s pouch cleft in a 36-year-old man who was diagnosed as having a pituitary adenoma with panhypopituitarism. Computed tomography scan revealed an isodense sellar and suprasellar mass. At operation, a thin-walled cyst was found within the expanded sella and suprasellar area. Histology revealed the collapsed cyst wall lined by a single layer of epithelial ciliated cells.

As is obvious from the prevalence of these cysts in autopsy material, most are asymptomatic. The majority of symptomatic cases occurs in adults with a 2 : 1 female predilection [31,34]. Most have a suprasellar extension and usually present with endocrine disturbances, visual complaints, or headache, and combinations thereof [34,35]. Rarely, the patient presents acutely with a clinical picture resembling pituitary apoplexy [33]. In two such cases seen by one of the authors (S.A.), there was intense mural inflammation, possibly related to leakage of mucus. This may also explain the reports of asptic meningitis [34] associated with Rathke’s cleft cysts. Progressive enlargement of the cyst can also lead to an “empty sella” [36]. Other unusual presentations include abscess formation in the cyst [37], the Tolosa–Hunt syndrome (painful ophthalmoplegia) caused by cyst rupture with an intense inflammatory reaction in the sella and cavernous sinuses [38], hypopituitarism with granulomatous hypophysitis also associated with cyst rupture [39], hemorrhage into the cyst [33], and occurrence in identical twins [40]. By most accounts, neither the CT nor the

Arachnoid Cysts Arachnoid cysts account for about 1% of intracranial space occupying lesions and about one-tenth of arachnoid cysts arise in the sellar/suprasellar region [48]. There is now general agreement that these are congenital lesions; in fact, some cases have been diagnosed prenatally [49]. The cysts arise when a split in the arachnoid fills with cerebrospinal fluid (CSF) through a unidirectional slit-valve; the pumping force is provided by arterial pulsation. This mechanism has been documented de visu by direct endoscopic observation [48]. Sellar arachnoid cysts become symptomatic by causing hydrocephalus (secondary to compression of the third ventricle), optochiasmatic and/or other neurological symptoms (such as gait disturbance), and endocrine dysfunction (pituitary insufficiency or precocious puberty) [49]. CT and MR studies show a cystic structure whose content has the same imaging characteristics as CSF. Earlier surgical approaches included cyst resection or fenestration, and cysto-peritoneal shunting. However, these often had significant complications and disappointing long-term outcomes. More recently, minimally invasive neuroendoscopic procedures seem to be gaining in acceptance, since they are rapid, well tolerated, and provide good long term outcome [49–51]. Techniques include cystocisternostomy, cystoventriculostomy, and cystoventriculocisternostomy. It is noteworthy however that in contrast to the other symptoms, the endocrine disturbances

Chapter 16

rarely regress, probably because of permanent hypothalamic damage [49]. TUMORS

Granular Cell Tumor This lesion is also known as choristoma, granular cell myoblastoma, granular cell pituicytoma, and granular cell schwannoma. Microscopic collections of granular cells (“tumorettes”) can be found in up to 17% of unselected autopsy pituitaries [52]; they are roughly evenly distributed between the infundibulum and the posterior lobe [52,53]. Since they are not seen in patients of less than 20 years of age, they appear to be acquired rather than congenital [52,53]. The association of granular cell tumors with either pituitary adenomas [54] or multiple endocrine neoplasia, type 1 (MEN-1) [55] may be coincidental rather than a reflection of a common etiology. Histologically, the tumors are composed of sheets and lobules of tightly packed, polyhedral cells whose key feature is their abundant, distinctly granular cytoplasm. These granules stain intensely with the periodic acid–Schiff stain and retain this property after diastase digestion. By electron microscopy, the granules appear as phagolysosomes filled with electron-dense material and membrane debris [56]. Tumors with an identical histological appearance occur in many other sites, especially the skin, tongue, breast, and biliary tree. This has led to considerable controversy as to their “cell of origin,” which in turn has generated a volume of literature that is completely out of proportion to the practical importance and relevance of the problem. Pending definitive settlement of this issue, their noncommittal and descriptive designation as granular cell tumor seems entirely appropriate. These tumors only rarely become large enough to produce symptoms: Schaller et al. present one case of their own and review 42 previously reported cases [57]. Most lesions present in the fourth or fifth decade with a 2 : 1 female predominance. The most common presentations are visual disturbances and/or hypopituitarism. Considering their location, diabetes insipidus is surprisingly rare, with only one case having been reported [58]. Radiologically, there are sellar changes in about half the cases [59]; imaging studies show suprasellar or supra- and intrasellar lesions which enhance due to their high vascularity [57,59], but these features are not sufficiently distinctive to allow a definite radiological diagnosis [57]. Treatment is surgical [57]; consideration should be given to post-operative radiotherapy for incompletely resected lesions [57].

Gangliocytoma and Mixed Adenoma–gangliocytoma A gangliocytoma is a neoplasm composed of mature neurons (i.e., ganglion cells) without a glial component.

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About 50 such neoplasms arising in the pituitary gland or sellar region have been reported [60–62]. Roughly onequarter are pure gangliocytomas while the remainder have a second component that is indistinguishable from a pituitary adenoma; these tumors are referred to as mixed adenoma–gangliocytomas. Tumors with both a mature neuronal and a glial component are called gandliogliomas, but these are very rare in the sella [60]. Histologically, the ganglionic component resembles hypothalamic neurons, and various hypothalamic releasing hormones and other hormones such as gastrin and vasopressin [60,62] and rarely pituitary hormones [63] have been demonstrated immunohistochemically in the tumor cells. The adenomatous component may be intimately admixed or form a separate, discrete nodule. About two-thirds of these tumors occur in women; most of the mixed tumors are associated with endocrine disturbances (usually acromegaly) [61,62] while most of the pure gangliocytomas are endocrinologically silent [62]. Three histogenetic hypotheses exist to explain the origin of the mixed adenoma–gangliocytomas: growth of the adenoma secondary to stimulation by hypothalamic releasing hormones secreted by the gangliocytoma [61], “aberrant” neuronal differentiation in an adenoma [64], or origin from a common neuronal–adenohypohyseal precursor cell [62].

Chordoma Chordomas are rare, slowly growing, locally aggressive bone tumors arising in the midline. Approximately 50% involve the sacrum, 35% occur in the clivus, and the remaining 15% arise in vertebrae [65]. Chordomas are thought to arise from remnants of the notochord which is the first organizer of the neuraxis during early embryogenesis and which normally disappears by the sixth week of gestation [65]. The nucleus pulposus represents its only persistent derivative; however, ectopic notochordal remnants can be found, especially at either end of the craniospinal axis [66]. In addition, incidental intradual notochordal rests called “ecchordosis physaliphora” can be seen occasionally in the region of the clivus [67] and these may give rise to the rare cases of purely intradural chordomas [68,69]. Histologically indistinguishable tumors of presumably identical histogenesis can arise in the nasopharynx [70]. Tumors of identical histological appearance arising in the soft tissues are called parachordomas. Pathology

Grossly, the tumor can be firm to semiliquid with a lobulated, gelatinous appearance and focal calcification (Fig. 16.2). Its margin can be expansile or infiltrative. The histology of chordomas is very characteristic. They are composed of lobules of large, polyhedral cells arranged in sheets and ribbons and separated by abundant mucinous ground substance. Their cytoplasm is variably vacuolated; highly

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F I G U R E 1 6 . 2 . A 56-year-old woman died 10 years after the diagnosis of parasellar chordoma. At autopsy a large lobulated, necrotic tumor mass was found infiltrating the entire clivus, the sphenoidal sinus, and the parasellar area as well as a portion of the ethmoidal sinus. Death was due to compression and necrosis of midbrain and basal forebrain.

vacuolated cells are called “physaliphorous” (Greek for “bubble-bearing”). In addition, there are smaller cells with nonvacuolated cytoplasm, stellate cells, and intermediate forms. The cytoplasmic vacuoles contain neutral mucins while the tumor matrix is rich in acid mucopolysaccharides. By electron microscopy, the tumor cells have typical ultrastructural features of epithelial cells, including microvilli and desmosomes. Chordomas also have a typical immunohistochemical profile [71,72]: they express epithelial markers such as keratin and epithelial membrane antigen (EMA), but also S-100 protein and the intermediate filament vimentin. This distinguishes them both from metastatic adenocarcinomas (keratin and EMA-positive, but generally S-100 protein and vimentin-negative) and cartilaginous tumors (keratin and EMA-negative, S-100 and vimentin positive). They can, however, express carcinoembryonic antigen, which is also frequently expressed by adenocarcinomas. Clinical Aspects

Chordomas of the cranial base usually present with headache, oculomotor disturbances (especially diplopia secondary to abducens paresis), other visual symptoms, intracranial hypertension, or cerebellopontine angle syndrome;

endocrine disturbance is possible but uncommon. The majority of chordomas occurs in adults, most often in the fourth decade [73,74]. Patients with clival chordomas tend to be younger than those with sacral tumors. Familial chordoma with probable autosomal dominant inheritance has been described [75]. Clival chordomas are infiltrative and arise in close vicinity to vital cerebral structures (optic pathways, carotid arteries, hypothalamus/pituitary gland, and brainstem). Radiological evaluation should include both CT and MR: the former is superior for determining the extent of bone involvement, while the latter is more accurate for delineation of soft tissue infiltration and the relationship of the tumor to vital cerebral structures [76]. Obviously, the optimal therapy should try to remove as much tumor as possible while causing minimal damage to these structures. Many papers have been published on the best approach to this difficult problem, sometimes with conflicting results. Multiple surgical approaches exist [77] and more than one approach may have to be used in a given patient, since the tumors are only rarely confined to a single cranial compartment [77]. A meta-analysis of the radiotherapy literature indicates that patients treated with surgery and radiotherapy do better than those treated with either modality alone [78]. There is also mounting evidence that proton-beam radiotherapy is more effective than photon-beam therapy [65,78]; unfortunately, the former is only available in a small number of specially equipped centers. Stereotactic radiosurgery can also be effective but is restricted to small tumors (greatest diameter less than 3 cm) which excludes most patients [79]; furthermore, the number of treated patients is small and follow-up is short so that these results need to be confirmed. Overall, 5-year recurrence-free survival rates of about 60–70% can be achieved [78,80]. Why female patients have a poorer prognosis in some series is not yet clear [65,73]. It is expected that advances in imaging techniques will allow more accurate radiotherapy planning, especially through three-dimensional reconstruction of the tumor and the surrounding normal structures [78], which will hopefully lead to further improvements in survival. Approximately 10% of cranial chordomas eventually metastasize [73], usually several years after diagnosis and following local recurrence. Preferred sites of metastasis are lung, liver, bone, and lymph nodes [81,82]. Chordomas do rarely occur in children. As reviewed elsewhere [74,83], chordomas in children less than 5 years of age are quite aggressive, with uncontrollable local disease and early metastases often leading to death within 18 months after diagnosis; in older children however, behavior is similar to that of adult cases. Variants

High-grade sarcomatous areas may be present in chordomas either de novo or appear in a recurrence or a metastasis. These tumors are called “dedifferentiated chordoma” by analogy with dedifferentiated chondrosarcoma. Of the

Chapter 16

14 cases reviewed by Belza and Urich, only two were intracranial [84]. The sarcomatous component most often has the appearance of a malignant fibrous histiocytoma, but osteosarcoma and fibrosarcoma also occur [84]. These tumors are considerably more aggressive than ordinary chordomas, with about 90% of patients developing metastases with a rapidly fatal course; there is some anecdotal evidence of partial and transient response to aggressive chemotherapy [85]. Another variant of chordoma is the so-called chondroid chordoma first described by Heffelfinger et al. in 1973 [86]. Histologically, it consists of a mixture of typical chordoma and areas that resemble cartilage. It occurs almost exclusively in the spheno-occipitial region; only rare sacrococcygeal cases have been described. Chondroid chordoma is a controversial lesion. For one thing its “true nature” is questioned. The original description was based only on routine histology and there are certainly some chordomas that contain areas that are indistinguishable from cartilage on routine stains. As reviewed elsewhere [71,72], many studies of chondroid chordoma have been published (using mostly immunohistochemistry) and the results cover the whole spectrum of possibilities, with some showing an epithelial (chordomatous) phenotype in both components, some showing a mesenchymal (cartilaginous) phenotype in both components, and yet others a truly biphasic pattern, with the authors concluding that chondroid chordoma is really a chordoma, a chondrosarcoma, or a true mixed tumor. Not only are there significant and unavoidable technical differences between these studies (choice of antibodies, etc.), but there is also no consensus of what exactly constitutes a true chondroid chordoma: what looks like a chondroid chordoma to one group [71] is considered a mixed hyaline/myxoid chondrosarcoma by another [72]. Given the lack of uniformity of diagnosis, it is not surprising that many studies have failed to confirm [73] the better prognosis for chondroid chordomas that was shown in the original description [86]; those which do show a better prognosis may have included chondrosarcomas in their material, which are known to have a better prognosis than chordoma [86].

Cartilaginous Tumors Cranial chondrosarcoma is rarer than chordoma [76], with whom it nevertheless shares a predilection for the sellar region and a similar infiltrative growth pattern. However, calcification is more frequent and abundant in the former than in the latter and chondrosarcomas tend to arise more laterally as opposed to the midline location of chordomas [76]. As for chordomas, imaging studies should include both CT and MR for evaluation of bone and soft tissue involvement, respectively [76]. Histologically, most sellar chondrosarcomas are well differentiated and resemble hyaline cartilage; these tumors may be histologically quite bland and their malignant character only apparent because of their

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destructive growth pattern. Although chordomas may have some chondroid foci (see above), chondrosarcomas do not contain the typical physaliphorous cells of chordomas and their immunohistochemical features are also different (see above). This distinction is of more than academic interest: with similar therapy, chondrosarcomas have a better prognosis than chordomas, with 5-year recurrence-free survival rates of around 90–95% [76,80]. Chondromas (also called enchondromas) are even rarer than chondrosarcomas [76]. They can occur as solitary lesions [87,88] or in the context of Ollier disease (multiple chondromas) [89] or Maffucci syndrome (multiple chondromas and hemangiomas) [90,91]; interestingly, some of the latter patients also had pituitary adenomas [91].

Craniopharyngioma Overall, craniopharyngioma constitutes about 3% of brain tumors [92], but up to 9% in children and adolescents [93,94]; it is in fact the most frequent sellar tumor in that age group. The adamantinomatous craniopharyngioma occurs at all ages, from the fetal and newborn period [95,96] to late senescence [97], but is most frequent in children and adolescents [98,99]. In contrast, the squamous papillary craniopharyngioma occurs almost exclusively in adults [98–101]. Most craniopharyngiomas are suprasellar, with or without intrasellar extension. Rare cases confined to the third ventricle or to the chiasm have been described [102–104]. In some patients, the tumor achieves giant proportions (up to 12 cm; “giant cystic craniopharyngioma”), and extends well beyond the sellar region in any direction [105]. Pathology

Craniopharyngiomas are mostly cystic or cystic-solid (Figs 16.3 and 16.4). The cysts are filled with a brownish, lipid and cholesterol-rich viscous fluid bearing more than a superficial resemblance to motor oil. Histologically, the classical craniopharyngioma contains nests of basaloid and stellate epithelial cells that resemble the dental ameloblastic organ and are also seen in adamantinoma (a rare bone tumor with ameloblastic differentiation); consequently, this variant is called adamantinomatous. In addition, there are various amounts of squamous epithelium. Calcifications are frequent. Portions of the tumor often degenerate; the keratinous debris elicits an intense inflammatory and foreign body giant cell reaction. The papillary squamous variant contains only squamous epithelium without any adamantinomatous component. Other features that distinguish it from the adamantinomatous variant are the presence of goblet cells [99], and the lack of calcification [98,99]. Although histologically benign, craniopharyngiomas are biologically aggressive tumors. They tend to surround and/ or infiltrate vital structures such as the hypothalamus, the optic pathways, and vessels of the circle of Willis. There is often intense gliosis in the brain structures adjacent to or

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invaded by the tumor; combined with the inflammatory reaction, this makes the tumor especially adherent to these structures and hinders attempts at complete resection. Malignant transformation has been described [106]; this appeared on the fifth recurrence after 35 years of follow-up and 8 years following radiotherapy.

F I G U R E 1 6 . 3 . A 77-year-old woman presented with a 2month history of personality changes, memory loss, and shuffling gait. Computed tomography scan disclosed hydrocephalus due to ventricular compression by a suprasellar mass. The patient died in the early postoperative period of bronchopneumonia. At autopsy there was a 2.5 ¥ 3 cm craniopharyngioma pushing upward and rostrally into the third ventricle and suprachiasmatic area.

Clinical Aspects

The clinical presentation of craniopharyngiomas is a direct result of their location and growth behavior. They compress the optic pathways, infiltrate the hypothalamus, and can extend into the third ventricle (Figs. 16.3, 16.4), thereby causing visual disturbances, hypothalamic–pituitary dysfunction, and hydrocephalus, or combinations thereof [107]. The most frequent endocrine manifestations are short stature secondary to GH-deficiency and diabetes insipidus [107]; somewhat surprisingly, the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has also been reported in rare patients [107]. Another very unusual presentation is hearing loss secondary to posterior fossa involvement [108]. MR is the imaging modality of choice, especially to determine the full extent of the tumor and its relationship to adjacent brain structures [109]. Some groups find significant imaging differences between adamantinomatous and squamous–papillary craniopharyngiomas [100], while others do not [92]. The traditional therapeutic approach centered on surgical resection, with or without postoperative radiotherapy. It is generally agreed that radical resection with total removal of the tumor (confirmed by postoperative MR) is associated with the lowest rate of recurrence; only 10% of such cases in a recent series recurred [110]. However, although multiple postoperative endocrinopathies are almost universal regardless of the extent of surgery, ADH deficiency with an abnormal sense of thirst is seen only after radical surgery and constitutes a major management problem with significant morbidity and mortality [94,110]. Another complication of radical surgery is damage to arteries of the circle of Willis, leading to either hemorrhage or cerebral infarction [110]. Therefore, there is a growing consensus not to aim

F I G U R E 1 6 . 4 . Low-power view of a craniopharyngioma whose growing edge occupied and expanded into the third ventricle. Note distension of infundibulum (hematoxylin and eosin staining; ¥5.2)

Chapter 16

for radical resection at all cost in every patient, but to reserve this for tumors where complete resection can be achieved without producing additional damage to vital structures [109]. As reviewed elsewhere, subtotal excision followed by adjuvant radiotherapy produces excellent results, with 10-year recurrence-free survivals of 80–90% reported in the recent literature [110,111]. Although some groups find better outcome with squamous papillary craniopharyngiomas than with adamantinomatous ones [98], others do not, once additional parameters, such as completeness of resection, are taken into account [99,101]. Alternative therapies aimed at minimizing surgical intervention have also been developed. One promising approach is the stereotactically guided instillation of b-emitting isotopes into craniopharyngioma cysts, which has been shown to produce results similar to those of conventional therapy [93,112]; however, this method can only be applied to predominantly cystic tumors without a significant solid component. In a similar vein, intracystic administration of bleomycin was successful in a giant cystic craniopharyngioma [113]. Stereotactic radiosurgery is another option [111].

Meningioma Meningiomas are tumors of arachnoid and meningothelial cells that account for approximately 25% of intracranial tumors in women and 13% in men [114]; this may be due to the expression of sex-steroid receptors by these tumors. They can arise anywhere in the cranial cavity; meningiomas of the sellar and parasellar regions account for about 20% of meningiomas [115]; the sphenoid ridge (Fig. 16.5) and

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the tuberculum sellae are more frequently involved than the clivus. Sellar involvement by a meningioma is usually the result of intrasellar extension of a suprasellar meningioma; purely intrasellar meningiomas are distinctly unusual: Nozaki et al. describe one case of their own and review 17 previously reported ones [116]. Interestingly, a few patients had a synchronous pituitary adenoma and sellar meningioma [117, 118]. One intrasellar meningioma occurred 8 years after radiotherapy for a pituitary adenoma [119]. Pathology

Meningiomas can have many different histological appearances, with about 10 recognized subtypes. The most frequent ones are the meningothelial, fibroblastic and transitional variants. Psammoma bodies and meningothelial whorls are helpful clues to the diagnosis. The papillary variant is recognized for its aggressive behavior with a propensity towards metastasis. Another aggressive variant with a hemangiopericytic pattern is nowadays considered as a true hemangiopericytoma of the meninges rather than as a hemangiopericytic meningioma. Malignant counterparts of the other subtypes also exist. Clinical Aspects

Intrasellar meningiomas mimic nonfunctioning pituitary adenomas clinically, since they present with visual disturbances, partial or complete hypopituitarism, hyperprolactinemia, or combinations thereof [116]. MR is superior to CT in delineating the lesion and its relationship to adjacent intracranial structures [116], but unless a dural origin of the tumor can be clearly demonstrated, radiographic distinction from pituitary adenoma remains difficult. Resection is the treatment of choice; a purely intrasellar meningioma can be resected transsphenoidally but tumors with a suprasellar component often require a combined transsphenoidal and transcranial approach. Meningiomas are highly vascular and massive intraoperative bleeding occurred in about one-third of the reported cases [116]; this can be prevented by selective preoperative endovascular embolization of the tumor’s feeding vessels [116]. More recently, stereotactic radiosurgery has been proposed as an alternative therapy, both for recurrent and primary skull base meningiomas, since it produces excellent long term tumor control with few complications [120].

Glioma

F I G U R E 1 6 . 5 . Meningioma of the planum sphenoidale. The well-demarcated mass in the suprasellar area compressed the anterior hypothalamus and infundibulum.

Glioma of the optic pathways is a well documented entity that predominantly occurs in children. It has a definite association with neurofibromatosis type 1 (NF1): between one-third [121–123] and two-thirds of cases [124] occur in patients with NF1, and conversely, up to 15% of randomly screened NF1 patients have a glioma of the optic pathways, often bilaterally [125]. In fact, bilateral optic pathway gliomas are diagnostic of NF1. Optic pathway

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gliomas have also been described in a few patients with Beckwith–Wiedemann syndrome [126]. Histologically, most of these tumors are of a particular type of low-grade glioma called pilocytic astrocytoma (Fig. 16.6); the term “pilocytic” refers to the elongated, “hairlike” shape of the tumor cells. One of their major manifestations is obviously loss of vision; however, very young children may not complain of visual disturbances until they are nearly blind [127]. Additional manifestations depend on the tumor’s location. For instance, a tumor of the optic nerve may cause proptosis while tumors with chiasmal and/or hypothalamic involvement may be associated with hydrocephalus and endocrinopathy, such as diabetes insipidus, hypopituitarism, or precocious puberty. There is some evidence that the presentation differs between NF1 and non-NF1 associated tumors: in one series, precocious puberty was seen only with the former while intracranial hypertension and nystagmus were only seen with the latter [128]. Therapy is controversial; the debate centers on the indication for surgery and the extent thereof as well as the role of radiotherapy and chemotherapy. NF1-associated tumors are more indolent than non NF1-associated cases. Most of the optic pathway gliomas discovered by routine screening in NF1 patients are asymptomatic and only a small minority progress after discovery [125,129]; in fact, even among symptomatic tumors, only about 10–20% progress [121,125]. Given the indolent nature of most NF1associated optic pathway gliomas, therapy should be as conservative as possible; guidelines for the management of these children have been published [130]. Optic pathway gliomas not associated with NF1 have a somewhat paradoxical behavior: even though about two-thirds will eventually progress or recur, prolonged survival is still the rule, even

with conservative management, with 5- and 10-year survival rates of about 90% and 75–85% being reported, respectively [121,123]. Quality of life therefore becomes a major issue, against which complications of radical surgery and radiotherapy have to be weighed [121,123]. Chemotherapy is being increasingly used, especially in younger children, since it can delay the need for radiotherapy by several years [121]. It should be noted that about half of these children will have some type of treatment-requiring, persistent endocrinopathy (usually anterior and/or posterior pituitary insufficiency), related either to direct effects of the tumor, the therapy, or both [121,122]. Gliomas involving the optic pathways in adults are usually anaplastic astrocytomas or glioblastoma multiforme that are highly infiltrative (Fig. 16.7). Given their location and aggressive nature, prognosis is poor: with a few exceptions [131], most patients die within a year of diagnosis [132–134]. Gliomas of the pituitary gland proper are very rare [135,136]. They can mimic nonfunctioning pituitary adenomas both radiologically [135] and endocrinologically by causing hypopituitarism and/or hyperprolactinemia [135,136], the latter presumably through stalk effect. Recently, a very unusual type of glioma occurring in the third ventricle/suprasellar region has been described as “chordoid glioma of the third ventricle” [137]. Of the nine definite [137,138] and one probable [139] cases reported so far, all arose in adults and all but one occurred in women. Both the radiologic and histologic features are remarkably constant. The tumors were large, rounded, uniformly enhancing masses involving the suprasellar region and/or the third ventricle. They were well demarcated and not invasive. Histologically, they were composed of epithelioid cells set in an abundant myxoid matrix with a prominent

F I G U R E 1 6 . 6 . Pilocytic astrocytoma involving hypothalamus and walls of the third ventricle.

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F I G U R E 1 6 . 8 . Germinoma infiltrated the optic tracts, infundibulum and anterior hypothalamus. The pineal gland was not involved.

F I G U R E 1 6 . 7 . This 49-year-old woman presented with blurred vision and a dense left homonymous hemianopsia. X-ray studies disclosed the presence of a large hypothalamic mass with involvement of the optic chiasm and right optic nerve. At craniotomy biopsy showed a malignant astrocytoma. The tumor progressed, and the patient developed uncontrollable seizures and died 8 months after the onset of symptoms. A ventral view of the brain at autopsy revealed a massive enlargement of the optic chiasm and right optic nerve. Coronal sections of the brain showed a noncontiguous tumor mass in the right cerebral convexity, indicative of multicentric glioma.

lymphoplasmacytic inflammatory infiltrate. Although the histologic picture suggests a low-grade chordomatous type of epithelial neoplasm, immunohistochemical and ultrastructural studies surprisingly indicate a glial phenotype. The histogenesis and long-term prognosis of this unusual neoplasm are unclear at this point.

Germ Cell Tumors Overall, germ cell tumors account for no more than 1% of intracranial tumors in Western countries [140]; in children, however, they constitute up to about 10% of brain tumors [140] and conversely, about 6% of pediatric germ cell

tumors are intracranial [141]. Although it is reported that they constitute up to 16% of brain tumors in Japan [140], epidemiological surveys indicate a lower proportion of 1.8–3.1% [142,143]. These tumors usually arise in the midline; about two-thirds occur in the pineal region, onethird in the suprasellar area (Fig. 16.8), and the remainder in the thalamus and basal ganglia. Rarely, they are centered on the pituitary fossa or limited to it [144–146]. There is a definite male predominance for pineal cases and an equally definite female predominance for suprasellar cases [147–149]; the reason for this is unknown. Intracranial germ cell tumors have been reported in association with Down syndrome [150], Klinefelter syndrome [151], and Cornelia de Lange syndrome [152]. Pathology

Just like other extragonadal germ cell tumors, these tumors are presumed to arise from residual primordial germ cells that became “displaced” during their migration from the yolk sac to the genital ridges; possible mechanisms for this aberrant migration are reviewed elsewhere [153]. More recently, origin from other types of embryonal cells has been proposed [154]. Histologically, these tumors are indistinguishable from their gonadal counterparts and are classified as germinomas (called seminomas in the testis and dysgerminomas in the ovary), embryonal carcinomas, teratomas (mature or immature), endodermal sinus tumors (also called yolk-sac tumor), or choriocarcinomas. This classification is based on the stage of embryonic development that the tumor most resembles [147]: primordial germ cells (germinoma), embryonal stem cells (embryonal carcinoma), embryonic tissues (teratoma), yolk-sac endoderm (yolk-sac

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tumor), or trophoblast (choriocarcinoma). Detailed histological descriptions can be found elsewhere [149,155]. (Suprasellar germinomas were sometimes called “ectopic pinealomas” in the past because they bear some histologic resemblance to the fetal pineal gland. However, since they are clearly of germ cell and not of neuroepithelial origin, this term has been abandoned.) Mixed malignant germ cell tumors composed of two or more types are not uncommon. It should be noted, however, that syncytiotrophoblastic giant cells can be present in tumors other than choriocarcinoma without altering the diagnosis; choriocarcinoma is only diagnosed if both cyto- and syncytiotrophoblastic elements are present. Immunohistochemistry is useful in identifying and confirming the presence of certain elements: syncytiotrophoblastic cells are positive for bhuman chorionic gonadotrophin (b-hCG), embryonal carcinoma stains for b-hCG, and a-fetoprotein (AFP), while endodermal sinus tumors usually stain only for AFP. Germinomas are usually negative for the aforementioned markers but express placental alkaline phosphatase. Documentation of expression of b-hCG and/or AFP is important for follow-up since their levels can be monitored in the patient’s blood and cerebrospinal fluid for early detection of recurrence.

Mature teratomas are theoretically benign and can be cured by complete surgical resection alone [140,143,155, 157]. However, these tumors can be very bulky, leading to significant surgical morbidity [157]. Pure germinomas are highly radiosensitive and current radiotherapy protocols can achieve long-term survival in about 70–80% of patients [140,143]; some authors even report 10-year survival rates of more than 90% [154]. The other types of germ cell tumors are more aggressive even when treated with a combination of surgery, radiotherapy, and chemotherapy; survival rates are about half of those reported for pure germinomas [140]. Since chemotherapy has produced significant improvement of survival in patients with nongerminomatous germ cell tumors of the gonads, there are a number of trials underway assessing its role in the treatment of intracranial germ cell tumors, both as adjuvant and as neoadjuvant (pre-irradiation) therapy [140]; some groups have even begun using chemotherapy and radiotherapy preoperatively [158]. In contrast to most other brain tumors, these tumors have the ability to metastasize along the CSF pathways and also outside of the central nervous system. Systemic metastases can be aided by a ventriculo–peritoneal shunt; over two dozen cases of this phenomenon have been reported, according to a recent review [159].

Clinical Aspects

The presenting symptoms of suprasellar germ cell tumors are mostly those of mass effect or precocious puberty [140,147–149]. Mass effect can produce hypopituitarism, diabetes insipidus, visual disturbances, hydrocephalus, and intracranial hypertension. Symptomatic suprasellar germinomas can be tiny: in one series of children considered to have “idiopathic” central diabetes insipidus, seven only had a thickened pituitary stalk on MR; in six of these, biopsy of the stalk showed a germinoma [156]. Precocious puberty may be caused by hypothalamic destruction with release of gonadal inhibition and/or by b-hCG secretion by the tumor. Other presentations include psychosis, dementia, seizures, bulimia, or anorexia [140,147–149]. As for most lesions discussed in this chapter, MR is superior to CT in evaluating the extent of the tumor and its relationship to normal adjacent structures; however, the radiologic appearance of these tumors is not sufficiently distinctive to allow subtyping by imaging [140]. Association with a pituitary adenoma has been reported [146]. With modern microsurgical techniques and management of intracranial hypertension, pretherapy biopsy of suspected intracranial germ-cell tumors has become the rule, at least in North America [140,148,157]. Since the histologic type is a major determinator of therapy and prognosis, open biopsy is preferred over stereotactic biopsy, because the latter yields considerably smaller samples that may not adequately represent the tumor, especially a mixed one [140,148,157]. Furthermore, surgical debulking of tumors can achieve rapid relief of mass effect on critical structures such as the optic pathways [148].

HEMATOLOGICAL PROLIFERATIONS

Lymphomas and Leukemias While clinically significant involvement of the CNS by lymphomas and leukemias is mostly meningeal and extradural [160], intraparenchymal infiltrates are not uncommon at autopsy, especially with high-grade lymphomas and lymphoblastic leukemia [161]. In regard to the pituitary gland, periglandular (subcapsular) infiltration is seen in almost half of cases of adult acute lymphoblastic leukemia, but true intraparenchymal deposits are very rare [162]. Pituitary function does not appear to be affected in most cases; occasional patients suffered from the syndrome of inappropriate secretion of antidiuretic hormone [160,162]. Very rarely, the pituitary gland may be massively enlarged to the point of causing symptomatic chiasmal compression [163]. Rare cases of primary CNS lymphomas can also present because of involvement of the hypothalamic–pituitary axis [164– 166]. The pituitary gland can also be involved in systemic angiotropic lymphoma [167].

Plasmacytoma Plasmacytomas can involve the sella and simulate nonfunctioning pituitary adenomas clinically. Most of the patients reported eventually developed full-blown multiple myeloma [168–170]; only very few cases can be considered as true solitary sellar plasmacytomas [171]. Histologically, a plasmacytoma composed of relatively well-differentiated plasma cells can be mistaken for a chromophobe adenoma [172].

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However, electron microscopy and immunohistochemistry will demonstrate lack of epithelial and neurosecretory features. Furthermore, clonal rearrangements of immunoglobulin genes typical of B-cell neoplasms can be demonstrated in plasmacytomas by molecular genetic studies.

Langerhans Cell Histiocytosis Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X, can be localized, multifocal, or disseminated. Solitary lesions, especially in bone, are also referred to as eosinophilic granuloma. Histologically, lesions of LCH contain a mixed cell population composed of lymphocytes, eosinophils, foamy macrophages, and Langerhans cells. The latter express S-100 protein and the CD1a antigen; on ultrastructural examination, they contain peculiar cytoplasmic organelles called Birbeck granules, which are pathognomonic. Langerhans cells must be demonstrated in a lesion for a definite diagnosis of LCH. Traditionally, LCH has been considered as a nonneoplastic, reactive histiocytic proliferation, triggered perhaps by some defect of immune regulation. However, molecular genetic clonality studies of both disseminated and localized forms have shown convincingly that all of them were clonal, and therefore neoplastic [173]. Furthermore, only the CD1a-positive cells are clonal, indicating that LCH is indeed a clonal proliferation of neoplastic Langerhans cells [173]. CNS involvement is described in a recent extensive review [174]. While not uncommon in disseminated forms of LCH (Fig. 16.9), isolated lesions confined to the hypothalamic–pituitary axis are very unusual (Fig. 16.10); this is sometimes referred to as Ayala’s disease or Gagel’s granuloma. Any part of the CNS can be involved, but the

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sites of predilection are the hypothalamic-pituitary axis and the pontocerebellar region. Diabetes insipidus is the most frequent manifestation, and once it is fully established, posterior pituitary function is essentially irreversibly lost, regardless of therapy [174]. Surgery and/or radiotherapy should be reserved for lesions causing mass effect [174]. Recently, debilitating progressive cerebellar degeneration in the absence of cerebellar parenchymal infiltration has been reported as a late and possibly paraneoplastic complication of LCH [175]. METASTASES In cancer patients, metastasis to the pituitary gland is more common than pituitary adenoma; in their series of 500 autopsies, Max et al. found a prevalence of 3.6% and 1.8%, respectively [176]. Metastases are also the most frequent tumor of the neurohypophysis [177], which is affected about twice as often as the adenohypophysis [176]. The prevalence of pituitary metastasis in autopsy series of cancer patients ranges up to 26.7% [178] with most reports quoting around 3–5%. In an autopsy study of 739 cancer patients, one-half of the pituitary metastases constituted the only metastatic deposit in the CNS [179]. Although any tumor can metastasize to the pituitary gland, carcinomas of the breast and lung account for 50% and 20% of cases respectively, based on a review of 220 cases by McCormick et al. [180]. Conversely, 15–25% of women with metastatic breast cancer will have pituitary metastases [181,182]. Occasionally, no primary tumor can be identified [183], even at autopsy [184,185]. The mechanism of spread to the pituitary gland is most likely hematogenous; the less frequent involvement of the

F I G U R E 1 6 . 9 . This patient had disseminated Langerhans’ cell histiocytosis. Note ill-defined infiltration of anterior hypothalamus. The lesion exhibited areas of hemorrhages, necrosis, and cavitation.

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F I G U R E 1 6 . 1 0 . Incidental finding of isolated histiocytosis X of the hypothalamus (Gagel’s granuloma, Ayala’s disease) in a 65year-old man. The patient had a sacral chordoma diagnosed 10 years previously and treated with several courses of radiotherapy. The tumor progressed with massive involvement of the pelvic organs. Shortly before death a computed tomography scan of the head showed a mass in the suprasellar hypothalamic area which histologically was composed of lymphocytes, histiocytes, and foamy macrophages in a fibrovascular stroma.

anterior lobe may be due to some “protective” effect of its indirect portal blood supply as opposed to the direct systemic supply of the posterior lobe. It is of note that in patients with metastatic breast carcinoma, pituitary metastases are statistically associated with metastases in other endocrine glands and in the heart, liver, and gut, suggesting that this pattern is not random [182]. The histology of the metastasis will obviously depend on the type of primary tumor, which is usually some type of adenocarcinoma. In patients without a known primary tumor, certain features may provide a clue to the origin of the lesion. For example, the presence of signet ring cells suggests a gastric carcinoma, while positive immunostaining for prostatic-specific antigen is a reliable and highly specific marker of prostatic origin. Most pituitary metastases are asymptomatic and constitute incidental autopsy findings in patients with widely disseminated cancer. However, among patients presenting with symptomatic pituitary metastases, many have no prior history of malignancy and the primary tumor is discovered only after diagnosis of the pituitary lesion. Such was the case of nine of 14 patients in one series [183]. Presenting symptoms [172] include headache, visual field defects due to chiasmal compression [186] as well as ophthalmoplegia and ptosis secondary to involvement of the cavernous sinus and its structures [184]. Involvement of the anterior lobe can lead to hypopituitarism [183,187] which can also be caused by an isolated metastasis in the infundibulum [188]. Posterior lobe involvement may lead to diabetes insipidus; in one series of 100 consecutive cases of diabetes insipidus, 14 were caused by metastasis. The imaging appearance is usually indistinguishable from that of a pituitary adenoma [172] which is in fact the most frequent clinical (mis)diag-

nosis; the correct diagnosis can be missed even histologically [180]. Since by definition these patients suffer form metastatic disease, treatment is palliative. However, surgical decompression with or without postoperative radiotherapy can provide improvement; in one series, mean survival was 22 months [183]. Pituitary metastases from a primary prostatic carcinoma can regress with androgen blockade [189,190]. It is noteworthy that increasing numbers of carcinomas metastatic to pituitary adenomas are being reported; the primary tumors have included carcinomas of the stomach [191], lung [192,193], breast [194,195], kidney [196], prostate [197], and pancreas [197] as well as a malignant carcinoid tumor of the mediastinum [198]. Sometimes, no primary lesion could be identified [192] or the patient had more than one potential primary tumor [199]. In a patient with a known, previously “stable” pituitary adenoma, a metastasis into the adenoma can cause a rapid increase in size [191,198] or a sudden worsening of mass effect [192,193]. POSTRADIOTHERAPY TUMORS Ionizing radiation is oncogenic and irradiation of the brain for any reason predisposes to the development of primary intracranial tumors, especially gliomas and meningiomas [200]. Even average doses as low as 1.5 Gy that were administered as therapy for tinea capitis produce a significant increase in the number of brain as well as head and neck tumors [200]. In one series of 334 patients with pituitary adenoma who underwent conservative surgery followed by radiotherapy, five developed a second brain tumor (two astrocytomas, two meningiomas, and one meningeal sarcoma); the cumulative risks were 1.3% and 1.9% at 10

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and 20 years, respectively [201]. Gliomas have occurred following radiotherapy for various sellar tumors, including pituitary adenomas [202,203], craniopharyngiomas [202,203], optic glioma [202], and suprasellar germ cell tumors [202,204]. All patients had received radiation doses of >40 Gy; latency periods ranged from 1 to 28 years [202,203]. They may involve the suprasellar structures, but also the cerebral hemispheres, brain stem, or cerebellum. About three-quarters are malignant (anaplastic) astrocytomas or glioblastoma multiforme [202]; these are aggressive tumors and most patients die within a few months of histological diagnosis. Meningiomas also occur following sellar radiotherapy [119,205–207]; radiation doses and latency periods are similar to those of postradiotherapy gliomas. Occasionally, an unfortunate patient develops more than one postradiotherapy tumor [208]. Postirradiation sarcoma is also a rare but well-recognized entity [209]. Kumar et al. found 29 reports of sarcomas developing after radiotherapy for pituitary adenoma; radiation doses ranged from 20 to 100 Gy and latency periods from 2.5 to 27 years [210]. As with most radiation-induced brain malignancies, prognosis was grim, with over 90% of these patients dying with 6 months of diagnosis [210].

MISCELLANEOUS LESIONS Both intra- and parasellar schwannomas have been reported. An intrasellar schwannoma can cause hypopituitarism and mimic a nonfunctioning pituitary adenoma both clinically and radiologically [211]. Tumors of bone that can involve the sellar and parasellar regions include giant cell tumor [212,213], chondromyxoid fibroma [214], and brown tumor of hyperparathyroidism [215]. Even a mundane bony spur can become clinically significant when located in the sella [216]! Most uncommon are hemangioblastoma (in association with von Hippel–Lindau disease) [217], cavernous hemangioma [218], glomangioma [219], leiomyoma [220], hemangiopericytoma [221], paraganglioma [222], primary melanoma [223], primary sellar thyroid follicular tumor [224], and “tumoral” extramedullary hematopoiesis [225]. Last but not least, sarcoidosis, one of the great imitators, should be mentioned here as a cause of pituitary “tumor.” The nervous system becomes clinically involved in about 5–10% of patients with sarcoidosis [226–228]. Most of the patients develop neurosarcoidosis during the course of systemic sarcoidosis; initial presentation because of nervous system involvement is rare. Any part of the central or peripheral nervous system can be affected, but the sites of predilection are the meninges at the base of the brain with cranial nerve palsies being the main complaint [226–228]. With regard to the pituitary–hypothalamic axis, the hypothalamus is more frequently affected than the other components [228], with partial or complete anterior and/or posterior pituitary insufficiency being the main manifestations. Histologically, sarcoidosis is characterized by non-

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caseating granulomatous inflammation. However, a definitive diagnosis absolutely requires negative mircobiological cultures to exclude an infectious process. (Negative special stains for microorganisms are not sufficient, since they are considerably less sensitive than cultures.) Corticosteroids are the mainstay of therapy [228]. REFERENCES 1 Scheithauer BW. Pathology of the pituitary and sellar region: exclusive of pituitary adenoma. Pathol Annu 1985;20:67–155. 2 Chakeres DW, Curtin A, Ford G. Magnetic resonance imaging of pituitary and parasellar abnormalities. Radiol Clin N Am 1989;27:265–281. 3 Donovan JL, Nesbit GM. Distinction of masses involving the sella and suprasellar space: specificity of imaging features. Am J Radiol 1996; 167:597–603. 4 Naheedy MH, Haag JR, Azar-Kia B et al. MRI and CT of sellar and parasellar disorders. Radiol Clin N Am 1987;25:819–847. 5 Zimmerman RA. Imaging of intrasellar, suprasellar and parasellar tumors. Sem Roentgenol 1990;25:174–197. 6 Isaacs RS, Donald PJ. Sphenoid and sellar tumors. Otolaryngol Clin N Am 1995;28:1191–1229. 7 Colohan ART, Grady MS, Bonnin JM et al. Ectopic pituitary gland simulating a suprasellar tumor. Neurosurgery 1987;20:43–48. 8 Ikeda H, Niizuma H, Suzuki J et al. A case of cebocephaly-holoprosencephaly with an aberrant adenohypophysis. Childs Nerv Syst 1987;3:251–254. 9 Niikawa S, Nokura H, Uno T et al. Precocious puberty due to an ectopic pituitary gland. Neurol Med Chir 1988;28:681–684. 10 Brooks BS, El Gammal T, Allison JD, Hoffman WH. Frequency and variation of the pituitary bright signal on MR images. Am J Neuroradiol 1989; 10:943–948. 11 Nagel BHP, Palmbach M, Petersen D, Ranke MB. Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion. Eur J Pediatr 1997;156:758–763. 12 Maghnie M, Moretta A, Valtorta A et al. Growth hormone response to growth-hormone-releasing hormone varies with the hypothalamic–pituitary abnormalities. Eur J Endocrinol 1996;135:198–204. 13 Siegel SF, Ahdab-Barmada M, Arslanian S, Foley TP. Ectopic posterior pituitary tissue and paracentric inversion of the short arm of chromosome 1 in twins. Eur J Endocrinol 1995;133:87–92. 14 Roessmann U, Velasco ME, Small EJ, Hori A. Neuropathology of “septo-optic dysplasia” (de Morsier syndrome) with immunohistochemical studies of the hypothalamus and pituitary gland. J Neuropathol Exp Neurol 1987;46:597–608. 15 Sorkin JA, Davis PC, Meacham LR et al. Optic nerve hypoplasia: absence of the posterior pituitary bright signal on magnetic resonance imaging correlates with diabetes insipidus. Am J Ophthalmol 1996;122:717–723. 16 Willnow S, Kiess W, Butenandt O et al. Endocrine disorders in septo-optic dysplasia (De Morsier syndrome)—evaluation and follow-up of 18 patients. Eur J Pediatr 1996;155:179–184. 17 Schochet SS, McCormick WF, Halmi NS. Salivary gland rests in the human pituitary. Light and electron microscopical study. Arch Pathol 1974;98:193–200. 18 Kato T, Aida T, Abe H et al. Ectopic salivary gland within the pituitary gland. Neurol Med Chir 1988;28:930–933. 19 Tatter SB, Edgar MA, Klibanski A, Swearingen B. Symptomatic salivary-rest cyst of the sella turcica. Acta Neurochir 1995;135:150–153. 20 Dickhoff P, Wallace CJ, MacRae ME, Campbell WN. Adenoid cystic carcinoma: an unusual sellar mass. Can Assoc Radiol J 1993;44:393–395. 21 Hirsch Pescovitz O, Comite F, Hench K et al. The NIH experience with precocious puberty: diagnostic subgroups and response to short-term luteinizing hormone releasing hormone analogue therapy. J Pediatr 1986; 108:47–54. 22 Kuzniecky R, Guthrie B, Mountz J et al. Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy. Ann Neurol 1997;42:60–67. 23 Kang S, Graham JM, Haskins Olney A, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister–Hall syndrome. Nat Genet 1997;15:266–268. 24 Pallister PD, Hecht F, Herrman J. Three additional cases of the congenital hypothalamic “hamartoblastoma” (Pallister–Hall) syndrome. Am J Med Genet 1989;33:500–501. 25 Squires LA, Constantini S, Miller DC, Wisoff JH. Hypothalamic hamartoma and the Pallister–Hall syndrome. Pediatr Neurosurg 1995;22:303–308.

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26 Iafolla K, Fratkin JD, Spiegel PK et al. Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister–Hall syndrome). Am J Med Genet 1989;33:489–499. 27 Shuangshoti S, Netsky MG, Nashold BS. Epithelial cysts related to sella turcica. Proposed origin from neuroepithelium. Arch Pathol 1970;90:444–450. 28 McGrath P. Cysts of sellar and pharyngeal hypophyses. Pathology 1971;3: 123–131. 29 Keyaki A, Hirano A, Llena JF. Asymptomatic and symptomatic Rathke’s cleft cysts. Neurol Med Chir 1989;29:88–93. 30 Barrow DL, Spector RH, Takei Y, Tindall GT. Symptomatic Rathke’s cleft cysts located entirely in the suprasellar region: review of diagnosis, management, and pathogenesis. Neurosurgery 1985;16:766–772. 31 Ross DA, Norman D, Wilson CB. Radiologic characteristics and results of surgical management of Rathke’s cysts in 43 patients. Neurosurgery 1992;30: 173–179. 32 Hanna E, Weissman J, Janecka IP. Sphenoclival Rathke’s cleft cysts: embryology, clinical appearance and management. Ear Nose Throat J 1998;77:396–399,403. 33 Kleinschmidt-DeMasters BK, Lillehei KO, Stears JC. The pathologic, surgical, and MR spectrum of Rathke cleft cysts. Surg Neurol 1995;44:19–27. 34 Voelker JL, Campbell RL, Muller J. Clinical, radiographic, and pathological features of symptomatic Rathke’s cleft cysts. J Neurosurg 1991;74:535–544. 35 El-Mahdy W, Powell M. Transsphenoidal management of 28 symptomatic Rathke’s cleft cysts, with special reference to visual and hormonal recovery. Neurosurgery 1998;42:7–17. 36 Baldini M, Mosca L, Princi L. The empty sella syndrome secondary to Rathke’s cleft cyst. Acta Neurochir 1980;53:69–78. 37 Obenchain TG, Becker DP. Abscess formation in a Rathke’s cleft cyst. Case report. J Neurosurg 1972;36:359–362. 38 Macaulay RJB. Ruptured Rathke’s cleft cyst: a possible cause of Tolosa–Hunt syndrome. Clin Neuropathol 1997;16:98–102. 39 Albini CH, MacGillivray MH, Fisher JE et al. Triad of hypopituitarism, granulomatous hypophysitis, and ruptured Rathke’s cleft cyst. Neurosurgery 1988;22:133–136. 40 Hayashi Y, Yamashita J, Muramatsu N et al. Symptomatic Rathke’s cleft cysts in identical twins. Case illustration. J Neurosurg 1996;84:710. 41 Yamakawa K, Shitara N, Genka S et al. Clinical course and surgical prognosis of 33 cases of intracranial epidermoid tumors. Neurosurgery 1989;24:568–573. 42 Abramson RC, Morawetz RB, Schlitt M. Multiple complications from an intracranial epidermoid cyst: case report and literature review. Neurosurgery 1989;24:574–578. 43 Lewis AJ, Cooper PW, Kassel EE, Schwartz ML. Squamous cell carcinoma arising in a suprasellar epidermoid cyst. Case report. J Neurosurg 1983;59: 538–541. 44 Torbiak CW, Mazagri R, Tchang SPK, Clein LJ. Parasellar epidermoid cyst presenting with subarachnoid hemorrhage. Can Assoc Radiol J 1995;46: 392–394. 45 Civit T, Pinelli C, Lescure JP et al. Stroke related to a dermoid cyst: case report. Neurosurgery 1997;41:1396–1399. 46 Cohen JE, Abdallah JA, Garrote M. Massive rupture of suprasellar dermoid cyst into ventricles. J Neurosurg 1997;87:963. 47 Chhang WH, Sharma BS, Singh K et al. A middle fossa arachnoid cyst in association with a suprasellar dermoid cyst. Indian Pediatr 1989;26:833–835. 48 Schroeder HWS, Gaab MR. Endoscopic observation of a slit-valve mechanism in a suprasellar prepontine arachnoid cyst: case report. Neurosurgery 1997;40: 198–200. 49 Pierre-Kahn A, Capelle L, Brauner R et al. Presentation and management of suprasellar arachnoid cysts. Review of 20 cases. J Neurosurg 1990;73:355– 359. 50 Schroeder HWS, Gaab MR, Niendorf WR. Neuroendoscopic approach to arachnoid cysts. J Neurosurg 1996;85:293–298. 51 Decq P, Brugières P, Le Guerinel C et al. Percutaneous endoscopic treatment of suprasellar arachnoid cysts: ventriculocystostomy or ventriculocystocisternostomy? Technical note. J Neurosurg 1996;84:696–701. 52 Shanklin WM. The origin, histology, and senescence of tumorettes in the human neurohypophysis. Acta Anat 1953;18:1–20. 53 Luse SA, Kernohan JW. Granular cell tumors of the stalk and posterior lobe of the pituitary gland. Cancer 1955;8:616–622. 54 Tomita T, Kuziez M, Watanabe I. Double tumors of anterior and posterior pituitary gland. Acta Neuropathol 1981;54:161–164. 55 Tuch BE, Carter JN, Armellin GM, Newland RC. The association of a tumour of the posterior pituitary gland with multiple endocrine neoplasia type 1. Aust NZ J Med 1982;12:179–181. 56 Landolt A. Granular cell tumor of the neurohypophysis. Acta Neurochir 1975;(Suppl)22:120–128.

57 Schaller B, Kirsch E, Tolnay M, Mindermann T. Symptomatic granular cell tumor of the pituitary gland: case report and review of the literature. Neurosurgery 1998;42:166–171. 58 Schlachter LB, Tindall GT, Pearl GS. Granular cell tumor of the pituitary gland associated with diabetes insipidus. Neurosurgery 1980;6:418–421. 59 Vaquero J, Leunda G, Cabezudo JM et al. Granular pituicytomas of the pituitary stalk. Acta Neurochir 1981;59:209–215. 60 Saeger W, Lüdecke DK, Losa M. Kombinierte neuronale und endokrine Tumoren der Sellaregion. Pathologe 1997;18:419–424. 61 Morikawa M, Tamaki N, Kokunai T, Imai Y. Intrasellar pituitary gangliocytoadenoma presenting with acromegaly: case report. Neurosurgery 1997;40:611–615. 62 Towfighi J, Salam MM, McLendon RE et al. Ganglion cell-containing tumors of the pituitary gland. Arch Pathol Lab Med 1996;120:369–377. 63 McCowen KC, Glickman JN, Black PM et al. Gangliocytoma masquerading as a prolactinoma. Case report. J Neurosurg 1999;91:490–495. 64 Horvath E, Kovacs K, Scheithauer BW et al. Pituitary adenoma with neuronal choristoma (PANCH): composite lesion or lineage infidelity? Ultrastruct Pathol 1994;18:565–574. 65 Halperin EC. Why is female sex an independent predictor of shortened overall survival after proton/photon radiation therapy for skull base chordomas? Int J Rad Oncol Biol Phys 1997;38:225–230. 66 Ulich TR, Mirra JM. Ecchordosis physaliphora vertebralis. Clin Orthopaed Rel Res 1982;163:282–289. 67 Ho KL. Ecchordosis physaliphora and chordoma: a comparative ultrastructural study. Clin Neuropathol 1985;4:77–86. 68 Mapstone TB, Kaufman B, Ratcheson RA. Intradural chordoma without bone involvement: nuclear magnetic resonance (NMR) appearance. J Neurosurg 1983;59:535–537. 69 Wolfe JT, Scheithauer BW. “Intradural chordoma” or “giant ecchordosis physaliphora”? Report of two cases. Clin Neuropathol 1987;6:98–103. 70 Perzin KH, Pushparaj N. Nonepithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx. A clinicopathologic study. XIV: Chordomas. Cancer 1986;57:784–796. 71 Walker WP, Landas SK, Bromley CM, Sturm MTM. Immunohistochemical distinction of classical and chondroid chordomas. Mol Pathol 1991;4:661–666. 72 Rosenberg AE, Brown GA, Bhan AK, Lee JM. Chondroid chordoma—a variant of chordoma. A morphologic and immunohistochemical study. Am J Clin Pathol 1994;101:36–41. 73 O’Connell JX, Renard LG, Liebsch NJ et al. Base of skull chordoma. A correlative study of histologic and clinical features of 62 cases. Cancer 1994;74:2261–2267. 74 Borba LAB, Al-Mefty O, Mrak RE, Suen J. Cranial chordomas in children and adolescents. J Neurosurg 1996;84:584–591. 75 Stepanek J, Cataldo SA, Ebersold MJ et al. Familial chordoma with probable autosomal dominant inheritance. Am J Med Genet 1998;75:335–336. 76 Weber AL, Brown EW, Hug EB, Liebsch NJ. Cartilaginous tumors and chordomas of the cranial base. Otolaryngol Clin N Am 1995;28:453–471. 77 Al-Mefty O, Borba LAB. Skull base chordomas: a management challenge. J Neurosurg 1997;86:182–189. 78 Tai PTH, Craighead P, Bagdon F. Optimization of radiotherapy for patients with cranial chordoma. A review of dose–response ratios for photon techniques. Cancer 1995;75:749–756. 79 Muthukumar N, Kondziolka D, Lunsford LD, Flickinger JC. Stereotactic radiosurgery for chordoma and chondrosarcoma: further experiences. Int J Rad Oncol Biol Phys 1998;41:387–392. 80 Gay E, Sekhar LN, Rubinstein E et al. Chordomas and chondrosarcomas of the cranial base: results and follow-up of 60 patients. Neurosurgery 1995;36: 887–897. 81 Volpe R, Mazabraud A. A clinicopathologic review of 25 cases of chordoma (a pleomorphic and metastasizing neoplasm). Am J Surg Pathol 1983;7:161–170. 82 Chambers PW, Schwinn CP. Chordoma. A clinicopathologic study of metastasis. Am J Clin Pathol 1979;72:765–776. 83 Benk V, Liebsch NJ, Munzenrider JE et al. Base of skull and cervical spine chordomas in children treated with high-dose irradiation. Int J Rad Oncol Biol Phys 1995;31:577–581. 84 Belza MG, Urich H. Chordoma and malignant fibrous histiocytoma. Evidence for transformation. Cancer 1986;58:1082–1087. 85 Fleming GF, Heimann PS, Stephens JK et al. Dedifferentiated chordoma. Response to aggressive chemotherapy in two cases. Cancer 1993;72:714–718. 86 Heffelfinger MJ, Dahlin DC, MacCarthy CS, Beabout JW. Chordomas and cartilaginous tumors at the skull base. Cancer 1973;32:410–420. 87 Angiari P, Torcia E, Botticelli RA et al. Ossifying parasellar chondroma. Case report. J Neurosurg Sci 1987;31:59–63.

Chapter 16 88 Dutton J. Intracranial solitary chondroma. Case report. J Neurosurg 1978;49:460–463. 89 Nakase H, Nagata K, Yonezawa T et al. Extensive parasellar chondroma with Ollier’s disease. Acta Neurochir 1998;140:100–101. 90 Bushe KA, Naumann M, Warmuth-Metz M et al. Maffucci’s syndrome with bilateral cartilaginous tumors of the cerebellopontine angle. Neurosurgery 1990;27:625–628. 91 Miki K, Kawamoto K, Kawamura Y et al. A rare case of Maffucci’s syndrome combined with tuberculum sellae enchondroma, pituitary adenoma and thyroid adenoma. Acta Neurochir 1987;87:79–85. 92 Eldevik OP, Blaivas M, Gabrielsen TO et al. Craniopharyngioma: radiologic and histologic findings and recurrence. Am J Neuroradiol 1996;17:1427–1439. 93 Voges J, Sturm V, Lehrke R et al. Cystic craniopharyngioma: long-term results after intracavitary irradiation with stereotactically applied colloidal b-emitting radioactive sources. Neurosurgery 1997;40:263–270. 94 De Vile CJ, Grant DB, Hayward RD, Stanhope R. Growth and endocrine sequelae of craniopharyngioma. Arch Dis Child 1996;75:108–114. 95 Azar-Kia B, Krishnan UR, Schechter MM. Neonatal craniopharyngioma. Case report. J Neurosurg 1975;42:91–93. 96 Jänisch W, Flegel HG. Kraniopahryngiom bei einem Feten. Zentralbl Allg Pathol 1989;135:65–69. 97 Lederman GS, Recht A, Loeffler JS et al. Craniopharyngioma in an elderly patient. Cancer 1987;60:1077–1080. 98 Adamson TE, Wiestler OD, Kleihues P, Yasargil MG. Correlation of clinical and pathological features in surgically treated craniopharyngiomas. J Neurosurg 1990;73:12–17. 99 Crotty TB, Scheithauer BW, Young WF et al. Papillary craniopharyngioma: a clinicopathological study of 48 cases. J Neurosurg 1995;83:206–214. 100 Sartoretti-Schefer S, Wichmann W, Aguzzi A, Valavanis A. MR differentiation of adamantinous and squamous-papillary craniopharyngiomas. Am J Neuroradiol 1997;18:77–87. 101 Weiner HL, Wisoff JH, Rosenberg ME et al. Craniopharyngiomas: a clinicopathological analysis of factors predictive of recurrence and functional outcome. Neurosurgery 1994;35:1001–1011. 102 Brodsky MC, Hoyt WF, Barnwell SL, Wilson CB. Intrachiasmatic craniopharyngioma: a rare cause of chiasmal thickening. Case report. J Neurosurg 1988;68:300–302. 103 Duff TA, Levine R. Intrachiasmatic craniopharyngioma. Case report. J Neurosurg 1983;59:176–178. 104 Kunishio K, Yamamoto Y, Sunami N et al. Craniopharyngioma in the third ventricle: necropsy findings and histogenesis. J Neurol Neurosurg Psychiatry 1987;50:1053–1056. 105 Young SC, Zimmerman RA, Nowell MA et al. Giant cystic craniopharyngiomas. Neuroradiology 1987;29:468–473. 106 Nelson GA, Bastian OF, Schlitt M, White RL. Malignant transformation in craniopharyngioma. Neurosurgery 1988;22:427–429. 107 Gonzales-Portillo G, Tomita T. The syndrome of inappropriate secretion of antidiuretic hormone: an unusual presentation for childhood craniopharyngioma. Report of three cases. Neurosurgery 1998;42:917–922. 108 Connolly ES, Winfree CJ, Carmel PW. Giant posterior fossa cystic craniopharyngiomas presenting with hearing loss. Report of three cases and review of the literature. Surg Neurol 1997;47:291–299. 109 Hintz RL. Management of craniopharyngioma. Acta Paediatr 1996;(Suppl)417: 81–82. 110 De Vile CJ, Grant DB, Kendall BE et al. Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted? J Neurosurg 1996;85:73–81. 111 Prasad D, Steiner M, Steiner L. Gamma knife surgery for craniopharyngioma. Acta Neurochir 1995;134:167–176. 112 Pollock BE, Lunsford LD, Kondziolka D et al. Phosphorus-32 intracavitary irradiation of cystic craniopharyngiomas: current technique and long-term results. Int J Rad Oncol Biol Phys 1995;33:437–446. 113 Cavalheiro S, De Castro Sparapani FV, Franco JOB et al. Use of bleomycin in intratumoral chemotherapy for cystic craniopharyngioma. J Neurosurg 1996;84:124–126. 114 Helseth A, Mørk SJ, Johansen A, Tretli S. Neoplasms of the central nervous system in Norway. IV. A population-based epidemiological study of meningiomas. Acta Pathol Microbiol Immunol Scand 1989;97:646–654. 115 Rohringer M, Sutherland GR, Louw DF, Sima AAF. Incidence and clinicopathologic features of meningioma. J Neurosurg 1989;71:665–672. 116 Nozaki K, Nagata I, Yoshida K, Kikuchi H. Intrasellar meningioma: case report and review of the literature. Surg Neurol 1997;47:447–454. 117 Zentner J, Gilsbach J. Pituitary adenoma and meningioma in the same patient: report of three cases. Eur Arch Psychiatry Neurosci 1989;238:144–148.

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118 Yamada K, Hatayama T, Ohta M, Sakoda K, Uozumi T. Coincidental pituitary adenoma and parasellar meningioma: case report. Neurosurgery 1986;19: 267–270. 119 Kasantikul V, Shuangshoti S, Phonprasert C. Intrasellar meningioma after radiotherapy for prolactinoma. J Med Assoc Thai 1988;71:524–527. 120 Kondziolka D, Levy EI, Niranjan A et al. Long-term outcomes after meningioma radiosurgery: physician and patient perspectives. J Neurosurg 1999;91:44–50. 121 Janss AJ, Grundy R, Cnaan A et al. Optic pathway and hypothalamic/ chiasmatic gliomas in children younger than age 5 years with a 6-year follow-up. Cancer 1995;75:1051–1059. 122 Collett-Solberg PF, Sernyak H, Satin-Smith M et al. Endocrine outcome in long-term survivors of low-grade hypothalamic/chiasmatic glioma. Clin Endocrinol 1997;47:79–85. 123 Sutton LN, Molloy PT, Sernyak H et al. Long-term outcome of hypothalamic/chiasmatic astrocytomas in children treated with conservative surgery. J Neurosurg 1995;83:583–589. 124 Listernick R, Charrow J. Neurofibromatosis type 1 in childhood. J Pediatr 1990;116:845–853. 125 Listernick R, Charrow J, Greenwald M, Mets M. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J Pediatr 1994;125:63–66. 126 Weinstein JM, Backonja M, Houston LW et al. Optic glioma associated with Beckwith–Wiedemann syndrome. Pediatr Neurol 1986;2:308–310. 127 Suharwardy J, Elston J. The clinical presentation of children with tumours affecting the anterior visual pathways. Eye 1997;11:838–844. 128 Listernick R, Darling C, Greenwald M et al. Optic pathway tumors in children: the effect of neurofibromatosis type 1 on clinical manifestations and natural history. J Pediatr 1995;127:718–722. 129 Pollack IF, Mulvihill JJ. Special issues in the management of gliomas in children with neurofibromatosis 1. J Neuro-Oncol 1996;28:257–268. 130 Listernick R, Louis DN, Packer RJ, Gutmann DH. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 optic pathway glioma task force. Ann Neurol 1997;41:143–149. 131 Albers GW, Hoyt WF, Forno LS, Shratter LA. Treatment response in malignant optic glioma of adulthood. Neurology 1988;38:1071–1074. 132 Hoyt WF, Meshel LG, Lessell S et al. Malignant optic glioma of adulthood. Brain 1973;96:121–132. 133 Rudd A, Rees JE, Kennedy P et al. Malignant optic nerve gliomas in adults. J Clin Neuro-Ophthalmol 1985;5:238–243. 134 Taphoorn MJB, de Vries-Knoppert WAEJ, Ponssen H, Wolbers JG. Malignant optic glioma in adults. Case report. J Neurosurg 1989;70:277–279. 135 Winer JB, Lidov H, Scaravilli F. An ependymoma involving the pituitary fossa. J Neurol Neurosurg Psychiatry 1989;52:1443–1444. 136 Nishizawa S, Yokoyama T, Hinokuma K et al. Pituitary astrocytoma: magnetic resonance and hormonal characteristics. Case illustration. J Neurosurg 1997;87:131. 137 Brat DJ, Scheithauer BW, Staugaitis SM et al. Third ventricular chordoid glioma: a distinct clinicopathologic entity. J Neuropathol Exp Neurol 1998;57:283–290. 138 Vajtai I, Varga Z, Scheithauer BW, Bodosi M. Chordoid glioma of the third ventricle: confirmatory report of a new entity. Hum Pathol 1999;30:723–726. 139 Wanschitz J, Schmidbauer M, Maier H et al. Suprasellar meningioma with expression of glial fibrillary acidic protein: a peculiar variant. Acta Neuropathol 1995;90:539–544. 140 Kretschmar CS. Germ cell tumors of the brain in children: a review of current literature and new advances in therapy. Cancer Invest 1997;15:187–198. 141 Dehner LP. Gonadal and extragonadal germ cell neoplasia of childhood. Hum Pathol 1983;14:493–511. 142 Kuratsu JI, Ushio Y. Epidemiological study of primary intracranial tumors: a regional survey in Kumamato prefecture in the Southern part of Japan. J Neurosurg 1996;84:946–950. 143 Matsutani M, Sano K, Takakura K et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 1997;86: 446–455. 144 Furukawa F, Haebara H, Hamashima Y. Primary intracranial choriocarcinoma arising from the pituitary fossa. Report of an autopsy case with literature review. Acta Pathol Jpn 1986;36:773–781. 145 Poon W, Ng HK, Wong K, South JR. Primary intrasellar germinoma presenting with cavernous sinus syndrome. Surg Neurol 1988;30:402–405. 146 Sugiyama M, Takumi I, Node Y et al. Neurohypophyseal germinoma with prolactinoma. Case illustration. J Neurosurg 1999;90:170. 147 Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985;63:155–167.

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Pituitary Tumors

148 Hoffman HJ, Otsubo H, Hendrick EB et al. Intracranial germ-cell tumors in children. J Neurosurg 1991;74:545–551. 149 Rueda-Pedraza ME, Heifetz SA, Sesterhenn IA, Clark GB. Primary intracranial germ cell tumors in the first two decades of life. A clinical, light-microscopic, and immunohistochemical analysis of 54 cases. Perspect Pediatr Pathol 1987; 10:160–207. 150 Tanabe M, Mizushima M, Anno Y et al. Intracranial germinoma with Down’s syndrome: a case report and review of the literature. Surg Neurol 1997;47: 28–31. 151 Prall JA, McGavran L, Greffe BS, Partington MD. Intracranial malignant germ cell tumor and the Klinefelter syndrome. Case report and review of the literature. Pediatr Neurosurg 1995;23:219–224. 152 Sato A, Kajita A, Sugita K et al. Cornelia de Lange syndrome with intracranial germinoma. Acta Pathol Jpn 1986;36:143–149. 153 Glenn OA, Barkovich AJ. Intracranial germ cell tumors: a comprehensive review of proposed embryologic derivation. Pediatr Neurosurg 1996;24:242–251. 154 Sano K. Pathogenesis of intracranial germ cell tumors revisited. J Neurosurg 1999;90:258–264. 155 Salzman KL, Rojiani AM, Buatti J et al. Primary intracranial germ cell tumors: clinicopathologic review of 32 cases. Pediatr Pathol Lab Med 1997;17:713–727. 156 Mootha SL, Barkovich AJ, Grumbach MM et al. Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab 1997;82:1362–1367. 157 Wolden SL, Wara WM, Larson DA et al. Radiation therapy for primary intracranial germ-cell tumors. Int J Rad Oncol Biol Phys 1995;32:943–949. 158 Ushio Y, Kochi M, Kuratsu JI et al. Preliminary observations for a new treatment in children with primary intracranial yolk sac tumor or embryonal carcinoma. Report of five cases. J Neurosurg 1999;90:133–137. 159 Rickert CH, Reznick M, Lenelle J, Rinaldi P. Shunt-related abdominal metastasis of cerebral teratocarcinoma: report of an unusual case and review of the literature. Neurosurgery 1998;42:1378–1383. 160 Sheehan T, Cuthbert RJG, Parker AC. Central nervous system involvement in haematological malignancies. Clin Lab Haematol 1989;11:331–338. 161 Jänisch W, Gerlach H, Schreiber D et al. Isolierte neoplastische Infiltrate im Zentralnervensystem bei generalisierten Non-Hodgkin-Lymphomen. Eine prospektive pathologisch-anatomische Untersuchung. Zentralbl Pathol Anat 1978;122:195–203. 162 Massé SR, Wolk RW, Conklin RH. Peripituitary gland involvement in acute leukemia in adults. Arch Pathol 1973;96:141–142. 163 Nemoto K, Ohnishi Y, Tsukada T. Chronic lymphocytic leukemia showing pituitary tumor with massive leukemic cell infiltration, and special reference to clinicopathological findings of CLL. Acta Pathol Jpn 1978;28:797–805. 164 Duchen LW, Treip CS. Microgliomatosis presenting with dementia and hypopituitarism. J Pathol 1969;98:143–146. 165 Gottfredsson M, Oury TD, Bernstein C et al. Lymphoma of the pituitary gland: an unusual presentation of central nervous system lymphoma in AIDS. Am J Med 1996;5:563–564. 166 Maiuri F. Primary cerebral lymphoma presenting as steroid-responsive chiasmal syndrome. Br J Neurosurg 1987;1:499–502. 167 Shanks JH, Harris M, Howat AJ, Freemont AJ. Angiotropic lymphoma with endocrine involvement. Histopathology 1997;31:161–166. 168 Urbanski SJ, Bilbao JM, Horvath E et al. Intrasellar plasmacytoma terminating in multiple myeloma: a report of a case including electron microscopical study. Surg Neurol 1980;14:233–236. 169 Vaquero J, Areitio E, Martinez R. Intracranial parasellar plasmacytoma. Arch Neurol 1982;39:738. 170 Bitterman P, Ariza A, Black RA et al. Multiple myeloma mimicking pituitary adenoma. Comput Radiol 1986;10:201–205. 171 Mancardi GL, Mandybur TI. Solitary intracranial plasmacytoma. Cancer 1983;51:2226–2233. 172 Juneau P, Schoene WC, Black P. Malignant tumors in the pituitary gland. Arch Neurol 1992;49:555–558. 173 Willman CL, McClain KL. An update on clonality, cytokines, and viral etiology in Langerhans cell histiocytosis. Hematol Oncol Clin N Am 1998; 12:407–416. 174 Grois NG, Favara BE, Mostbeck GH, Prayer D. Central nervous system disease in Langerhans cell histiocytosis. Hematol Oncol Clin N Am 1998;12:287–305. 175 Goldberg-Stern H, Weitz R, Zaizov R et al. Progressive spinocerebellar degeneration “plus” associated with Langerhans cell histiocytosis: a new paraneoplastic syndrome? J Neurol Neurosurg Psychiatry 1995;58:180–183. 176 Max MB, Deck MDF, Rottenberg DA. Pituitary metastasis: incidence in cancer patients and clinical differentiation from pituitary adenoma. Neurology 1981;31:998–1002.

177 Felix IA. Pathology of the neurohypophysis. Pathol Res Pract 1988;183: 535–537. 178 Roessmann U, Kaufman B, Friede RL. Metastatic lesions in the sella turcica and pituitary gland. Cancer 1970;25:478–480. 179 Schreiber D, Bernstein K, Schneider J. Tumormetastasen im Zentralnervensystem. Eine prospektive Studie. 3. Mitteilung: Metastasen in Hypophyse, Epiphyse und Plexus chorioidei. Zentralbl Allg Pathol 1986;126: 64–73. 180 McCormick PC, Post KD, Kandji AD, Hays AP. Metastatic carcinoma to the pituitary gland. Br J Neurosurg 1989;3:71–80. 181 Gurling KJ, Scott GBD, Baron DN. Metastasis in pituitary tissue removed at hypophysectomy in women with mammary carcinoma. Br J Cancer 1957; 11:519–523. 182 De la Monte SM, Hutchins GM, Moore GW. Endocrine organ metastases from breast carcinoma. Am J Pathol 1984;114:131–136. 183 Branch CL, Laws ER. Metastatic tumors of the sella turcica masquerading as primary pituitary tumors. J Clin Endocrinol Metab 1987;65:469–474. 184 Duvall J, Cullen JF. Metastatic disease in the pituitary: clinical features. Transact Ophthalmol Soc UK 1982;102:481–486. 185 Kovacs K. Metastatic cancer of the pituitary gland. Oncology 1973;27:533– 542. 186 Kattah JC, Silgals RM, Manz H et al. Presentation and management of parasellar and suprasellar metastatic mass lesions. J Neurol Neurosurg Psychiatry 1985;48:44–49. 187 Teears RJ, Silverman EM. Clinicopathologic review of 88 cases of carcinoma metastatic to the pituitary gland. Cancer 1975;36:216–220. 188 Allen EM, Kannan SR, Powell A. Infundibular metastasis and panhypopituitarism. J Natl Med Assoc 1989;81:325–330. 189 Szuwart U, König HJ, Bennefeld H et al. Klinik der hypophysären Metastasierungen. Onkologie 1988;11:66–69. 190 Losa M, Grasso M, Giugni E et al. Metastatic prostatic adenocarcinoma presenting as a pituitary mass: shrinkage of the lesion and clinical improvement with medical treatment. Prostate 1997;32:241–245. 191 Van Seters AP, Bots GTAM, van Dulken H et al. Metastasis of an occult gastric carcinoma suggesting growth of a prolactinoma during bromocriptine therapy: a case report with a review of the literature. Neurosurgery 1985;16:813–817. 192 Post KD, McCormick PC, Hays AP, Kandji AG. Metastatic carcinoma to pituitary adenoma. Report of two cases. Surg Neurol 1988;30:286–292. 193 Molinatti PA, Scheithauer BW, Randall RV, Laws ER. Metastasis to pituitary adenoma. Arch Pathol Lab Med 1985;109:287–289. 194 Richardson JF, Katayama I. Neoplasm to neoplasm metastasis. An acidophil adenoma harbouring metastatic carcinoma: a case report. Arch Pathol 1971;91:135–139. 195 Zager EL, Hedley-Whyte ET. Metastasis within a pituitary adenoma presenting with bilateral abducens palsies: case report and review of the literature. Neurosurgery 1987;21:383–386. 196 James RL, Arsenis G, Stoler M et al. Hypophyseal metastatic renal cell carcinoma and pituitary adenoma. Case report and review of the literature. Am J Med 1984;76:337–340. 197 Ramsay JA, Kovacs K, Scheithauer BW et al. Metastatic carcinoma to pituitary adenomas: a report of two cases. Exp Clin Endocrinol 1988;92: 69–76. 198 Abe T, Matsumoto K, Iida M et al. Malignant carcinoid tumor of the anterior mediastinum metastasis to a prolactin-secreting pituitary adenoma: a case report. Surg Neurol 1997;48:389–394. 199 Hurley TR, D’Angelo CM, Clasen RA et al. Adenocarcinoma metastatic to a growth-hormone secreting pituitary adenoma: case report. Surg Neurol 1992;37:361–365. 200 Hubert D, Bertin M. Tumeurs du système nerveux radio-induites chez l’homme. Bull Cancer 1993;80:971–983. 201 Brada M, Ford D, Ashley S et al. Risk of second brain tumour after conservative surgery and radiotherapy for a pituitary adenoma. Br Med J 1992;304:1343–1346. 202 Salvati E, Artico M, Caruso R et al. A report on radiation-induced gliomas. Cancer 1991;67:392–397. 203 Simmons NE, Laws ER. Glioma occurrence after sellar irradiation: case report and review. Neurosurgery 1998;42:172–178. 204 Kitanaka C, Shitara N, Nakagomi T et al. Postradiation astrocytoma. Report of two cases. J Neurosurg 1989;70:469–474. 205 Okamoto S, Handa H, Yamashita J et al. Post-irradiation brain tumors. Neurol Med Chir 1985;25:528–533. 206 Salvati M, Cervoni L, Puzzilli F et al. High-dose radiation-induced meningiomas. Surg Neurol 1997;47:435–442.

Chapter 16 207 Bhaskara Rao M, Rout D, Radhakrishnan VV. Suprasellar meningioma subsequent to treatment for a pituitary adenoma: case report. Surg Neurol 1997;47:443–446. 208 Alexander MJ, DeSalles AAF, Tomiyasu U. Multiple radiation-induced intracranial lesions after treatment for pituitary adenoma. Case report. J Neurosurg 1998;88:111–115. 209 Cahan WG. Radiation-induced sarcoma—50 years later. Cancer 1998;82:6–7. 210 Kumar PP, Good RR, Skultety FM et al. Radiation-induced neoplasms of the brain. Cancer 1987;59:1274–1282. 211 Civit T, Pinelli C, Klein M et al. Intrasellar schwannoma. Acta Neurochir 1997;139:160–161. 212 Wolfe JT, Scheithauer BW, Dahlin DC. Giant-cell tumor of the sphenoid bone. J Neurosurg 1983;59:322–327. 213 Wu KK, Ross PM, Mitchell DC, Sprague HH. Evolution of a case of multicentric giant cell tumor over a 23-year period. Clin Orthopaed Rel Res 1986;213:279–288. 214 Keel SB, Bhan AK, Liebsch NJ, Rosenberg AE. Chondromyxoid fibroma of the skull base: a tumor which may be confused with chordoma and chondrosarcoma. A report of three cases and review of the literature. Am J Surg Pathol 1997;21:577–582. 215 Shenker Y, Lloyd RV, Weatherbee L et al. Ectopic prolactinoma in a patient with hyperparathyroidism and abnormal sellar radiography. J Clin Endocrinol Metab 1986;62:1065–1069. 216 Petrus M, Mignonat M, Netter JC et al. Association épine intrasellaire et hyperprolactinémie. Ann Pediatr 1988;35:201–203. 217 Sawin PD, Follett KA, Wen BC, Laws ER. Symptomatic intrasellar hemangioblastoma in a child treated with subtotal resection and adjuvant radiosurgery. Case report. J Neurosurg 1996;84:1046–1050.

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218 Sansone ME, Liwnicz BH, Mandybur TI. Giant pituitary cavernous hemangioma. Case report. J Neurosurg 1980;53:124–126. 219 Asa SL, Kovacs K, Horvath E et al. Sellar glomangioma. Ultrastruct Pathol 1984;7:49–54. 220 Kleinschmidt-DeMasters BK, Mierau GW, Sze CI et al. Unusual dural and skull-based mesenchymal neoplasms: a report of four cases. Hum Pathol 1998;29:240–245. 221 Morrison DA, Bibby K. Sellar and suprasellar hemangiopericytoma mimicking pituitary adenoma. Arch Ophthalmol 1997;115:1201–1203. 222 Bilbao JM, Horvath E, Kovacs K et al. Intrasellar paraganglioma associated with hypopituitarism. Arch Pathol Lab Med 1978;102:95–98. 223 Aubin MJ, Hardy J, Comtois R. Primary sellar haemorrhagic melanoma: case report and review of the literature. Br J Neurosurg 1997;11:80–83. 224 Ruchti C, Balli-Antunes M, Gerber HA. Follicular tumor in the sellar region without primary cancer of the thyroid. Heterotopic carcinoma? Am J Clin Pathol 1987;87:776–780. 225 Aarabi B, Haghshenas M, Rakeii V. Visual failure caused by suprasellar extramedullary hematopoiesis in beta thalassemia: case report. Neurosurgery 1998;42:922–926. 226 Briner VA, Müller A, Gebbers JO. Die Neurosarkoidose. Schw Med Wochenschr 1998;128:799–810. 227 Sato N, Sze G, Kim JH. Cystic pituitary mass in neurosarcoidosis. Am J Neuroradiol 1997;18:1182–1185. 228 Sharma OP. Neurosarcoidosis. A personal perspective based on the study of 37 patients. Chest 1997;112:220–228.

S e c t i o n 4

Pituitary Disease in Systemic Disorders

C h a p t e r

17 Pituitary Function in Systemic Disorders Harold E. Carlson

The pituitary gland may be affected by a wide variety of systemic disorders (Table 17.1). In some instances, the pituitary is directly involved by the same processes that also afflict other organs, while in other disorders, the primary disease process has indirect, distant effects on pituitary function. DISORDERS DIRECTLY AFFECTING THE PITUITARY

Iron Overload Patients with excessive tissue iron deposits, either from idiopathic hemochromatosis, multiple transfusions, or prolonged use of pharmaceutic iron supplements, often develop hypogonadism [1–9]. Female patients appear to suffer from this complication less frequently than male, perhaps because of the protective effects of monthly menstrual blood loss. Although occasional patients appear to have primary testicular failure or hypothalamic pathology as the cause of the hypogonadism [4,5,10,11], pituitary gonadotropic insufficiency is responsible for the hypogonadism in the vast majority of cases. This conclusion is supported by findings of low basal gonadotropin levels, impaired gonadotropin responses to gonadotropin-releasing hormone (GnRH) [1,3–15], even with prolonged, pulsatile GnRH administration [9,10,13,14], and generally intact testosterone responses to human chorionic gonadotropin (hCG) stimulation [1,5,7,9,14]. In nearly all patients, the secretion of growth hormone (GH), thyrotropin (thyroid-stimulating hormone;TSH), and adrenocorticotropic hormone (ACTH) is normal [1,3–6,9,12,16], although GH deficiency has been identified in some patients with transfusion iron overload [17]. A minority of patients have a modest impairment in prolactin (PRL) secretion, primarily revealed as diminished PRL responses in stimulation tests with thyrotropinreleasing hormone (TRH) or chlorpromazine [5,6,12,18].

These findings correlate well with histochemical observations localizing pituitary iron deposits primarily to the gonadotrophs and, less frequently, to the lactotrophs [19]. Pituitary iron deposition may also be visualized radiologically; in hemochromatosis, the anterior pituitary may have abnormally low signal intensity on T1-weighted magnetic resonance (MR) images [20]. In a few cases, gonadotropin secretion and gonadal function have improved following iron depletion therapy [10,21], but in most patients pituitary function is unchanged by these procedures [9,12,13]. In children who receive multiple transfusions for thalassemia major, early intensive iron chelation therapy may prevent pituitary damage, allowing normal pubertal development to take place [1].

Sarcoidosis Sarcoid granulomas involve the central nervous system (CNS) in about 5% of cases, and there is evidence of hypothalamic or pituitary dysfunction in about one-third of these [22,23]. Anatomically, both the hypothalamus and pituitary may be affected; visual symptoms often result from involvement of the optic chiasm [22–27]. On computed tomography (CT) scanning, CNS sarcoid lesions usually show contrast enhancement, generally without surrounding edema or calcification [28,29]. The appearance of CNS sarcoid granulomas on MR scanning is more variable; the majority of lesions are hyperintense on T2-weighted images, however [29,30]. Patients with hypothalamic–pituitary involvement usually have extensive involvement of many organ systems with sarcoidosis, but occasional instances of isolated hypothalamic–pituitary disease have been reported [24,25]. Studies using provocative testing have demonstrated a high prevalence of hypothalamic dysfunction, with intact 613

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Table 17.1.

Pituitary Disease in Systemic Disorders

Systemic disorders affecting the pituitary

Direct involvement

Indirect involvement

Iron overload Sarcoidosis Wegener’s granulomatosis Tuberculosis HIV infection Syphilis Bacterial or fungal abscess Toxoplasmosis Korean hemorrhagic fever Snakebite (Russell’s viper) Langerhans’ cell histiocytosis Metastatic cancer Multiple endocrine neoplasia syndrome Polyglandular endocrine autoimmunity Amyloidosis

Any severe systemic illness Aging Obesity Diabetes mellitus Renal failure Liver disease Breast diseases (?) Primary hypothyroidism Thyrotoxicosis Hypoadrenalism Malnutrition

pituitary hormonal responses to releasing factors but impaired responses to clomiphene, metyrapone, and insulin hypoglycemia [31–34]. Hyperprolactinemia occurs [25, 32,35–39], but is not a universal finding in patients with hypothalamic–pituitary involvement [24,31–33,38]. Disturbances of water metabolism are common and include diabetes insipidus, primary polydipsia, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [22,31–35,40–42]. Other reported features of hypothalamic dysfunction have included polyphagia with morbid obesity [42] and disordered temperature regulation and vascular control [43]. Corticosteroid therapy usually does not improve hypothalamic–pituitary function, but occasional beneficial responses have been noted [32,44]. Hormone replacement therapy is given as indicated.

Wegener’s Granulomatosis A small number of patients have been reported with Wegener’s granulomatosis involving the pituitary [45,46]; in one patient, the disease was limited to this organ. Diabetes insipidus is the most common endocrine manifestation, but anterior pituitary hypofunction has also been described [45,46].

Infectious Diseases Tuberculosis has a predilection for involvement of the basilar meninges and may therefore occasionally involve tissues in the sellar region, sometimes producing anterior or posterior pituitary insufficiency [47–53]. Tuberculous meningitis may also cause SIADH [54]. Healed tuberculous meningitis,

which may be associated with deficiencies of anterior pituitary hormones, often results in calcifications visible on roentgenograms [48,49]. Syphilitic infections of the hypothalamus or pituitary are rare; they usually take the form of a gumma which may be asymptomatic or may produce local mass effects or pituitary hypofunction [49,55]. Pyogenic and fungal infections of the pituitary, usually in the form of abscesses, are rare [49,56]. Although Lyme disease may affect the central nervous system (CNS), there have been no reports of pituitary dysfunction in this condition. In the acquired immune deficiency syndrome (AIDS), the hypothalamus and pituitary may be infected with the human immunodeficiency virus (HIV) or any of a variety of opportunistic pathogens, including cytomegalovirus, Pneumocystis carinii, Cryptococcus neoformans and Toxoplasma gondii [57–60]; in one of these cases [58], pituitary function was impaired. CNS lymphomas may also involve the pituitary of AIDS patients [60]. Even in the absence of pituitary infection, functional abnormalities of the pituitary are common in AIDS, reflecting the changes accompanying any severe systemic illness (see below); these include the euthyroid sick syndrome and hypogonadotropic hypogonadism [61–66]. Occasional patients may have ACTH deficiency [67,68], GH deficiency [69], hypergonadotropic hypogonadism [70], increased gonadal function [71] and enhanced secretion of ACTH, TSH, LH, GH and PRL [72,73]. Hyponatremia due to SIADH is common and usually secondary to pulmonary or CNS pathology [62, 66,74]. It is clear that the spectrum of endocrine abnormalities in AIDS is broad, and that much more study is needed to define their pathogenesis. Korean hemorrhagic fever is a viral illness characterized by fever, hypotension, disseminated intravascular coagulation, and acute renal failure. Approximately half of the infected patients in one series developed radiologically demonstrable pituitary atrophy and decreased secretory reserve of pituitary hormones; basal pituitary secretion was usually normal. Autopsy studies have shown pituitary necrosis, apparently on a vascular basis [75]. A wide variety of viral infections causing encephalitis may occasionally result in hypothalamic–pituitary dysfunction, presumably from damage to neural structures [49].

Langerhans’ Cell Histiocytosis Langerhans’ cell histiocytosis (also known as histiocytosis X or Hand–Schuller–Christian disease) is characterized by involvement of more than one site or system by lesions composed of lipid-laden histiocytes, eosinophils, lymphocytes, and plasma cells. The hypothalamus and posterior pituitary are frequent sites of involvement, which may be demonstrated radiologically as enhancing mass lesions on CT or as bright, gadolinium-enhancing areas on MR scanning [76–81]. Diabetes insipidus (DI) is the most common endocrine disturbance, occurring in about half of the

Chapter 17

patients, followed by growth retardation (5–40%) and other anterior pituitary hormone deficiencies in a minority of subjects [79,81–83]. Hypothalamic pathology appears to be responsible for the majority of cases of GH and gonadotropin deficiency, since these patients do respond to GH-releasing hormone (GHRH) and GnRH, especially when given in repeated pulsatile doses [84–86]. Hyperprolactinemia, seen in a majority of patients, also points to a hypothalamic disturbance, and may contribute to the suppression of gonadotropins [85,87]. Although the mass effect of hypothalamic lesions may itself result in DI, there is also evidence that autoimmune factors may play a role in the condition’s pathogenesis. Scherbaum et al. [88] have detected autoantibodies to vasopressin-secreting hypothalamic cells in 54% of patients with DI due to Langerhans’ cell histiocytosis. Since the Langerhans’ cell histiocyte may function as an antigenpresenting cell, infiltration of these cells in the hypothalamus could lead to immunologically mediated destruction of vasopressin neurons [88]. Such a mechanism could conceivably account for the occurrence of DI in patients who have no hypothalamic or posterior pituitary lesions at autopsy [89]. Hormone replacement is indicated in the treatment of endocrine deficiencies in histiocytosis; corticosteroids, cytotoxic chemotherapy, and radiation therapy have rarely been effective in restoring endocrine function in patients with hypothalamic involvement [81,82,89].

Snakebite In south Asia, bites and envenomation by Russell’s viper are common. The venom contains powerful procoagulants whose action results in disseminated intravascular coagulation, while other toxins damage capillary endothelia, leading to spontaneous hemorrhage, edema, and shock. Acute renal failure is the usual cause of death [90]. Autopsy studies frequently show fibrin thrombi in the anterior pituitary, along with hemorrhage and necrosis [90], and recent investigations have documented a high prevalence of hypopituitarism in long-term survivors [91,92]. It is likely that hypopituitarism may contribute to the morbidity and mortality of the acute stage of illness in the initial hours and days postenvenomation [91,92]. Pituitary necrosis and hypopituitarism appear to be uncommon following bites of other species of poisonous snakes, with only one other case being reported following a bite by the jararacucu of Brazil [93].

Metastatic Cancer Cancer metastases have been found in the hypothalamus or pituitary in 1–12% of autopsied cancer cases [94–98]. Pituitary metastases are frequently located in the posterior lobe, which receives blood from the systemic circulation via the inferior hypophysial artery. In contrast, the anterior lobe does not have a significant direct, systemic blood supply,

Pituitary Function in Systemic Disorders

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being supplied principally by the hypothalamic–pituitary portal system. Breast and lung cancers are the most common types associated with pituitary metastases [94–99]. Most pituitary and hypothalamic metastases are asymptomatic, but about 7% result in DI and a smaller number show anterior pituitary insufficiency [99–102]. Occasionally, pituitary metastasis may be the presenting feature of an occult primary cancer [101,103,104], leading to confusion with a primary pituitary adenoma. The presence of headache, extraocular palsies and DI has been put forth as features suggesting pituitary metastasis [98,104].

Polyglandular Syndromes Pituitary tumors occur commonly in the syndrome of multiple endocrine neoplasia (MEN) type I (Werner’s syndrome), along with pancreatic islet cell tumors and parathyroid hyperplasia [105,106]. Pituitary neoplasms may also occasionally be found in patients with features of MEN type IIa (Sipple’s syndrome, consisting of medullary carcinoma of the thyroid, pheochromocytoma, and parathyroid hyperplasia); these cases have raised the concept of “overlap” syndromes [106–110]. Many of these “overlap” cases involve the cooccurrence of pheochromocytoma and acromegaly [106]; detailed examination of two of these cases has shown that the pheochromocytoma was producing GHRH and the pituitary lesion was actually somatotroph hyperplasia rather than an adenoma [106,111]. Thus, at least some of these “overlap” cases may represent an isolated pheochromocytoma with secondary pituitary hyperfunction due to production of a hormonal stimulating factor by the adrenal tumor. Similarly, other presumed cases of MEN type I have been shown to actually represent an isolated pancreatic islet cell tumor which produced GHRH, resulting in somatotroph hyperplasia and acromegaly [112]. Somatostatinproducing tumors have also been recognized with increasing frequency. As expected, patients harboring such tumors often demonstrate decreased GH responses to provocative testing [113]. Another recently described syndrome, termed the “Carney complex,” consists of myxomas, spotty mucocutaneous pigmentation, and endocrine overactivity (testicular tumors, pigmented nodular adrenocortical hyperplasia, and acromegaly). The syndrome is inherited in an autosomal dominant fashion. No other pituitary lesions have been found in the cases described to date and acromegaly has occurred in only about 10% of patients [114–118]. In polyglandular autoimmune states, clinical involvement of the pituitary is rare [119]. Lymphocytic hypophysitis, an uncommon disorder of pregnant and postpartum women, is associated in some cases with other evidence of endocrine autoimmunity [120]. Antibodies to pituitary PRL-secreting cells have been found in about 7% of patients with a variety of other endocrine autoimmune disorders, but PRL secretion was normal in most of those tested [121]. Antibodies

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to vasopressin-secreting cells have been demonstrated in 31% of patients with idiopathic central DI, many of whom had other endocrine autoimmune disease, suggesting that immune mechanisms may be important in the pathogenesis of the DI [88]. Finally, antipituitary antibodies have been found in some patients with the primary empty sella syndrome, but, to date, there has been no association with extrapituitary autoimmunity [122].

Amyloidosis Microscopic amyloid deposits are frequently seen in blood vessel walls and interstitial areas in normal human pituitaries from elderly subjects [123], and amyloid may be deposited in pituitary blood vessels in patients with systemic amyloidosis [124]. Pituitary function is usually intact, however; very few cases of hypopituitarism have been reported [125].

lished, free T4 levels are probably normal [141–143], with the fall in total T4 being produced by circulating inhibitors of T4 binding to its carrier proteins [142,144]. Normal free T4 levels would predict normal levels of TSH and, indeed, this seems to be the case in most patients [141–143]. During the recovery phase, serum TSH may be transiently mildly elevated, with a later return to normal as serum T4 normalizes [145–146]. No benefit has been shown when patients with the euthyroid sick syndrome have been treated with either T3 or T4 [147,148].

PRL Stress, injury and illness often raise serum PRL [126, 133,149], though levels return to normal with recovery.

GH

Illness, injury and stress, if sufficiently severe, produce a constellation of endocrine changes that are, in general, independent of the specific type of illness.

GH secretion is frequently stimulated by stress, injury and illness [126,131,149], though serum insulin-like growth factor-I (IGF-I) is low [150]. In cases where basal GH is only minimally elevated, GH responses to arginine infusion and insulin hypoglycemia are impaired. Normal GH dynamics return after recovery [132,151].

ACTH and Adrenal Function

Gonadotropins

With stress and illness, ACTH and cortisol secretion are increased [126–136]. Although this is, in part, due to increased release of corticotropin-releasing hormone (CRH), other factors (e.g., vasopressin, interleukin-1) may also play a role in stimulating ACTH secretion [127,135–139]. Adrenal androgen secretion is also acutely stimulated early in the course of illness but falls below normal when the illness continues for a week or more [128,129]; the adrenal androgen response to exogenous ACTH is also impaired in prolonged illness [128]. Additionally, adrenal aldosterone secretion is impaired in critical illness despite stimulation with angiotensin II [140]. Taken together, these observations suggest an adaptive adrenocortical shift in steroid production away from androgens and mineralocorticoids in order to maximize cortisol secretion.

In the initial hours of stress or surgery, there is a transient rise in serum luteinizing hormone (LH) which rapidly returns to normal [126,130,149,152]. When stress or illness continues for days to weeks, serum LH and folliclestimulating hormone (FSH) remain normal or fall to low levels, associated with a fall in serum total testosterone and free testosterone in men [130,132,152–157]; similar decreases in serum gonadotropins have been observed in women [154,156,158–160]. Controversy exists regarding the site of the defect in gonadotropin secretion with both blunted [130,160] and intact [130,132,152,153,159] gonadotropin responses to GnRH reported. These discrepancies may relate to the duration and severity of illness and to the need for repetitive GnRH stimulation to elicit gonadotropin responses in hypothalamic disorders [161]. The mechanisms producing hypogonadotropic hypogonadism during illness are unclear; possibilities include hypercortisolism and overproduction of endogenous opioids, both of which may suppress gonadotropin secretion [162–164]. A decrease in LH bioactivity may also be seen during illness [165], and may account for a fall in testosterone despite normal immunoreactive serum LH. Several authors have drawn parallels between the hypogonadism of severe illness and the euthyroid sick syndrome; indeed, the occurrence of hypogonadism seems to correlate with depressed serum thyroid hormone levels [155,159,160]. Although the mechanisms may be different, the changes in both cases may operate to conserve the body’s resources during periods of extreme stress.

GENERAL EFFECTS OF SYSTEMIC ILLNESS ON PITUITARY FUNCTION

TSH Prolonged physical stress or illness (e.g., major surgery, severe infections) results in the so-called “euthyroid sick syndrome” [130,141,142]. In its milder form, there is an alteration in the peripheral metabolism of thyroxine (T4) such that production of triiodothyronine (T3) is decreased; deiodination of reverse T3 is impaired, so its concentration rises. Serum T4 and TSH levels are normal, and T3 and reverse T3 concentrations return to normal following recovery [141,142]. In severe, usually life-threatening illness, the same changes in serum T3 and reverse T3 occur but, in addition, serum T4 falls [141,142]. Although conflicting data have been pub-

Chapter 17

PITUITARY ALTERATIONS IN SPECIFIC SYSTEMIC DISORDERS

Aging Though not strictly a disease, aging is associated with certain changes in the pituitary. Pituitary size, assessed radiologically, decreases mildly with age [166,167], although the weight of the gland is maintained [168,169]. This change in density suggests a qualitative change in the pituitary; indeed, there is a decrease in pituitary parenchymal cells with age [169] and an increase in fibrosis [170]. Most of the decrease in pituitary parenchymal cells is due to fewer and smaller somatotrophs [169]; lactotrophs change little [169,171] and gonadotrophs may be enlarged [172]. The prevalence of pituitary adenomas does not appear to change with age [173]. Functional changes also occur. The most dramatic, of course, is the loss of ovarian function at the menopause, with a consequent elevation of serum LH and FSH due to activation of normal feedback mechanisms. Similar changes, albeit more gradual and of lesser magnitude, take place in many normal elderly men, in whom some degree of primary testicular failure develops, with feedback elevations of serum gonadotropins [165,174–177]; elderly men who are in particularly good health may have a lower prevalence of testicular failure [177,178]. In addition to increases in serum immunoreactive gonadotropins, there is also evidence for diminished LH and FSH bioactivity in elderly men [169,179]. This cannot be the only cause of decreased serum testosterone levels, however, because testicular responsiveness to hCG is also decreased [177]. Spontaneous LH pulsatility is intact in elderly men [180–182], but the peak LH response to bolus injections of GnRH is delayed, and serum LH is in the normal range in many hypogonadal elderly men, suggesting an alteration in hypothalamic function [180,182,183]. Gonadotropin suppressibility by sex steroids is either normal [184] or enhanced [181]. The only firm conclusion that can be drawn at present is that aging men suffer a variable degree of hypogonadism. Data on the finer points of gonadotropin regulation are frequently contradictory, due, at least in part, to the confounding effects of increasing adiposity and concurrent illnesses [180]. GH secretion also declines with age, and 24-hour integrated serum GH concentrations are reduced in elderly subjects. This is primarily due to a reduction in the amplitude and duration of GH secretory pulses, especially those occurring during sleep [175,185]. As a consequence, serum IGF-I and GH-dependent IGF binding proteins are also decreased [185–187]. It is not clear whether the primary defect in GH secretion is at the hypothalamic or pituitary level, since GH responses in the elderly to insulin hypoglycemia, arginine, and L-dopa have been reported to be either normal [188,189] or reduced [190,191]. GH responses to GHRH have been shown to be reduced in the elderly [192–195], although the changes did not always reach statistical significance [195]. Consistent with this

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finding, the number and size of somatotrophs in the pituitary has been shown to be reduced in aged subjects [169]. These findings could be explained either by a chronic decrease in endogenous GHRH, an increase in somatostatin tone, or a primary pituitary process, independent of hypothalamic regulatory factors. There are few data bearing on this point; an interesting observation, however, has been that patients with early onset Alzheimer’s dementia, who are believed to have decreased somatostatin production [196], have larger GH responses to GHRH than nondemented elderly subjects [197]. IGF-I responses to either endogenous or exogenous GH are intact in the elderly [195,198–200]. It has been suggested that decreased GH secretion and decreased serum IGF-I are causally related to the decrease in lean body mass and increase in adiposity seen with aging [198]. In a therapeutic trial, administration of recombinant biosynthetic human GH to elderly men for 6 months normalized serum IGF-I levels, increased lean body mass, decreased adipose tissue mass, and produced a small increase in vertebral bone density [198]. Despite these apparent benefits, small but significant increases in blood pressure, serum insulin, and blood glucose concentrations in subjects given GH do raise questions about the safety of its long-term administration to wide segments of the adult population. There is also a theoretical concern that increased GH or IGF-I could promote the development or progression of neoplasia. Basal serum PRL concentrations are probably changed little with aging, as are PRL responses to various secretagogues [175,201], although individual studies have reported decreased, increased, or unaltered responses. Major confounding effects of illness, drugs, and decreased gonadal function may account for these discrepant results. With aging, serum T3 levels fall modestly while serum T4 remains nearly stable [175,202–204]; in most studies, serum TSH increases slightly with advancing age [175,202,203]. The rise in average TSH levels may be due to a high prevalence of autoimmune thyroid failure, however; if subjects with positive antithyroid antibodies are excluded from consideration, average TSH levels actually fall with aging [204]. Most studies agree that the TSH response to TRH is diminished in the elderly [175]. In the absence of disease, the pituitary–adrenal axis appears to be generally intact in the elderly; minimal changes in plasma cortisol and ACTH are seen, and the ACTH and cortisol responses to CRH are intact [175,176,205]. In contrast, both basal and stimulated plasma levels of dehydroepiandrosterone (DHEA) and DHEA-sulfate are markedly diminished in elderly subjects [176,205–207].

Obesity Several aspects of pituitary function are altered in obesity. Most dramatic is the decrease in GH secretion. Both spontaneous and stimulated GH secretion are markedly blunted [208–210], and are improved following weight loss. The

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neuroendocrine mechanism underlying decreased GH secretion in obesity is unknown, although increased hypophysial somatostatinergic tone has been suggested [210]. Despite decreased GH secretion, serum IGF-I levels are generally within the normal range [211,212], although perhaps somewhat lower than age-matched subjects of normal weight [185,213]. Upper-body obesity, in particular, may be important in lowering serum IGF-I, and may involve interrelationships between sex steroids, insulin, and IGF-binding proteins [214]. PRL secretion is minimally altered in obesity. Basal and 24-hour integrated PRL levels are normal in obese subjects [208,209], although PRL responses to a variety of pharmacologic agents (TRH, dopamine antagonists) are moderately blunted in obesity [180,181]. Although most of these responses improve after weight loss [209], the blunted PRL response to insulin-induced hypoglycemia persists, suggesting an intrinsic hypothalamic abnormality [215,216]. As with lowering of serum IGF-I levels, upper-body obesity may be particularly important in blunting PRL responses to these stimuli [217]. In most obese men, testicular function is normal. Serum testosterone may be low, however, due to reduced concentrations of its carrier protein, sex hormone-binding globulin [209,218,219]; free testosterone concentrations are usually normal [209,218]. In these men, basal serum LH and FSH are normal, as are gonadotropin responses to GnRH and clomiphene [209]. In some extremely obese men, however, even free testosterone is depressed [209,220]; this appears to be due to suppression of LH by excessive estrogens produced by aromatization of androgens in adipose tissue [209,221]. In such men, administration of dexamethasone suppresses adrenal androgen production with a consequent decrease in serum estrogens and a rise in gonadotropin secretion [222]. Weight loss restores these parameters to or toward normal [209,223,224]. Obese postmenopausal women also have increased aromatization of androgens to estrogens in adipose tissue. Obese premenopausal women, especially those with upper-body obesity, may suffer from hyperandrogenism, increased serum LH, and the polycystic ovary syndrome [209]. Serum concentrations of thyroid hormones and TSH are normal in obesity, both basally and following stimulation by TRH [209]. Likewise, serum cortisol, urinary free cortisol, and plasma ACTH are normal in obese subjects, as are the adrenal response to ACTH and ACTH responses to CRH [209,225].

Diabetes Mellitus A variety of pituitary abnormalities have been reported in diabetics. Infarction of the adenohypophysis may occur without antecedent hypotension, and may lead to hypopituitarism [226]. Functional abnormalities may also occur in the absence of anatomic changes; many of these reports have been contradictory, with normal, increased or decreased

responses to various stimulation tests recorded [227,228]. The most consistent abnormality has been an elevation of basal serum GH in poorly controlled diabetics [229,230]; most [229] but not all [231] investigators have found that basal GH returns to normal when the diabetes is better controlled. Despite the chronic hyperglycemia, GH responses to provocative stimuli are generally intact in diabetes [229]. Serum IGF-I and IGF-II are decreased in poorly controlled diabetics and normalize with improved diabetic control [232,233]. It has been suggested that GH excess may be, in part, responsible for poor glucose control in some diabetics—in particular, for early morning hyperglycemia (the “dawn phenomenon”) [234]; pharmacologic suppression of GH secretion has produced improvements in glycemic control [235].

Renal Failure A host of endocrine abnormalities occur in uremia; many affect the pituitary. Basal serum GH is elevated in uremia [236] and GH regulation is disturbed, with diminished responses to hypoglycemia [237–239], exaggerated responses to L-dopa and GHRH [237,240] and paradoxical GH responses to TRH and hyperglycemia [237,241]. Serum IGF-I concentrations are probably normal in uremic plasma [242], but somatomedin bioactivity is decreased due to the presence of circulating inhibitors [243]. Serum PRL is modestly increased in many uremic patients, due principally to increased hormone secretion rather than decreased PRL clearance [244]. It persists despite dialysis, but is reversed by successful renal transplantation [244]. PRL bioactivity may be low [245] or normal [246] in uremia. Hyperprolactinemia may contribute to disordered sexual functioning in uremia. Hypogonadism is common in uremia and probably multifactorial in origin; gonadal function is not improved by dialysis, but is usually normalized by renal transplantation [244]. There is evidence for both central and gonadal defects in the pathogenesis of uremic hypogonadism. In most patients, serum gonadotropins are normal or elevated, with a normal or blunted response to GnRH; testicular responsiveness to hCG is also blunted [244]. The pituitary–thyroid axis is mildly deranged in uremia. Thyroid hormone concentrations are normal or low, and serum TSH is normal [141,247,248]. Conversion of T4 to T3 is decreased, although reverse T3 levels are normal [247]. The serum TSH response to TRH is depressed and delayed [247]. In general, the changes seen in uremia resemble those seen in the “euthyroid sick” syndrome, with the exception of the normal serum reverse T3 level [141,247,248]. Dialysis has little effect on the disordered thyroid function, but renal transplantation may correct most of the defects; residual abnormalities persisting after transplantation may be due to the effects of immunosuppressive therapy [141,247]. The hypothalamic–pituitary–adrenal axis is probably basically intact in renal failure, with normal serum concentra-

Chapter 17

tions of cortisol and a normal diurnal rhythm [244,249,250]. Nevertheless, a prolonged half-life of cortisol in the serum, coupled with accelerated degradation and poor oral absorption of dexamethasone results in incomplete suppressibility of cortisol in uremia [250,251]; measurements of serum dexamethasone can insure a valid test.

Liver Disease Chronic liver disease produces a wide variety of endocrine disturbances. In patients with cirrhosis, basal serum GH is increased, and paradoxical increases in GH are observed following glucose ingestion or TRH administration [252–255]. These features appear to be independent of the etiology or structural changes seen in liver disease, as they may be observed with alcoholic fatty liver [254], alcoholic cirrhosis [252,254,255], schistosomal hepatic fibrosis [255], primary biliary cirrhosis, and primary sclerosing cholangitis [253]. Portosystemic shunting rather than parenchymal cell damage may be important in the pathogenesis of disordered GH regulation [255]. Serum levels of IGF-I are depressed in patients with chronic liver disease [255–257]; reduced negative feedback effects of IGF-I on GH secretion may contribute to the disordered GH regulation, as may changes in brain neurotransmitters that occur as a result of altered amino acid metabolism [258]. The abnormalities of GH secretion appear to return toward normal after successful liver transplantation, although the effects of immunosuppressive drugs and residual encephalopathy complicate interpretation of the data [253]. Thyroid hormone measurements are altered in patients with most chronic liver diseases, primarily as a consequence of changes in peripheral thyroid hormone metabolism. Thus, serum T3 is usually reduced and serum reverse T3 elevated in cirrhosis, while serum T4 is generally normal and serum TSH normal or mildly elevated [141,259,260]. This picture of the “euthyroid sick” syndrome appears to be related to the degree of hepatocyte dysfunction and is not a feature of portosystemic shunting [261]. Independent of liver damage, ethanol may have a toxic effect on the thyroid, resulting in shrinkage and fibrosis of the gland [262,263]. In contrast to alcoholic cirrhosis, patients with infectious hepatitis, chronic active hepatitis, and primary biliary cirrhosis may have elevated serum levels of thyroxine-binding globulin, thereby raising total serum T4 and T3, although free hormone levels and serum TSH are usually normal [141,260]. The pituitary–adrenal axis is altered minimally in cirrhosis. Serum concentrations of corticosteroid-binding globulin are often decreased, and the serum half-life of both cortisol and dexamethasone are prolonged in cirrhotics, apparently as a consequence of hepatic parenchymal damage [251,264]. The pulsatility of cortisol secretion may be slightly diminished in cirrhosis [264]. Gonadal function and gonadotropin secretion are altered in patients with cirrhosis; many of the changes appear to

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correlate with the degree of liver dysfunction, although some may be specifically due to the toxic effects of ethanol on the testis. Men with advanced cirrhosis usually have decreased serum concentrations of total and free testosterone; estradiol is normal or mildly increased, and estrone considerably increased. The increased estrogen concentrations are primarily a consequence of increased peripheral aromatization of androgens (especially androstenedione) rather than decreased hepatic removal. Serum LH is normal or moderately elevated [265–274]. It has been argued that the failure of LH to rise substantially in the face of low free testosterone concentrations suggests concurrent hypothalamic– pituitary dysfunction [275]; however, these findings may be due to the gonadotropin suppressing effects of elevated serum estradiol, estrone, and other estrogen metabolites (e.g., 16-hydroxy-estrone) [276]. Seminiferous tubule damage may be seen in cirrhotics and alcoholics, with a rise in serum FSH concentrations [266,267,273,277]. Gonadotropin responses to GnRH are generally intact [267, 277,278], as are testosterone responses to hCG [266, 277,278]; responses to clomiphene have been variable [266, 279]. Additional factors that may be operative in alcoholics include increased peripheral aromatase (which might include the pituitary and hypothalamus, although this is speculative), increased tissue responsiveness to estrogens, altered hypothalamic–pituitary metabolism of estrogens, and the presence in many alcoholic beverages of plant-derived phytoestrogens [280,281]. Premenopausal women with alcoholic liver disease have lower serum estradiol but higher serum estrone levels than healthy women, again presumably due to alterations in peripheral steroid metabolism. Gonadotropin concentrations are normal or low, and respond normally to GnRH [282, 283]. Thus, in summary, gonadal function is depressed in cirrhotics, and further worsened by alcoholism [266,272,279]. There is partial reversal of these abnormalities following liver transplantation [274]. Serum PRL is sometimes mildly elevated in cirrhotic patients [267,273,283–287]; this may reflect the potentiating effects of estrogens on PRL release plus disordered hypothalamic neurotransmitter function [287].

Breast Diseases The mean serum PRL level in women with fibrocystic breast disease is modestly higher than in control women, though usually in the normal range [288–293]. PRL may possibly play a role in the pathogenesis of benign breast disease, since some fibrocystic breast tissue contains PRL receptors [294] and suppression of PRL with bromocriptine may result in clinical improvement [295,296]. Nearly all studies reporting a tendency to higher serum PRL levels in benign breast disease are flawed, however, by the failure to match subjects for parity; two studies have shown that a first pregnancy is associated with a permanent 50% fall in basal serum PRL [297,298]. It is also not clear whether higher

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levels of serum PRL cause fibrocystic breast disease or result from it via a nerual reflex arc linking thoracic wall or nipple stimulation to increased PRL secretion [299,300]. Additionally, mild hyperprolactinemia could be merely a marker of increased estrogen effect on the pituitary. The relationship of PRL to human breast cancer remains controversial [298,301–303]. Nevertheless, several authors have reported minimal to modest increases in serum PRL in some breast cancer patients, their relatives, or patients believed to be at high risk for breast cancer [289,304–309]. Again, some of these studies did not control for parity, an important factor since serum PRL concentrations are reset at a lower level following the first pregnancy [297,298]. Additionally, thoracic nerve irritation from cancer deposits or from surgery could also play a role in the patients, though not in their relatives.

Hypothyroidism Besides elevating serum TSH concentrations, primary hypothyroidism may have other effects on the pituitary. Activation of the thyrotrophs by loss of thyroid hormone negative feedback may result in thyrotroph hyperplasia, sometimes sufficient to mimic a pituitary tumor [310–317]. Moderate hyperprolactinemia (usually less than 100 ng/ml) is occasionally seen, generally in patients with severe hypothyroidism [310–313,315,317–322]; the mechanism is unclear, but may involve an increase in TRH [323]. GH synthesis is decreased, and its secretion blunted, both spontaneously and in response to provocative testing [324–326]. Although cortisol turnover is decreased, serum cortisol and ACTH concentrations are generally normal [326]. Gonadotropin secretion is usually normal in hypothyroid adults; some, but not all, men with severe primary hypothyroidism may have hypergonadotropic hypogonadism which is correctable with thyroxine therapy [327,328]. Severely hypothyroid children may experience precocious puberty associated with elevated serum FSH levels [329,330].

Hyperthyroidism TSH secretion is suppressed by negative feedback in patients with thyroid hormone excess. In addition, PRL response to TRH or DA antagonists are usually blunted in hyperthyroidism, though the basal serum PRL level is normal [331–335]. Serum gonadotropin concentrations are frequently mildly elevated in hyperthyroid patients [328,336,337]. GH secretion is normal or blunted [338].

Adrenal Insufficiency In addition to the expected feedback elevation of ACTH secretion, patients with primary adrenal insufficiency may have elevations in serum TSH and PRL levels. Although this is often due to coexistent primary hypothyroidism, in some patients the elevations in TSH and PRL appear to be related

to glucocorticoid deficiency, and fall rapidly with cortisol replacement therapy [339–344].

Malnutrition Malnutrition impairs production of IGF-I [257,345,346], and is often associated with increased basal GH secretion, perhaps due to decreased negative feedback [326,347–352]; additionally, paradoxical increases in GH may be seen following glucose loading or TRH administration [348,349,353]. Basal serum PRL concentrations are usually not altered by fasting or malnutrition, but the PRL response to TRH may be diminished or modestly increased [354–356] or unchanged [357–359]. ACTH and cortisol secretion are unchanged [351,352,358,360–365]. Starvation or severe carbohydrate restriction induces the “euthyroid sick” syndrome, often accompanied by a slight decrease in basal and TRH-stimulated TSH secretion [141,142,351,352,357–359,366]. The timing of the TRHinduced TSH peak is delayed [352]. Changes in gonadotropin secretion induced by nutrition have been more variable; hypogonadism is frequently seen in states of prolonged decreases in calorie intake. However, although most studies have reported normal or decreased serum gonadotropins [352,260–362,367–371], others report increased serum gonadotropin concentrations [372]. These differences may reflect varying prevalences of specific nutrient deficiencies, initial body weight, and concurrent illness. The gonadotropin response to GnRH is, on balance, probably normal [352,367–369], although the LH peak may be delayed [352] and the ratio of FSH to LH responses may be increased. Taken together, these findings suggest a primary hypothalamic abnormality in malnutrition- or fasting-induced pituitary hormone changes. REFERENCES 1 Bronspiegel-Weintrob N, Olivieri NF, Tyler B et al. Effect of age at the start of iron chelation therapy on gonadal function in b-thalassemia major. N Engl J Med 1990;323:713–719. 2 Bezwoda WR, Bothwell TH, Van Der Walt LA et al. An investigation into gonadal dysfunction in patients with idiopathic hemochromatosis. Clin Endocrinol 1977;6:377–385. 3 Schafter Al, Cheron RG, Dluhy R et al. Clinical consequences of acquired transfusional iron overload in adults. N Engl J Med 1981;304:319–324. 4 Charbonnel B, Chupin M, LeGrand A, Guillon J. Pituitary function in idiopathic haemochromatosis: hormonal study in 36 male patients. Acta Endocrinol 1981;98:178–183. 5 McNeil LW, McKee LC Jr, Lorber D, Rabin D. The endocrine manifestations of hemochromatosis. Am J Med Sci 1983;285:7–13. 6 Walton C, Kelly WF, Laing I, Bu’lock DE. Endocrine abnormalities in idiopathic haemochromatosis. Q J Med 1983;52:99–110. 7 Kley HK, Stremmel W, Niederau C et al. Androgen and estrogen response to adrenal and gonadal stimulation in idiopathic hemochromatosis: evidence for decreased estrogen formation. Hepatology 1985;5:251–256. 8 Stremmel W, Niederau C, Berger M et al. Abnormalities in estrogen, androgen, and insulin metabolism in idiopathic hemochromatosis. Ann NY Acad Sci 1988;526:209–223. 9 Wang C, Tso SC, Todd D. Hypogonadotropic hypogonadism in severe b-thalassemia: effect of chelation and pulsatile gonadotropin-releasing hormone therapy. J Clin Endocrinol Metab 1989;68:511–516.

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42 Vesely DL. Hypothalamic sarcoidosis: a new cause of morbid obesity. South Med J 1989;82:758–761. 43 Wathen CG, Campbell I, Douglas AC. Hypothalamic malfunction in cerebral sarcoidosis with abnormalities in temperature regulation and vascular control. Sarcoidosis 1988;5:74–76. 44 Shealy CN, Kahana L, Engel FL, McPherson HT. Hypothalamic–pituitary sarcoidosis. A report on four patients, one with prolonged remission of diabetes insipidus following steroid therapy. Am J Med 1961;30:46–55. 45 Rosete A, Cabral AR, Kraus A, Alarcon-Segovia D. Diabetes insipidus secondary to Wegener’s granulomatosis: report and review of the literature. J Rheumatol 1991;18:761–765. 46 Roberts GA, Eren E, Sinclair H et al. Two cases of Wegener’s granulomatosis involving the pituitary. Clin Endocrinol 1995;42:323–328. 47 Flannery MT, Pattani S, Wallach PM, Warner E. Case report: hypothalamic tuberculoma associated with secondary panhypopituitarism. Am J Med Sci 1993;306:101–103. 48 Lanigan CJ, Buckley MP. Adult panhypopituitarism with normal stature following tuberculous meningitis: a case report. Irish Med J 1983;76:353–354. 49 Berger SA, Edberg SC, David G. Infectious disease in the sella turcica. Rev Infect Dis 1986;8:747–755. 50 Esposito V, Fraioli B, Ferrante L, Palma L. Intrasellar tuberculoma: case report. Neurosurgery 1987;21:721–723. 51 Garg SK, Bandyopadhyay PK, Dash RJ. Hypogonadotropic hypogonadism. An unusual complication of tuberculous meningitis. Trop Geogr Med 1987;39:296–298. 52 Delsedime M, Aguggia M, Cantello R et al. Isolated hypophyseal tuberculoma: case report. Clin Neuropathol 1988;7:311–313. 53 Petrossians P, Delvenne P, Flandroy P et al. An unusual pituitary pathology. J Clin Endocrinol Metab 1998;83:3454–3458. 54 Smith J, Godwin-Austen R. Hypersecretion of anti-diuretic hormone due to tuberculous meningitis. Postgrad Med J 1980;56:41–44. 55 Fink EB. Gumma of the hypophysis and hypothalamus. Arch Pathol 1933;15:631–635. 56 Bevan JS, Burke CW, Esiri MM, Adams CBT. Misinterpretation of prolactin levels leading to management errors in patients with sellar enlargement. Am J Med 1987;82:29–33. 57 Ferreiro J, Vinters HV. Pathology of the pituitary gland in patients with the acquired immune deficiency syndrome (AIDS). Pathology 1988;20:211–213. 58 Milligan SA, Katz MS, Craven PC et al. Toxoplasmosis presenting as panhypopituitarism in a patient with the acquired immune deficiency syndrome. Am J Med 1984;77:760–764. 59 Sano T, Kovacs K, Scheithauer BW et al. Pituitary pathology in acquired immunodeficiency syndrome. Arch Pathol Lab Med 1989;113:1066–1070. 60 Mosca L, Costanzi G, Antonacci C et al. Hypophyseal pathology in AIDS. Histol Histopathol 1992;7:291–300. 61 Dobs AS, Dempsey MA, Ladenson PW, Polk BF. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med 1987; 84:611–616. 62 Aron DC. Endocrine complications of the acquired immunodeficiency syndrome. Arch Intern Med 1989;149:330–333. 63 Tang WW, Kaptein EM. Thyroid hormone levels in the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. West J Med 1989;151:627–631. 64 Lo Presti JS, Fried JC, Spencer CA, Nicoloff JT. Unique alternations of thyroid hormone indices in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989;110:970–975. 65 Raffi F, Brisseau J-M, Planchon B et al. Endocrine function in 98 HIVinfected patients: a prospective study. AIDS 1991;5:729–733. 66 Sellmeyer DE, Grunfeld C. Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev 1996;17:518–532. 67 Membreno L, Irony I, Dere W et al. Adrenocortical function in acquired immunodeficiency syndrome (AIDS). J Clin Endocrinol Metab 1987; 65:482–487. 68 Root RK, Biglieri EG. Adrenocortical function in the acquired immunodeficiency syndrome (AIDS). West J Med 1988;148:70–73. 69 Ng TTC, O’Connel IPM, Wilkins EGL. Growth hormone deficiency coupled with hypogonadism in AIDS. Clin Endocrinol 1994;41:689–694. 70 Croxson TS, Chapman WE, Miller LK et al. Changes in the hypothalamic–pituitary–gonadal axis in human immunodeficiency virusinfected homosexual men. J Clin Endocrinol Metab 1989;68:317–321. 71 Merenich JA, McDermott MT, Asp AA et al. Evidence of endocrine involvement early in the course of human immunodeficiency virus infection. J Clin Endocrinol Metab 1990;70:566–571.

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72 Lortholary O, Christeff N, Casassus P et al. Hypothalamo–pituitary–adrenal function in human immunodeficiency virus-infected men. J Clin Endocrinol Metab 1996;81:791–796. 73 Wilson LD, Truong MPM, Barber AR, Aoki TT. Anterior pituitary and pituitary-dependent target organ function in men infected with the human immunodeficiency virus. Metabolism 1996;45:738–746. 74 Agarwal A, Soni A, Ciechanowsky M et al. Hyponatremia in patients with the acquired immunodeficiency syndrome. Nephron 1989;53:317–321. 75 Lim TH, Chang KH, Han MC et al. Pituitary atrophy in Korean (epidemic) hemorrhagic fever: CT correlation with pituitary function and visual field. AJNR 1986;7:633–637. 76 Tien RD, Newton TH, McDermott MW et al. Thickened pituitary stalk on MR images in patients with diabetes insipidus and Langerhans cell histiocytosis. AJNR 1990;11:703–738. 77 Maghnie M, Arico M, Villa A et al. MR of the hypothalamic–pituitary axis in Langerhans cell histiocytosis. AJNR 1992;13:1365–1371. 78 Maghnie M, Genovese E, Arico M et al. Evolving pituitary hormone deficiency is associated with pituitary vasculopathy: dynamic MR study in children with hypopituitarism, diabetes insipidus, and Langerhans cell histiocytosis. Radiology 1994;193:493–499. 79 Egeler RM, D’Angio GJ. Langerhans cell histiocytosis. J Pediatr 1995; 127:1–11. 80 Maghnie M, Bossi G, Klersy C et al. Dynamic endocrine testing and magnetic resonance imaging in the long term follow-up of childhood Langerhans cell histiocytosis. J Clin Endocrinol Metab 1998;83:3089–3094. 81 Grois NG, Favara BE, Mostbeck GH, Prayer D. Central nervous system disease in Langerhans cell histiocytosis. Hematol Oncol Clin N Am 1998;12:287–305. 82 Dunger DB, Broadbent V, Yeoman E et al. The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis. N Engl J Med 1989;321:1157–1162. 83 Dean HJ, Bishop A, Winter JS. Growth hormone deficiency in patients with histiocytosis X. J Pediatr 1986;109:615–618. 84 Rothman JG, Snyder PJ, Utiger RD. Hypothalamic endocrinopathy in Hand–Schuller–Christian disease. Ann Intern Med 1978;88:512–513. 85 Langer A, Fettes I. Multifocal eosinophilic granuloma with a pituitary stalk lesion. West J Med 1985;142:829–831. 86 Gelato MC, Loriaux DL, Merriam GR. Growth hormone responses to growth hormone-releasing hormone in Hand–Schuller–Christian disease. Neuroendocrinology 1989;50:259–264. 87 Nishio S, Mizuno J, Barrow DL et al. Isolated histiocytosis X of the pituitary gland: case report. Neurosurgery 1987;21:718–721. 88 Scherbaum WA, Wass JAH, Besser GM et al. Autoimmune cranial diabetes insipidus: its association with other endocrine diseases and with histiocytosis X. Clin Endocrinol 1986;25:411–420. 89 Gramatovici R, D’Angio GJ. Radiation in soft-tissue lesions in histiocytosis X (Langerhans’ cell histiocytosis). Med Ped Oncol 1988;16:259–262. 90 Than-Than, Francis N, Tin-Nu-Swe et al. Contribution of focal haemorrhage and microvascular fibrin deposition of fatal envenoming by Russell’s viper (Vipera russelli siamensis) in Burma. Acta Trop 1989;46:23–38. 91 Tun-Pe, Warrell DA, Tin-Nu-Swe et al. Acute and chronic pituitary failure resembling Sheehan’s syndrome following bites by Russell’s viper in Burma. Lancet 1987;ii:763–767. 92 Proby C, Tha-Aung, Thet-Win et al. Immediate and long-term effects on hormone levels following bites by the Burmese Russell’s viper. Q J Med 1989;75:399–411. 93 Milani R, Jorge MT, Ferraz de Campos FP et al. Snake bites by the jararacucu (Bothrops jararacussu): clinico pathological studies of 29 proven cases in Sao Paulo state, Brazil. Q J Med 1997;90:323–334. 94 Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma—analysis of 1000 autopsied cases. Cancer 1950;3:74–85. 95 Kovascs K. Metastatic cancer of the pituitary gland. Oncology 1973; 27:533–542. 96 Delarue J, Chomette G, Pinaudeau Y et al. Les metastases hypophysairesfrequence-etude histopathologique. Arch Anat Pathol 1964;12:179–182. 97 Hagerstrand I, Schonebeck J. Metastases to the pituitary gland. Acta Pathol Microbiol Scand 1969;75:64–70. 98 Max MB, Deck MDF, Rottenberg DA. Pituitary metastasis: incidence in cancer patients and clinical differentiation from pituitary adenoma. Neurology 1981;8:998–1002. 99 Teears RJ, Silverman EM. Clinicopathologic review of 88 cases of carcinoma metastatic to the pituitary gland. Cancer 1975;36:216–220. 100 Nugent JL, Bunn PA Jr, Matthews MJ et al. CNS metastases in small cell bronchogenic carcinoma. Cancer 1979;44:1885–1893.

101 Chiang M-F, Brock M, Patt S. Pituitary metastases. Neurochirurgia 1990; 33:127–131. 102 Mayr NA, Yuh WTC, Muhonen MG et al. Pituitary metastases: MR findings. J Comput Assist Tomogr 1993;17:432–437. 103 Buonaguidi R, Ferdeghini M, Faggionato F, Tusini G. Intra-sellar metastasis mimicking a pituitary adenoma. Surg Neurol 1983;20:373–378. 104 Branch CL Jr, Laws ER Jr. Metastatic tumors of the sella turcica masquerading as primary pituitary tumors. Clin Endocrinol Metab 1987;65:469–474. 105 Ballard HS, Frame B, Hartsock RJ. Familial multiple endocrine adenoma–peptic ulcer complex. Medicine 1964;43:481–516. 106 Scheithauer BW, Laws ER Jr, Kovacs K et al. Pituitary adenomas of the multiple endocrine neoplasia type I syndrome. Sem Diag Pathol 1987; 4:205–211. 107 Alberts MW, McMeekin JO, George JM. Mixed multiple endocrine neoplasia syndromes. JAMA 1980;244:1236–1237. 108 Myers JH, Eversman JJ. Acromegaly, hyperparathyroidism, and pheochromocytoma in the same patient. A multiple endocrine disorder. Arch Intern Med 1981;141:1521–1522. 109 Anderson RJ, Lufkin EG, Sizmore GW et al. Acromegaly and pituitary adenoma with pheochromocytoma: a variant of multiple endocrine neoplasia. Clin Endocrinol 1981;14:605–612. 110 Bertrand J-H, Ritz P, Reznik Y et al. Sipple’s syndrome associated with a large prolactinoma. Clin Endocrinol 1987;27:607–614. 111 Roth KA, Wilson DM, Eberwine J et al. Acromegaly and pheochromocytoma: a multiple endocrine syndrome caused by a plurihormonal adrenal medullary tumor. J Clin Endocrinol Metab 1986;63:1421–1426. 112 Thorner MO, Perryman RL, Cronin MJ et al. Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet cell tumor secreting a growth hormone-releasing factor. J Clin Invest 1982;70:965–977. 113 Berelowitz, M. Somatostatin-producing tumors. In: Patel YC, Tannenbaum GS, eds. Somatostatin. New York: Plenum Publishing, 1985:475–487. 114 Carney JA, Gordon H, Carpenter PC et al. The complex of myxomas, spotty pigmentation and endocrine overactivity. Medicine 1985;64:270–283. 115 Carney JA, Hruska LS, Beauchamp GD, Gordon H. Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Mayo Clin Proc 1986;61:165–172. 116 Leedman PJ, Cohen AK, Matz LR. The complex of myxomas, spotty pigmentation and endocrine overactivity. Clin Endocrinol 1986;25:527–534. 117 Danoff A, Jormark S, Lorber D, Fleischer N. Adrenocortical micronodular dysplasia, cardiac myxomas, lentigines, and spindle cell tumors. Report of a kindred. Arch Intern Med 1987;147:443–448. 118 Carney JA. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Arch Intern Med 1987;147:418–419. 119 Meyerson J, Lechuga-Gomez EE, Bigazzi PE, Walfish PC. Polyglandular autoimmune syndrome: current concepts. Can Med Assoc J 1988;138:605–612. 120 Cosman F, Post KD, Holub DA, Wardlaw SL. Lymphocytic hypophysitis. Report of 3 new cases and review of the literature. Medicine 1989;68:240–256. 121 Bottazzo GF, Florin-Christensen A, Pouplard A, Doniach D. Autoantibodies to prolactin-secreting cells of human pituitary. Lancet 1975;ii:97–101. 122 Komatsu M, Kondo T, Yamauchi K et al. Antipituitary antibodies in patients with the primary empty sella syndrome. J Clin Endocrinol Metab 1988;67:633–638. 123 Storkel S, Bohl J, Schneider H-M. Senile amyloidosis: principles of localization in a heterogeneous form of amyloidosis. Virchows Arch (Pathol Anat) 1983;44:145–161. 124 Ishihara T, Nagasawa T, Yokota T et al. Amyloid protein of vessels in leptomeninges, cortices, choroid plexuses, and pituitary glands from patients with systemic amyloidosis. Hum Pathol 1989;20:891–895. 125 Las MS, Surks MI. Hypopituitarism associated with systemic amyloidosis. NY State J Med 1983;83:1183–1185. 126 Sowers JR, Raj RP, Hershman JM et al. The effect of stressful diagnostic studies and surgery on anterior pituitary hormone release in man. Acta Endocrinol 1977;86:25–32. 127 Vaughan GM, Becker RA, Allen JP et al. Cortisol and corticotropin in burned patients. J Trauma 1982;22:263–273. 128 Parker LN, Levin ER, Lifrak ET. Evidence for adrenocortical adaptation to severe illness. J Clin Endocrinol Metab 1985;60:947–952. 129 Semple CG, Gray SE, Beastall GH. Adrenal androgens and illness. Acta Endocrinol 1987;116:155–160. 130 Semple CG. Hormonal changes in non-endocrine disease. Br Med J 1986;293:1049–1052.

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Chapter 17 238 Rodger RSC, Dewar JH, Turner SJ et al. Anterior pituitary dysfunction in patients with chronic renal failure treated by hemodialysis or continuous ambulatory peritoneal dialysis. Nephron 1986;43:169–172. 239 Diez JJ, Iglesias P, Sastre J et al. Growth hormone responses to growth hormone-releasing hormone and clonidine before and after erythropoietin therapy in CAPD patients. Nephron 1996;74:548–554. 240 Ramirez G, Bercu BB, Bittle PA et al. Response to growth hormone-releasing hormone in adult renal failure patients on hemodialysis. Metabolism 1990;39: 764–768. 241 Samaan N, Cumming WS, Craig JW et al. Serum growth hormone and insulin levels in severe renal disease. Diabetes 1996;15:546. 242 Powell DR, Rosenfeld RG, Baker BK et al. Serum somatomedin levels in adults with chronic renal failure: the importance of measuring insulin-like growth factor I (IGF-I) and IGF-II in acid-chromatographed uremic serum. J Clin Endocrinol Metab 1986;63:1186–1192. 243 Phillips LS, Fusco AC, Unterman TG, Del Greco F. Somatomedin inhibitor in uremia. J Clin Endocrinol Metab 1984;59:764–772. 244 Handelsman DJ. Hypothalamic–pituitary gonadal dysfunction in renal failure, dialysis and renal transplantation. Endocr Rev 1985;6:151–182. 245 Mooradian AD, Morley JE, Korchik WP et al. Comparison between bioactivity and immunoreactivity of serum prolactin in uraemia. Clin Endocrinol 1985;22: 241–247. 246 Smith CR, Butler J, Iggo N, Norman MR. Serum prolactin in uraemia: correlations between bioactivity in two immunoassays. Acta Endocrinol 1989;120:295–300. 247 Kaptein EM. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr Rev 1996;17:45–63. 248 Liewendahl K, Tikanoja S, Mahonen H et al. Concentrations of iodothyronines in serum of patients with chronic renal failure and other nonthyroidal illnesses: role of free fatty acids. Clin Chem 1987;33:1382–1386. 249 Feldman HA, Singer I. Endocrinology and metabolism in uremia and dialysis: a clinical review. Medicine 1974;54:345–376. 250 Workman RJ, Vaughn WK, Stone WJ. Dexamethasone suppression testing in chronic renal failure: pharmacokinetics of dexamethasone and demonstration of a normal hypothalamic–pituitary–adrenal axis. J Clin Endocrinol Metab 1986;63:741–746. 251 Kawai S, Ichikawa Y, Homma M. Differences in metabolic properties among cortisol, prednisolone, and dexamethasone in liver and renal diseases: accelerated metabolism of dexamethasone in renal failure. J Clin Endocrinol Metab 1985;60:848–854. 252 Zanoboni A, Zanoboni-Muciaccia W. Elevated basal growth hormone levels and growth hormone response to TRH in alcoholic patients with cirrhosis. J Clin Endocrinol Metab 1977;45:576–578. 253 Van Thiel DH, Gavaler JS, Sanghvi A. Pituitary and thyroid hormone levels before and after orthotopic hepatic transplantation and their responses to thyrotropin-releasing hormone. J Clin Endocrinol Metab 1985;60:569–574. 254 Agner T, Hagen C, Andersen BN, Hegedus L. Pituitary–thyroid function and thyrotropin, prolactin and growth hormone responses to TRH in patients with chronic alcoholism. Acta Med Scand 1986;220:57–62. 255 Assaad SN, Cunningham GR, Samaan NA. Abnormal growth hormone dynamics in chronic liver disease do not depend on severe parenchymal disease. Metabolism 1990;39:349–356. 256 Zapf J, Rinderknecht E, Humbel RE, Froesch ER. Nonsuppressible insulinlike activity (NSILA) from human serum: recent accomplishments and their physiologic implications. Metabolism 1978;27:1803–1828. 257 Phillips LS, Vassilopoulou-Sellin R. Somatomedins. N Engl J Med 1980;302:438–446. 258 Naomi S, Tajiri J, Inoue J et al. Interrelation between plasma amino acid composition and growth hormone secretion in patients with liver cirrhosis. Endocrinol Jpn 1984;31:557–564. 259 Faber J, Thomsen HE, Lumholtz IB et al. Kinetic studies of thyroxine, 3,5, 3¢-triiodothyronine, 3,3¢,5¢-triiodothyronine, 3¢,5¢-diiodothyronine, 3,3¢diiodothyronine, and 3¢-monoiodothyronine in patients with liver cirrhosis. J Clin Endocrinol Metab 1981;53:978–984. 260 Klachko DM, Johnson ER. The liver and circulating thyroid hormones. J Clin Gastroenterol 1983;5:465–471. 261 Kalk WJ, Russet D, Seftel HC, Van der Walt LA. Pituitary and thyroid function before and after portocaval anastomosis in patients with normal liver. J Clin Endocrinol Metab 1980;51:1450–1453. 262 Hegedus L. Decreased thyroid gland volume in alcoholic cirrhosis of the liver. J Clin Endocrinol Metab 1984;58:930–933. 263 Hegedus L, Rasmussen N, Ravn V et al. Independent effects of liver disease and chronic alcoholism of thyroid function and size: the possibility of a toxic effect of alcohol on the thyroid gland. Metabolism 1988;37:229–233.

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264 Rosman PM, Farag A, Benn R et al. Modulation of pituitary–adrenocortical function: decreased secretory episodes and blunted circadian rhythmicity in patients with alcoholic liver disease. J Clin Endocrinol Metab 1982;55:709–717. 265 Kley HK, Nieschlag E, Wiegelmann W et al. Steroid hormones and their binding in plasma of male patients with fatty liver, chronic hepatitis and liver cirrhosis. Acta Endocrinol 1975;79:275–285. 266 Baker HWG, Burger HG, De Kretser DM et al. A study of the endocrine manifestations of hepatic cirrhosis. Q J Med 1976;45:145–178. 267 Valimaki M, Salaspuro M, Harkonen M, Ylikahri R. Liver damage and sex hormones in chronic male alcoholics. Clin Endocrinol 1982;17:469–477. 268 Johnson PJ. Sex hormones and the liver. Clin Sci 1984;66:369–376. 269 Bannister P, Handley T, Chapman C, Losowsky MS. Hypogonadism in chronic liver disease: impaired release of luteinising hormone. Br Med J 1986;293:1191–1193. 270 Guechot J, Vaubourdolle M, Ballet F et al. Hepatic uptake of sex steroids in men with alcoholic cirrhosis. Gastroenterology 1987;92:203–207. 271 Gluud C and the Copenhagen Study Group for Liver Diseases. Serum testosterone concentrations in men with alcoholic cirrhosis: background for variation. Metabolism 1987;36:373–378. 272 Bannister P, Oakes J, Sheridan P, Losowsky MS. Sex hormone changes in chronic liver disease: a matched study of alcoholic versus non-alcoholic liver disease. Q J Med 1987;63:305–313. 273 De Besi L, Zucchetta P, Zotti S, Mastrogiacomo I. Sex hormones and sex hormone binding globulin in males with compensated and decompensated cirrhosis of the liver. Acta Endocrinol 1989;120:271–276. 274 Handelsman DJ, Strasser S, McDonald JA et al. Hypothalamic–pituitary–testicular function in end-stage non-alcoholic liver disease before and after liver transpantation. Clin Endocrinol 1995;43:331–337. 275 Van Thiel DH, Lester R, Sherins RJ. Hypogonadism in alcoholic liver disease: evidence for a double defect. Gastroenterology 1974;67;1188–1199. 276 Fishman J, Martucci C. Biological properties of 16a-hydroxyestrone: implications in estrogen physiology and pathophysiology. J Clin Endocrinol Metab 1980;51:611–615. 277 Distiller LA, Sagel J, Dubowitz B et al. Pituitary–gonadal function in men with alcoholic cirrhosis of the liver. Horm Metab Res 1976;8:461–465. 278 Mowat NAG, Edwards CRW, Fisher R et al. Hypothalamic–pituitary–gonadal function in men with cirrhosis of the liver. Gut 1976;17:345–350. 279 Van Thiel DH, Gavaler JS, Spero JA et al. Patterns of hypothalamic–pituitary–gonadal dysfunction in men with liver disease due to differing etiologies. Hepatology 1981;1:39–46. 280 Van Thiel DH, Gavaler JS. Hypothalamic–pituitary–gonadal function in liver disease with particular attention to the endocrine effects of chronic alcohol abuse. Prog Liver Dis 1986;8:273–282. 281 Gavaler JS, Rosenblum ER, Van Thiel DH et al. Biologically active phytoestrogens are present in bourbon. Alcohol Clin Exp Res 1987;11:399–406. 282 Valimaki M, Pelkonen R, Salaspuro M et al. Sex hormones in amenorrheic women with alcoholic liver disease. J Clin Endocrinol Metab 1984;59:133–138. 283 Bell H, Raknerud N, Falch JA et al. Inappropriately low levels of gonadotropins in amenorrheic women with alcoholic and non-alcoholic cirrhosis. Eur J Endocrinol 1995;132:444–449. 284 Wernze H, Schmitz E. Plasma prolactin and prolactin release in liver cirrhosis. Acta Hepato-Gastroenterol 1977;24:97–101. 285 Morgan MY, Jakobovits AW, Gore MBR et al. Serum prolactin in liver disease and its relationship to gynaecomastia. Gut 1978;19:170–174. 286 Van Thiel DH, McClain CJ, Elson MK, McMillin MJ. Hyperprolactinemia and thyrotropin-releasing factor (TRH) responses in men with alcoholic liver disease. Alcohol Clin Exp Res 1978;2:344–348. 287 Borzio M, Caldara R, Ferrari C et al. Growth hormone and prolactin secretion in liver cirrhosis: evidence for dopaminergic dysfunction. Acta Endocrinol 1981;97:441–447. 288 Cole EN, Sellwood RA, England PC, Griffiths K. Serum prolactin concentrations in benign breast disease throughout the menstrual cycle. Europ J Cancer 1977;13:597–603. 289 Bohnet HG, Gabel AK, Kreutzer P. Prolactin secretion patterns in patients with mammary tumors. Preliminary results. Prog Reprod Biol 1980;6: 172–178. 290 Peters F, Schuth W, Scheurich B, Breckwoldt M. Serum prolactin levels in patients with fibrocystic breast disease. Obstet Gynecol 1984;64:381–385. 291 Kumar S, Mansel RE, Hughes LE et al. Prolactin response to thyrotropinreleasing hormone stimulation and dopaminergic inhibition in benign breast disease. Cancer 1984;53:1311–1315. 292 Dogliotti L, Faggiuolo R, Ferruso A et al. Prolactin and thyrotropin response to thyrotropin-releasing hormone in premenopausal women with fibrocystic disease of the breast. Horm Res 1985;21:137–144.

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293 Watt-Boolsen S, Eskildsen PC, Blaehr H. Release of prolactin, thyrotropin, and growth hormone in women with cyclical mastalgia and fibrocystic disease of the breast. Cancer 1985;56:500–502. 294 Di Carlo R, Muccioli G, Bellussi G et al. Presence and characterization of prolactin receptors in human benign breast tumors. Eur J Cancer Clin Oncol 1984;20:635–638. 295 Kumar S, Mansel RE, Hughes LE et al. Prediction of response to endocrine therapy in pronounced cyclical mastalgia using dynamic tests of prolactin release. Clin Endocrinol 1985;23:699–704. 296 Sandrucci S, Mussa A, Festa V et al. Comparison of tamoxifen and bromocriptine in management of fibrocystic breast disease: a randomized blind study. Ann NY Acad Sci 1986;464:626–628. 297 Musey VC, Collins DC, Musey PI et al. Long-term effect of a first pregnancy on the secretion of prolactin. N Engl J Med 1987;316:229–234. 298 Wang DY, De Stavola BL, Bulbrook RD et al. The relationship between blood prolactin levels and risk of breast cancer in premenopausal women. Eur J Cancer Clin Oncol 1987;23:1541–1548. 299 Herman V, Kalk WJ, De Moor NG, Levin J. Serum prolactin after chest wall surgery: elevated levels after mastectomy. J Clin Endocrinol Metab 1981;52: 148–151. 300 Kapcala LP, Lakshmanan MC. Thoracic stimulation and prolactin secretion. J Endocrinol Invest 1989;12:815–821. 301 Nagasawa H. Prolactin and human breast cancer: a review. Eur J Cancer 1979;15:267–279. 302 Simon WE, Albrecht M, Trams G et al. In vitro growth promotion of human mammary carcinoma cells by steroid hormones, tamoxifen and prolactin. J Natl Cancer Inst 1984;73:313–321. 303 Manni A, Wright C, Davis G et al. Promotion by prolactin of the growth of human breast neoplasms cultured in vitro in the soft agar clonogenic assay. Cancer Res 1986;46:1669–1672. 304 Henderson BE, Gerkins V, Rosario I et al. Elevated serum levels of estrogen and prolactin in daughters of patients with breast cancer. N Engl J Med 1975;293:790–795. 305 McFadyen IJ, Prescott RJ, Groom GV et al. Circulating hormone concentrations in women with breast cancer. Lancet 1976;i:1100–1102. 306 Malarkey WB, Schroeder LL, Stevens VC et al. Disordered nocturnal prolactin regulation in women with breast cancer. Cancer Res 1977;37:4650–4654. 307 Willis KJ, London DR, Ward HWC et al. Recurrent breast cancer treated with the antioestrogen tamoxifen: correlation between hormonal changes and clinical course. Br Med J 1977;1:425–428. 308 Holtkamp W, Nagel GA, Wander H-E et al. Hyperprolactinemia is an indicator of progressive disease and poor prognosis in advanced breast cancer. Int J Cancer 1984;34:323–328. 309 Goettler DM, Levin L, Chey WY. Postprandial levels of prolactin and gut hormones in breast cancer patients: association with stage of disease but not dietary fat. J Natl Cancer Inst 1990;82:22–29. 310 Keye WR, Yuen BH, Knopf RF, Jaffe RB. Amenorrhea, hyperprolactinemia, and pituitary enlargement secondary to primary hypothyroidism. Successful treatment with thyroid replacement. Obstet Gynecol 1976;48:697–702. 311 Bigos ST, Ridgway EC, Kourides IA, Maloof F. Spectrum of pituitary alterations with mild and severe thyroid impairment. J Clin Endocrinol Metab 1978;46:317–325. 312 Guerrero LA, Carnovale R. Regression of pituitary tumor after thyroid replacement in primary hypothyroidism. South Med J 1983;76:529–531. 313 Groff TR, Shulkin BL, Utiger RD, Talbert LM. Amenorrhea-galactorrhea, hyperprolactinemia, and suprasellar pituitary enlargement as presenting features of primary hypothyroidism. Obstet Gynecol 1984;63:S86–S89. 314 Scheithauer BW, Kovacs K, Randall RV, Ryan N. Pituitary gland in hypothyroidism. Histologic and immunocytologic study. Arch Pathol Lab Med 1985;109:499–504. 315 Bilaniuk LT, Moshang T, Cara J et al. Pituitary enlargement mimicking pituitary tumor. J Neurosurg 1985;63:39–42. 316 Lecky BRF, Lightman SL, Williams TDM et al. Myxoedema presenting with chiasmal compression: resolution after thyroxine replacement. Lancet 1987;i:1347–1350. 317 Hutchins WW, Crues JV, Miya P, Pojunas KW. MR demonstration of pituitary hyperplasia and regression after therapy for hypothyroidism. AJNR 1990; 11:410. 318 Honbo KS, Van Herle AJ, Kellett KA. Serum prolactin levels in untreated primary hypothyroidism. Am J Med 1978;64:782–787. 319 Grubb MR, Chakeres D, Malarkey WB. Patients with primary hypothyroidism presenting as prolactinomas. Am J Med 1987;83:765–769. 320 Fish LH, Mariash CN. Hyperprolactinemia, infertility, and hypothyroidism. A case report and literature review. Arch Intern Med 1988;148:709–711.

321 Takai T, Yamamoto K, Saito K et al. Galactorrhea in subclinical hypothyroidism. Endocrinol Jpn 1987;34:539–544. 322 Otive KE, Hennessey JV. Marked hyperprolactinemia in sub-clinical hypothyroidism. Arch Intern Med 1988;148:2278–2279. 323 Rondeel JMM, De Greef WJ, Van der Schoot P et al. Effect of thyroid status and paraventricular area lesions on the release of thyrotropin-releasing hormone and catecholamines into hypolhysial portal blood. Endocrinology 1988;123:523–527. 324 Mirell CJ, Yanagisawa M, Lau R et al. Influence of thyroidal status on pituitary content of thyrotropin b- and a-subunit, growth hormone, and prolactin messenger ribonucleic acids. Mol Endocrinol 1987;1:408–412. 325 Valcavi R, Dieguez C, Preece M et al. Effect of thyroxine replacement therapy on plasma insulin-like growth factor I levels and growth hormone responses to growth hormone releasing factor in hypothyroid patients. Clin Endocrinol 1987;27:85–90. 326 Cohen KL. Metabolic, endocrine, and drug-induced interference with pituitary function tests: a review. Metabolism 1977;26:1165–1177. 327 Kumar BJ, Khurana ML, Ammini AC et al. Reproductive endocrine functions in men with primary hypothyroidism: effect of thyroxine replacement. Horm Res 1990;34:215–218. 328 Velazquez EM, Arata GB. Effects of thyroid status on pituitary gonadotropin and testicular reserve in men. Arch Androl 1997;38:85–92. 329 Buchanan CR, Stanhope R, Adlard P et al. Gonadotropin, growth hormone and prolactin secretion in children with primary hypothyroidism. Clin Endocrinol 1988;29:427–436. 330 Bruder JM, Samuels MH, Bremner WJ et al. Hypothyroidism-induced macroorchidism: use of a gonadotropin-releasing hormone agonist to understand its mechanism and augment adult stature. J Clin Endocrinol Metab 1995;80:11–16. 331 Snyder PJ, Jacobs LS, Utiger RD, Daughaday WH. Thyroid hormone inhibition of the prolactin repsonse to thyrotropin-releasing hormone. J Clin Invest 1973;52:2324–2329. 332 Yamaji T. Modulation of prolactin release by altered levels of thyroid hormones. Metabolism 1974;23:745–751. 333 Onishi T, Miyai K, Izumi K et al. Prolactin response to chlorpromazine and thyrotropin-releasing hormone in hyperthyroidism. J Clin Endocrinol Metab 1975;40:30–32. 334 Carlson HE, Sawin CT, Krugman LG et al. Effect of thyroid hormones on the prolactin response to thyrotropin-releasing hormone in normal persons and euthyroid goitrous patients. J Clin Endocrinol Metab 1978;47:275–279. 335 Ciccarelli E, Zini M, Grottoli S et al. Impaired prolactin response to arginine in patients with hyperthyroidism. Clin Endocrinol 1994;41:371–374. 336 Kidd GS, Glass AR, Vigersky RA. The hypothalamic–pituitary–testicular axis in thyrotoxicosis. J Clin Endocrinol Metab 1979;48:798–802. 337 Erfurth EM, Hedner P. Increased plasma gonadotropin levels in spontaneous hyperthyroidism reproduced by thyroxine but not by triiodothyronine administration to normal subjects. J Clin Endocrinol Metab 1987;64:698–703. 338 Tolis G, Lerman S. The pituitary. In: Ingbar SH, Braverman LE, eds. Werner’s, The Thyroid, 5th edn. Philadelphia: JB Lippincott, 1986:1181–1187. 339 Gharib H, Gastineau CF, Hodgson SF et al. Reversible hypothyroidism in Addison’s disease. Lancet 1972;ii:734–736. 340 Barnett AH, Donald RA, Espiner EA. High concentrations of thyroidstimulating hormone in untreated glucocorticoid deficiency: indication of primary hypothryoidism? Br Med J 1982;285:172–173. 341 Lever EG, McKerron CG. Auto-immune Addison’s disease associated with hyperprolactinemia. Clin Endocrinol 1984;21:451–457. 342 Stryker TD, Molitch ME. Reversible hyperthyrotropinemia, hyperthyroxinemia, and hyperprolactinemia due to adrenal insufficiency. Am J Med 1985; 79:271–276. 343 Kelver ME, Nagamani M. Hyperprolactinemia in primary adrenocortical insufficiency. Fertil Steril 1985;44:423–425. 344 Ismail AAA, Burr WA, Walker PL. Acute changes in serum thyrotropin in treated Addison’s disease. Clin Endocrinol 1989;30:225–230. 345 Caufriez A, Golstein J, Lebrun P et al. Relations between immunoreactive somatomedin C, insulin and T3 patterns during fasting in obese subjects. Clin Endocrinol 1984;20:65–70. 346 Abdenur JE, Pugliese MT, Cervantes C et al. Alterations in spontaneous growth hormone (GH) secretion and the response to GH-releasing hormone in children with non-organic nutritional dwarfing. J Clin Endocrinol Metab 1992;75:930–934. 347 Samuel AM, Deshpande UR. Growth hormone levels in protein calorie malnutrition. J Clin Endocrinol Metab 1972;35:863–867. 348 Alvarez LC, Dimas CO, Castro A et al. Growth hormone in malnutrition. J Clin Endocrinol Metab 1972;34:400–409.

Chapter 17 349 Pimstone B, Barbezat G, Hansen JDL, Murray P. Growth hormone and protein-calorie malnutrition. Lancet 1967;ii:1333–1334. 350 Ho KY, Veldhuis JD, Hohnson ML et al. Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 1988;81:968–975. 351 Palmblad J, Levi L, Burger A et al. Effects of total energy withdrawal (fasting) on the levels of growth hormone, thyrotropin, cortisol, adrenaline, noradrenaline, T4, T3, and rT3 in healthy males. Acta Med Scand 1977; 201:15–22. 352 Vigersky RA, Andersen AE, Thompson RH, Loriaux DL. Hypothalamic dysfunction in secondary amenorrhea associated with simple weight loss. N Engl J Med 1977;297:1141–1145. 353 Becker D, Kronheim S, Pimstone B. Serum growth hormone responses to thyrotropin releasing hormone in children with protein-calorie malnutrition. Horm Metab Res 1975;7:358–359. 354 Becker DJ, Vinik AI, Pimstone BL, Paul M. Prolactin responses to thyrotropinreleasing hormone in protein-calorie malnutrition. J Clin Endocrinol Metab 1975:41:782–783. 355 Vinik AI, Kalk WJ, McLaren H, Paul M. Impaired prolactin response to synthetic thyrotropin-releasing hormone after a 36 hour fast. Horm Metab Res 1974;6:499–501. 356 Lamberts SWJ, Visser TJ, Wilson JHP. The influence of caloric restriction on serum prolactin. Int J Obesity 1979;3:75–81. 357 Rojdmark S, Nygren A. Thyrotropin and prolactin responses to thyrotropinreleasing hormone: influence of fasting- and insulin-induced changes in glucose metabolism. Metabolism 1983;32:1013–1018. 358 Rojdmark S. Are fasting-induced effects on thyrotropin and prolactin secretion mediated by dopamine? J Clin Endocrinol Metab 1983;56:1266–1270. 359 Carlson HE, Drenick EJ, Chopra IJ, Hershman JM. Alterations in basal and TRH-stimulated serum levels of thyrotropin, prolactin, and thyroid hormones in starved obese men. J Clin Endocrinol Metab 1977;45:707–713. 360 Lee PA, Wallin JD, Kaplowitz N et al. Endocrine and metabolic alterations with food and water deprivation. Am J Clin Nutr 1977;30:1953–1962.

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361 Couzinet B, Young J, Brailly S et al. Functional hypothalamic amenorrhoea: a partial and reversible gonadotrophin deficiency of nutritional origin. Clin Endocrinol 1999;50:229–235. 362 Cameron JL, Weltzin TE, McConaha C et al. Slowing of pulsatile luteinizing hormone secretion in men after forty-eight hours of fasting. J Clin Endocrinol Metab 1991;73:35–41. 363 Galvao-Teles A, Graves L, Burke CW et al. Free cortisol in obesity; effect of fasting. Acta Endocrinol 1976;81:321–329. 364 Vance ML, Thorner MO. Fasting alters pulsatile and rhythmic cortisol release in normal man. J Clin Endocrinol Metab 1989;68:1013–1018. 365 Bergendahl M, Vance ML, Iranmanesh A et al. Fasting as a metabolic stress paradigm selectively amplifies cortisol secretory burst mass and delays the time of maximal nyctohemeral cortisol concentrations in healthy men. J Clin Endocrinol Metab 1996;81:692–699. 366 Matzen LE, Kvetny J. The influence of caloric deprivation and food composition on TSH, thyroid hormones and nuclear binding of T3 in mononuclear blood cells in obese women. Metabolism 1989;38:555–561. 367 Veldhuis JD, Iranmanesh A, Evans WS et al. Amplitude suppression of the pulsatile mode of immunoradiometric luteinizing hormone release in fastinginduced hypoandrogenemia in normal men. J Clin Endocrinol Metab 1993;76:587–593. 368 Nakamura Y, Yoshimura Y, Oda T et al. Clinical and endocrine studies on patients with amenorrhea associated with weight loss. Clin Endocrinol 1985;23:643–651. 369 Rojdmark S. Increased gonadotropin responsiveness to gonadrotropin-releasing hormone during fasting in normal subjects. Metabolism 1987;36:21–26. 370 Klibanski A, Beitins IZ, Badger T et al. Reproductive function during fasting in men. J Clin Endocrinol Metab 1981;53:258–263. 371 Hoffer LJ, Beitins IZ, Kyung N-H, Bistrian BR. Effects of severe dietary restriction on male reproductive hormones. J Clin Endocrinol Metab 1986;62:288–292. 372 Smith SR, Chhetri MK, Johanson AJ et al. The pituitary–gonadal axis in men with protein-calorie malnutrition. J Clin Endocrinol Metab 1975;41:60–69.

C h a p t e r

18 The Pituitary Gland in Pregnancy and the Puerperium Harold E. Carlson

NORMAL PREGNANCY In response to a changing hormonal milieu, the human pituitary gland undergoes a remarkable transformation during pregnancy. Substances produced by the fetoplacental unit greatly modify maternal hypophyseal structure and function. In the case of some, for example, prolactin (PRL) or oxytocin, such changes clearly play an important functional role in pregnancy, labor and the puerperium. In the case of others, such as growth hormone (GH), the changes in the maternal pituitary seem to be a coincidental side effect of processes involved in stimulating fetal growth.

Anatomic Changes During pregnancy, the anterior pituitary enlarges greatly; pituitary weight increases by about 33% [1], as does crosssectional area (assessed histologically [2]) and gland volume (assessed radiologically by magnetic resonance imaging [MRI] techniques [3]). This enlargement results in an upward convexity of the superior surface of the gland when visualized radiologically [3]. The adenohypophysis also becomes hyperintense on T1-weighted images during pregnancy [4]. The pituitary stalk remains in its normal midline position, but the posterior pituitary, normally seen as an intense T1-weighted signal on MRI, is not visualized in the third trimester of gestation [3]. Postpartum, adenohypophysial enlargement regresses, although perhaps not totally [1–3]. Microscopically, the anterior pituitary enlargement was noted by Erdheim and Stumme in 1909 to be due to the presence of large numbers of “pregnancy cells” [1]; later investigators identified these cells as lactotrophs [2,5,6]. The percentage of lactotrophs in the pituitary gland rises from about 15–20% of total pituitary cells in men and nulliparous women to approximately 50% at the end of normal gesta628

tion [2,6]. Pregnancy lactotrophs are large, mitotically active, and contain PRL immunoreactivity in both cytoplasmic granules and in the Golgi region [2]. Using in situ hybridization measurements, prolactin messenger RNA is increased in pregnancy lactotrophs [7]. PRL cells increase in number during pregnancy not only in the lateral wings of the pituitary (where they are most abundant in the nonpregnant state) but also in the central area as well [2,6]. Following delivery, the percentage of lactotrophs falls, especially if lactation is not continued [2,6]; regression may not be complete, however, as shown by the finding that about 25% of total pituitary cells in nonpregnant multiparous women are lactotrophs [6]. Other changes noted during pregnancy in immunohistochemical studies include a modest diminution in the relative number of somatotrophs [2,7], a major decrease in the proportion of stainable gonadotrophs [2], and no change in the proportions of thyrotrophs or corticotrophs [2]. Some of the somatotrophs may convert to mammosomatotrophs or lactotrophs during pregnancy [7]. In the human fetus, a distinct intermediate lobe of the pituitary exists. After birth, this structure gradually regresses, so that in the adult there is no recognizable intermediate lobe [8]. Based on limited evidence, this situation does not change during pregnancy. HORMONE SECRETION The changes that occur in circulating pituitary hormones during normal pregnancy are listed in Table 18.1.

PRL To prepare the breast for lactation, the secretion of PRL increases greatly during pregnancy; serum levels rise to

Chapter 18 Table 18.1. Summary of maternal pituitary function changes during normal pregnancy and postpartum period Hormone

Pregnancy

Postpartum

Prolactin

Increases progressively throughout gestation

Stimulated by suckling; falls rapidly in absence of breast-feeding

Gonadotropins

Suppressed in first few weeks and remain low throughout gestation

In absence of breast-feeding, return to normal within 1–2 months; suppressed by active lactation

Thyrotropin

No change except for a transient dip at 9–13 weeks gestation

No change

Growth hormone Suppressed during second half of gestation

Return to normal within a few weeks postpartum

Corticotropin

Probable modest increase in plasma ACTH, remaining in normal range

Return to normal within 1 week

Vasopressin

No change in plasma levels, though production rate increased in third trimester

No change in plasma levels

Oxytocin

No change except for increase Stimulated acutely by nipple in plasma levels during labor stimulation and maternal psychic factors

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approximately 20–40 ng/ml at the end of the first trimester, 50–150 ng/ml by the end of the second trimester, and 100–400 ng/ml at term (Fig. 18.1) [9,10]. The massive hyperestrogenemia of pregnancy is generally deemed responsible for this increase in PRL secretion, since estrogen is a known stimulus to both PRL synthesis and secretion, as well as lactotroph proliferation [11–19]. It is not clear, however, whether the effect of estrogen is predominantly a direct stimulatory effect on the lactotroph, an indirect effect mediated by decreased hypothalamic dopamine (DA) release into the portal circulation, or perhaps an indirect effect mediated by other potential trophic factors (e.g., vasoactive intestinal polypeptide, VIP [18]) acting on the lactotroph. Recently, animal evidence has suggested that estrogen may induce changes in the pattern of pituitary blood supply, such that a greater fraction of adenohypophysial blood flow is derived from the systemic circulation (with low DA concentration) and less from the hypothalamic–pituitary portal circulation (with high DA concentrations) [20]. It is likely that some combination of these factors is responsible for the hyperprolactinemia of pregnancy. During pregnancy, PRL is also produced by uterine tissues, principally the decidua, and secreted into the amniotic fluid [21,22]. PRL is found in extremely high concentration in amniotic fluid, peaking at about 4000– 6000 ng/ml near the end of the second trimester, and falling to about 200–800 ng/ml at term [23–25]. Very little of this decidual PRL enters the maternal circulation, however, as revealed by low serum PRL concentrations despite high amniotic fluid PRL in pregnant women with preexisting

FIGURE 18.1. Mean (± SD) serum prolactin concentrations during normal pregnancy and the postpartum period. The number of subjects sampled at each time point is indicated. From Hwang et al. [11]

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PRL deficiency [26–28] and pregnant women in whom pituitary PRL secretion has been suppressed by bromocriptine [20–31]. Elevated serum PRL levels in the fetus appear to be largely derived from fetal pituitary secretion and reach 80–500 ng/ml at term [9,23,31]. The dynamics of normal PRL regulation appear to be preserved in pregnancy. Although baseline serum PRL levels are elevated, responses to thyrotropin-releasing hormone (TRH), sleep, arginine infusion, and meals are present [9,32–37]. In absolute terms, the observed increments in serum PRL in response to these stimuli are normal. Since baseline PRL levels are elevated, however, the proportional increase (expressed as multiples of baseline) is diminished during pregnancy. Following delivery, serum PRL levels decline fairly quickly in nonnursing mothers, falling to approximately normal prepregnancy levels by 1–3 weeks postpartum (Fig. 18.1) [9,38]. In nursing mothers, each episode of suckling activates a neural reflex arc to acutely stimulate PRL release, prolonging the decline in baseline levels; somewhat larger PRL responses occur with afternoon or evening suckling episodes compared to the morning [9,32,39]. Nevertheless, as nursing episodes become less frequent, baseline serum PRL values eventually return to near prepregnancy levels, despite continued intermittent bursts of PRL secretion coincident with episodes of suckling (Fig. 18.2). As the suckling episodes become less frequent, the magnitude of the suckling-induced bursts of PRL secretion also diminishes [9,32,38,39]. The maintenance of hyperprolactinemia by frequent nursing episodes results in prolonged suppression of gonadotropins and extends the period of postpartum amenorrhea and infertility [40]. A recent study has reported that there is a permanent 50% decrease in basal and stimulated levels of serum PRL following the first pregnancy in women. This change occurred regardless of the maternal age at first pregnancy

and was not influenced by breast-feeding or by subsequent pregnancies [41]. The authors of this report speculated that such changes in PRL secretion might bear some relationship to the known protective effects of an early first pregnancy against breast cancer. In addition to the changes in total serum PRL concentrations during pregnancy, there are qualitative changes in the circulating molecular species of PRL as well. In nonpregnant women, gel filtration chromatography has revealed that most circulating PRL has an apparent molecular weight of about 22 kDa; small amounts appear at column elution positions corresponding to approximately 45 kDa and 100 kDa [42–45]. The relative abundance of the 22 kDa form may increase modestly during pregnancy [42,45,46]. In contrast, more dramatic changes appear to take place in the proportion of circulating PRL which is glycosylated. In nonpregnant women in the basal state, the majority of circulating PRL is glycosylated; during late pregnancy and lactation, most circulating PRL is nonglycosylated [47–49]. Since glycosylation may alter the biological activity of PRL [50–53], regulation of this step may be important in initiating and sustaining lactation.

Gonadotropins Confirming the immunohistochemical observation that pituitary gonadotrophs are decreased in number during pregnancy [2], maternal pituitary content of luteinizing hormone (LH) is also gradually diminished through the course of gestation [54]; although pituitary follicle-stimulating hormone (FSH) content during pregnancy has not been specifically measured, it presumably also decreases, since immunologically stainable FSH is diminished [2]. Basal maternal serum levels of both LH and FSH are decreased as early as 6–7 weeks of gestation and are frequently undetectable thereafter [55–59]. Urinary FSH, a

FIGURE 18.2. Serum prolactin responses to suckling in normal postpartum women. Note the diminished response beyond 80 days postpartum. From Tyson et al. [9]

Chapter 18

reflection of maternal serum FSH, is also decreased [60]. (Note: although human chorionic gonadotropin (hCG) crossreacts in many routine LH assays, serum LH can be assayed in the presence of hCG through the use of antisera raised against the specific b-subunit of LH.) The LH and FSH response to gonadotropin-releasing hormone (GnRH) decreases in parallel with the decrease in basal serum levels of these hormones, and remains suppressed into the puerperium [55–59]. The decreased pituitary content of gonadotropins, decreased serum levels of LH and FSH, and the decreased pituitary responsiveness to GnRH all appear to reflect a profound suppression of pituitary gonadotropin synthesis and secretion in response to marked increases in estrogen and progesterone [59,61] (initially from the corpus luteum and decidua, and later from the placenta), PRL (from the maternal pituitary) and inhibin (from the corpus luteum and placenta [62–65]). In addition to stimulating the corpus luteum, hCG may also have a direct suppressive effect on LH (but not FSH) secretion [66]. As the serum concentrations of these suppressive substances fall in the puerperium, maternal gonadotropin secretion resumes, along with responsiveness to GnRH [55,57,61,67]. LH and FSH responses to GnRH are actually exaggerated in the second postpartum month before settling back to normal [67,68]. Gonadotropin secretion by the human fetal pituitary is present by the end of the first trimester, and fetal serum LH and FSH levels peak at about 20 weeks gestation at adult castrate values; serum levels of both LH and FSH are several times higher in female fetuses than males. In both sexes, serum gonadotropin concentrations then fall in the last trimester of pregnancy, reaching low prepubertal values at term [69–71]. Fetal gonadotropins are excreted into the amniotic fluid, but do not reach the maternal circulation in significant amounts [72].

Thyrotropin The well-known increase in serum thyroxine-binding globulin which occurs during pregnancy in response to hyperestrogenemia results in a progressive rise in maternal total serum thyroxine (T4) and triiodothyronine (T3) concentrations [73,74]. Serum concentrations of free T4 and free T3 are either normal throughout [73,74] or slightly increased [75] during early pregnancy. Maternal serum thyrotropin (thyroid-stimulating hormone;TSH) concentrations are generally stable throughout pregnancy except for a small decrease around 9–13 weeks gestation, coincident with peak maternal serum hCG concentrations (Fig. 18.3) [73,75,76]. Since hCG has weak thyroid-stimulating activity [77–79], it has been postulated that the high concentrations of hCG near the end of the first trimester result in mild thyroid overactivity that, in turn, slightly suppresses maternal pituitary TSH secretion [73,75,76,80,81]. Although early research suggested there might be another

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FIGURE 18.3. Mean (± SE) serum concentrations of hCG, TSH and bioassayable thyroid-stimulating activity (Bio-TSH) during normal pregnancy. Note the transient dip in immunoreactive TSH coincident with the peak of serum hCG at 9–12 weeks gestation. From Harada et al. [75]

placental thyroid stimulator (termed chorionic thyrotropin [82–84]), most recent studies have concluded that no such hormone exists, and that the thyroid-stimulating properties of placental extracts can be completely accounted for by chorionic gonadotropin [75,85]. Maternal TSH responsiveness to TRH is usually normal in pregnancy [34,57,73,86,87]. In the fetus, serum T4 and TSH are low until midgestation, at which point TSH begins to increase, rising to mildly elevated levels (10–15 mU/ml) by the end of the second trimester, and declining slightly to about 10 mU/ml at term; the elevation in serum TSH in the second half of gestation is associated with (and presumably causes) a progressive rise in fetal serum T4. Throughout pregnancy, fetal and maternal TSH secretion proceed independently, since the placenta is impermeable to TSH and only modestly permeable to thyroid hormones [88,89]. Within 30 minutes of delivery, there is an acute surge of fetal TSH secretion which may reach 60–80 mU/ml; decline from this peak is fairly rapid over the next several days of life [88].

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Adrenocorticotropin (ACTH) The maternal hypothalamic–pituitary–adrenal (HPA) axis undergoes significant changes during pregnancy. The causes and consequences of these changes are still unclear, however. There is general agreement that maternal total serum cortisol gradually increases throughout pregnancy, with a preservation of normal diurnal rhythmicity [90–102]. Part of the rise in total serum cortisol is attributed to an estrogeninduced increase in its principal serum carrier protein, corticosteroid-binding globulin (CBG) [96,100–106]. There is, in addition, a clear rise in serum free cortisol [93,96,100,101,105,107], salivary free cortisol [99,102], and urinary free cortisol [90,93,95,100,108,109]; values for urinary free cortisol at term are above the usual normal range and are comparable to levels seen in nonpregnant patients with Cushing’s syndrome. Since the hypercortisolemia is also seen in molar pregnancy [91] and with administration of exogenous estrogen [100,103–105], it is apparently derived principally from the maternal adrenals. Maternal plasma ACTH is generally within the normal range, although mean levels have been variously reported as higher [90,91,97–99,108] or lower [94,110] than those seen in nonpregnant women. Plasma ACTH levels rise gradually through pregnancy [94,97,108]. Complicating this picture is the observation that the placenta produces ACTH [90,108,111,112]; the relative contribution of placental ACTH to total maternal plasma ACTH is unknown. Finally, plasma concentrations of corticotropin-releasing hormone (CRH), presumably of predominantly placental origin [112–115], have recently been shown to be greatly elevated in late pregnancy [90,97,98,116–118]. Much of this CRH is bound to a specific serum carrier protein and is not biologically active in the maternal circulation [98,119,120], although it may have local paracrine effects in the placenta [112,114], and probably contributes to the activation of the maternal HPA axis during pregnancy [90]. In an effort to further define the regulation of the HPA axis during pregnancy, a variety of stimulation and suppression tests have been performed. Maternal adrenals are hyperresponsive to ACTH during pregnancy, after both acute and more prolonged (8 hour) stimulation [106]. Total serum cortisol, the serum free cortisol index, and urine free cortisol all show incomplete suppression following dexamethasone administration, in both the overnight test [106] and after prolonged dexamethasone ingestion [108]. Finally, maternal ACTH responses to exogenous CRH are blunted during pregnancy, and larger CRH doses than usual are required to elicit a response [98,99,121]. The mechanisms underlying these changes are, at present, largely speculative; possibilities include the following: 1. An increase in CBG levels due to hyperestrogenemia, although simple elevation in CBG does not appear to raise free cortisol [102]. 2. Antagonism of glucocorticoid action by progesterone [122–124], resulting in a state of

3.

4.

5.

6.

relative cortisol resistance, with an elevation in the set point for negative feedback by cortisol on ACTH secretion. A recent study has shown, however, that a relatively brief (days) elevation of serum progesterone to pregnancy levels is not sufficient to elevate free cortisol [102]. Autonomous secretion of ACTH by the placenta, leading to non-suppressibility of maternal ACTH and cortisol. However, this would result in the loss of the normal diurnal rhythm. Tonic hypersecretion of CRH by the placenta with resulting mild chronic ACTH and cortisol hypersecretion, along with downregulation of the acute response to CRH. An effect of estrogen, through undefined mechanisms, to raise the set point for feedback of free cortisol on ACTH secretion [102]. A synergistic stimulatory effect of vasopressin and CRH on ACTH secretion, an effect which may not suppress readily with dexamethasone [125]. Vasopressin secretion is enhanced in late pregnancy in order to overcome the enhanced vasopressin degradation due to placental vasopressinase [126].

Whatever the mechanism, the changes in the maternal HPA axis rapidly return to normal within a few days postpartum [92,95,97,99,101,118].

GH The secretion of GH (somatotropin) by the maternal pituitary is profoundly suppressed during the second half of pregnancy. When measured by the usual clinical radioimmunoassay (RIA) or immunoradiometric assay (IRMA) methodologies, both basal and stimulated serum GH levels are low in maternal plasma [32,127–132]. Despite this, maternal serum levels of insulin-like growth factor-I (IGFI; somatomedin-C) are, if anything, slightly elevated in pregnancy [131,132], and are normalized in pregnant women with GH deficiency [133,134]. Recent information has begun to clarify this apparent paradox. The placenta secretes large amounts of a variant form of growth hormone (termed hGH-V) which is apparently not produced by other tissues [130,135–138]. This variant form of GH is not measured in most commercial assays for hGH, although it may crossreact partially in some research RIAs [130–132,134]. Variant or placental GH is secreted into the maternal circulation; its concentration rises progressively to term, and then falls rapidly after delivery [130]. Placental GH binds with high affinity to human and rabbit hepatic GH receptors [130,131], suggesting it is probably biologically quite potent. When assayed by a human liver radioreceptor method, measurements of total serum “GH-like” activity in pregnancy yield values of about 65 ng/ml; only 3% of this is derived from maternal pituitary secretion of “normal” GH, and only 12% from the GH-like

Chapter 18

actions of chorionic somatomammotropin (placental lactogen) [131]. The elevated serum levels of variant GH probably exert a negative feedback effect on the maternal hypothalamus and pituitary, resulting in a blunting of pituitary GH secretion. High serum levels of estrogen present during pregnancy may be responsible for the relatively unchanged maternal serum IGF-I levels, since estrogens block the normal stimulation of IGF-I production by GH [139,140]. It is of interest that neither placental lactogen or placental GH appear essential in normal human pregnancy, since a woman with a deletion of both of these genes experienced a normal pregnancy which produced a normal infant and normal placenta [141]. The placenta also produces GH-releasing hormone (GHRH) [142]; its role in the regulation of placental or fetal GH production is unknown. Similarly, human placental explants have been shown to produce IGF-I [143], but it is not known whether this process is stimulated by GH-like hormones or whether placental IGF-I production plays any important role in the regulation of growth or metabolism during pregnancy. The fetal pituitary secretes GH normally during gestation [144]; this may not be necessary for fetal IGF production, however, since serum IGF-I and IGF-II are normal in anencephalic fetuses [145].

Posterior Pituitary During pregnancy, the plasma osmolality set point for vasopressin release is lowered from the nonpregnant value of about 285 mOsm/kg to about 275–280 mOsm/kg. Peripheral plasma vasopressin levels and vasopressin responses to changes in plasma tonicity remain normal [146,147]. Vasopressin degradation is increased in pregnancy, however, due to placental vasopressinase, and vasopressin secretion rises in order to keep pace and maintain normal plasma vasopressin levels [126]. Plasma oxytocin concentrations do not appear to rise during pregnancy until the late stages of labor; then, stretching of the vaginal wall results in reflex release of oxytocin which stimulates myometrial contractions and thereby assists in expelling the fetus and placenta. In the postpartum period, oxytocin also assists with breast-feeding; nipple stimulation and/or maternal awareness of a hungry infant reflexively release oxytocin, which produces contraction of the myoepithelial cells of the mammary gland, resulting in milk ejection [148–151].

SHEEHAN’S SYNDROME Postpartum necrosis of the pituitary (Sheehan’s syndrome) may be the most common cause of hypopituitarism worldwide [152]. Hypotension, usually caused by severe hemorrhage at the time of delivery, is the major causal factor [153]. Antepartum hemorrhage due to nonobstetric causes may

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also result in pituitary infarction [154,155]. The hyperplastic pituitary of pregnancy may have a tenuous blood supply to begin with, and the enlarged gland may also compress its feeding blood vessels against the wall of the sella. Additionally, local or systemic vasoconstrictors released during shock may lead to vasospasm of pituitary arterioles [156], further contributing to tissue hypoperfusion. In its complete form, Sheehan’s syndrome typically presents the picture of gradually-evolving postpartum panhypopituitarism [153]. Failure to lactate and rapid breast involution are usually the earliest signs, followed by a failure to resume menses and a lack of regrowth of shaved pubic and/or axillary hair. Signs and symptoms of hypothyroidism and hypoadrenalism gradually develop over a period of months to years. Skin pigmentation decreases, especially in the areolar and genital areas, and poor tanning is noted. Posterior pituitary involvement may also occur. Overt diabetes insipidus (DI) has been reported but is unusual [157–161]; more subtle defects in vasopressin secretion and maximal urinary concentrating ability are common [162–165] and correspond to the high incidence of posterior pituitary infarcts and neuronal loss in the supraoptic and paraventricular nuclei seen in anatomic studies [166,167]. In some patients, latent DI becomes overt when glucocorticoid therapy is instituted, probably due to the suppressive effects of glucocorticoids on residual vasopressin secretion [168] and perhaps also to direct renal effects of glucocorticoids in facilitating free water excretion [169]. Mental disturbance is common in Sheehan’s syndrome, and is usually manifest as an organic psychosis [170–172]; this frequently responds to hormone replacement therapy. As in other forms of secondary adrenal insufficiency, basal mineralocorticoid production is not impaired, although there may be blunted responses of both renin and aldosterone to upright posture and volume depletion. This blunting is largely corrected by thyroid hormone and glucocorticoid replacement [173,174]. Other features of Sheehan’s syndrome include hyperlipidemia, which is probably related to hypothyroidism [175,176]. One case of bone marrow aplasia which responded to hormone replacement has been reported [177], and one case of hypomagnesemia with cardiac arrhythmia [178]. Pituitary infarction in Sheehan’s syndrome is frequently not total, and partial hypopituitarism is common, with selective loss of one or more hormones [28,165,179–183]. Preservation of gonadotropin secretion may allow normal menses and even subsequent pregnancy [184–187]. Special mention should be made of the increased vulnerability of the pituitary to infarction in pregnant patients with diabetes mellitus [188,189], probably related to preexisting vascular disease. In pregnant diabetics, pituitary infarction may be seen without antecedent hypotension and may occur antepartum [190,191].

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Diagnosis of Sheehan’s Syndrome To confirm the clinical diagnosis, pituitary function is tested in the usual fashion. The finding of low or normal serum levels of TSH, ACTH, LH and FSH in the presence of subnormal levels of T4, cortisol and estradiol, respectively, supports the diagnosis of secondary end-organ failure. In most patients, a subnormal serum level of IGF-I (somatomedinC) can be taken as prima facie evidence of GH deficiency. Stimulation tests (insulin hypoglycemia, arginine infusion, GHRH infusion) may be used to establish a diagnosis of GH deficiency, and are usually necessary to diagnose PRL deficiency, since basal PRL levels are rarely so low as to be considered subnormal. Deficient PRL responses to TRH or dopamine antagonists are among the most consistent abnormalities seen in patients with Sheehan’s syndrome [181,183,192,193]. Assessment of TSH, LH and FSH reserve with TRH and GnRH tests has yielded interesting results. Despite hypothyroidism, basal TSH levels are often within the normal range and frequently show a small or normal response to TRH, sometimes with a delayed peak [175,176,181,183,193,194]. Similarly, basal LH and FSH levels may be normal in hypogonadal patients, and often show some response to GnRH [181,183,193]. These findings suggest suprapituitary disease, and may be due either to anatomic damage to the hypothalamus [167] or, perhaps more likely, to the survival of islands of anterior pituitary tissue no longer supplied with hypothalamic releasing factors due to destruction of the portal circulation [156]. Radiologic studies of the pituitary are also generally performed to exclude the presence of a mass lesion. In longstanding Sheehan’s syndrome, the sella turcica is frequently “empty”, filled only with CSF [179,182,195–198]. In a substantial minority of patients, small remnants of pituitary tissue may be seen on CT scan [182,195,198]. Sellar volume is small in patients with Sheehan’s syndrome, and shows no relation to the time elapsed since the postpartum hemorrhage [198]. This suggests that the sella in Sheehan’s syndrome patients may have been small to begin with; in a small, rigid sella, the hyperplastic pituitary may be more likely to compress its blood supply, thus predisposing the gland to infarction if hypotension ensues [199].

pituitary. Since the extensive review by Cosman et al. in 1989 [200], many more proven cases have been reported, bringing the current total to approximately 128. All but 14 of the cases have been female; most of the women have been in their reproductive years, and in nearly all of these the disorder presented in late pregnancy or up to about one year postpartum. Patients whose symptoms develop during pregnancy generally present with features of a sellar mass (headache, visual disturbance), while patients presenting postpartum may have signs and symptoms of hypopituitarism in addition to those due to pituitary enlargement [200–202]. Radiologically, the pituitary mass cannot easily be distinguished from adenoma or other neoplasms on CT or MRI [201,203]. Pituitary function testing may reveal complete or partial hypopituitarism; interestingly, when partial defects occur, ACTH deficiency is commonly present, and gonadal function is often preserved, a contrast to the usual findings in patients with pituitary tumors [200–202]. This pattern of hormone loss presumably reflects specific immunologic damage to a target cell population. Approximately 40% of the patients have prolaction deficiency and 40% have hyperprolactinemia [200], probably due to stalk compression. Sixteen per cent of patients have had DI in the absence of surgical intervention.

Pathogenesis When sectioned, the pituitary is firm and sometimes gritty. It may be enlarged early in the course of the disease and later frequently becomes atrophic. Microscopically, the gland is infiltrated with lymphocytes and plasma cells, sometimes forming germinal centers. Fibrosis is often present, especially in the later stages, when pituicytes are scanty. The posterior pituitary is usually spared [200]. Consistent with this picture of autoimmune hypophysitis, circulating antipituitary antibodies have been found in a small number of cases. About 30% of the patients have had evidence of other endocrine autoimmunity, including thyroiditis, pernicious anemia, adrenalitis, diabetes mellitus and parathyroiditis. Antinuclear and anti-mitochondrial antibodies have also been reported [200–202].

Treatment of Sheehan’s Syndrome

Course and Treatment

In most instances, end-organ replacement hormone therapy with L-thyroxine, glucocorticoid and sex hormones are given as indicated. Hormone replacement is particularly important in patients with Sheehan’s syndrome who become pregnant, since both fetal and maternal mortality is increased in unreplaced patients [184].

About 15% of the patients have died of lymphocytic hypophysitis, probably from adrenal insufficiency [202]. In surviving patients, surgery has been effective in relieving visual symptoms and headache. Bromocriptine has produced partial improvement in visual disturbance in a few patients [201,202]. Glucocorticoids may have decreased the size of the pituitary mass in a few patients [204], but these cases are difficult to distinguish from spontaneous shrinkage [205]. Some patients are left with an empty sella turcica, prompting confusion with Sheehan’s syndrome [205].

LYMPHOCYTIC HYPOPHYSITIS Lymphocytic hypophysitis is a rare disorder characterized by lymphocytic infiltration and destruction of the anterior

Chapter 18

In some patients, pituitary function spontaneously improves, whereas in others, including one presumptive case, partial defects worsen with time [200–202,206]. Treatment therefore consists of hormone replacement as needed, and surgery to relieve visual symptoms due to suprasellar extension. There has been no adequate trial of high-dose corticosteroids or other immunosuppressive therapy. PROLACTINOMA The problem of prolactinoma during pregnancy is discussed in Chapter 12. CUSHING’S SYNDROME Pregnancy rarely occurs in patients with Cushing’s syndrome. Gonadotropin secretion is suppressed by excess cortisol and androgens [207–209], resulting in oligomenorrhea or amenorrhea in 75% of patients [210,211]. The presence of physiologic hypercortisolism during normal pregnancy [90–109] and the frequent occurrence of weight gain, hypertension and hyperglycemia in pregnancy combine to obscure the diagnosis of Cushing’s syndrome in pregnant women. In a review of 60 patients, Sheeler et al. [212] pointed out that the most common cause (50%) of Cushing’s syndrome in pregnancy is an adrenal tumor, most of which (80%) are benign. This is in distinct contrast to the the situation in nonpregnant adults, where pituitary-dependent bilateral adrenal hyperplasia (Cushing’s disease) accounts for about two-thirds of all cases, and where adrenal adenomas and carcinomas occur with approximately equal frequency [213,214]. The reasons for this unusual occurrence of hyperfunctioning adrenal adenomas is unclear. One hypothesis which has been advanced is that benign hyperfunctioning adrenal adenomas are less likely to be associated with andro-

Table 18.2.

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gen overproduction than are the other causes of Cushing’s syndrome; the lack of androgen excess may result in less suppression of ovulation and, hence, a greater chance of pregnancy occurring during active Cushing’s syndrome. Alternatively, the high frequency of benign adrenal adenomas could conceivably relate to excessive stimulation of adrenal growth during pregnancy by placental ACTH [90,108,111,112], placental variant GH [130,135–138], or other growth factors. Recently, three patients have been described with ACTH-independent Cushing’s syndrome during pregnancy associated with bilateral adrenal hyperplasia, either diffuse or macronodular; in all cases, the hypercortisolism resolved spontaneously following delivery, suggesting that an adrenal stimulator produced by the fetoplacental unit might be responsible for the Cushing’s syndrome. A possible mechanism might involve the ectopic expression of hormone receptors in the adrenal glands, which become activated only when normal pregnancy hormones (e.g., hCG) are present [215–217]. In one of these cases, cortisol production was, in fact, stimulated by hCG and LH [217]. As previously discussed, plasma total and free cortisol are increased during normal pregnancy, as is urinary free cortisol, and suppression of these parameters by exogenous dexamethasone is incomplete [106,108,218]. These measurements must therefore be compared to pregnancy norms in order to make the diagnosis of Cushing’s syndrome during pregnancy (Table 18.2). Careful examination of diurnal rhythmicity of serum cortisol may be valuable, since this rhythm is preserved in normal pregnancy and is generally absent in Cushing’s syndrome [93,95]. Additionally, urinary 17-hydroxycorticosteroids are not increased during normal pregnancy, so this parameter, rather than urinary free cortisol, may be a useful measurement [219]. Complete nonsuppressibility of plasma or urinary cortisol

Pituitary–adrenal function tests during pregnancy

Test

Nonpregnant

Pregnant

Plasma cortisol (mean (SD) mg/dl)

a.m. 12.3 (6.6) p.m. 1.4 (1.2)

Urinary free cortisol (UFC) (mg/24 h) Urinary 17-hydroxysteroids (17-OHCS) (mg/24 h) Overnight dexamethasone suppression test (plasma cortisol; mg/dl) Low-dose dexamethasone (0.5 mg q 6 h ¥ 2 days) suppression test* Response to cosyntropin, 0.25 mg (plasma cortisol; mg/dl)

<100 2–10 £5 (mean 1.5 (1.2)) Urinary 17-OHCS £ 4 mg UFC £ 20 mg Increment > 7 Peak > 18 Mean increment 14.4 (2.1)

Second trimester: a.m. 26.9 (9.5) p.m. 12.7 (3.7) Third trimester: a.m. 26.4 (11.3) p.m. 14.3 (3.4) 60–250 2–10 Mean 4.6 (0.8) (in third trimester) Urinary 17-OHCS £ 4 mg UFC 40–80 mg Second trimester: increment 23.7 (8.7) Third trimester: increment 26 (14.6)

* Urinary 17-OHCS or UFC excreted in 24 hours. All values, especially those for urinary free cortisol, are approximate, and are subject to considerable interlaboratory variability; patient values should be compared to local norms.

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by high-dose dexamethasone would suggest autonomous production by an adrenal tumor or ectopic ACTH syndrome, but borderline suppressibility in low-dose or overnight testing may still be normal [108,218]. Short-term administration of dexamethasone for testing purposes poses little or no risk to either mother or fetus. Measurements of plasma ACTH have been undetectable in most but not all cases of adrenal tumor causing Cushing’s syndrome in pregnancy [220–222], and in the high-normal range in pregnant patients with pituitary-dependent Cushing’s disease [223,224]. Thus, a detectable level of ACTH in plasma does not necessarily exclude adrenal tumor [222]; this ACTH may originate from the placenta [90,108,111,112]. Radiologic studies to evaluate the pituitary and adrenal glands during pregnancy are necessarily limited; ultrasonography and MRI are the preferred techniques. The major risks to the fetus of maternal Cushing’s syndrome are premature labor, which occurs in about 50–60% of patients [212], and intrauterine growth retardation, seen in about 38% [225]. Although the fetal HPA axis may be suppressed by excess maternal cortisol crossing the placenta, neonatal adrenal insufficiency is unusual [225]. The major maternal complications are hypertension (65%) and gestational diabetes mellitus (32%) [225]. Pulmonary edema occurs in 11% of patients [225]. Poor wound healing and postoperative infections often complicate Caesarean section performed on patients with uncontrolled Cushing’s syndrome. Mild cases of Cushing’s syndrome during pregnancy are often best managed expectantly, deferring definitive therapy until after delivery. Severe cases, including those in which adrenal carcinoma is suspected, need surgical intervention. To date, only three patients with pituitary-dependent Cushing’s disease have been subjected to transsphenoidal adenomectomy during pregnancy [223–225], with cure of the Cushing’s disease in two. Drug treatment with metyrapone has been used in several cases, usually with no apparent harm to the fetus [215,216,225,226], although in one patient metyrapone therapy exacerbated maternal hypertension and may have contributed to preeclampsia [221]. ACROMEGALY Patients with acromegaly frequently have menstrual disturbances, and many are amenorrheic [227,228], either from anatomic interference with normal pituitary function or concurrent hyperprolactinemia [227,229]; the intrinsic PRL-like actions of GH may possibly also contribute to suppression of gonadotropins [229]. Nevertheless, patients with acromegaly occasionally become pregnant. In general, the presence of GH excess does not alter the pregnancy in any important way; theoretically, there could be a tendency toward more maternal hypertension and gestational diabetes mellitus, but this has apparently not been borne out

[29,227–235]. Similarly, the occurrence of pregnancy usually does not alter the course of acromegaly, apart from occasional occurrences of pituitary tumor enlargement during pregnancy [236]; it is not clear if patients with concurrent tumor production of PRL are particularly vulnerable to this complication. In most pregnant patients with untreated acromegaly, therapy for the acromegaly can be safely deferred until after delivery. If treatment is necessary during gestation because of significant tumor enlargement or serious complications of GH excess, transsphenoidal surgery can be performed or bromocriptine may be administered safely [29,228,231–233,235–238]. In one case, visual field defects developed in a pregnant acromegalic due to the combination of mass effects from the pituitary adenoma and physiologic lactotroph hyperplasia; treatment with bromocriptine suppressed PRL secretion and restored normal vision, allowing definitive surgical therapy to be deferred until after delivery [235]. To date, only a few acromegalic patients have received octreotide therapy during pregnancy, and only one for the entire gestation; in that patient, administration of octreotide had no apparent deleterious effect on the course of the pregnancy or on its ultimate successful outcome [238]. POSTERIOR PITUITARY DISORDERS DI may occur for the first time during pregnancy or the postpartum period, or may be exacerbated by pregnancy. Additionally, a unique form of transient DI may occur during pregnancy in the apparent absence of any true defect in vasopressin secretion [126].

Pre-existing DI Patients with idiopathic central DI generally have normal fertility, normal pregnancies and normal deliveries [126]. Oxytocin secretion is usually normal [239,240]. Most women with central DI require larger doses of arginine vasopressin (AVP) to control polyuria during pregnancy, with a return to normal AVP requirements after delivery [126,239]. This increased vasopressin requirement during pregnancy is primarily due to the presence in pregnancy plasma of large amounts of vasopressinase, an enzyme which rapidly degrades vasopressin and oxytocin. Vasopressinase is a cystine aminopeptidase which is produced by the placenta; plasma levels increase throughout pregnancy, peak at term, and disappear rapidly (over 2–4 weeks) following delivery. Thus, in normal third-trimester pregnant women, AVP clearance from plasma is about three times faster than in the postpartum period [126]. Postpartum, breast-feeding may be associated with an amelioration of central DI [126]. Since breast-feeding briskly releases oxytocin but not vasopressin [149,151], this suggests that high oxytocin levels may have some antidiuretic effect in these patients.

Chapter 18

Transient DI of Pregnancy Three forms of transient DI of pregnancy have been distinguished. A vasopressin (AVP)-responsive form probably occurs only in patients with mild or subclinical central DI; in these subjects, the normal pregnancy increase in vasopressin requirements due to placental vasopressinase cannot be met because of a limitation in AVP secretory capacity [126,241]. Vasopressin (AVP)-resistant forms may be due either to true renal vasopressin resistance (rare) or to abnormally high vasopressin clearance due to unusually elevated plasma vasopressinase activity [126,242–245]. These AVPresistant forms can be distinguished by the presence or absence of a renal response to the vasopressin analog desamino-D-arginine vasopressin (DDAVP). Patients with true renal resistance (nephrogenic DI) do not respond to either AVP or DDAVP; in contrast, patients with transient DI due to abnormally high vasopressinase activity do not respond to exogenous AVP, but do respond normally to DDAVP, which is resistant to degradation by vasopressinase [126]. Thus, DDAVP is the preparation of choice for treating either central DI or transient DI in pregnancy. True nephrogenic DI may be managed with thiazide diuretics [126]. Several interesting features of transient DI of pregnancy due to excess vasopressinase have been pointed out in a review of 17 cases by Krege et al. [245]. Symptoms always appeared in the third trimester. Three patients had twins or triplets. Hypertension, proteinuria, hyperuricemia and elevated liver enzymes were commonly seen. Both excessive vasopressinase production (due to large placentas, as in multiple gestations) and decreased vasopressinase clearance (perhaps due to liver abnormalities) may play a role in elevated plasma vasopressinase in these patients.

Postpartum DI Central diabetes insipidus appearing in the immediate postpartum period is most likely to be due to Sheehan’s syndrome [126]; much less commonly, DI may occur in lymphocytic hypophysitis [202]. REFERENCES 1 Erdheim J, Stumme E. Über die schwangerschaftsveranderung der hypophyse. Beitr Z Pathol Anat 1909;46:1–132. 2 Scheithauer BW, Sano T, Kovacs KT et al. The pituitary gland in pregnancy: a clinico-pathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 1990;65:461–474. 3 Dinc H, Esen F, Demirci A et al. Pituitary dimensions and volume measurements in pregnancy and post partum. MR assessment. Acta Radiol 1998;39:64–69. 4 Miki Y, Asato R, Okumura R et al. Anterior pituitary gland in pregnancy: hyperintensity at MR. Radiology 1993;187:229–231. 5 Goluboff LG, Ezrin C. Effect of pregnancy on the somatotroph and the prolactin cell of the human hypophysis. J Clin Endocrinol Metab 1969;29: 1533–1538. 6 Asa SL, Penz G, Kovacs K, Ezrin C. Prolactin cells in the human pituitary: a quantitative immunocytochemical analysis. Arch Pathol Lab Med 1982;106: 360–363.

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7 Stefaneanu L, Kovacs K, Lloyd RV et al. Pituitary lactotrophs and somatotrophs in pregnancy: a correlative in situ hybridization and immunocytochemical study. Virchows Archiv B Cell Pathol 1992;62:291–296. 8 Visser M, Swaab DF. Life span changes in the presence of a-melanocytestimulating-hormone-containing cells in the human pituitary. J Dev Physiol 1979;1:161–178. 9 Tyson JE, Hwang P, Guyda H, Friesen HG. Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 1972;113:14–20. 10 Rigg LA, Lein A, Yen SSC. Pattern of increase in circulating prolactin levels during human gestation. Am J Obstet Gynecol 1977;129:454–456. 11 Hwang P, Guyda H, Friesen H et al. A radioimmunoassay for human prolactin. Proc Natl Acad Sci USA 1971;68:1902–1906. 12 Lloyd HM, Meares JD, Jacobi J. Effects of oestrogen and bromocriptine on in vivo secretion and mitosis in prolactin cells. Nature 1975;255:497–498. 13 Stone RT, Maurer RA, Gorski J. Effect of estradiol-17b on preprolactin messenger ribonucleic acid activity in the rat pituitary gland. Biochemistry 1977;16:4915–4921. 14 Jacobi J, Lloyd HM, Meares JD. Onset of oestrogen-induced prolactin secretion and DNA synthesis by the rat pituitary gland. J Endocrinol 1977;72: 35–39. 15 De Nicola AF, von Lawzewitsch I, Kaplan SE, Libertun C. Biochemical and ultrastructural studies on estrogen-induced pituitary tumors in F344 rats. J Natl Cancer Inst 1978;61:753–763. 16 Lloyd RV. Estrogen-induced hyperplasia and neoplasia in the rat anterior pituitary gland: an immunohistochemical study. Am J Pathol 1983;113:198–206. 17 Prysor-Jones RA, Silverlight JJ, Jenkins JS. Oestradiol, vasoactive intestinal peptide and fibroblast growth factor in the growth of human pituitary tumor cells in vitro. J Endocrinol 1989;120:171–177. 18 Prysor-Jones RA, Silverlight JJ, Kennedy SJ, Jenkins JS. Vasoactive intestinal peptide and the stimulation of lactotroph growth by oestradiol in situ. J Endocrinol 1988;116:259–265. 19 Nogami H, Yoshimura F, Carrillo AJ et al. Estrogen induced prolactin mRNA accumulation in adult male rat pituitary as revealed by in situ hybridization. Endocrinol Jpn 1985;32:625–634. 20 Elias KA, Weiner RI. Direct arterial vascularization of estrogen-induced prolactin-secreting anterior pituitary tumors. Proc Natl Acad Sci USA 1984;81: 4549–4553. 21 Golander A, Hurley T, Barrett J et al. Prolactin synthesis by human-chorion decidual tissue: a possible source of amniotic fluid prolactin. Science 1978;202:311–313. 22 Riddick DH, Luciano AA, Kusmik WF, Maslar IA. De novo synthesis of prolactin by human decidua. Life Sci 1978;23:1913–1922. 23 Fang VS, Kim MH. Study on maternal, fetal, and amniotic human prolactin at term. J Clin Endocrinol Metab 1975;41:1030–1034. 24 Chochinov RH, Ketupanya A, Mariz IK et al. Amniotic fluid reactivity detected by somatomedin C radioreceptor assay: correlation with growth hormone, prolactin and fetal renal maturation. J Clin Endocrinol Metab 1976;42:983–986. 25 Rosenberg SM, Maslar IA, Riddick DH. Decidual production of prolactin in late gestation: further evidence for a decidual source of amniotic fluid prolactin. Am J Obstet Gynecol 1980;138:681–685. 26 Riddick DH, Luciano AA, Kusmik WF, Maslar IA. Evidence for a nonpituitary source of amniotic fluid prolactin. Fertil Steril 1979;31:35–39. 27 Kauppila A, Chatelain P, Kirkinen P et al. Isolated prolactin deficiency in a woman with puerperal alactogenesis. J Endocrinol Metab 1987;64:309–312. 28 Lee D, Leon C, Milanes BA. Serum prolactin during pregnancy induced by pituitary gonadotropins in a patient with post partum hypopituitarism (Sheehan’s syndrome). Arch Invest Med 1981;12:29–41. 29 Bigazzi M, Ronga R, Lancranjan I et al. A pregnancy in an acromegalic woman during bromocriptine treatment: effects on growth hormone and prolactin in the maternal, fetal, and amniotic compartments. J Clin Endocrinol Metab 1979;48:9–12. 30 Bergh T, Nillius SJ, Enoksson P, Wide L. Bromocriptine-induced regression of a suprasellar extending prolactinoma during pregnancy. J Endocrinol Invest 1984;7:133–137. 31 Anderson AN, Pedersen H, Westergaard JG et al. Normal and abnormal prolactin levels during human pregnancy. Acta Obstet Gynecol Scand 1984;63: 145–148. 32 Tyson JE, Friesen HG. Factors influencing the secretion of human prolactin and growth hormone in menstrual and gestational women. Am J Obstet Gynecol 1973;116:377–387. 33 Hershman JM, Kojima A, Friesen HG. Effect of thyrotropin-releasing hormone on human pituitary thyrotropin, prolactin, placental lactogen and chorionic thyrotropin. J Clin Endocrinol Metab 1973;36:497–501.

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Chapter 18 194 Singer PA, Mestman JH, Manning PR et al. Hypothalamic hypothyroidism secondary to Sheehan’s syndrome. West J Med 1974;120:416–418. 195 Fleckman AM, Schubart UK, Danziger A, Fleischer N. Empty sella of normal size in Sheehan’s syndrome. Am J Med 1983;75:585–591. 196 Knobel B, Ben-Yosef S, Rosman P. Sheehan’s syndrome and empty sella turcica. Israel J Med Sci 1984;20:232–235. 197 Barkan A. Case report: pituitary atrophy in patients with Sheehan’s syndrome. Am J Med Sci 1989;298:38–40. 198 Sherif IH, Vanderley CM, Beshyah S, Bosairi S. Sella size and contents in Sheehan’s syndrome. Clin Endocrinol 1989;30:613–618. 199 Gotshalk HC, Tilden IL. Necrosis of the anterior pituitary following parturition. JAMA 1940;114:33–35. 200 Cosman F, Post KD, Holub DA, Wardlaw SL. Lymphocytic hypophysitis. Report of 3 new cases and review of the literature. Medicine 1989;68:240–256. 201 Powrie JK, Powell M, Ayers AB et al. Lymphocytic adenohypophysitis: magnetic resonance imaging features of two new cases and a review of the literature. Clin Endocrinol 1995;42:315–322. 202 Hashimoto K, Takao T, Makino S. Lymphocytic adenohypophysitis and lymphocytic infundibuloneurohypophysitis. Endocrine J 1997;44:1–10. 203 Saiwai S, Inoue Y, Ishihara T et al. Lymphocytic adenohypophysitis: skull radiographs and MRI. Neuroradiol 1998;40:114–120. 204 Stelmach M, O’Day J. Rapid change in visual fields associated with suprasellar lymphocytic hypophysitis. J Clin Neuro-ophthalmol 1991;11:19–24. 205 Ishihara T, Hino M, Kurahachi H et al. Long-term clinical course of two cases of lymphocytic hypophysitis. Endocrine J 1996;43:433–440. 206 Gagneja H, Arafah B, Taylor HC. Histologically proven lymphocytic hypophysitis: spontaneous resolution and subsequent pregnancy. Mayo Clin Proc 1999;74:150–154. 207 Boccuzzi G, Angeli A, Bisbocci D et al. Effect of synthetic luteinizing hormone releasing hormone (LH-RH) on the release of gonadotropins in Cushing’s disease. J Clin Endocrinol Metab 1975;40:892–895. 208 Melis GB, Mais V, Gambacciani M et al. Dexamethasone reduces the postcastration gonadotropin rise in women. J Clin Endocrinol Metab 1987;65: 237–241. 209 Gabrilove JL, Seman AT, Sabet R et al. Virilizing adrenal adenoma with studies on the steroid content of the adrenal venous effluent and a review of the literature. Endocr Rev 1981;2:462–469. 210 Urbanic RC, George JM. Cushing’s disease—18 years experience. Medicine 1981;60:14–24. 211 Howlett TA, Rees LH, Besser GM. Cushing’s syndrome. Clin Endocrinol Metab 1985;14:911–945. 212 Sheeler LR. Cushing’s syndrome and pregnancy. Endocrinol Metab Clin North Am 1994;23:619–627. 213 Gold EM. The Cushing syndromes: changing views of diagnosis and treatment. Ann Intern Med 1979;90:829–844. 214 Ross EJ, Linch DC. Cushing’s syndrome—killing disease. Discriminatory value of signs and symptoms aiding early diagnosis. Lancet 1982;1:646–649. 215 Close CF, Mann MC, Watts JF, Taylor KC. ACTH-independent Cushing’s syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone. Clin Endocrinol 1993;39:375–379. 216 Wallace C, Toth EL, Lewanczuk RZ, Siminoski K. Pregnancy-induced Cushing’s syndrome in multiple pregnancies. J Clin Endocrinol Metab 1996;81: 15–21. 217 Lacroix A, N’Diaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocrine Rev 2001;22:75–110. 218 Nolten WE, Lindheimer MD, Oparil S, Ehrlich EN. Desoxycorticosterone in normal pregnancy. I. Sequential studies of the secretory patterns of desoxycorticosterone, aldosterone and cortisol. Am J Obstet Gynecol 1978;132: 414–420. 219 Kreines K, Perin E, Salzer R. Pregnancy in Cushing’s syndrome. J Clin Endocrinol Metab 1964;24:75–79. 220 Martin RW, Lucas JA, Martin JN et al. Conservative management of Cushing’s syndrome in pregnancy. A case report. J Reprod Med 1989;34:493–495.

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221 Connell JMC, Cordiner J, Davies DL et al. Pregnancy complicated by Cushing’s syndrome: potential hazard of metyrapone therapy. Case report. Br J Obstet Gynecol 1985;92:1192–1195. 222 Bevan JS, Gough MH, Gillmer MDG, Burke CW. Cushing’s syndrome in pregnancy: the timing of definitive treatment. Clin Endocrinol 1987;27: 225–233. 223 Casson IF, Davis JC, Jeffreys RV et al. Successful management of Cushing’s disease during pregnancy by transsphenoidal adenomectomy. Clin Endocrinol 1987;27:423–428. 224 Ross RJM, Chew SL, Perry L et al. Diagnosis and selective cure of Cushing’s disease during pregnancy by transsphenoidal surgery. Eur J Endocrinol 1995;132:722–726. 225 Pinette MG, Pan YQ, Oppenheim D et al. Bilateral inferior petrosal sinus corticotropin sampling with corticotropin-releasing hormone stimulation in a pregnant patient with Cushing’s syndrome. Am J Obstet Gynecol 1994;171: 563–564. 226 Lo KW-K, Lau T-K. Cushing’s syndrome in pregnancy secondary to adrenal adenoma. Gynecol Obstet Invest 1998;45:209–212. 227 Nabarro JDN. Acromegaly. Clin Endocrinol 1987;26:481–512. 228 Herman-Bonert V, Seliverstov M, Melmed S. Pregnancy in acromegaly: successful therapeutic outcome. J Clin Endocrinol Metab 1998;83:727–731. 229 DePablo F, Eastman RC, Roth J, Gorden P. Plasma prolactin in acromegaly before and after treatment. J Clin Endocrinol Metab 1981;53:344–352. 230 Bloch B. Pituitary tumours in pregnancy. A case report. S Afr Med J 1979; 55:57–59. 231 Luboshitzky R, Dickstein G, Barzilai D. Bromocriptine-induced pregnancy in an acromegalic patient. JAMA 1980;244:584–586. 232 Miyakawa I, Taniyama K, Koike H et al. Successful pregnancy in an acromegalic patient during 2-Br-alpha-ergocryptine (CB-154) therapy. Acta Endocrinol 1982;101:333–338. 233 Cundy T, Grundy EN, Melville H, Sheldon J. Bromocriptine treatment of acromegaly following spontaneous conception. Fertil Steril 1984;42:134– 136. 234 Beckers A, Stevenaert A, Foidart J-M et al. Placental and pituitary growth hormone secretion during pregnancy in acromegalic women. J Clin Endocrinol Metab 1990;71:725–731. 235 Yap AS, Clouston WM, Mortimer RH, Drake RF. Acromegaly first diagnosed in pregnancy: the role of bromocriptine therapy. Am J Obstet Gynecol 1990; 163:477–478. 236 Kupersmith MJ, Rosenberg C, Kleinberg D. Visual loss in pregnant women with pituitary adenomas. Ann Intern Med 1994;121:473–477. 237 Vance ML, Thorner MO. Prolactinomas. Endocrinol Metab Clin North Am 1987;16:731–753. 238 Colao A, Merola B, Ferone D, Lombardi G. Acromegaly. J Clin Endocrinol Metab 1997;82:2777–2781. 239 Rubens R, Thiery M. Diabetes insipidus and pregnancy. Eur J Obstet Gynecol Reprod Biol 1987;26:265–270. 240 Shangold MM, Freeman R, Kumaresan P et al. Plasma oxytocin concentrations in a pregnant woman with total vasopressin deficiency. Obstet Gynecol 1983;61: 662–667. 241 Hughes JM, Barron WM, Vance ML. Recurrent diabetes insipidus associated with pregnancy: pathophysiology and therapy. Obstet Gynecol 1989;73:462– 464. 242 Ford SM. Transient vasopressin-resistant diabetes insipidus of pregnancy. Obstet Gynecol 1986;68:288–289. 243 Durr JA, Hoggard JG, Hunt JM, Schrier RW. Diabetes insipidus in pregnancy associated with abnormally high circulating vasopressinase activity. N Engl J Med 1987;361:1070–1074. 244 Iwasaki Y, Oiso Y, Kondo K et al. Aggravation of subclinical diabetes insipidus during pregnancy. N Engl J Med 1991;324:522–526. 245 Krege J, Katz VL, Bowes WA Jr. Transient diabetes insipidus of pregnancy. Obstet Gynecol Surv 1989;44:789–795.

C h a p t e r

19 Drugs and Pituitary Function Harold E. Carlson

Many drugs, both therapeutic and recreational, alter the function of the pituitary gland, usually as a side effect unrelated to the primary indication for which the drug was given. Tables 19.1 to 19.7 summarize the most important drug-related changes in pituitary hormone secretion. ALCOHOLIC BEVERAGES Consumption of beverages containing ethanol may alter pituitary function in several ways: (i) by direct effects on the brain or pituitary gland; (ii) by altering the function of end organs (e.g., testis) and provoking feedback-mediated changes in pituitary hormone secretion; and (iii) by modifying the peripheral metabolism or action of hormones with resulting effects on pituitary function. In some studies, the acute administration of ethanol has been reported to stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion [1–6]; however, these findings have not been confirmed by others [7–15]. The reasons for these discrepancies are unclear, but may in part be related to dose of ethanol [9], the presence or absence of nausea [12], the subjects’ alcohol dehydrogenase genotype [10] or family history of alcoholism [4,6]. Chronic consumption of ethanol may lead to persistent elevation of serum cortisol [2,16], and a small number of alcoholics may develop physical stigmata of Cushing’s syndrome along with nonsuppression of plasma ACTH and cortisol by dexamethasone, the so-called “alcohol-induced pseudoCushing’s syndrome” [2,16–18]. The syndrome usually resolves after days to months of abstinence [2,16–20]. Paradoxically, the ACTH and cortisol responses to insulininduced hypoglycemia and other stimuli are frequently blunted in alcoholics [2,16,18,21]. Ethanol may also stimulate the secretion of b-endorphin in some subjects [6,11,14,22]. 642

Growth hormone (GH) secretion is variably affected by ethanol. Acute administration of alcohol after an overnight fast produces a small rise in serum GH [1], but longer fasting appears to abolish this response [2], perhaps due to elevated serum concentrations of free fatty acids which are known to blunt GH secretion. Acute alcohol consumption in the evening, several hours after a meal, resulted in either unaltered or suppressed serum GH levels [23–25]. Chronic alcohol consumption may also blunt the GH response to various provocative tests [2], possibly again due to the suppressive effects of free fatty acids [2,26]. Daytime serum concentrations of thyrotropin (thyroidstimulating hormone; TSH) and thyroid hormones are not altered by acute ethanol consumption [23,24,27,28], although the nocturnal TSH surge has been reported to be suppressed [25]. The thyroid gland has been reported to be smaller than normal in chronic alcoholics, but this does not seem to be associated with functional impairment [29]. Chronic alcoholics may have a blunted TSH response to thyrotropin-releasing hormone (TRH), although the basal TSH level is normal [19]. Alcohol-induced liver damage can result in the “euthyroid sick” syndrome, generally with low serum triiodothyronine (T3), elevated reverse T3, normal or low thyroxine (T4), and normal or slightly elevated TSH [30]. Reports concerning the effects of ethanol on gonadal function have yielded conflicting data. These inconsistencies may result from the use of different study populations, varying doses of alcohol, performing studies at different times of the day with blood sampling at varying intervals, the development of tolerance to the effects of alcohol, and the presence of variable degrees of hepatic dysfunction in chronic studies [31]. Acute ingestion of ethanol in males has been reported to have no effect on plasma testosterone and luteinizing hormone (LH) [23,32], to suppress testosterone

Chapter 19 Table 19.1.

Recreational drugs that alter pituitary function

Alcoholic beverages Cigarettes and nicotine Marijuana Opiates Cocaine Amphetamines and methylphenidate Caffeine Benzodiazepines

Table 19.2.

Drugs that alter prolactin secretion

Increase

Decrease

Beer Nicotine Opiates Cocaine (?) Amphetamines (i.v.) Imipramine (±) Desipramine (±) Chlorimipramine Amoxapine Monoamine oxidase inhibitors Antipsychotics Buspirone Metoclopramide Sulpiride Domperidone Physostigmine Reserpine (±) Methyldopa (±) Labetalol Verapamil (±) Cimetidine (i.v.) Ranitidine (i.v.) Estrogens

Apomorphine Dopamine L-Dopa Bromocriptine Glucocorticoids

i.v. = intravenous administration.

and raise LH during intoxication [33], to suppress LH [24], to raise LH with no change in testosterone [28], to suppress testosterone and raise LH only during hangover [34], to suppress testosterone with no change in LH [8,13] or to enhance the testosterone but not the LH response to gonadotropin-releasing hormone (GnRH) [35]. Chronic alcohol consumption, in the apparent absence of liver disease, may lower serum testosterone concentrations by inhibiting testicular synthesis and increasing hepatic metabolism of testosterone [36–39]; serum LH may rise, at least transiently, as a consequence. A later fall in LH may occur as a response to rising serum estrogen levels produced by increased hepatic aromatase activity [37–39]. Additionally, plant-derived phytoestrogens are present in alcoholic beverages and could also contribute to gonadotropin suppression

Table 19.3.

Drugs and Pituitary Function

643

Drugs that alter growth hormone secretion

Increase

Decrease

Nicotine Methadone Fentanyl Enkephalin Amphetamines Methylphenidate Benzodiazepines (±) Imipramine Desipramine Chlorimipramine Apomorphine Dopamine L-dopa Bromocriptine Physostigmine Propranolol Clonidine Estrogens Androgens

Atropine Pirenzepine Yohimbine Phentolamine Cimetidine (?) Glucocorticoids

Table 19.4. Drugs that alter gonadotropin (luteinizing hormone/follicle-stimulating hormone) secretion Increase

Decrease

Opiate antagonists Cancer chemotherapy Ketoconazole

Opiates Dopamine Bromocriptine Verapamil Estrogens Androgens Glucocorticoids Digitoxin

Table 19.5.

Drugs that alter thyrotropin secretion

Increase

Decrease

Lithium Metoclopramide Sulpiride Domperidone Estrogens (±)

Dopamine L-dopa Bromocriptine Verapamil Androgens (±) Glucocorticoids Phenytoin

[40]. Ethanol is also toxic to the seminiferous tubules, and may produce testicular atrophy and elevated serum folliclestimulating hormone (FSH) levels [38,41]. In women, acute administration of ethanol has generally been reported to be without effect on serum LH or estradiol concentrations [42–45], although one study reported a

644

SECTION 4

Table 19.6.

Pituitary Disease in Systemic Disorders

Drugs that alter adrenocorticotropin secretion

Increase

Decrease

Nicotine Opiate antagonists Amphetamines Methylphenidate Imipramine Desipramine Chlorimipramine Physostigmine

Opiates Glucocorticoids

Table 19.7.

Drugs that alter vasopressin secretion

Increase

Decrease

Nicotine Lithium Chlorpropamide

Opiates Glucocorticoids

small rise in estradiol following alcohol ingestion [46]; additionally, ethanol enhances the estradiol response to a GnRH-induced LH pulse [47]. Chronic administration, however, has produced a variety of disturbances in the menstrual cycle [48–51]. In postmenopausal woman, serum gonadotropins are altered minimally by ethanol [50,51]. The effects of alcohol on prolactin (PRL) are controversial. Most studies have reported no acute effect of ethanol ingestion on serum PRL concentrations [23,25,27,28, 43,45,52–54]. One study reported an acute decrease in serum PRL following ethanol ingestion [44], while several studies have found a small but statistically significant doserelated rise in serum PRL following ethanol administration [4,8,15,42,55–58]. In one of these, the PRL rise was seen only in subjects who became nauseated during the study [42]. Interestingly, beer is a fairly potent stimulus to PRL secretion [53,59], an effect that appears to be independent of its ethanol content [53]. Serum PRL is elevated in a minority of patients with alcoholic liver disease [60]. In some studies ethanol has had a transient suppressive effect on oxytocin and vasopressin secretion [61–65], while in others vasopressin has been unchanged or even increased [12,66,67]. Chronic alcoholics have been reported to have a decrease in the number of vasopressin-containing neurons in the supraoptic and paraventricular nucleus of the hypothalamus [68]. SMOKING

Cigarette Smoking and Nicotine Cigarette smoking results in the acute release of several pituitary hormones, and the effects appear to be due to nicotine. Several studies have reported increases in plasma

cortisol, ACTH and b-endorphin/b-lipotropin in response to rapidly smoking one or more medium or high-nicotine cigarettes; sham smoking or smoking low-nicotine cigarettes had no such effect [69–84]. Similarly, a rise in serum GH following smoking has been consistently observed [55,69–71,74,81,82], and three studies have reported a rise in serum PRL induced by smoking [71,74,81]. Two reports [74,76] have ascribed these hormonal changes to nausea induced by rapid smoking, but other studies have noted similar hormonal increments in subjects who did not experience nausea [69–73,75,77,82]. In contrast to the hormone-stimulating effects of rapid smoking, more gradual smoking as practiced by smokers under natural circumstances results in lower serum nicotine levels and no stimulation of cortisol secretion [77,78,80,81,84–89]. Nicotine infusion also stimulates ACTH and cortisol secretion [79]. While a direct nicotine action on each of the appropriate hypothalamic regulatory centers is possible, it is also possible that nicotine-induced vasopressin release (see below) may contribute in a minor way to ACTH and bendorphin/b-lipotropin secretion, and that b-endorphin release may, in turn, stimulate PRL secretion [79,90–92]. In humans, serum TSH, LH, and FSH are not acutely altered by smoking [70,74]. Chronic smokers may have slightly lower serum levels of TSH than nonsmokers, a situation that may reflect direct or indirect nicotine effects on thyroid hormone secretion, metabolism or action [93–95]. Release of vasopressin and its precursor protein, neurophysin I, is stimulated by smoking or nicotine infusion [61,72,79,82,91,92,96–101], while oxytocin and neurophysin II are not affected [97,99–101].

Marijuana Although animal studies have shown a wide variety of effects of marijuana on hormonal systems, it has been difficult to show consistent changes in human studies, in which lower doses of marijuana or tetrahydrocannabinol are given. Additional experimental difficulties in some studies involve possible inaccuracies of reported intake, uncertainty regarding concurrent use of alcohol or other drugs, and the development of tolerance to the effects of marijuana. One study has reported that serum testosterone in males is lowered by marijuana smoking [102], but other investigators have failed to confirm this finding [103–108]. Similarly, one group has reported acute suppression of serum LH in males following acute marijuana smoking [108], but others have seen no change in gonadotropins [102,105,106]. Very few similar studies have been performed in women; one outpatient study has reported that female marijuana smokers had shorter luteal phases but no change in serum gonadotropins [109], while a more rigidly controlled inpatient study has found a small but significant fall in serum LH in response to acute marijuana smoking in young women [110]. Marijuana smoking had no effect on serum LH in postmenopausal women [111].

Chapter 19

Serum T4 and TSH are not altered by marijuana smoking [102,107], nor is serum GH [108]. Serum PRL also shows little or no change following marijuana or tetrahydrocannabinol administration [102,108,112–114]. Marijuana smoking elevated serum cortisol in one study [108] but oral administration of marijuana extract or tetrahydrocannabinol had no effect on serum cortisol in another [115].

OPIATES AND OPIATE ANTAGONISTS

Opiates Acute administration of opiates (e.g., morphine, heroin, codeine, fentanyl, b-endorphin, enkephalins) has profound and generally consistent effects on human pituitary function. In males, serum LH is lowered, followed by a fall in serum testosterone [116–120]. In females, b-endorphin suppressed serum LH in premenopausal subjects [120], but had no effect in postmenopausal women [121]. However, both morphine and an enkephalin analog did suppress LH in postmenopausal women [120,122], indicating that specific opiate receptor subtypes may mediate different actions on gonadotropin secretion. Deltorphin did not decrease serum LH in luteal phase women, but did blunt the naloxoneinduced rise [123]. Serum FSH is also acutely decreased by opiates, but to a lesser degree [116,122,124]. Based primarily on animal studies, it appears that opiates suppress gonadotropin secretion by inhibiting GnRH release [125]; opiates do not impair the gonadotropin response to GnRH in humans [122]. PRL secretion is stimulated by all opiates, in both sexes [116,118,119,121,126–139]. This effect may be due to a decrease in tuberoinfundibular dopamine (DA) release [140], to an antagonism of the PRL-suppressive effects of DA at the pituitary level [141,142], or to secretion of hypothalamic PRL-releasing factors [143]. In several human studies, basal serum TSH was not altered by acute opiate administration [118,126,127,131, 139], but others have reported small but significant increases in TSH in response to opiates [116,119,136,137]. One group has reported that the TSH response to TRH is enhanced by an enkephalin analog [144]. In contrast, opiate effects on GH secretion depend on the compound administered. Neither morphine nor b-endorphin release GH in humans when given systemically [118,119,126, 127,131,132,136,139], but methadone, fentanyl, and an enkephalin analog all stimulate GH secretion [116,133–135, 145,146], suggesting involvement of specific opiate receptor subtypes in GH regulation. There is some evidence that stimulation of GH release by enkephalin analogs may involve a reduction in somatostatin secretion [146]. Intraventricular morphine stimulated both GH and PRL secretion [139]. Opiates acutely suppress ACTH and cortisol secretion [116,119,130–133,135,136,139,147–149]. This effect may be exerted at the pituitary level, since opiates blunt the

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ACTH response to lysine vasopressin and corticotropinreleasing hormone (CRH) [149,150] and since loperamide, an opiate agonist which does not cross the blood–brain barrier, suppresses cortisol secretion [148]. Alternatively, since opiates do not directly alter ACTH secretion in vitro [150], the suppressive effect of opiates may involve other suprapituitary factors. Although conflicting data have been obtained, opiates, on balance, appear to inhibit vasopressin secretion [151]. Plasma oxytocin concentrations were decreased by morphine administration during labor [152] but not in late pregnancy before the onset of labor [153]. Chronic administration of opiates, as in narcotic addiction, results in partial tolerance to their euphoric and endocrine effects. Nevertheless, chronic heroin or methadone administration may result in a slight decrease in serum testosterone with little or no change in serum gonadotropins [117,125,154–157]. Thyroid function and serum TSH are normal [157], as is GH secretion [157]. Serum PRL is mildly elevated [157]. Serum cortisol is normal or slightly decreased, but may show exaggerated responses to hypoglycemia or meals [157]. Chronic methadone maintenance has been reported to produce a mild impairment in renal concentrating ability that responds to vasopressin administration, suggesting decreased endogenous vasopressin secretion [157]. Men with chronic heroin and cocaine dependence have been reported to have mild pituitary enlargement, perhaps due to lactotroph hyperplasia [158].

Opiate Antagonists Naloxone, naltrexone and nalmefene are opiate antagonists, nearly devoid of agonist activity, that have proved invaluable in exploring the role of endogenous opiates in human pituitary function. All three drugs cause an acute increase in serum LH in men and luteal-phase women, with little or no effect in the early follicular phase of the menstrual cycle or in postmenopausal women; smaller changes are generally seen in serum FSH [120–123,159–169]. Most investigators have found no effect of naloxone or nalmefene on basal serum TSH, GH and PRL [144,159,162,169–172], although one group has reported a small rise in serum PRL following naloxone administration during the luteal phase [165] and another study reported that naloxone decreased nocturnal TSH secretion [173]. Cortisol and ACTH secretion are acutely stimulated by naloxone [159,162,168,171, 174–177]. Chronic naltrexone administration, however, did not alter serum testosterone or gonadotropins [178], in contrast to the acute response. Taken together, these data suggest that endogenous opiates may play a significant inhibitory role in the physiologic regulation of ACTH and gonadotropin secretion. Naloxone has little or no effect on vasopressin secretion [151,179], but may bring out an oxytocin response to nicotine [179] and inhibit the oxytocin response to orgasm

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[180]. Naloxone had no effect on plasma oxytocin concentrations in late pregnancy or during labor [152,153]. COCAINE Despite the widespread use of cocaine, there is little information on the endocrine effects of this drug. There are only two reports on the acute effects of cocaine in naïve subjects; these studies reported that cocaine acutely increased serum LH, FSH and cortisol and suppressed prolactin, but did not change serum testosterone [181,182]. In newlyabstinent cocaine abusers, the only finding of note has been the observation that some individuals have mild or moderate hyperprolactinemia which lasts for weeks after withdrawal. The incidence of hyperprolactinemia is uncertain, ranging from 0% to 70% [183–188]. Hyperprolactinemia, if present, may result from disordered dopaminergic or opioidergic neurotransmission induced by the drug [189], and may result in sexual dysfunction in cocaine users [183]. Despite the hyperprolactinemia, serum LH and testosterone have been reported to be normal [184,190], as has serum cortisol [184,185,187,190]. Serum GH may be mildly increased [185,187]. There are no data on serum thyroid hormone or TSH concentrations in cocaine abusers. AMPHETAMINES AND METHYLPHENIDATE These stimulant drugs act by promoting the release and/or inhibiting the neuronal reuptake of DA, norepinephrine and, to a lesser extent, serotonin [191,192]. Acute oral administration of dextroamphetamine consistently stimulates GH and cortisol release [193,194] but has either no effect [194] or a suppressive action [195] on serum PRL. Intravenous amphetamine stimulates GH and cortisol secretion [191,196,197] but, in contrast, also appears to slightly stimulate PRL release [191,198,199], suggesting that high serum amphetamine concentrations achieved by bolus intravenous administration may activate additional neurotransmitter systems (e.g., serotonergic mechanisms). This interpretation is supported by the finding that a slower, prolonged intravenous infusion of amphetamine suppresses rather than stimulates serum PRL [200]. Acute oral administration of methylphenidate probably stimulates GH [193] and cortisol [201] secretion, although there is some disagreement on both of these points [193,201]. Plasma b-endorphin rose following oral methylphenidate in one study [201]. Intravenous methylphenidate raises serum GH, ACTH, and cortisol [192,202,203], while serum PRL is either suppressed [192] or unchanged [202,204]. A troublesome observation has been the finding that chronic treatment of children with attention deficit disorder with these stimulant drugs commonly produces slowing of linear growth [205]. The mechanism of this growth retardation is unclear; GH secretion, serum IGF-I and serum GH-binding protein are all normal [206,207].

CAFFEINE Caffeine, a widely consumed stimulant, exerts its major actions through antagonism at adenosine receptors [208]; metabolites generated in vivo, such as theophylline and theobromine, may also contribute to the drug’s effects [208]. Acute administration of large doses (500 mg, equivalent to five cups of coffee) to naïve normal subjects has minimal effect on pituitary function, producing only slight increases in plasma cortisol, b-endorphin/b-lipotropin, and GH; TSH and PRL are unchanged [209–213]. There are no data regarding caffeine effects on gonadotropin secretion in humans, although theophylline, a related methylxanthine, has been reported to have no effect on serum LH concentrations [214]. Chronic consumption of caffeine produces tolerance to most of the drug’s actions, suggesting that long-term endocrine sequelae are unlikely [208,209]. BENZODIAZEPINES Several studies have reported that acute administration of benzodiazepines (diazepam, bromazepam, metaclazepam) stimulates GH secretion in some normal males [215–222]. The response is seen in one-third to one-half of normal men and even less frequently in women [216,218–223]. Intravenous drug administration is generally more effective than oral dosing [218,220]. Serum PRL,TSH, LH, and FSH are not affected [215,216,219–221,224]. Basal secretion of cortisol, b-endorphin, and b-lipotropin is not altered by diazepam [220,223,225], but alprazolam and temazepam appear to modestly suppress serum cortisol [224,226]; additionally, diazepam blocks the cortisol, b-endorphin and blipotropin responses to hypoglycemia [225]. It is not clear whether these effects on cortisol are due to specific actions at hormone regulatory centers or reflect a more general relief of anxiety and stress by the drugs. In favor of a specific action on hormone regulation are observations that diazepam suppresses nocturnal release of cortisol and GH [227], and that alprazolam suppresses the release of ACTH and cortisol induced by naloxone or metyrapone administration [228,229]. With chronic benzodiazepine administration, basal serum GH and PRL levels are normal and the GH response to diazepam appears to be blunted [230]. Thus, signs and symptoms of GH excess do not develop in patients receiving long-term benzodiazepine therapy. Flumazenil, a benzodiazepine receptor antagonist, had no effect on basal or naloxone-stimulated release of ACTH or cortisol, suggesting endogenous benzodiazepine-like ligands do not tonically regulate ACTH secretion [231]. ANTIDEPRESSANTS Acute oral or intravenous administration of imipramine, desipramine, and chlorimipramine has been reported to stimulate GH, PRL, cortisol, and ACTH in normal subjects

Chapter 19

[232–238], although others have not confirmed these effects [233,239,240]. Many of these discrepancies appear to be due to the use of different drug doses [232,235,238]. Amitriptyline has little effect on any of these hormones [233,240]. A single study has reported that acute administration of chlorimipramine had no effect on serum LH and TSH concentrations [237] and oral fluvoxamine did not alter basal or stimulated secretion of LH, FSH, PRL, GH,TSH or cortisol [241]. Oral nefazodone was reported to stimulate PRL release [242]. Chronic administration of chlorimipramine modestly raised serum PRL to about twice baseline in most [237–239,243] but not all [244] studies, while chronic treatment with desipramine, imipramine, nortriptyline, and amitriptyline had little or no effect on serum PRL [237,240,244–248]. There is probably little or no change in serum cortisol, TSH or GH during chronic treatment with the tricyclic antidepressants, selective serotonin reuptake inhibitors or monoamine oxidase inhibitors [243,244,247, 249–252]. Amoxapine, an antidepressant structurally related to the antipsychotic agent, loxapine, has DA antagonist activity and is a modest stimulator (three to four times basal) of PRL secretion [246,253]. Bupropion, a nontricyclic antidepressant, has no effect on serum PRL or GH [254]. Monoamine oxidase inhibitors such as chlorgyline and pargyline also double basal PRL concentrations when given chronically [255]. Thus, with the exception of amoxapine, chlorimipramine, and the monoamine oxidase inhibitors, most antidepressants have either no effect on anterior pituitary hormone secretion or minimal effects. In particular, these drugs rarely cause significant hyperprolactinemia (over 30 mg/L) and rarely produce galactorrhea. Hyponatremia, apparently due to inappropriate secretion of antidiuretic hormone (ADH), has been reported with many antidepressants, including tricyclics, monoamine oxidase inhibitors, and bupropion [256–261]. LITHIUM Used primarily in the treatment of bipolar affective disorder, lithium has only two major effects on pituitary function, both indirect. Lithium acts on the thyroid gland to inhibit hormone release [262], resulting in activation of feedback mechanisms and increased pituitary secretion of TSH [263]. In most normal subjects, this TSH rise is minor and transient [263,264], but in susceptible individuals (often those with preexisting thyroid damage due to autoimmune thyroiditis or radiation) frank hypothyroidism may be produced and goiter may develop [263,264]. To detect such cases of emerging hypothyroidism, serum T4 and TSH should be monitored every 3–4 months during the first year of lithium therapy, and yearly thereafter. Lithium also impairs the action of vasopressin on the kidney [265]. This mild nephrogenic diabetes insipidus results in enhanced vasopressin release with no change in

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the osmotic threshold for vasopressin secretion [266,267]. Lithium may also mildly stimulate thirst [267], an additional action that could also contribute to the polyuria and polydipsia seen in some patients receiving lithium therapy. ANTIPSYCHOTIC DRUGS The major antipsychotic drugs (also known as neuroleptics) act as antagonists at the D-2 DA receptor; the phenothiazines, butyrophenones, and thioxanthenes all share this property, which is probably the basis of their antipsychotic action [268–271]. Since D-2 DA receptors participate in the regulation of pituitary hormone secretion, it is not suprising that these drugs have important effects on pituitary function. The most consistent endocrine effect of the classic neuroleptic drugs is elevation of serum PRL. This effect is due to antagonism of the PRL-inhibitory effects of endogenous DA at the pituitary lactotroph D-2 DA receptor [270–276]. There is a reasonably good correlation between antipsychotic potency, D-2 DA receptor antagonism and PRL stimulation [269–271,275–278]. The major exceptions are clozapine and quetiapine, atypical neuroleptics with weak D-2 binding affinity which produce only minimal elevations in serum PRL [269,279–283]. Olanzapine, another atypical neuroleptic, has a higher affinity than clozapine for D2 receptors, and has a slightly higher incidence of mild hyperprolactinemia [277,284,285]. Chronic administration of classical neuroleptics may result in tolerance to the PRLelevating effects of the drugs, with some patients demonstrating normal serum PRL concentrations after long-term therapy [270,272,286]. There have been a few reports of PRL-secreting pituitary tumors developing during chronic neuroleptic therapy [287,288], but these are so infrequent as to suggest that the relationship is coincidental rather than causal. Hyperprolactinemia induced by neuroleptic drugs can suppress GnRH and gonadotropin secretion with consequent hypogonadism and amenorrhea [278,286,289–291], although this effect is highly variable, and many patients have normal gonadal function despite mild hyperprolactinemia [286,291–293]. Neuroleptics may have an inhibitory effect on GH secretion, especially that stimulated by DA agonists [268,294]. Clinically, there is no evidence of GH deficiency in patients receiving neuroleptics. Neuroleptic drugs have little or no effect on ACTH and TSH secretion [268,271,276,286,292,295,296], although a rare side effect of neuroleptic drugs, the syndrome of inappropriate secretion of ADH (SIADH), has been reported in about a dozen patients [258,297,298].

Other DA Antagonists Metoclopramide and domperidone are potent D-2 DA antagonists which, like the antipsychotics, stimulate PRL

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secretion [299–301]. Since TSH and LH, like PRL, are also under mild tonic inhibition by DA, acute administration of these drugs produces a small, transient rise in serum TSH and LH [299,302,303]. Chronic endocrine effects are similar to those of the antipsychotics [300,304,305]. Acutely, metoclopramide, but not sulpiride, domperidone or haloperidol, stimulates vasopressin secretion [306]. Buspirone, an antianxiety drug, interacts with DA as well as serotonin receptors, and acutely elevates serum PRL and GH in man [307–310]. DA AGONISTS Drugs with DA agonist activity suppress PRL secretion; these include apomorphine, DA, L-dopa, L-dopa/carbidopa combinations, and the dopaminergic ergot alkaloids [294,311–315]. Additionally, there is also an acute suppressive effect on TSH and LH, although these effects are not seen with chronic administration [312,316,317]; DA infusions, given for hypotension, may contribute to the hypothyroxinemia seen in severe systemic illness by suppressing TSH [316]. Dopaminergic drugs acutely stimulate GH secretion [294,318–322], probably by actions on the hypothalamus. CHOLINERGIC AGONISTS AND ANTAGONISTS Muscarinic blockers such as atropine and pirenzepine appear to enhance somatostatin release from the median eminence of the hypothalamus and thereby decrease GH secretion [323–328]. The GH response to insulin-induced hypoglycemia is relatively less affected by these drugs than other GH-provocative tests [322,325]. Cholinergic agonists such as physostigmine and pyridostigmine have an opposite effect, inhibiting somatostatin and stimulating GH [329–332]. In addition, physostigmine has been reported to stimulate PRL, ACTH, cortisol, and b-endorphin, effects which were blocked by the cholinergic antagonist scopolamine [332]. ANTIHYPERTENSIVES Reserpine, which depletes catecholamines, and methyldopa, which both depletes catecholamines and serves as a precursor for false neurotransmitters, stimulate PRL secretion modestly, although in many patients serum PRL concentrations are still within the normal range [333–338]. Methyldopa has also been reported to cause inappropriate secretion of ADH [339]. b-Adrenergic blockade with propranolol enhances the GH response to various stimuli [321,322,340]; selective b1-antagonists do not share this action [341]. Most bblockers have little or no effect on other pituitary hormones [337,342–344]. However, labetolol, a drug with both a- and b-adrenergic blocking effects as well as b-agonist

actions, stimulates PRL secretion via unknown mechanisms [345]. Clonidine and related a2-adrenergic agonists stimulate GH secretion without altering other anterior pituitary hormones [346–349]. Clonidine has been used to enhance GH secretion in the treatment of constitutional short stature, with mixed success [350,351]. Yohimbine, an a2-adrenergic antagonist, and phentolamine, a nonspecific a-blocker, blunt the GH response to a variety of stimuli, but prazosin, an a1antagonist, does not [322,340,352]. Clonidine has been reported to cause SIADH [353]. Angiotensin-converting enzyme inhibitors have minimal effects on pituitary hormones. One study reported that enalapril slightly decreased the PRL response to hypoglycemia [354], while there are conflicting reports regarding drug effects on metoclopramide-induced PRL secretion, with one study claiming no effect while another reported an enhanced PRL response during enalapril therapy [355,356]. Calcium channel blockers have divergent effects on pituitary hormone secretion. Diltiazem and nifedipine appear to have little or no effect, but verapamil has been reported to decrease gonadotropin and TSH secretion and enhance PRL release [357–359]. Mild hyperprolactinemia and galactorrhea have occurred in patients receiving verapamil therapy [360–362]. ANTIHISTAMINES

H1-antihistamines H1 histamine receptors appear to play little role in the regulation of human pituitary function. Intravenous diphenhydramine, an H1-antagonist, had no effect on serum GH, PRL, or TSH [363], and did not alter the TSH and PRL response to TRH or the GH response to L-dopa [364]. However, other H1-antihistamines (meclastine and chlorpheniramine) have been reported to blunt the GH response to arginine infusion but not the response to hypoglycemia [365]. It is possible that this effect is due to the anticholinergic properties of these drugs (see above). These same drugs did not alter the PRL response to arginine or hypoglycemia [366].

H2-antihistamines Cimetidine, the first marketed H2-antihistamine, stimulates PRL secretion when given as an intravenous bolus that achieves high serum drug levels [363,367,368]; other pituitary hormones are not affected [363,367–369]. These properties are share by another H2-antihistamine, ranitidine [370–372], but not by nizatidine, which has no effect on serum PRL [373]. Animal studies suggest that the PRLreleasing effects of cimetidine and ranitidine are not mediated by H2-histamine antagonism [374]. Acute oral dosing with cimetidine has no effect on PRL secretion [367,375],

Chapter 19

probably because relatively low drug concentrations are achieved in the serum. The endocrine effects of long-term cimetidine therapy are controversial. Most investigators have found no change in serum PRL [375–380], although a few have noted slight increases [381–383]. Cimetidine has antiandrogenic actions and competes for androgen binding to the androgen receptor [384,385], raising the possibility that the drug might induce changes in the hypothalamic–pituitary– gonadal axis. Serum gonadotropins have been unchanged [375,377,380,382], decreased [376,379] or slightly increased [371,380] and the gonadotropin response to GnRH decreased [376,379], unchanged [377,382,383], or increased [371]. Serum testosterone has been unchanged [371,375,377,379,382,383] or increased [376,380] and free testosterone has been reported to be unchanged [375]. Serum estradiol has been found to be unchanged [375,377,379,380,382,383]. In one uncontrolled study, sperm counts were mildly decreased during chronic cimetidine therapy [376] but this was not confirmed in a controlled investigation [386]. The GH response to insulin-induced hypoglycemia was reduced by cimetidine in one study [387] but unchanged in another [379]. Cimetidine did not alter the GH response to L-dopa [364] or arginine infusion [387]. Interestingly, it has been reported that cimetidine decreases spontaneous nocturnal GH surges [379]. Basal serum cortisol, the cortisol diurnal rhythm, and the cortisol response to insulin hypoglycemia are unchanged by cimetidine, although urinary free cortisol is decreased, suggesting an alteration in the renal handling of cortisol [379]. Serum concentrations of thyroid hormones and TSH are not altered by long term cimetidine therapy [377,379]. In summary, considering all the conflicting data, there are probably no important hormonal changes occurring during cimetidine therapy in most patients. Cases of gynecomastia due to cimetidine are probably due to peripheral androgen antagonism at the level of the breast tissue, rather than alterations in serum hormone concentrations. Ranitidine and nizatidine have no antiandrogenic actions and do not alter serum testosterone, gonadotropins, or PRL when administered chronically [371,373,380,388,389]. ANTINEOPLASTIC CHEMOTHERAPY There is little evidence that cytotoxic drugs directly alter anterior pituitary function [390]. A report suggesting that L-asparaginase suppresses TSH secretion may primarily reflect a decrease in serum thyroxine-binding globulin [391]. Cancer chemotherapy commonly produces gonadal damage, with a consequent rise in serum FSH and LH due to activation of normal feedback mechanisms; a wide variety of drugs have been implicated in this regard [390,392–394]. Recovery may spontaneously take place years later in some male patients, while females may show progressive ovarian failure [390,394].

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Many cancer chemotherapeutic agents have been reported to cause SIADH [390]; these include cyclophosphamide [395], melphalan [396], vincristine [397], vinblastine [398], cisplatin [399–401], and combination chemotherapy [402,403]. ESTROGENS Estrogens have several effects on the human pituitary gland. GH secretion is potentiated, both basally and in response to a variety of provocative tests [321,404–406]. The GH response to GH-releasing hormone (GHRH) is not enhanced by estrogen, however, suggesting that the estrogen effect is exerted at the hypothalamic level [405]. PRL secretion is also increased, and is related to the dose of estrogen given [407–411]. There appears to be some autoregulation of the PRL response to estrogen, with an initial modest rise in serum PRL followed by a subsequent fall after several months of estrogen administration [409,410]. There is no evidence that exogenous estrogen is involved in the genesis of pituitary prolactinomas in humans [410,412–416]. Gonadotropin secretion is suppressed by estrogen, especially at high doses [417–421]. Estrogen also exerts a positive feedback effect on gonadotropins; this is seen most vividly in the surge of LH and FSH secretion at the midpoint of the normal menstrual cycle [422,423]. Males may also exhibit positive feedback of estrogens on LH release [420,423]. The secretion of TSH in response to TRH may be slightly enhanced by exogenous estrogens, although some studies have failed to show this effect [316]. ANTIESTROGENS Antiestrogens can have a variety of effect son pituitary hormone secretion, depending on the ambient hormonal milieu. In premenopausal women and adult men, drugs such as clomiphene, tamoxifen and raloxifene act as estrogen antagonists and block the negative feedback effects of estrogen on gonadotropin secretion, resulting in increased serum LH and FSH [424,425]. In contrast, opposite effects are seen in postmenopausal women, where the weak estrogen-agonist activity of these compounds predominates, resulting in partial suppression of gonadotropin secretion [426]. ANDROGENS Androgens suppress gonadotropin secretion through actions on both the hypothalamus and pituitary. While part of this effect may be attributable to estrogens produced by biotransformation in vivo, nonaromatizable androgens also suppress gonadotropins [418,427–432]. Fluoxymesterone, a nonaromatizable androgen, exerts a modest suppressive effect on TSH secretion but does not alter PRL [433]. Studies examining the effect of testosterone on these two hormones have been confounded by the con-

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current increases in serum estrogens produced by aromatization in vivo [430]. Spontaneous GH secretion is enhanced by testosterone administration, producing a concurrent rise in serum insulin-like growth factor-I (IGF-I); the synthetic nonaromatizable androgen, oxandrolone, did not raise either mean serum GH or IGF-I in this study [434]. In other reports, however, oxandrolone was effective in enhancing the GH response to GHRH and sleep in some children [435,436] and in increasing mean 24-hour serum GH concentrations [437]. ANTIANDROGENS Finasteride, a 5a-reductase inhibitor, has generally had no effect on serum LH, FSH, cortisol, TSH or T4 in men [438–440], through two studies reported increases in LH [441,442]. In women, finasteride was found to modestly increase serum LH, FSH and testosterone [442]. Flutamide, an androgen receptor blocker, has been reported to increase serum LH and testosterone in men, with no change in FSH or PRL [443–445]. In postmenopausal women, LH and FSH were unchanged by flutamide while serum testosterone fell [446]. In normal and hirsute premenopausal women, no change was observed in serum LH, FSH or testosterone [447–449]. GLUCOCORTICOIDS In addition to the expected feedback suppression of ACTH and b-lipotropin secretion [450,451], glucocorticoids in large doses also exert suppressive effects on GH [452–455], TSH [316], gonadotropins [456–459], PRL [460,461], and vasopressin [462]. It is not clear whether the effects of glucocorticoids on GH are mediated by changes in somatostatinergic tone [453,454]. By suppressing TSH, lowering serum thyroxine-binding globulin and blocking extrathyroidal conversion of T4 to T3, large doses of glucocorticoids may contribute to the derangements of pituitary–thyroid function seen in the “euthryoid sick” syndrome [316]. In the absence of concomitant illness, the thyroid axis changes produced by glucocorticoids are modest and usually do not result in diagnostic confusion. MISCELLANEOUS DRUGS Chlorpropamide, a sulfonylurea, may produce SIADH by both increasing ADH secretion and by potentiating ADH action on the renal tubule [463–465]. Other oral hypoglycemic agents do not alter ADH release or action [463]. Digitoxin has structural similarities to steroid hormones, binds to the estrogen receptor and can act as an estrogen agonist [466]; as such, it exerts a suppressive effect on gonadotropin secretion [467]. Anticonvulsants may influence pituitary hormone secretion. Phenytoin may slightly raise serum concentrations of

gonadotropins [468], PRL and GH [469], and inhibit the secretion of TSH and ADH [470,471]. Carbamazepine may cause SIADH [472], but does not appear to have any major effect on serum LH, FSH or prolactin [473,474]. Sodium valproate inhibits the vasopressin response to hypernatremia and upright posture [475] and the oxytocin response to angiotensin II [476]. Ketoconazole, an antifungal agent, interferes with the biosynthesis of testosterone and cortisol and can lead to elevations in serum gonadotropins and, less often, ACTH, by activating feedback mechanism [477–482]. Blockade of cortisol biosynthesis by ketoconazole has been used as adjunctive therapy in the treatment of Cushing’s syndrome [483]. Erythropoietin, given to treat anemia in patients with renal failure, has been reported to have diverse effects on pituitary function in dialysis patients; no consensus has emerged, however, since the reports have provided contradictory results (see [484] for review). Fenfluramine, an anorectic agent, enhances serotonergic effects in the brain; given acutely, large oral doses of fenfluramine have been reported to modestly increase serum PRL, ACTH and cortisol, with no effect on GH [485–487]. In obese subjects, smaller oral doses of fenfluramine suppressed the ACTH and cortisol responses to naloxone [488]. Heparin therapy has been reported to precipitate pituitary apoplexy in one patient [489]. Bexarotene, a retinoid X-receptor agonist used in the treatment of cutaneous T-cell lymphoma, suppresses TSH secretion and has resulted in central hypothyroidism [490].

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206 Greenhill LL, Puig-Antich J, Chambers W et al. Growth hormone, prolactin, and growth responses in hyperkinetic males treated with D-amphetamine. J Am Acad Child Psychiatry 1981;20:84–103. 207 Toren P, Silbergeld A, Eldar S et al. Lack of effect of methylphenidate on serum growth hormone (GH), GH-binding protein, and insulin-like growth factor I. Clin Neuropharmocol 1997;20:264–169. 208 Benowitz NL. Clinical pharmacology of caffeine. Ann Rev Med 1990;41: 277–288. 209 Spindel ER, Wurtman RJ, McCall A et al. Neuroendocrine effects of caffeine in normal subjects. Clin Pharmacol Therap 1984;36:402–407. 210 Charney DS, Heninger GR, Jatlow PI. Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 1985;42:233–243. 211 Uhde TW, Bierer LM, Post RM. Caffeine-induced escape from dexamethasone suppression. Arch Gen Psychiatry 1985;42:737–738. 212 Daubresse J-C, Luyckx A, Demey-Ponsart E et al. Effects of coffee and caffeine on carbohydrate metabolism, free fatty acid, insulin, growth hormone and cortisol plasma levels in man. Acta Diabet Lat 1973;10:1069–1084. 213 Uhde TW, Tancer ME, Rubinow DR et al. Evidence for hypothalamo-growth hormone dysfunction in panic disorder: profile of growth hormone (GH) responses to clonidine, yohimbine, caffeine, glucose, GRF and TRH in panic disorder patients versus healthy volunteers. Neuropsychopharmacol 1992;6: 101–118. 214 Ensinck JW, Stoll RW, Gale CC et al. Effect of aminophylline on the secretion of insulin, glucagon, luteinizing hormone and growth hormone in humans. J Clin Endocrinol Metab 1970;31:153–161. 215 Ajlouni K, El-Khateeb M. Effect of glucose on growth hormone, prolactin and thyroid-stimulating hormone response to diazepam in normal subjects. Horm Res 1980;13:160–164. 216 D’Armiento M, Bisignani G, Reda G. Effect of bromazepam on growth hormone and prolactin secretion in normal subjects. Horm Res 1981;15: 224–227. 217 Kannan V. Diazepam test of growth hormone secretion. Horm Metab Res 1981;13:390–393. 218 Laakmann G, Treusch J, Schmauss M et al. Comparison of growth hormone stimulation induced by desipramine, diazepam and metaclazepam in man. Psychoneuroendocrinol 1982;7:141–146. 219 Laakmann G, Treusch J, Eichmer A et al. Inhibitory effect of phentolamine on diazepam-induced growth hormone secretion and lack of effect of diazepam on prolactin secretion in man. Psychoneuroendocrinol 1982;7:135–139. 220 Levin ER, Sharp B, Carlons HE. Failure to confirm consistent stimulation of growth hormone by diazepam. Horm Res 1984;19:86–90. 221 D’Armiento M, Bigi F, Pontecorvi A et al. Diazepam-stimulated GH secretion in normal subjects: relation to oestradiol plasma levels. Horm Metab Res 1984;16:155. 222 Monteiro MG, Schuckit MA, Hauger R et al. Growth hormone response to intravenous diazepam and placebo in 82 healthy men. Biol Psychiatry 1990;27:702–710. 223 Breier A, Charney DS, Heninger GR. Intravenous diazepam fails to change growth hormone and cortisol secretion in humans. Psychiatr Res 1986;18: 293–299. 224 Beary MD, Lacey JH, Bhat AV. The neuro-endocrine impact of 3-hydroxydiazepam (temazepam) in women. Psychopharmacol 1983;79:295–297. 225 Petraglia F, Bakalakis S, Facchinetti F et al. Effects of sodium valproate and diazepam on beta-endorphin, beta-lipotropin and cortisol secretion induced by hypoglycemic stress in humans. Neuroendocrinol 1986;44:320–325. 226 Charney DS, Breier A, Jatlow PI, Heninger GR. Behavioral, biochemical, and blood pressure responses to alprazolam in healthy subjects: interactions with yohimbine. Psychopharmacol 1986;88:133–140. 227 Tormey WP, Dolphin C, Darragh AS. The effects of diazepam on sleep, and on the nocturnal release of growth hormone, prolactin, ACTH and cortisol. Br J Clin Pharmacol 1979;8:90–92. 228 Torpy DJ, Grice JE, Hockings GI et al. Alprazolam blocks the naloxonestimulated hypothalamo–pituitary–adrenal axis in man. J Clin Endocrinol Metab 1993;76:388–391. 229 Arvat E, Macagno B, Ramunni J et al. The inhibitory effects of alprazolam, a benzodiazepine, overrides the stimulatory effect of metyrapone-induced lack of negative cortisol feedback on corticotroph secretion in humans. J Clin Endocrinol Metab 1999;84:2611–2615. 230 Shur E, Petursson H, Checkley S, Lader M. Long-term benzodiazepine administration blunts growth hormone response to diazepam. Arch Gen Psychiatry 1983;40:1105–1108. 231 Torpy DJ, Jackson RV, Grice JE et al. Effect of flumazenil on basal and naloxone-stimulated ACTH and cortisol release in humans. Clin Exp Pharmacol Physiol 1994;21:157–161.

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294 Lal S, De la Vega CE, Sourkes TL, Friesen HG. Effect of apomorphine on growth hormone, prolactin, luteinizing hormone and follicle-stimulating hormone levels in human serum. J Clin Endocrinol Metab 1973;37:719–724. 295 Naber D, Steinbock H, Greil W. Effects of short- and long-term neuroleptic treatment on thyroid function. Prog Neuro-psychopharmacol 1980;4:199–206. 296 Meador-Woodruff JH, Greden JF. Effects of psychotropic medications on hypothalamic–pituitary–adrenal regulation. Endocrinol Metab Clin North Am 1988;17:225–234. 297 Matuk F, Kalyanaraman K. Syndrome of inappropriate secretion of antidiuretic hormone in patients treated with psychotherapeutic drugs. Arch Neurol 1977;34:374–375. 298 Ananth J, Lin K-M. SIADH: a serious side effect of psychotropic drugs. Int J Psychiatry Med 1986–87;16:401–407. 299 Sowers JR, McCallum RW, Hershman JM et al. Comparison of metoclopramide with other dynamic tests of prolactin secretion. J Clin Endocrinol Metab 1976;43:679–681. 300 Soykan I, Sarosiek I, McCallum RW. The effect of chronic oral domperidone therapy on gastrointestinal symptoms, gastric emptying, and quality of life in patients with gastroparesis. Am J Gastroenterol 1997;92:976–980. 301 Camanni F, Genazzani AR, Massara F et al. Prolactin-releasing effects of domperidone in normoprolactinemic and hyperprolactinemic subjects. Neuroendocrinol 1980;30:2–6. 302 Ghigo E, Goffi S, Molinatti GM et al. Prolactin and TSH responses to both domperidone and TRH in normal and hyperprolactinemic women after dopamine synthesis blockade. Clin Endocrinol 1985;23:155–160. 303 Seki K, Nagata I. Effects of a dopamine antagonist (metoclopramide) on the release of LH, FSH, TSH and PRL in normal women throughout the menstrual cycle. Acta Endocrinol 1990;122:211–216. 304 Falaschi P, Frajese G, Sciarra F et al. Influence of hyperprolactinaemia due to metoclopramide on gonadal function in men. Clin Endocrinol 1978;8:427–433. 305 Tamagna EI, Lane W, Hershman JM et al. Effect of chronic metoclopramide therapy on serum pituitary hormone concentrations. Horm Res 1979;11: 161–169. 306 Norbiato G, Bevilacqua M, Chebat E et al. Metoclopramide increases vasopressin secretion. J Clin Endocrinol Metab 1986;63:747–750. 307 Meltzer HY, Flemming R, Robertson A. The effect of buspirone on prolactin and growth hormone secretion in man. Arch Gen Psychiatry 1983;40:1099–1102. 308 Meltzer HY, Lee HS, Nash JF Jr. Effect of buspirone on prolactin secretion is not mediated by 5-HT-1a receptor stimulation. Arch Gen Psychiatry 1992;49:163–164. 309 Meltzer HY, Maes M. Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects. Biol Psychiatry 1994;35:316– 323. 310 Maskall DD, Zis AP, Lam RW et al. Prolactin response to buspirone challenge in the presence of dopaminergic blockade. Biol Psychiatry 1995;38:235–239. 311 Vance ML, Evans WS, Thorner MO. Bromocriptine. Ann Intern Med 1984;100:78–91. 312 De Leo V, Petraglia F, Bruno MG et al. Different dopaminergic control of plasma luteinizing hormone, follicle-stimulating hormone and prolactin in ovulatory and postmenopausal women: effect of ovariectomy. Gynecol Obstet Invest 1989;27:94–98. 313 Crosignani PG, Ferrari C, Malinverni A et al. Effect of central nervous system dopaminergic activation on prolactin secretion in man: evidence for a common central defect in hyperprolactinemic patients with and without radiological signs of pituitary tumors. J Clin Endocrinol Metab 1980;51: 1068–1073. 314 Carlson HE. Carbidopa plus L-DOPA pretreatment inhibits the prolactin (PRL) response to thyrotropin-releasing hormone and thus cannot distinguish central from pituitary sites of prolactin stimulation. J Clin Endocrinol Metab 1986;63:249–251. 315 Crosignani PG, Ferrari C, Liuzzi A et al. Treatment of hyperprolactinemic states with different drugs: a study with bromocriptine, metergoline, and lisuride. Fertil Steril 1982;37:61–67. 316 Morley JE. Neuroendocrine control of thyrotropin secretion. Endocr Rev 1981;2:396–436. 317 Johnston DG, Prescott RWG, Kendall-Taylor P et al. Hyperprolactinemia. Long-term effects of bromocriptine. Am J Med 1983;75:868–874. 318 Vance ML, Kaiser DL, Frohman LA et al. Role of dopamine in the regulation of growth hormone secretion: dopamine and bromocriptine augment growth hormone (GH)-releasing hormone-stimulated GH secretion in normal man. J Clin Endocrinol Metab 1987;64:1136–1141. 319 Boyd AE, Lebovitz HE, Pfeiffer JB. Stimulation of human growth hormone secretion by L-DOPA. N Engl J Med 1970;283:1425–1429.

320 Dammacco F, Rigillo N, Tafaro E et al. Effects of 2-bromo-a-ergocryptine and pimozide on growth hormone secretion in man. Horm Metab Res 1976;8: 247–248. 321 Dieguez C, Page MD, Scanlon MF. Growth hormone neuroregulation and its alterations in disease states. Clin Endocrinol 1988;28:109–143. 322 Delitala G, Tomasi P, Virdis R. Neuroendocrine regulation of human growth hormone secretion. Diagnostic and clinical applications. J Endocrinol Invest 1988;11:441–462. 323 Casanueva FF, Villanueva L, Cabranes JA et al. Cholinergic mediation of GH secretion elicited by arginine, clonidine and physical exercise in man. J Clin Endocrinol Metab 1984;59:526–530. 324 Delitala G, Maoili M, Pacifico A et al. Cholinergic receptor control mechanism for L-DOPA, apomorphine and clonidine-induced growth hormone secretion in man. J Clin Endocrinol Metab 1983;57:1145–1149. 325 Evans PJ, Dieguez C, Foord S et al. The effect of cholinergic blockade on the growth hormone and prolactin response to insulin hypoglycaemia. Clin Endocrinol 1985;22:733–735. 326 Massara F, Ghigo E, Goffi S et al. Blockade of hpGRF 40 induced growth hormone release in normal men by a cholinergic muscarinic antagonist. J Clin Endocrinol Metab 1984;58:1025–1026. 327 Peters JR, Evans PJ, Page MD et al. Cholinergic muscarinic receptor blockaed with pirenzepine abolishes slow wave sleep-related growth hormone release in normal adult males. Clin Endocrinol 1986;25:213–217. 328 Richardson SB, Hollander CS, D’Eletto R et al. Acetylcholine inhibits the release of somatostatin from rat hypothalamus in vitro. Endocrinology 1980;107:122–129. 329 Leveston SA, Cryer PE. Endogenous cholinergic modulation of growth hormone secretion in normal and acromegalic humans. Metabolism 1980;29:703–706. 330 Ghigo E. Mazza E, Imperiale E et al. Growth hormone responses to pyridostigmine in normal adults and in normal and short children. Clin Endocrinol 1987;27:669–673. 331 Ross RJM, Tsagarakis S, Grossman A et al. GH feedback occurs through modulation of hypothalamic somatostatin under cholinergic control: studies with pyridostigmine and GHRH. Clin Endocrinol 1987;27:727–733. 332 Risch SC, Janowsky DS, Mott MA et al. Central and peripheral cholinesterase inhibition: effects on anterior pituitary and sympathomimetic function. Psychoneuroendocrinol 1986;11:221–230. 333 Lee PA, Kelly MR, Wallin JD. Increased prolactin levels during reserpine treatment of hypertensive patients. JAMA 1976;235:2316–2317. 334 Camanni E, Strumia E, Portaleone P, Molinatti GM. Prolactin secretion during reserpine and syrosingopine treatment. Eur J Clin Pharmacol 1981;20:347–349. 335 Ross RK, Paganini-Hill A, Krailo MD et al. Effects of reserpine on prolactin levels and incidence of breast cancer in postmenopausal women. Cancer Res 1984;44:3106–3108. 336 Steiner J, Cassar J, Mashiter K et al. Effects of methyldopa on prolactin and growth hormone. Brit Med J 1976;1:1186–1188. 337 Taylor RG, Hoffbrand BI, Crisp AJ et al. Plasma sex hormone concentrations in men with hypertension treated with methyldopa and/or propranolol. Postgrad Med J 1981;57:425–426. 338 Baldini M, Cornelli U, Molinari M, Cantalamessa L. Effect of methyldopa on prolactin serum concentration. Eur J Clin Pharmacol 1988;34:513–515. 339 Varkel Y, Braaester A, Nusem D, Shkolnik T. Methyldopa-induced syndrome of inappropriate antidiuretic hormone secretion and bone marrow granulomatosis. Drug Intell Clin Pharmacy 1988;22:700–702. 340 Blackard WG, Heidingsfelder SA. Adrenergic receptor control mechanism for growth hormone secretion. J Clin Invest 1968;47:1407–1414. 341 Lauridsen UB, Christensen NJ, Lyngsoe J. Effects of nonselective and b1selective blockade on glucose metabolism and hormone responses during insulin-induced hypoglycemia in normal man. J Clin Endocrinol Metab 1983;56:876–882. 342 Lauridsen UB, Eskildsen PC, Kirkegaard C, Lund B. Prolactin release after TRH during altered adrenergic a and b receptor influence. Horm Metab Res 1978;10:452–454. 343 Saxton CA, Faulkner JK, Groom GV. The effect on plasma prolactin, growth hormone and luteinising hormone concentrations of single oral doses of propranolol and tolamolol in normal man. Eur J Clin Pharmacol 1981;21: 103–108. 344 Dart AM, McHardy K, Barber HE. The effect of propranolol on luteinising hormone and prolactin concentrations in hypertensive women. Brit J Clin Pharmacol 1982;14:839–841. 345 Barbieri C, Larovere MT, Mariotti G et al. Prolactin stimulation by intravenous labetalol is mediated inside the central nervous system. Clin Endocrinol 1982;16:615–619.

Chapter 19 346 Lal S, Tolis G, Martin JB et al. Effect of clonidine on growth hormone, prolactin, luteinizing hormone, follicle-stimulating hormone, and thyroidstimulating hormone in the serum of normal men. J Clin Endocrinol Metab 1975;41:827–832. 347 Lancranjan I, Marbach P. New evidence for growth hormone modulation by the a-adrenergic system in man. Metabolism 1977;26:1225–1230. 348 Lanes R, Hurtado E. Oral clonidine—an effective growth hormone-releasing agent in prepubertal subjects. J Pediatrics 1982;100:710–714. 349 Grossman A, Weerasuriya K, Al-Damluji S et al. Alpha 2-adrenoceptor agonists stimulate growth hormone secretion but have no acute effects on plasma cortisol under basal conditions. Horm Res 1987;25:65–71. 350 Loche S, Puggioni R, Fanni T et al. Augmentation of growth hormone secretion in children with constitutional growth delay by short-term clonidine administration: a pulse amplitude-modulated phenomenon. J Clin Endocrinol Metab 1989;68:426–430. 351 Pescovitz OH, Tan E. Lack of benefit of clonidine treatment for short stature in a double-blind, placebo-controlled trial. Lancet 1988;2:874–877. 352 Tatar P, Vigas M. Role of alpha-1 and alpha-2 adrenergic receptors in the growth hormone and prolactin response to insulin-induced hypoglycaemia in man. Neuroendocrinol 1984;39:275–280. 353 Burrows AW, Gribbin B. Clonidine-induced dilutional hyponatremia. Postgrad Med J 1979;55:42–44. 354 Winer LM, Molteni A, Molitch ME. Effect of angiotensin-converting enzyme inhibition on pituitary hormone responses to insulin-induced hypoglycemia in humans. J Clin Endocrinol Metab 1990;71:256–259. 355 Dupont AG, Vander Niepen P, Van Steirteghen AC, Vanhaelst L. Enhanced response of plasma prolactin to metoclopramide during chronic converting enzyme inhibition. Horm Metab Res 1987;19:212–215. 356 Anderson PW, Malarkey WB, Salk J et al. The effect of angiotensin-converting enzyme inhibition on prolactin responses in normal and hyperprolactinemic subjects. J Clin Endocrinol Metab 1989;69:518–522. 357 Schoen RE, Frishman WH, Shamoon H. Hormonal and metabolic effects of calcium channel antagonists in man. Am J Med 1988;84:492–504. 358 Kamal TJ, Molitch ME. Effects of calcium channel blockade with verapamil on the prolactin responses to TRH, L-Dopa and bromocriptine. Am J Med Sci 1992;304:289–293. 359 Kelley SR, Kamal TJ, Molitch ME. Mechanism of verapamil calcium channel blockade-induced hyperprolactinemia. Am J Physiol 1996;270:E96–E100. 360 Gluskin LE, Strasberg B, Shah JH. Verapamil-induced hyperprolactinemia and galactorrhea. Ann Intern Med 1981;95:66–67. 361 Fearrington EL, Rand CH, Rose JD. Hyperprolactinemia–galactorrhea induced by verapamil. Am J Cardiol 1983;51:1466–1467. 362 Tanner LA, Bosco LA. Gynecomastia associated with calcium channel blocker therapy. Arch Intern Med 1988;148:379–380. 363 Carlson HE, Ippoliti AF. Cimetidine, an H2-antihistamine, stimulates prolactin secretion in man. J Clin Endocrinol Metab 1977;45:367–370. 364 Carlson HE, Chang RJ. Studies on the role of histamine in human pituitary function. Clin Endocrinol 1980;12:461–466. 365 Pontiroli AE, Viberti G, Vicari A, Pozza G. Effect of the antihistaminic agents meclastine and dexchlorpheniramine on the response of human growth hormone to arginine infusion and insulin hypoglycemia. J Clin Endocrinol Metab 1976;43:582–586. 366 Pontiroli AE, Gala RR, Pellicciotta G et al. Antihistaminics H1 and H2 do not modify the human prolactin response to arginine infusion and insulin hypoglycemia. Horm Metab Res 1980;12:557–558. 367 Burland WL, Gleadle RI, Lee RM et al. Prolactin responses to cimetidine. Brit J Clin Pharmacol 1979;7:19–21. 368 Caldara R, Bierti L, Barbieri C et al. Stimulation of prolactin release by intravenous cimetidine: a dose-response study. J Endocrinol Invest 1979;2:79–81. 369 Carlson HE, Chang RJ, Meyer NV et al. Effect of cimetidine on serum prolactin in normal women and patients with hyperprolactinemia. Clin Endocrinol 1981;15:491–498. 370 Knigge U, Wollesen F, Dejgaard A et al. Comparison between dose-responses of prolactin, thyroid stimulating hormones and growth hormone to two different histamine H2-receptor antagonists in normal men. Clin Endocrinol 1981;15:585–592. 371 Knigge U, Dejgaard A, Wollesen F et al. The acute and long term effect of the H2-receptor antagonists cimetidine and ranitidine on the pituitary–gonadal axis in men. Clin Endocrinol 1983;18:307–313. 372 Delitala G, Devilla L, Pende A, Canessa A. Effects of the H2-receptor antagonist ranitidine on anterior pituitary hormone secretion in man. Eur J Clin Pharmacol 1982;22:207–211. 373 Callaghan JT, Bergstrom RF, Rubin A et al. A pharmacokinetic profile of nizatidine in man. Scand J Gastroenterol 1987;22(Suppl. 136):9–17.

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374 Knigge U, Matzen S, Warberg J. Effects of H2-receptor antagonists on prolactin secretion: specificity and mediation of the response. Acta Endocrinol 1987;115:461–468. 375 Carlson HE, Ippoliti AF, Swerdloff RS. Endocrine effects of acute and chronic cimetidine administration. Dig Dis Sci 1981;26:428–432. 376 Van Thiel DH, Gavaler JS, Smith WJ, Paul G. Hypothalamic–pituitary–gonadal dysfunction in men using cimetidine. N Engl J Med 1979;300:1012–1015. 377 Barber SG, Hoare AM. Cimetidine effects on prolactin release and production. Horm Metab Res 1979;11:220–221. 378 Masala A, Alagna S, Faedda R et al. Prolactin secretion in man following acute and long-term cimetidine administration. Acta Endocrinol 1980;93:392–395. 379 Valk TW, England BG, Marshall JC. Effects of cimetidine on pituitary function: alterations in hormone secretion profiles. Clin Endocrinol 1981;15:139–149. 380 Peden NR, Boyd EJS, Browning MCK et al. Effects of two histamine H2receptor blocking drugs on basal levels of gonadotropins, prolactin, testosterone and oestradiol-17b during treatment of duodenal ulcer in male patients. Acta Endocrinol 1981;96:564–568. 381 Delle Fave GF, Tamburrano G, DeMagistris L et al. Gynecomastia with cimetidine. Lancet 1977;1:1319. 382 Bohnet HG, Greiwe H, Hanker JP et al. Effects of cimetidine on prolactin, LH, and sex steroid secretion in male and female volunteers. Acta Endocrinol 1978;88:428–434. 383 Tytgat GNJ, Hameeteman W, Mulder CJJ et al. Five-year cimetidine maintenance trial for peptic ulcer disease. Scand J Gastroenterol 1990;25: 974–980. 384 Funder JW, Mercer JE. Cimetidine, a histamine H2 receptor antagonist, occupies androgen receptors. J Clin Endocrinol Metab 1979;48:189–196. 385 Winters SJ, Banks JL, Loriaux DL. Cimetidine is an antiandrogen in the rat. Gastroenterol 1979;76:504–508. 386 Enzmann GD, Leonard JM, Paulsen CA, Rogers J. Effect of cimetidine on reproductive function. Clin Res 1981;29:26A. 387 Pontiroli AE, Pellicciotta G, Alberetto M et al. Repeated cimetidine administration reduces the growth hormone (GH) response to insulinhypoglycemia. Horm Metab Res 1980;12:172–173. 388 Pasquali R, Corinaldesi R, Miglioli M et al. Effect of prolonged administration of ranitidine on pituitary and thyroid hormones, and their response to specific hypothalamic-releasing factors. Clin Endocrinol 1981;15:457–462. 389 Van Thiel DH, Gavaler JS, Heyl A, Susen B. An evaluation of the antiandrogen effects associated with H2 antagonist therapy. Scand J Gastroenterol 1987;22(Suppl. 136):24–28. 390 Yeung S-CJ, Chiu AC, Vassilopoulou-Sellin R, Gagel RF. The endocrine effects of nonhormonal antineoplastic therapy. Endocr Rev 1998;19:144–172. 391 Heidemann PH, Stubbe P, Beck W. Transient secondary hypothyroidism and thyroxine binding globulin deficiency in leukaemic children during polychemotherapy: an effect of L-asparaginase. Eur J Ped 1981;136:291–295. 392 Bramswig JH, Heimes U, Heiermann E et al. The effects of different cumulative doses of chemotherapy on testicular function. Cancer 1990;65: 1298–1302. 393 Simmes MA, Rautonen J. Small testicles with impaired production of sperm in adult male survivors of childhood malignancies. Cancer 1990;65:1303–1306. 394 Gradishar WJ, Schilsky RL. Effects of cancer treatment on the reproductive system. Crit Rev Oncol Hematol 1988;8:153–171. 395 Harlow PJ, DeClerck YA, Shore NA et al. A fatal case of inappropriate ADH secretion induced by cyclophosphamide therapy. Cancer 1979;44:896–898. 396 Greenbaum-Lefkoe B, Rosenstock JG, Belasco JB et al. Syndrome of inappropriate antidiuretic hormone secretion. A complication of high-dose intravenous melphalan. Cancer 1985;55:44–46. 397 Tomiwa K, Mikawa H, Hazama F et al. Syndrome of inappropriate secretion of antidiuretic hormone caused by vincristine therapy: a case report of the neuropathology. J Neurol 1983;229:267–272. 398 Fraschini G, Recchia F, Holmes FA. Syndrome of inappropriate antidiuretic hormone secretion associated with hepatic arterial infusion of vinblastine in three patients with breast cancer. Tumori 1987;73:513–516. 399 Littlewood TJ, Smith AP. Syndrome of inappropriate antidiuretic hormone secretion due to treatment of lung cancer with cisplatin. Thorax 1984;39: 636–637. 400 Porter AT. Syndrome of inappropriate antidiuretic hormone secretion during cis-dichlorodiammine platinum therapy in a patient with an ovarian carcinoma. Gynecol Oncol 1985;21:103–105. 401 Ritch PS. Cis-dichlorodiammine platinum II-induced syndrome of inappropriate secretion of antidiuretic hormone. Cancer 1988;61:448–450. 402 Ravikumar TS, Grage TB. The syndrome of inappropriate ADH secretion secondary to vinblastine-bleomycin therapy. J Surg Oncol 1983;24:242–245.

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403 Hayes DF, Lechan RM, Posner MR et al. The syndrome of inappropriate antidiuretic hormone secretion associated with induction chemotherapy for squamous cell carcinoma of the head and neck. J Surg Oncol 1986;32:150–152. 404 Frasier SD. A review of growth hormone stimulation tests in children. Pediatrics 1974;53:929–937. 405 Ross RJM, Grossman A, Davies PSW et al. Stilboestrol pretreatment of children with short stature does not affect the growth hormone response to growth hormone-releasing hormone. Clin Endocrinol 1987;27:155–161. 406 Ho KY, Evans WS, Blizzard RM et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 1987;64:51–58. 407 Yoshida T, Hattori Y, Suzuki H, Noda K. Effect of sex steroid hormones on the serum prolactin concentration. Tohoku J Exp Med 1979;127:119–122. 408 Hwang PLH, Ng CSA, Cheong ST. Effect of oral contraceptives on serum prolactin: a longitudinal study in 126 normal premenopausal women. Clin Endocrinol 1986;24:127–133. 409 Josimovich JB, Lavenhar MA, Devanesan MM et al. Heterogeneous distribution of serum prolactin values in apparently healthy young women, and the effects of oral contraceptive medication. Fertil Steril 1987;47:785–791. 410 Gooren LJG, Harmsen-Louman W, Van Kessel H. Follow-up of prolactin levels in long-term oestrogen-treated male-to-female transsexuals with regard to prolactinoma induction. Clin Endocrinol 1985;22:201–207. 411 Asscheman H, Gooren LJG, Assies J et al. Prolactin levels and pituitary enlargement in hormone-treated male-to-female transsexuals. Clin Endocrinol 1988;28:583–588. 412 Coulam CB, Annegers JF, Abboud CF et al. Pituitary adenoma and oral contraceptives: a case-control study. Fertil Steril 1979;31:25–28. 413 Shy KK, McTiernan AM, Daling JR, Weiss NS. Oral contraceptive use and the occurrence of pituitary prolactinoma. JAMA 1983;249:2204–2207. 414 Pituitary adenoma study group. Pituitary adenomas and oral contraceptives: a multicenter case-control study. Fertil Steril 1983;39:753–760. 415 Hulting A-L, Werner S, Hagenfeldt K. Oral contraceptive steroids do not promote the development or growth of prolactinomas. Contraception 1983;27:69–73. 416 Scheithauer BW, Kovacs KT, Randall RV, Ryan N. Effects of estrogen on the human pituitary: a clinicopathologic study. Mayo Clin Proc 1989;64:1077–1084. 417 Yen SSC, Vandenberg G, Siler TM. Modulation of pituitary responsiveness to LRF by estrogen. J Clin Endocrinol Metab 1974;39:170–177. 418 Santen RJ. Is aromatization of testosterone to estradiol required for inhibition of luteinizing hormone secretion in men? J Clin Invest 1975;56:1555–1563. 419 Givens JR, Andersen RN, Wiser WL et al. The effectiveness of two oral contraceptives in suppressing plasma androstenedione, testosterone, LH, and FSH, and in stimulating plasma testosterone-binding capacity in hirsute women. Am J Obstet Gynecol 1976;124:333–339. 420 Hendricks SE, Graber B, Rodriguez-Sierra JF. Neuroendocrine responses to exogenous estrogen: no differences between heterosexual and homosexual men. Psychoneuroendocrinol 1989;14:177–185. 421 Rigg LA, Milanes B, Villanueva B, Yen SSC. Efficacy of intravaginal and intranasal administration of micronized estradiol-17b. J Clin Endocrinol Metab 1977;45:1261–1264. 422 Liu JH, Yen SSC. Induction of midcycle gonadotropin surge by ovarian steroids in women: a critical evaluation. J Clin Endocrinol Metab 1963;57: 797–802. 423 Gooren L. The neuroendocrine response of luteinizing hormone to estrogen administration in heterosexual, homosexual, and transsexual subjects. J Clin Endocrinol Metab 1986;63:583–588. 424 Baker VL, Draper M, Paul S et al. Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles. J Clin Endocrinol Metab 1998;83:6–13. 425 Draper MW, Flowers DE, Neild JA et al. Antiestrogenic properties of raloxifene. Pharmacology 1995;50:209–217. 426 Jordan VC, Fritz NF, Tormey DC. Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer. Cancer Res 1987;47:624–630. 427 Snyder PJ. Clinical use of androgens. Annual Rev Med 1984;35:207–217. 428 Scheckter CB, Matsumoto AM, Bremner WJ. Testosterone administration inhibits gonadotropin secretion by an effect directly on the human pituitary. J Clin Endocrinol Metab 1989;68:397–401. 429 Bagatell CJ, McLachlan RI, De Kretser DM et al. A comparison of the suppressive effects of testosterone and a potent new gonadotropin-releasing hormone antagonist on gonadotropin and inhibin levels in normal men. J Clin Endocrinol Metab 1989;69:43–48. 430 Mooradian AD, Morley JE, Korenman SG. Biological actions of androgens. Endocr Rev 1987;8:1–28.

431 Wilson JD. Androgen abuse by athletes. Endocr Rev 1988;9:181–199. 432 Matsumoto AM. Effects of chronic testosterone administration in normal men: safety and efficacy of high dosage testosterone and parallel dose-dependent suppression of luteinizing hormone, follicle-stimulating hormone, and sperm production. J Clin Endocrinol Metab 1990;70:282–287. 433 Morley JE, Sawin CT, Carlson HE et al. The relationship of androgen to the thyrotropin and prolactin responses to thyrotropin-releasing hormone in hypogonadal and normal men. J Clin Endocrinol Metab 1981;52:173–176. 434 Link K, Blizzard RM, Evans WS et al. The effect of androgens on the pulsatile release and the twenty-four-hour mean concentration of growth hormone in peripubertal males. J Clin Endocrinol Metab 1986;62:159–164. 435 Loche S, Corda R, Lampis A et al. The effect of oxandrolone on the growth hormone response to growth hormone-releasing hormone in children with constitutional growth delay. Clin Endocrinol 1986;25:195–200. 436 Clayton PE, Shalet SM, Price DA, Addison GM. Growth and growth hormone responses to oxandrolone in boys with constitutional delay of growth and puberty (CDGP). Clin Endocrinol 1988;29:123–130. 437 Ulloa-Aguirre A, Blizzard RM, Garcia-Rubi E et al. Testosterone and oxandrolone, a nonaromatizable androgen, specifically amplify the mass and rate of growth hormone (GH) secreted per burst without altering GH secretory burst duration or frequency or the GH half-life. J Clin Endocrinol Metab 1990;71:846–854. 438 Gormley GJ, Stoner E, Rittmaster RS et al. Effects of finasteride (MK-906), a 5a-reductase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab 1990;70:1136–1141. 439 Rittmaster RS, Lemay A, Zwicker H et al. Effect of finasteride, a 5a-reductase inhibitor, on serum gonadotropins in normal men. J Clin Endocrinol Metab 1992;75:484–488. 440 Stoner E, Finasteride Study Group. The clinical effects of a 5a-reductase inhibitor, finasteride, on benign prostatic hyperplasia. J Urol 1992;147: 1298–1302. 441 Gormley GJ, Stoner E, Bruskewitz RC et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327:1185–1191. 442 Moghetti P, Castello R, Magnani CM et al. Clinical and hormonal effects of the 5a-reductase inhibitor finasteride in idiopathic hirsutism. J Clin Endocrinol Metab 1994;79:1115–1121. 443 Knuth UA, Hano R, Nieschlag E. Effects of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men. J Clin Endocrinol Metab 1984;59:963–969. 444 Urban RJ, Davis MR, Rogol AD et al. Acute androgen receptor blockade increases luteinizing hormone secretory activity in men. J Clin Endocrinol Metab 1988;67:1149–1155. 445 Stone N, Clejan SJ. Response of prostate volume, prostate-specific antigen, and testosterone to flutamide in men with benign prostatic hyperplasia. J Androl 1991;12:376–380. 446 Rossmanith WG, Beuter M, Benz R, Lauritzen C. How do androgens affect episodic gonadotrophin secretion in post-menopausal women? Maturitas 1991;13:325–335. 447 Couzinet B, Thomas G, Thalabard JC et al. Effects of a pure anti-androgen on gonadotropin secretion in normal women and in polycystic ovarian disease. Fertil Steril 1989;52:42–50. 448 Marcondes JAM, Minnani SL, Luthold WW et al. Treatment of hirsutism in women with flutamide. Fertil Steril 1992;57:543–547. 449 Couzinet B, Pholsena M, Young J, Schaison G. The impact of a pure antiandrogen (flutamide) on LH, FSH, androgens and clinical status in idiopathic hirsutism. Clin Endocrinol 1993;39:157–162. 450 Donald RA. ACTH and related peptides. Clin Endocrinol 1980;12:491–524. 451 Abou Samra AB, Dechaud H, Estour B et al. b-lipotropin and cortisol responses to an intravenous infusion dexamethasone suppression test in Cushing’s syndrome and obesity. J Clin Endocrinol Metab 1985;61:116–119. 452 Thompson RG, Rodriguez A, Kowarski A, Blizzard RM. Growth hormone: metabolic clearance rates, integrated concentrations, and production rates in normal adults and the effect of prednisone. J Clin Invest 1972;51:3193– 3199. 453 Kaufmann S, Jones KL, Wehrenberg WB, Culler FL. Inhibition by prednisone of growth normone (GH) response to GH-releasing hormone in normal men. J Clin Endocrinol Metab 1988;67:1258–1261. 454 Del Balzo P, Salvatori R, Cappa M, Gertner JM. Pyridostigmine does not reverse dexamethasone-induced growth hormone inhibition. Clin Endocrinol 1990;33:605–612. 455 Giustina A, Girelli A, Doga M et al. Pyridostigmine blocks the inhibitory effect of glucocorticoids on growth hormone-releasing hormone stimulated growth hormone secretion in normal man. J Clin Endocrinol Metab 1990;71:580–584.

Chapter 19 456 Sakakura M, Takebe K, Nakagawa S. Inhibition of luteinizing hormone secretion induced by synthetic LRH by long-term treatment with glucocorticoids in human subjects. J Clin Endocrinol Metab 1975;40:774–779. 457 MacAdams MR, White RH, Chipps BE. Reduction of serum testosterone levels during chronic glucocorticoid therapy. Ann Intern Med 1986;104:648– 651. 458 Melis GB, Mais V, Gambacciani M et al. Dexamethasone reduces the postcastration gonadotropin rise in women. J Clin Endocrinol Metab 1987;65: 237–241. 459 Saketos M, Sharma N, Santoro NF. Suppression of the hypothalamic–pituitary–ovarian axis in normal women by glucocorticoids. Biol Reprod 1993;49:1270–1276. 460 Copinschi G, L’Hermite M, Leclercq R et al. Effects of glucocorticoids on pituitary hormonal responses to hypoglycemia. Inhibition of prolactin release. J Clin Endocrinol Metab 1975;40:442–449. 461 Sowers JR, Carlson HE, Brautbar N, Hershman JM. Effect of dexamethasone on prolactin and TSH responses to TRH and metoclopramide in man. J Clin Endocrinol Metab 1977;44:237–241. 462 Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med 1989;321:492–496. 463 Skillman TG, Feldman JM. The pharmacology of sulfonylureas. Am J Med 1981;70:361–372. 464 Tanay A, Firemann Z, Yust I, Abramov AL. Chlorpropamide-induced syndrome of inappropriate antidiuretic hormone secretion. J Am Geriat Soc 1981;29: 334–336. 465 Moses AM, Numan P, Miller M. Mechanism of chlorpropamide induced antidiuresis in man: evidence of release of ADH and enhancement of peripheral action. Metabolism 1973:22:59–66. 466 Rifka SM, Pita JC, Vigersky RA et al. Interaction of digitalis and spironolactone with human sex steroid receptors. J Clin Endocrinol Metab 1977;46:338–344. 467 Burckhardt D, Vera CA, La Due JS. Effect of digitalis on urinary pituitary gonadotropin excretion. Ann Intern Med 1968;68:1069–1071. 468 Toone BK, Wheeler M, Nanjee M et al. Sex hormones, sexual activity and plasma anticonvulsant levels in male epileptics. J Neurol Neurosurg Psychiatry 1983;46:824–826. 469 Elwes RDC, Dellaportas C, Reynolds EH et al. Prolactin and growth hormone dynamics in epileptic patients receiving phenytoin. Clin Endocrinol 1985;23:263–270. 470 Surks MI, Ordene KW, Mann DN, Kumara-Siri MH. Diphenylhydantoin inhibits thyrotropin response to thyrotropin-releasing hormone in man and rat. J Clin Endocrinol Metab 1983;56:940–945. 471 Landolt AM. Treatment of acute post-operative inappropriate antidiuretic hormone secretion with diphenylhydantoin. Acta Endocrinol 1974;76:625– 628. 472 Appleby L. Rapid development of hyponatraemia during low-dose carbamazepine therapy. J Neurol Neurosurg Psychiat 1984;47:1138.

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473 Isojarvi JIT, Pakarinen AJ, Myllyla VV. Effects of carbamazepine on the hypothalamic–pituitary–gonadal axis in male patients with epilepsy. A prospective study. Epilepsia 1989;30:446–452. 474 Isojarvi JIT. Serum steroid hormones and pituitary function in female epileptic patients during carbamazepine therapy. Epilepsia 1990;31:438–445. 475 Chiodera P, Gnudi A, Volpi R et al. Effects of the GABAergic agent sodium valproate on the arginine vasopressin responses to hypertonic stimulation and upright posture in man. Clin Endocrinol 1989;30:389–395. 476 Chiodera P, Coiro V. Different effects of the GABAergic agent sodium valproate on the oxytocin responses to antiotensin II and insulin-induced hypoglycemia in normal men. Horm Res 1991;36:27–31. 477 Pont A, Graybill JR, Craven PC et al. High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch Intern Med 1984;144: 2150–2153. 478 Rajfer J, Sikka SC, Rivera F, Handelsman DJ. Mechanism of inhibition of human testicular steroidogenesis by oral ketoconazole. J Clin Endocrinol Metab 1986;63:1193–1198. 479 Glass AR. Ketoconazole-induced stimulation of gonadotropin output in men: basis for a potential test of gonadotropin reserve. J Clin Endocrinol Metab 1986;63:1121–1125. 480 Venturoli S, Fabbri R, Dal Prato L et al. Ketoconazole therapy for women with acne and/or hirsutism. J Clin Endocrinol Metab 1990;71:335–339. 481 Tucker WS, Snell BB, Island DP et al. Reversible adrenal insufficiency induced by ketoconazole. JAMA 1985;253:2413–2414. 482 Hyns W, Drochmans A, Van Der Schueren E, Verhoeven G. Endocrine effects of high dose ketoconazole therapy in advanced prostatic cancer. Acta Endocrinol 1985;110:276–283. 483 Shepherd FA, Hoffert B, Evans WK et al. Ketoconazole. Use in the treatment of ectopic adrenocorticotropic hormone production and Cushing’s syndrome in small-cell lung cancer. Arch Intern Med 1985;145:863–864. 484 Carlson HE, Graber ML, Gelato MC, Hershman JM. Endocrine effects of erythropoietin. Int J Artif Organs 1995;18:309–314. 485 Mitchell PB, Smythe GA. Endocrine and amine response to D,L-fenfluramine in normal subjects. Psychiatry Res 1991;39:141–153. 486 O’Keane V, Dinan TG. Prolactin and cortisol responses to d-fenfluramine in major depression: evidence for diminished responsivity of central serotonergic function. Am J Psychiatry 1991;148:1009–1015. 487 Coccaro EF, Kavoussi RJ, Cooper TB, Hauger RL. Hormonal responses to d- and d,l-fenfluramine in healthy human subjects. Neuropsychopharmacology 1996;15:595–607. 488 Boushaki FZ, Rasio E, Serri O. Hypothalamic–pituitary–adrenal axis in abdominal obesity: effects of dexfenfluramine. Clin Endocrinol 1997;46: 461–466. 489 Oo MM, Krishna AY, Bonavita GJ, Rutecki GW. Heparin therapy for myocardial infarction: an unusual trigger for pituitary apoplexy. Am J Med Sci 1997;314:351–353. 490 Sherman SI, Gopal J, Haugen BR et al. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 1999;340:1075–1079.

S e c t i o n 5

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C h a p t e r

20 Pituitary Imaging Barry D. Pressman

HISTORY OF PITUITARY IMAGING Imaging of the sella turcica and of the pituitary received tremendous attention almost from the inception of radiography at the turn of the century. It was soon recognized that changes in and around the sella turcica could reflect numerous intracranial conditions, and not solely those of the pituitary itself. Further, the importance of the pituitary gland’s intricate function spurred interest in the evaluation of the sella turcica. Plain radiography was the first and, for many decades, only technique for imaging of the sella turcica and of the pituitary. Accordingly, there is a remarkably extensive literature pertaining to the size, shape, contour, and bony density of the sella turcica and its many components. The advent of tomography and its evolution from linear to state-of-theart high-resolution, thin-section, multidirectional techniques, increased the ability to recognize and to define variations of the normal and pathologic tissues. However, advances in surgical treatment, and the effect this has had on the evaluation of the true significance of radiographic findings, indicated that even these exquisite tomographic techniques were inadequate for the ever increasing requirement to adequately diagnose pituitary pathology. These requirements have expanded as a result of improvement in medical, as well as surgical, treatment. Pneumoencephalography (PEG) and angiography were powerful diagnostic tools for pituitary evaluation. With their development it was no longer necessary to simply rely on plain film images. Rather, indirect visualization of the pituitary gland itself was available. PEG allowed for evaluation of suprasellar masses, and normal variations such as the empty sella. When supplemented with tomography, PEG is a remarkably excellent technique for imaging the sella turcica and parasellar area, but was performed with some

difficulty because of the potential for complication and patient discomfort. PEG was such an excellent technique that it was some time before computed topography (CT) totally replaced it for pituitary and sella turcica imaging. Many institutions continued to use PEG until the early 1980s, long after CT was developed and accepted, because they did not feel that CT offered comparable fine detail required for diagnosis and therapeutic planning. Angiography was also an important tool for evaluation of the pituitary gland. It offered information, otherwise unavailable, concerning the status of the vital vascular structures in the parasellar area. Angiographic techniques and resolution continue to improve and to be utilized in pituitary imaging, but conventional angiography has been largely replaced by CT, magnetic resonance imaging (MRI), and magnetic resonance angiography. Conventional angiography, like PEG, had an element of patient discomfort and even greater risk. Most importantly, neither modality imaged the pituitary itself and, therefore, both were subject to the inadequacies of indirect techniques. In the early 1970s the wedding of radiographic and computer technology in the form of computer-assisted tomography (CAT), now know as CT, resulted in a revolution in neuroimaging. At first, spatial resolution and contrast sensitivity were limited but these were rapidly improved. Accordingly, although CT initially was of limited value in the diagnosis of pituitary disease, it is now capable of fine detail evaluation of the sella turcica, the pituitary, the suprasellar space, the cavernous sinuses, and, to a greater or lesser degree, the contiguous vascular structures and the optic chiasm. The rapid progression of CT technology was remarkable, as was its impact on pituitary imaging. As CT appeared to be reaching its limits of resolution, MRI literally exploded on the scene and relatively rapidly replaced CT for most pituitary imaging. The spatial resolu663

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tion of MRI is not yet equivalent to that of CT, the latter having a much greater capability of defining bone detail. However, MRI has the capability of delineating intraglandular pathology as well or better than CT, and it far surpasses CT in definition of the parasellar and suprasellar regions (Fig. 20.1). Further, intravenous iodinated contrast is not required with MRI as it is with CT, and there is no iodizing radiation exposure of the patient with MRI. MRI may be performed in any plane, and does not require extension of the neck, as does CT, to obtain the very important direct coronal plane (see below). PLAIN FILMS AND TOMOGRAMS The sella turcica is best visualized on lateral views of the skull. The sellar floor can be studied on frontal radiographs angled tangentially to the plane of the floor. Usually the Caldwell view is the best.

Size and Shape of Sella Numerous studies of the “normal” sella turcica size were performed and reported prior to CT and MRI. Enlargement of the sella turcica was thought to be an indicator of pituitary pathology, as were distortion of shape and contour of the sella. A wide range of normal exists, and this has been expanded with information gained from CT and MRI. For instance, visualization of an “enlarged” empty sella in a symptomatic patient indicates that sella turcica size alone is not a valid determinant of pituitary disease. A small sella turcica may be associated with pituitary insufficiency, but the correlation is poor [1] and most small sellas are of no significance. According to Taveras and Wood [1], 17 mm is the upper limit of normal for the maximum anteroposterior diameter of the sella. The depth, measured perpendicular to the sella floor, from a line drawn between dorsum and tuberculum, should not exceed 13 mm in most cases. The normal width varies between 10 and 15 mm. These are only guidelines and sella turcica enlargement can only be used as a suggestion of pituitary abnormality and is certainly not sufficient for diagnosis. Accordingly, investigators have attempted to use the area and the volume of the sella turcica to serve as better predictors of pituitary disease. The volume is the product of onehalf the length ¥ the width ¥ the height. An area greater than 130 mm2 and a volume greater than 1092 mm3 have been reported to be abnormal [2]. These techniques are limited because they do not necessarily reflect true pituitary size. Study of the shape and bony density of the sella turcica are both techniques limited in their value as predictors of pituitary and/or parasellar disease. Focal erosion of the lateral margins often secondary to an aneurysm, focal erosions of the floor by pituitary lesions, and selective erosion of the posterioinferior floor secondary to chronic increased

intracranial pressure [3,4] are some of the more dependable findings. Thickening of the tuberculum or of the clinoid processes, and blistering of the planum sphenoidale have frequently been reported in association with meningiomas of the sella turcica. The sellar floor may become sclerotic in some cases of craniopharyngioma and nasopharyngeal carcinoma [1]. Intrasellar, parasellar, or suprasellar fat and calcifications may be excellent indicators of pathology. Craniopharyngiomas are often associated with fat and or calcification. Aneurysms may demonstrate eggshell or other calcification patterns. Meningiomas frequently calcify, and on rare occasions pituitary tumors calcify (pituitary stone). Thin section (1–2 mm), high-resolution, multidirectional tomography was initially expected to improve the sensitivity for diagnosis of pituitary lesions, particularly microadenomas. Initial enthusiasm emphasized visualization of small areas of sella floor erosion and/or depression. Unfortunately this has not stood the close scrutiny of subsequent carefully performed radiologic/pathologic/surgical studies [3,4]. In cases in which surgery showed a microadenoma, and in which tomograms were considered positive, the correlation between the actual location of the lesion and the radiograph findings was quite poor. Eventually it was recognized that tomograms added little to the diagnosis of microadenomas, although they were useful to better define such bony changes as sclerosis, bone destruction, and the presence of calcification. ANGIOGRAPHY Angiography initially had a role in the diagnosis of pituitary lesions. Lateral displacement and medial concavity of the cavernous carotid artery are signs of an intrasellar mass. Tumor vascularity and tumor blush were also helpful but frequently difficult to detect, requiring carefully performed subtraction images. Suprasellar extension of intrasellar masses could be detected by elevation of the anterior cerebral and anterior communicating arteries. Hypervascularity of meningiomas and delineation of aneurysm are areas in which angiography is useful. However, angiography is of no value in the diagnosis of microadenomas. Angiography was widely performed prior to pituitary surgery either by craniotomy or the transsphenoidal approach, because surgeons were anxious to identify the location of the carotid arteries and to exclude an intrasellar aneurysm. Subsequently, CT and then MRI have replaced the need for angiography in most cases because the position of the carotid arteries, and the possibility of an aneurysm, may be clarified by these techniques with little or no patient risk or discomfort (Fig. 20.1). CT The successful application of CT to the evaluation of intrasellar pathology awaited several technical improvements.

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FIGURE 20.1. Coronal T1-weighted MRI of a microadenoma (arrow) which is hypointense relative to the remainder of the gland. Note focal superior convexity of the pituitary gland above the lesion (curved arrow). The optic chiasm is undisturbed and the carotid arteries (black arrows) can be visualized.

High resolution required 1–2 mm sections, a 256 ¥ 256 matrix, and equipment with excellent signal/noise ratios without unacceptable ionizing radiation levels. Initially, axial views with coronal and sagittal computerized reformations were applied to the sella. Although this technique was useful for depiction of suprasellar and parasellar pathology, it was frequently inadequate to evaluate intrasellar disease, especially microadenomas. To obtain direct coronal imaging, gantry tilts of 15–20° were required but initially were not available. Unfortunately, direct coronal imaging also requires that the patient maximally extend their neck while in the prone or supine position (Fig. 20.2) to allow for imaging planes as close to direct coronal as obtainable. Many individuals, particularly older patients, found this impossible, necessitating the less adequate axial examinations. Another difficulty not infrequently encountered with direct coronal images, is the occurrence of metallic streak artifacts from dental devices and fillings (Figs 20.2–20.4). Careful set up to the patient and appropriate angulation of the gantry may obviate this problem but frequently results in less than optimal coronal angulation. CT tissue contrast is limited within the pituitary if no iodinated contrast is administered. Although fat and calcium are well defined on noncontrast CT, these are infrequently associated with intrapituitary lesions, compared to their increased association with suprasellar and parasellar lesions. Fortunately most pituitary tumors enhance with intravenous contrast less rapidly than normal pituitary tissue, resulting in increased conspicuity of these tumors. However,

FIGURE 20.2. Lateral skull localizer image obtained for planning direct coronal CT of the pituitary. The patient is supine with hyperextension of the neck. The localizer lines indicate the angle of the CT gantry and location of the sections to be obtained. Note that the most anterior sections pass through metallic dental appliances/fillings (arrows) which potentially may cause disturbing artefacts.

FIGURE 20.3. Same case as depicted in Fig. 20.1. Artifacts from metallic dental devices obscure the pituitary tumor. By readjusting the angle of gantry these artifacts were avoided and Fig. 20.31 obtained.

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FIGURE 20.4. Contrast-enhanced direct coronal CT. Diffusely enlarged pituitary gland with a hypodense macroadenoma (white arrow). A small rim of normal pituitary tissue is seen on the right (curved arrow). Depression of the sella floor is defined (black arrowheads).

there is a small but definite risk attendant to the use of such agents and some patients have medical conditions that contraindicate the use of iodinated contrast agents, e.g., reduced renal function, multiple myeloma, and sickle cell disease. One further drawback of CT is that it utilizes ionizing radiation, albeit with much greater soft tissue contrast than conventional radiographic techniques. The critical tissue at risk for radiation exposure is the optic lens. The lens is directly irradiated, with axial CT imaging of the pituitary, receiving as much as 3–5 rads of radiation. Direct coronal imaging reduces lens radiation to a minimum (£0.5 rads) and is thus additionally advantageous compared to axial imaging. Although CT has to a great extent been replaced by MRI for pituitary evaluation, it still offers some advantages. Therefore, CT’s technical factors and diagnostic considerations will be discussed.

CT: Technical Factors Direct coronal imaging with the patient supine or prone almost always requires some gantry tilt, even with maximal neck extension (Fig. 20.2). Most modern CT scanners offer a form of localizing radiograph that may be used to determine the proper gantry tilt. The gantry tilt is also chosen to exclude possible artifacts from dental devices and fillings (Figs 20.3 and 20.4). Contiguous or slightly overlapping sections of 1–2 mm thickness are recommended. Thicker sections reduce spatial

resolution and thus the likelihood of delineation of microadenomas (<10 mm in size). Although slightly overlapping sections reduce the negative impact of patient motion, they do increase examination time and radiation to a small extent. The acquisition and display matrix should be at least 256 ¥ 256, with 512 ¥ 512 being even more desirable for visualization of the smaller microadenomas. Resolution is inadequate with coarser matrices. Intravenous iodinated contrast may be administered by bolus, drip infusion, or a combination. A bolus causes rapid achievement of an adequate blood level and therefore early opacification of the cavernous sinus and the normally vascularized pituitary gland. Drip infusion alone may result in slow development of an adequate circulating blood level, and thus reduce the definable difference in contrast enhancement between the normal gland and the lesion, thereby reducing the detectability of lesions. The disadvantage of bolus techniques is the increased incidence of nausea and vomiting that may actually interfere with the performance to the study. For these reasons many centers choose to give approximately one-third of the total contrast dose by rapid bolus in order to achieve a rapid blood level, and the remainder by rapid drip infusion to maintain the blood level throughout imaging. A total dose of 40–45 g iodine has proven sufficient for most pituitary studies. Increasing the dose is unlikely to improve diagnostic accuracy but does increase the risk of morbidity, especially renal toxicity. A large number of commercially available iodinated contrast agents are available (Hypague, Renografin, Conray). Until recently all were ionic but now several nonionic, lower osmolarity agents are available (iohexol, iopamidol). It is still controversial as to whether these newer agents have overriding safety advantages justifying their substantially increased costs. In 2002, most data support the use of low-osmolarity iodinated contrast agents in patients with increased likelihood of contrast allergy, cardiac dysfunction, sickle cell anemia, and multiple myeloma.

CT: Bone Detail High-resolution CT scanners are capable of producing images with superb bone detail. Sections as fine as 1 mm are available. Reconstruction algorithms (computer programs) for bone detail enhancement and soft tissue evaluation may be applied to the same raw data. Images of the pituitary should be viewed with bone and soft tissue windows regardless of which algorithm(s) is used, to allow for the accurate interpretation of osseous as well as soft tissue detail and pathology. CT is so effective for bone delineation that tomography is no longer necessary for evaluation of the bony sella turcica. Resolution is greater with tomography, but CT resolution is sufficient to allow diagnostic evaluation of bone thickening, thinning, erosion, and deformity. Additionally, CT is many times more sensitive to calcification than is

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FIGURE 20.6. Contrast-enhanced direct coronal CT shows a nonenhancing microadenoma on the left (arrow). The normal pituitary enhances diffusely with the iodinated contrast (white darts). The cavernous sinuses (long arrows) and carotid arteries (curved arrows) are visualized but not as well as with MRI. Neural structures are seen as low-density (nonenhancing) areas in the cavernous sinuses (broad arrow).

CT: Normal Anatomy

FIGURE 20.5. The lower image is one of a series of axial CT sections through a normal pituitary gland. The upper image is a computerized reformation in the sagittal plane at the level of the double broken line. The pituitary (white arrow) can be seen as a contrast enhancing structure in the sella turcica, and the bony margins of the sella turcica are well defined (black arrowheads).

tomography. Bone information is available on a CT study of the pituitary without the additional radiation exposure and expense required by also performing conventional tomography. Sella turcica bony changes are definable by highresolution, thin-section CT in the coronal and or axial planes. The sagittal and coronal reformations are very helpful for clarifying bony changes and sella shape and size, and less so for intrasellar pathology (Figs 20.4 and 20.5). The axial CT sections must be relatively fine (1–3 mm) and contiguous or overlapping for adequate detail on computerized sagittal reformations.

The primary value of pituitary imaging by CT is not the high-resolution bone detail available but rather the direct visualization of the gland and surrounding soft tissue structures. With the use of intravenous contrast, soft tissue contrast is sufficient to define the pituitary gland, intraglandular pathology, the infundibulum, the cavernous sinuses and, to a greater or lesser extent, the suprasellar space and the optic chiasm (Figs 20.6 and 20.7). Pathologic fat and calcification deposits may be exquisitely defined (Fig. 20.8c). The normal pituitary gland enhances with ionizing intravenous contrast because of the absence of a blood–brain barrier. It is therefore hyperdense or enhanced CT. Without iodinated contrast, gland visualization is often inadequate and pathologic conditions within the gland, the sella turcica, and the suprasellar and parasellar spaces, are frequently not demonstrated. The infundibular stalk, like the pituitary itself, has no blood–brain barrier and, accordingly, also enhances (Fig. 20.7). Since the cavernous sinuses are mainly bloodfilled, they too enhance and the lateral margins of the pituitary may be obscured (Fig. 20.6). Carotid artery enhancement is equivalent to that of the cavernous sinuses, so that the intracavernous portions of these vessels are often not delineated but the supracavernous portions are usually well defined (Fig. 20.7). The horizontal portions of the

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osseous structures (Figs 20.4, 20.6, and 20.7). The optic nerve and chiasm are variably defined, best visualized in those patients with a greater suprasellar volume of CSF. The infundibulum extends to the superior margin of the pituitary from the undersurface of the hypothalamus (tuber cinereum) immediately posterior to the optic chiasm. It enhances with contrast, is relatively uniform in size, is midline in position, and its maximum diameter does not normally exceed 3–4 mm. MRI: TECHNIQUE AND ANATOMY

FIGURE 20.7. Contrast-enhanced direct coronal CT. A pituitary tumor diffusely enhances and enlarges the gland and the sella turcica. The tumor has a convex superior margin (arrow). The carotid arteries (arrowheads), the anterior cerebral artery (small arrowheads) and infundibulum (short arrow) are seen in the suprasellar space.

anterior and middle cerebral arteries are often well visualized. Intracavernous neural structures do not enhance and therefore are seen as low-density structures within the enhanced sinus (Fig. 20.6). Cranial nerves III and IV are superolateral in position in the cavernous sinuses and most often are seen as a single structure. Laterally placed in the cavernous sinuses are the first and second divisions of cranial nerve V, which usually are visualized individually. The third division of the trigeminal nerve does not enter the cavernous sinus but exits the cranial cavity through the foramen ovale after leaving the trigeminal ganglion in Meckel’s cave, which may be seen as a fluid density posterior to the cavernous sinus. If the nerve is seen within Meckel’s cave it may be an area of relative isodensity to brain. More often than not the abducens nerve medial to cranial nerve V is not separately defined because it is relatively small. Medial to the cavernous sinus and caudad to the sella turcica is the sphenoid sinus, the shape of which may be quite variable (Fig. 20.6). Pneumatization may not be equal on the two sides, thereby resulting in asymmetrical sella turcica floor thickness. At the junction of the sphenoid septum with the sellar floor, there may be a slight depression of the floor simulating an area of pathologic erosion. Intrasellar and suprasellar cerebrospinal fluid (CSF) is low in density, well contrasted against the hyperdense pituitary and

Excellent spatial resolution, not quite equivalent to that of CT, is available with MRI. Additionally, MRI contrast sensitivity is much greater than that of CT and it can be performed in any plane without patients being required to hyperextend their necks. Furthermore, MRI of the pituitary does not require contrast administration (although this may be useful on occasion, as will be discussed below), and does not use ionizing radiation. MRI has therefore become the clear procedure of choice for pituitary imaging. Highresolution MRI requires at least a medium field-strength magnet (0.5 T), and preferably a high field-strength magnet (1.0–1.5 T). Although the suprasellar contents may be adequately depicted on low and medium field-strength units, confidence of diagnosis of intraglandular pathology requires the very high resolution that is obtainable only on high fieldstrength units. Slice thickness should be 3 mm or less and the matrix 256 ¥ 256 in order to obtain a pixel size (the area of each resolution element) of no greater than 1 mm (Fig. 20.9). Since intraglandular pathology often measures no more than 1–3 mm, gaps of 1–3 mm between slices might result in missed pathology, as has been empirically discovered. Therefore, contiguous sections are required. Several alternative methods are available to accomplish contiguous sections without interslice “cross talk.” The radiologist’s preference and machine options will usually determine the technique chosen. High signal/noise ratios are required to avoid small lesions being obscured. Therefore, multiple averages (excitations or repeat data acquisitions), usually four, are necessary, resulting in relatively long image acquisition time (7–10 minutes). Two averages may be used to save time for sagittal plane imaging, since experience has shown that the sagittal plane is less valuable than the coronal for defining intraglandular lesions. Coronal and sagittal images are usually sufficient. Axial imaging is reserved for those few cases with large masses in which the axial plane helps to define lateral extension (Fig. 20.8). T1-weighted (short repetition time (TR), the interval between successive radiofrequency excitatory pulse and the formation of the spin echo signal (TE)) spin echo images have proven to be very useful for pituitary and parasellar/suprasellar imaging. Normal anatomy and pathologic conditions are well depicted by this technique. The

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(a)

(c)

FIGURE 20.8. Craniopharyngioma (a) Sagittal T1-weighted MRI. Large suprasellar mass with very variegated signal, characteristic of craniopharyngioma (arrows). (b) Axial T1-weighted MRI. The lateral extent of the cystic component (low signal area indicated by arrow) of the tumor is well defined. (c) Axial computed tomogram sections through the most cephalad portion of the mass shows calcification (arrow) that could not be appreciated on any of the MRIs. This helps confirm the diagnosis of craniopharyngioma.

(b)

additional use of T2-weighted images (long TR, long TE) is not often required except in an attempt to further define tissue characteristics of lesions (such as to differentiate fat from hemorrhage, both of which have high signal on T1weighted images but only hemorrhage maintains this high signal on T2-weighted images). T2-weighted sequences may be performed in a multitude of manners, but the time required is usually at least 7–8 minutes, adding substantial time but not necessarily providing added diagnostic information. If a contrast agent (gadolinium) is to be used, T1 images are again the most useful. T2-weighted images add

no further information in a contrast-enhanced study. The rationale for contrast utilization is discussed below. Some authors advocate dynamic scanning as a technique to increase sensitivity to pituitary lesions. They suggest that with scanning during the early infusion of contrast, differentiation between normal and neoplastic tissue can be detected due to differing dynamics of contrast enhancement. In one study of 64 patients with microadenomas, only the dynamic sequence demonstrated the lesion in 11–14% of cases [5]. In that study, the standard sequence was also seen to be necessary because in 8–9% of cases with lesions,

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(a)

(a)

(b)

(b) FIGURE 20.9. (a) Midline sagittal T1-weighted MRI, 10 mm thick section, with a wide field of view. It appears that the pituitary (arrow) is normal and that there is a suprasellar mass (curved arrow). (b) Same patient as (a). Sagittal T1-weighted MRI with 3 mm sections and a small field of view. The mass (arrow) is actually an intrasellar pituitary lesion extending into the suprasellar space.

they were only detected on the standard sequence and not on the dynamic sequence. The anterior pituitary generates a homogeneous or slightly heterogeneous signal, approximately isointense (of similar signal) to cortical brain on T1-weighted images (Figs 20.10 and 20.11). The signal throughout the anterior pituitary is moderately to markedly increased with contrast

FIGURE 20.10. Normal 37-year-old woman. (a) Coronal T1-weighted MRI. The pituitary gland (arrow) is slightly concave superiorly. The infundibular stalk (long arrow), optic chiasm (broad arrow) and third ventricle (arrowheads) are well visualized. (b) Midline sagittal T1-weighted MRI. Chiasm (broad arrow), infundibular stalk (long arrow), anterior pituitary (arrow), posterior pituitary (curved arrow), and sphenoid sinus (arrowheads) are visualized.

administration (Fig. 20.12). In infants up to 2–3 months of age, the anterior pituitary is hyperintense in signal, thought to be secondary to rapid hormone production [6–8]. The cavernous sinuses are hypointense relative to the pituitary and contiguous brain and therefore easily recog-

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(a)

FIGURE 20.11. Normal 45-year-old man. The anterior pituitary (arrow) is lower in signal than the posterior pituitary (curved arrow). The superior margin of the pituitary is flat or slightly concave. The infundibular stalk (long arrow) and chiasm (broad arrow) are isointense to brain tissue.

nized (Fig. 20.13). They also show enhancement with contrast (Fig. 20.12). The medial dural margin of the cavernous sinus is not well seen as a separate structure whereas the lateral dural wall is usually well defined. The intracavernous neural structures are of lower intensity than is the sinus itself. Rapid flow in the carotid arteries results in a signal void that clearly defines these vessels within the cavernous sinuses, on noncontrast scans (Fig. 20.13). Since the cavernous sinuses enhance approximately equally to the pituitary, the margin between the two is less conspicuous on contrast-enhanced scans. However, the carotid arteries and the neural structures remain visible because of the signal void of the carotid arteries (rapid flow) and the low signal (but greater than the carotid signal) of the normally nonenhancing neural structures. The diaphragma sellae is a dural membrane that separates the pituitary fossa from the suprasellar space. The infundibulum passes through a hiatus in the diaphragma. The diaphragma appears as a hypointense thin band at the superior aspect of the sella approximately extending from the tuberculum to dorsal sellae. The direction of displacement of the diaphragma may be useful in differentiating masses arising within the sella from those arising in the suprasellar space, in those instances when the mass is large enough to bridge both spaces [9]. A sellar osseous spine and bone rising from the anterior surface of the dorsum sellae may impinge upon and deform an otherwise normal functioning gland

(b)

FIGURE 20.12. (a) Gadolinium-enhanced coronal T1weighted MRI in a patient with suspected Cushing’s disease. A lesion is suspected in the left side of the pituitary gland because of the superior convexity (arrow) of the gland and the depression of the floor. However, there are no signal abnormalities present to confirm this impression. The enhanced infundibulum (long arrow), pituitary gland, and cavernous sinuses are of equal intensity. (b) Nonenhanced coronal T1-weighted MRI. The tumor is definitely defined as an area of decreased signal in the left side of the gland (arrow). The gadolinium enhancement of the tumor apparently was equivalent to that of the normal gland, obscuring the lesion on Fig. 20.12a.

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FIGURE 20.14. A coronal T1-weighted MRI. The sella turcica is enlarged and filled with cerebrospinal fluid (empty sella). A thin rim of pituitary tissue is present inferiorly (arrow) and a thickened area of pituitary tissue on the right was a prolactinoma (curved arrow). The carotid (hooked arrow) and anterior cerebral artery (broad arrow) are seen as signal voids in the suprasellar space.

(a)

(b)

FIGURE 20.13. Normal 29-year-old woman. (a) Coronal and (b) sagittal T1-weighted MRI. The pituitary gland (arrow) is superiorly convex and measures 10 mm in height. However, there are no focal areas of signal abnormality. This is a common appearance in normal women of childbearing age. The cavernous sinuses are hypointense to the pituitary (short arrows), and the carotid arteries are seen as a signal void in the cavernous sinuses (long arrows).

[10]. Duplication has been reported associated with the median cleft syndrome [11]. In the suprasellar space the carotid, anterior, and middle cerebral arteries are usually well visualized because of the signal void created by the rapid blood flow (Figs 20.14 and

20.15). The optic chiasm, optic nerves, and infundibulum are clearly delineated on T1-weighted images and thereby provide excellent contrast for the vessels and neural structures. The optic chiasm and nerves do not enhance with gadolinium administration because of their blood–brain barrier, but the infundibulum enhances similarly to the pituitary (Fig. 20.12), because of the absence of a blood–brain barrier. The posterior pituitary is normally hyperintense (bright) on T1-weighted images (Fig. 20.13). Initially this was thought to be secondary to fat in the sella turcica posterior to the pituitary. Subsequently it has become clear that the high signal emanates from the posterior pituitary itself, and specifically from the phospholipid vesicles containing the neurosecretory granules [12–14]. It has been suggested that absence of high signal in the posterior pituitary reflects loss of function [15,16]. However, several studies have now shown that a small percentage of normal patients do not demonstrate this high signal [13,17,18] (Fig. 20.16). Many, but not all patients with diabetes insipidus lack the posterior pituitary “bright spot” [15,19]. Idiopathic growth hormone deficiency is often associated with an hypoplastic anterior pituitary, a thin or absent stalk, and an aberrantly located posterior pituitary bright spot [20–22]. An absent or transected stalk will preclude transport of the neurosecretory granules from the hypothalamus, with development of an ectopic “bright spot” in the hypothalamus or proximal stalk. This is seen in trauma and surgical transection.

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FIGURE 20.16. Midsagittal T1-weighted MRI of a small anterior pituitary (arrow) and no high-signal posterior pituitary in the posterior sella turcica (curved arrow). The patient had normal function of the anterior and posterior pituitary.

(a)

(b)

FIGURE 20.15. (a) Coronal T1-weighted and (b) T2weighted MRI of a macroadenoma (arrow). On the T2-weighted image all contrast detail between the tumor (arrow), the optic chiasm (curved arrow), and the brain, is lost because all are relatively hyperintense, whereas these structures are clearly defined in (a). The anterior cerebral (arrowhead) and middle cerebral (larger arrowhead) arteries are clearly seen as signal voids.

A thickened stalk has been reported in idiopathic central diabetes insipidus. This is probably related to an infiltrative process including lymphocytic adenohypophysitis, Langerhans histiocytosis, and tumors such as a germinoma [23].

Although the posterior pituitary may be differentiated from the anterior pituitary on MR because it enhances to a lesser degree, this is not true on contrast-enhanced MR where enhancement of the anterior pituitary reduces the contrast between the two lobes. On T2-weighted images CSF in the suprasellar space becomes hyperintense, and the pituitary signal is relatively hypointense. The cavernous sinuses and optic chiasm are isointense to the pituitary, further reducing contrast compared to T1-weighted images. In addition, the high signal of the CSF in the suprasellar space often obscures details of structures within this region (Fig. 20.15). Signal void in the carotid arteries continues to result in good visualization of these vessels. Spatial resolution of MRI is not quite equivalent to CT, but definition of sellar size and shape are sufficiently clear with MRI to be diagnostic of most significant changes. Although it is true that cortical bone produces little if any signal on MRI, thus reducing fine bony detail, the significance of delineation of subtle bone changes has been markedly reduced with MRI because of its capability of directly defining pathologic changes within the soft tissues. Further, MRI is very effective in defining infiltration of medullary bone, exceeding CT in this respect, and this may be important in the detection of bony extension of disease processes. Nuclear medicine may play a role in pituitary evaluation. Parasellar and intrasellar masses may be detected with brain imaging radiopharmaceuticals especially with SPECT imaging. Indium (111) labeled octreotide may be useful in detection of growth hormone secreting tumors and following their response to treatment [24].

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Table 20.1. Maximum cephalo-caudad dimensions (mm) of “normal” pituitary on MRI

hypoplasia are frequently seen in patients with pituitary dwarfism [35].

Age (years)

MICROADENOMAS Male Female Pregnancy

0–11

12–50

>50

5 5 –

7 9 12

5 5 –

The above are guidelines based on data from [16–23].

PITUITARY SIZE AND SHAPE Numerous studies in the literature discuss the appearance of the normal pituitary on CT and MRI [25–32] (Table 20.1). Review of these indicates a continued evolution in assessment of normal values. Initially, gland heights of greater than 7 mm, and superior convexity of the gland, were said to be abnormal. A series of papers was then published that established greater normal heights for pituitary glands in females in the childbearing years [25,27] (Fig. 20.13). In addition superior convexity appeared common in this group and it was not verified as an absolute indicator of pituitary pathology in nonpregnant females and in males. Both boys and girls may develop an increase in pituitary height during puberty [33]. In the elderly all pituitary dimensions diminish and the posterior pituitary “bright spot” may be absent in as many as 29%. According to Terano [34] the neurosecretory granule depletion in the elderly may be secondary to persistently raised serum osmolality. Loss of glandular size with aging may result in the “empty sella.” Weiner et al. [29] reported a mean (±SD) normal gland height of 5.4 (±0.9) mm, while Roppoll et al. [30] found a greater mean gland height for females than males (4.2 ± 1.4 mm vs 3.6 ± 0.9 mm, respectively). The mean height was said to increase from 3.3 ± 0.4 mm, under age 11 years, 4.2 ± 1.5 mm, for ages 12 through 60 years and to decline to 3.9 ± 1.0 mm after age 60 [30,31]. Wolpert et al. [31] found females in the childbearing years to have a pituitary gland height as great as 9 mm. Swartz et al. [32] reported an average gland height of 7.1 ± 1.1 mm in women in the childbearing years; Gonzalez et al. [27] found a significant increase in pituitary dimensions in pregnant females with an increase of 2.6 mm in all three dimensions occurring by the end of pregnancy. It is now generally accepted that the normal gland may be concave, flat, or have a superior convexity (Figs 20.11 and 20.13). Marked superior convexity is not common in normal individuals other than women who are pregnant or in the childbearing years [31]. “Small” glands are most often normal [30,31]. They are frequently associated with intrasellar fluid, the so-called “empty sella” (Figs 20.14 and 20.16) which itself has no predictive value for pituitary pathology (see below). Pituitary gland and infundibular

Pituitary adenomas occur very commonly, with an incidence as high as 27% in some autopsy series. Prolactin (PRL)-containing cells are seen in up to 41% of these lesions. Therefore, the incidence of prolactinomas in the general population could be as high as 10% [36,37]. Prolactinomas have been diagnosed with an increasing frequency in recent years. Several factors may be involved, including the development of an excellent serum assay and constantly improving neuroradiologic imaging. CT and MRI have added the capability of direct visualization of the pituitary gland and its contents to a broad array of indirect imaging techniques. Prolactinomas are most often found in the posterolateral aspect of the anterior pituitary lobe. The diagnosis of a central lesion as a prolactinoma should be suspect. Lactotropes are primarily located in the lateral aspect of the anterior lobe [38]. Growth hormone (GH)-producing lesions may be central or lateral [38,39]. Pars media cysts are usually central, which may be their only differentiating feature from prolactinomas. These cysts occurred in 13–20% of an unselected autopsy series [40]. A number of imaging criteria have been advanced for the diagnosis of microadenomas. The most reliable, on both CT and MRI, is direct visualization of an intrapituitary lesion [41–58]. Most pituitary microadenomas are hypodense relative to the remainder of the gland on contrastenhanced CT (Figs 20.4 and 20.6). A few have been reported to be hyperdense and others isodense (Fig. 20.7) and therefore may not be visualized unless they cause secondary findings. Since technical factors, such as quantum mottle (graininess of a radiographic image attributed to the corpuscular nature of radiation [photons] and statistical variation in their distribution) and noise (noise-spurious electrical pulses which degrade an image contrast-enhanced, high-resolution CT [59]), may result in a mottled heterogeneity of the gland on CT, small hypodense lesions of 1–3 mm may not be recognized. David et al. [58] reported that 43% of surgically proven microadenomas were isodense on CT. Most microadenomas detected by MRI are seen as an area of relative hypointensity on T1-weighted MRI images (Figs 20.1 and 20.17) but a few hyperintense lesions have been reported [49,58]. Bromocriptine therapy usually shrinks prolactinomas but may cause cellular changes and/or hemorrhage resulting in an increased signal within the gland on T1 images [49,60] (Figs 20.18 and 20.19). A case of three pituitary microadenomas has been reported [61]. Focal superior convexity of the gland without definite glandular enlargement has a greater predictive value for intraglandular pathology than does general convexity of the superior margin (Figs 20.1 and 20.12). However, the

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(a)

FIGURE 20.18. Effects of bromocriptine on coronal T1weighted MRI. A hemorrhagic pituitary mass (arrow) demonstrates high signal as a result of extracellular methemoglobin. Patient received bromocriptine therapy to treat the mass and marked hyperprolactinemia.

(b)

FIGURE 20.17. (a) Coronal T1-weighted MRI. Low-signal macroadenoma (arrow) distorts and displaces the high-signal posterior pituitary (curved arrow). (b) Sagittal T1-weighted MRI. The posterior pituitary (high-signal, curved arrow) is elevated by the low-signal tumor (arrow).

superior convexity of the gland may be relatively marked in normal females of childbearing age, especially in pregnancy. Eccentric position of the infundibulum in the transverse plane is of limited value since it is present infrequently with microadenomas [56]. However, when present and otherwise unexplained it should increase suspicion for the presence of an intraglandular lesion. In most cases of significant infundibular displacement it is displaced away from the

lesion (Fig. 20.19), but displacement may be towards the lesions. The infundibulum can be seen in virtually all T1-weighted coronal MRI studies performed with contiguous thin sections (Fig. 20.11). Since the infundibulum enhances with iodinated contrast, it is also seen in most CT studies. It may be difficult to visualize if a mass elevates or distorts it. Enlargement of the gland to a height greater than 8 mm has also been found to be a poor criterion for microadenomas. Only five of 39 patients with proven microadenomas had gland heights greater than 8 mm [59]. Abnormality of the sellar floor and size are the least valuable indicators of glandular disease [36,45,56]. The presence of such abnormalities was frequently not correlated with the location of the lesion in the gland, and very often no such abnormalities were present in cases with proven microadenomas. The size of the sella turcica poorly correlated with pituitary size, especially when suprasellar fluid extends into the sella (partially empty sella, see below).

Gadolinium Enhancement Gadolinium is a paramagnetic agent that can change the magnetic properties of tissues in which it collects, thereby causing enhancement of the structure on MRI (brighter image). Gadolinium enhancement has been used in an attempt to increase the conspicuousness of pituitary

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(a) (a)

(b)

FIGURE 20.19. (a) T1-weighted coronal MRI of a 48-yearold woman treated with bromocriptine for hyperprolactinemia. The gland is unusual in shape (arrows), the infundibular stalk is deviated to the right (long arrow) and there is a large area of relatively decreased signal inferiorly, probably representing residual tumor (curved arrow). (b) When bromocriptine treatment was discontinued the prolactin level increased dramatically and this repeat MRI demonstrated marked tumor enlargement (arrows).

microadenomas [41,55,58]. Greater enhancement of the normal gland relative to the lesion will result in the lesion being seen as a hypointense area (Fig. 20.20). The physiology of gadolinium deposition is similar to that of iodinated contrast used for CT, and therefore gadolinium enhancement with MRI can be expected to be at least as sensitive. Since contrast sensitivity of MRI is much greater

(b)

FIGURE 20.20. (a) Coronal T1-weighted MRI demonstrates a macroadenoma (arrow) of the left side of the pituitary. (b) The medial margin of the tumor (black arrow) is not seen until the study is repeated with gadolinium enhancement.

than that of CT, gadolinium enhancement has the potential to add significantly to the diagnosis of intraglandular lesions. Strict attention to technical detail is required for diagnostic accuracy. Scanning must be performed within several minutes after the gadolinium is administered to allow for the greatest differential enhancement between the normal gland and the lesion. As time passes the lesion will also

Chapter 20

enhance and may become equal in intensity to the normal gland, and its conspicuousness will actually decrease. Even with proper scan timing, some lesions may enhance at the same rate as the normal gland (Fig. 20.12), and thereby be obscured. It is for these reasons, as well as the high cost and minimal (but possible) morbidity (headache in 5–10% of patients) of gadolinium, that initial evaluation of the pituitary using MRI should be by nonenhanced scans. If these do not adequately answer the clinical question, gadolinium may then be administered. However, the necessity of the additional examination, with its attendant expense and minimal but real risk of morbidity, depends on the importance of defining a microadenoma. (See below for discussion of gadolinium enhancement for macroadenomas, and for suprasellar and parasellar masses.) In the case of prolactinomas, a noncontrast scan is often sufficient even if negative because it will exclude a mass impinging upon the chiasm or extending into the cavernous sinuses or temporal fossae. Medical therapy may then be safely instituted, based upon hormonal studies, without the necessity of absolute verification of the presence of a microadenoma. On the other hand, for Cushing’s disease and acromegaly or gigantism, surgery is often indicated and it is highly desirable to define the exact location of the responsible lesion (Fig. 20.12). Since excess ACTH production may occur from a pituitary tumor, or an extrapituitary tumor ectopically secreting ACTH, treatment depends on an exact localization of the offending lesion [56]. Nonvisualization of an ACTH-producing pituitary tumor may result in an unnecessary, expensive, and, on occasion, invasive procedure to locate the lesion. It is therefore essential that the imaging of the pituitary be done with strict attention to technical detail as previously discussed. If noncontrast scans are negative, gadolinium-enhanced studies with imaging immediately after the administration of the gadolinium should be performed. Dwyer et al. [49] determined a total eight of 12 pituitary Cushing’s tumors on noncontrast MRI and 10 of 12 on contrast MRI. Only after such careful evaluation of the pituitary is it appropriate to consider the MRI study negative and to proceed with additional evaluation including adrenal imaging and chest CT. Saris et al. [60] found a low sensitivity (30%) of CT in the detection of ACTHproducing tumors. Others indicated a less than 50% accuracy of CT in locating proven intrapituitary ACTHproducing tumors [62]. Dynamic imaging may improve detectability, but due to lower resolution there is a reduced specificity [63]. MR cannot be considered definitive in excluding pituitary sources of excess cortisol production, and if negative, venous sampling should be considered. Fortunately most GH-producing tumors are large and easily located by CT and MRI. Careful attention to technique in imaging will improve the sensitivity for diagnosis of the few microadenomas that are found associated with excess GH production.

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MACROADENOMAS Regardless of the hormonal activity of pituitary macroadenomas, the optimal imaging technique remains the same as for microadenomas. However, with most macroadenomas contrast administration is desirable. Noncontrast MRI studies of macroadenomas will demonstrate one or more of the following: (i) enlargement of the sella turcica; (ii) depression or focal erosion of the sellar floor; (iii) undercutting of the tuberculum; (iv) erosion of the dorsum; (v) focal or diffuse superior convexity of the pituitary gland; (vi) a mass extending from the sella into the suprasellar space, and/or the cavernous sinuses; (vii) a focal area of decreased signal within the gland; (viii) displacement of the infundibulum; (ix) elevation of the chiasm; and (x) less commonly, a distortion of the posterior pituitary bright spot (Figs 20.15, 20.17, 20.19, 20.21, and 20.23) [51,53,64–67]. Whereas microadenomas are often difficult to detect, macroadenomas are easily diagnosed, but require careful delineation of the extent of the lesion. An exception is the small to moderate-sized diffuse macroadenoma and diffuse hyperplasia which may be impossible to differentiate from a normal gland in a female in the child-bearing years. Once a macroadenoma has been recognized, or gland enlargement noted, gadolinium enhancement is often of great value. It may define an otherwise isointense lesion within the gland by enhancing the normal gland to a greater extent and/or more rapidly. Gadolinium enhancement will improve definition of the margins of large lesions extending into the suprasellar space and impressing upon the chiasm or brain parenchyma. The margins of such lesions may otherwise be indistinct on a noncontrast MRI examination (Figs 20.20 and 20.21). Cavernous sinus invasion by pituitary tumors is often difficult to ascertain on CT and MRI. If lesion contrast enhancement is not as great as that of the cavernous sinus, a margin between the two may be clarified by enhanced studies [53,64] (Fig. 20.22). However, the medial dural margin of the cavernous sinuses is frequently indistinct, even in normal patients, and it is often very difficult to differentiate impingement upon the sinus from the true invasion (Fig. 20.23). The most reliable criterion for sinus invasion is visualization of the lesion extending to the lateral margin of the carotid artery, and surrounding it (Figs 20.22 and 20.23). Widening of the posterior double leaflets of the cavernous sinus has been suggested as an additional useful sign but is difficult to appreciate [68]. The artery is seen as a signal void on MRI, but cannot be separated from the remainder of the cavernous sinus on CT since both sinus and the vessel enhance. Even lateral bulging of the sinus could be secondary to lateral displacement of the sinus, and is not diagnostic of invasion. Recognition of sinus involvement is very important preoperatively for prognostic purposes, as the chance of total excision is greatly reduced.

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(a) (a)

(b)

(b)

FIGURE 20.21. (a) Coronal T1-weighted MRI. The left lateral margin of the extensive pituitary tumor is difficult to determine. (b) Coronal T1-weighted MRI with gadolinium enhancement. The left lateral margin of the tumor (arrows) is now obvious. The medial left temporal lobe is now clearly defined whereas in (a) it appeared to be part of the tumor.

Pituitary carcinomas tend to be large (Fig. 20.24). The associated bone structure is often more irregular and/or infiltrative compared to the smooth enlargement of the sellar margins seen with benign lesions. Since these very rare malignancies may invade normal brain, gadolinium enhancement is particularly valuable to define the margins of the lesion.

FIGURE 20.22. (a) Coronal T1-weighted MRI in an acromegalic male. The gland is diffusely enlarged. Cavernous sinus invasion bilaterally is suggested by similar signal of the pituitary tumor (arrows) and the cavernous sinuses (long arrows). (b) Coronal gadolinium-enhanced T1-weighted MRI shows signal in the left cavernous sinus (arrow) similar to that within the pituitary tumor (long arrow) confirming left cavernous sinus invasion. However, the right cavernous sinus (curved arrow) enhances normally and greater than the pituitary tumor, indicating no tumor involvement.

Macroadenomas, whether hormonally active or not, whether benign or malignant, often develop cystic, necrotic, and hemorrhagic areas. The former appear as low signal regions on T1-weighted images, and high signal on T2weighted images, whereas hemorrhage causes high signal on both sequences.

Chapter 20

FIGURE 20.23. Coronal T1-weighted MRI. Pituitary macroadenoma (arrow) filling the right cavernous sinus (short arrows) which is of similar signal intensity to the pituitary tumor, and higher intensity than the normal left cavernous sinus. The tumor extends into the right foramen ovale (black arrow). The right carotid artery (broad arrow) is surrounded by tumor, indicating definite invasion of the cavernous sinus rather than compression and displacement.

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Pituitary hyperplasia will image as diffuse glandular enlargement. Infiltrative processes such as lymphoma, granulomatous diseases [69], and lymphocyte adenohypophysitis [70] (which is usually associated with stalk enlargement) may have a similar appearance. Clinical and hormonal information is crucial to the diagnosis and to differentiate these processes from macroadenomas. Rarely a pituitary abscess may enlarge all or part of the gland [71]. Bromocriptine therapy for PRL-producing tumors results in an increased incidence of hemorrhage and/or other as yet not fully understood changes in the tumor that result in high signal on T1-weighted images [60] (Fig. 20.18). Termination of bromocriptine therapy may be followed by rapid tumor enlargement (Fig. 20.19). In cases of pituitary apoplexy, CT will show high density within the gland for the first 7–10 days after the hemorrhage, whereas MRI will show high intensity of the gland on T1-weighted images obtained after the first several days. Initially, T1weighted images may only show an increased size of the gland or an area of relative hypointensity [72]. One of the most important considerations in evaluation of macroadenomas is the effect of the mass on the optic chiasm. In fact, a primary reason for MRI’s superiority to CT for pituitary imaging is that it enables optimal evaluation of the suprasellar space and chiasm in virtually all cases, whereas with CT this is the exception rather than the rule. Elevation and deformity of the chiasm are best defined by coronal T1-weighted images, although the sagittal plane may add additional information on some occasions (Fig. 20.15). POSTERIOR PITUITARY

FIGURE 20.24. Coronal T1-weighted MRI. A large pituitary carcinoma has destroyed the sellar floor, and fills the sphenoid sinus (arrow) and suprasellar space (long arrow). Brain invasion is also demonstrated (curved arrow).

The posterior pituitary normally appears as an area of high signal on T1-weighted images, probably reflecting the presence of neurosecretory granules (Figs 20.13, 20.15, and 20.17). Specifically, it has been suggested that the phospholipid membrane of the vesicles is responsible for T1 shortening and the attendant high signal [12–16,25,73,74]. Absence of the high signal in the posterior pituitary may be an indication of a non-functioning neurohypophysis [15,16,19,28,35,36,41,45,74] (Fig. 20.25). However, subsequent reports have shown that a small percentage of normal patients do not demonstrate this high signal area [15,17] (Fig. 20.16). On the other hand, many patients with diabetes insipidus do not show the “bright” spot of the posterior pituitary [16,19,74] (Fig. 20.25). A high signal area, thought to represent aberrant location of the pituitary, or at least of neurosecretory granules, has been reported in normal patients and in cases of presumed traumatic disruption of the pituitary stalk, hypophysectomy, and pituitary tumors destroying the posterior pituitary. These patients may or may not manifest diabetes insipidus [19]. Since the high signal is related to the neurosecretory granules produced in the hypothalamus, it is not surprising that it may be seen in the stalk or the hypothalamus if there is

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(a) FIGURE 20.25. Sagittal T1-weighted MRI. A normal size empty sella with a thin rim of pituitary tissue inferiorly (arrow). This patient, evaluated for diabetes insipidus, does not demonstrate a posterior pituitary “bright spot.”

disruption in the normal transportation of neurosecretory products to the pituitary from the hypothalamus. OTHER INTRASELLAR MASSES

Rathke’s Cleft Cysts Rathke’s cleft cysts may present in the intrasellar and/or suprasellar compartments, most frequently crossing into both spaces. The anterior sella turcica and anterior suprasellar cistern are the areas of most frequent involvement. These lesions infrequently are greater than 1 cm in size, and are most often spherical. On CT, most are hypodense suggesting the presence of a fluid-filled cyst, but they may be isodense and, on a few occasions, even hyperdense (Fig. 20.26). MRI appearance is also variable with most demonstrating low signal on T1-weighted images and high signal on T2weighted images, similar to CT [75] (Fig. 20.26). However, they may be isointense or hyperintense on T1 images [51] and several have been reported to be isointense rather than hyperintense to brain on T2-weighted images [76]. Rathke’s cleft cysts are almost always sharply defined and usually appear separate from the pituitary and infundibulum (Fig. 20.26). On occasion, however, they may be quite difficult to differentiate from pituitary tumors. In such cases hormonal studies may be the only differentiating feature. Fortunately, most Rathke’s cleft cysts are asymptomatic, probably because of their relatively small size and infrequence of compression of the chiasm. When detected in patients being evaluated for headache, they present a difficult therapeutic dilemma. Some authors suggest a transsphe-

(b)

FIGURE 20.26. (a) Rathke’s cleft cyst (arrow) is beautifully visualized on this T1-weighted coronal MRI. The compressed pituitary (long arrow) and chiasm (curved arrow) are both clearly separate from the lesion. (b) An axial CT shows an intrasellar mass (arrow) but does not allow definition of the lesion as distinct from the pituitary.

noidal approach and cyst drainage as the treatment of choice in symptomatic cases [77].

Craniopharyngiomas Craniopharyngiomas arise from epithelial rests of the craniopharyngeal canal. They may be suprasellar, intrasellar,

Chapter 20

FIGURE 20.27. Coronal T1-weighted MRI. Suprasellar craniopharyngioma (arrow) has high signal as a result of lipid content.

or both. Solid and cystic components are usually present. When intrasellar, the sella turcica may be enlarged similarly to pituitary tumors. Some authors report increased density of the bony margins of the sella turcica which may be differential features from pituitary tumors. Calcification is very common, occurring in half or more of children and a lesser but significant percentage of adults (Fig. 20.8). Calcification may involve the solid component or the wall of the cyst and is another differentiating feature from pituitary tumors, which infrequently calcify [78–80]. The cystic component of a craniopharyngioma may contain lipid-like substances and therefore be low in density on CT and high in signal on T1-weighted MRI, with a lesser signal on T2-weighted images (Figs 20.8 and 20.27). Hemorrhage is often present and may have a characteristic appearance on CT (high density when recent, low density when older), and MRI (high signal on T1- and T2-weighted images if the hemorrhage is more than several days old). Gadolinium may improve definition of solid components of these tumors, similar to microadenomas. Calcifications are poorly seen on MRI, whereas the CT definition of calcification is excellent, so that CT may on occasion improve the specificity of diagnosis in the case of craniopharyngiomas (Fig. 20.8). However, since most craniopharyngiomas are relatively distinctive in their MRI appearance, with both cystic and solid components, lipid-like areas, and variegated signal, CT is rarely necessary. Intrasellar aneurysms arising from the cavernous carotid are rare. Prior to CT and MRI, the fear of such lesions or of medially positioned or tortu-

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ous carotid arteries extending into the sella turcica necessitated angiography in the preoperative evaluation for pituitary surgery. Such aneurysms may rarely cause sellar enlargement, simulating pituitary tumors. More often and characteristically they produce erosion along the lateral sellar margin at the carotid sulcus. CT and MRI have obviated the need for angiography in most instances because they directly demonstrate the carotid artery or the aneurysm. If an aneurysm is visualized, angiography will usually be required for better definition prior to surgical or endovascular therapy. Particularly for cavernous aneurysms, endovascular therapy often may be more desirable than surgical treatment. Should there be a question as to the interpretation of CT or MRI regarding the presence of an aneurysm or tortuous vessel in the sella turcica, magnetic resonance angiography is now available and usually sufficient to clarify the diagnosis without requiring conventional angiography (Fig. 20.28). On occasion, cavernous carotid aneurysms may compress the lateral aspect of the pituitary gland sufficiently to result in elevation of the superior margin of the gland, simulating a pituitary tumor on sagittal magnetic resonance images. Such aneurysms should be easily recognizable as signal voids or mixed high and low signal on MRI, or as areas of contrast enhancement deforming the normal shape of the cavernous sinus, on contrast-enhanced CT (Fig. 20.28). OTHER PARASELLAR MASSES Several types of tumor occur in the parasellar and suprasellar space and secondarily involve the sella turcica or its margins. Meningiomas are the most common, often arising from the sellar margins, especially the tuberculum sellae. They are recognizable on CT and/or MRI by their distinctive features, including sclerosis or blistering of the bone, calcification best seen on CT, hyperdensity on CT and relative isodensity or mild hyperintensity on T2-weighted MRI, as well as dense homogeneous contrast enhancement on both CT and MRI (Fig. 20.29). A meningioma arising from the arachnoid membrane of the stalk has been reported [81]. Optic glioma, sarcoid, eosinophilic granuloma, hypothalamic glioma, chordoma, nasopharyngeal carcinomas, chondomas, and metastatic disease as well as other tumors may on occasion involve the sella turcica and its contents [82]. MRI will usually clarify the area of primary origin of these masses and characterize the lesion sufficiently to allow for appropriate differential diagnosis and exclusion of the pituitary as the tissue of origin. EMPTY SELLA The “empty sella” refers to a sella turcica that contains CSF communicating with the suprasellar space through a normal or enlarged infundibular hiatus in the diaphragma sellae.

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(a) (c)

FIGURE 20.28. (a) Midline sagittal T1-weighted MRI shows an enlarged pituitary (arrow) with superior convexity of the gland. (b) Coronal T1-weighted MRI indicates that the gland is actually compressed between two parasellar masses (arrows) which have very variegated MRI signal. This results in the false impression of gland enlargement in the sagittal plane. (c) Magnetic resonance angiogram, coronal projection, shows these parasellar masses to be bilateral cavernous carotid aneurysms (arrows).

(b)

There is almost always some pituitary tissue present, and very often the pituitary is normal in size and/or function (Figs 20.11, 20.25, and 20.30). The sella turcica may or may not be enlarged. If enlarged, it usually is symmetrically expanded, or the floor is depressed without expansion of the anterior and posterior walls (Fig. 20.30). Undercutting of tuberculum and thinning of the clinoids may occur. There are no specific bony deformities that may be used to differentiate the empty sella from an expansile intrasellar mass. In a study of 189 normal subjects by CT, it was found that there was a tendency for decreasing size of the pitu-

itary with advancing age. Whereas in normal subjects under 29 years, especially females, the pituitary gland generally filled the sella, after age 50 years the gland was often flattened and there was increased CSF in the sella, i.e., a partially empty sella [83]. In another study of 56 patients without a pituitary disorder 39% had moderate or marked empty sella [84]. There are, however, a number of etiologies for the empty sella other than simply normal variation, and these are classified as primary and secondary empty sella depending on the etiology. Primary empty sella is associated with an incompetent diaphragma sellae with intrasellar extension of cisternal CSF,

Chapter 20

(a)

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683

FIGURE 20.30. Coronal T1-weighted MRI of an enlarged empty sella. The optic chiasm is “V”-shaped (arrow) indicating downward displacement.

(b)

FIGURE 20.29. (a) A left parasellar meningioma (arrows) is poorly appreciated on this T2-weighted axial MRI because there is no signal difference from the opposite side. (b) The contrastenhanced (arrow) meningioma is now obvious on this postgadolinium-enhanced T1-weighted axial MRI.

or a hypoplastic pituitary gland. The normal diaphragma may be a complete dural covering of the sella with only a small opening for the infundibulum. However, this opening may be wider than the infundibulum. The diaphragma may cover only a peripheral rim of the sella. In the latter two instances, which occur in approximately 40% of the popu-

lation, there is a potential for downward extension of suprasellar fluid and, rarely, the suprasellar visual system (Fig. 20.30). The continued pulsation of the CSF through this widened opening in the diaphragma sellae may progressively result in a partially empty sella with a depressed superior margin of the pituitary and/or an enlarged sella [85]. A multitude of etiologies have been reported to cause secondary empty sella. In these instances the sella turcica may or may not be enlarged, depending on whether the primary condition expanded the sella or the constant pulsation of the intrasellar CSF eventually results in an enlarged sella. Pituitary microadenomas may coexist with an empty sella. In the face of pituitary hormonal excess, the finding of a partially empty sella does not exclude the presence of pituitary microadenoma. A partially regressed macroadenoma may in fact be the etiology of the empty sella (Fig. 20.14). In addition, hyperprolactinemia has been seen associated with an empty sella in the absence of a pituitary tumor [86]. Downward herniation of the suprasellar visual system (optic chiasm, optic nerves, optic tracts) into the sella may occur in association with the primary or secondary empty sella (Fig. 20.30), Visual disturbances may or may not be present and, when present, may be progressive or static [87–89].

Imaging of the Empty Sella Prior to CT being available, PEG was required to definitively diagnose the empty sella. Air enters the intrasellar

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of the leak is best accomplished by high-resolution, thinsection CT performed immediately after opacification of the subarachnoid cisterns by intrathecal contrast, usually administered by lumbar puncture (Fig. 20.31).

MRI vs CT

FIGURE 20.31. Axial CT through the sella turcica several minutes after lumbar instillation of intrathecal contrast agent. The empty sella (arrow) is filled with contrast-enhanced cerebrospinal fluid (CSF) and is therefore hyperdense. The infundibular stalk is visible (long arrow). The left sphenoid sinus and posterior ethmoid air cells (curved arrows) are also contrast filled, indicating that they communicate with the intracranial CSF, explaining the CSF rhinorrhea in this patient with idiopathic intracranial hypertension.

compartment through the suprasellar cistern with which it communicates. Intrasellar masses would indent the suprasellar cistern allowing for their diagnosis. CT obviated the necessity for PEG in the evaluation of patients for the empty sella. However, initially CT resolution was not adequate to define intrasellar contents so that intrathecal contrast was necessary to clearly define intrasellar extension of cisternal CSF (Fig. 20.31). As CT resolution improved, a direct diagnosis of the empty sella became possible, especially with direct coronal images. Visualization of a nondisplaced pituitary stalk differentiates an empty sella from a cystic pituitary tumor on CT studies [90]. MRI has made the diagnosis of the empty sella quite routine. T1-weighted images clearly define the pituitary, infundibulum, and intrasellar CSF, and if there is any question of an associated mass, gadolinium enhancement will usually suffice for clarification. Furthermore, herniation of the suprasellar visual system is exquisitely defined by MRI on both coronal and sagittal T1-weighted images that will show an empty sella when present. Intrathecal enhanced CT is still of value in those cases of the empty sella associated with CSF rhinorrhea [91–93]. This association has been extensively studied and probably does not have a single explanation. Pituitary tumor, intrasellar cyst, or increased intracranial pressure may coexist with the empty sella and be responsible for the rhinorrhea. However, there may be no associated conditions. Location

A multitude of papers have addressed the issue of the relative value of MRI and CT in pituitary imaging [43,45,46,50,51,54,79,94]. It should be obvious from the foregoing that this author clearly and strongly favors MRI as the primary, and usually the only, imaging technique required for pituitary evaluation. Certainly there are instances where CT may add information, such as better definition of bone detail or the presence of calcification. However, in the vast majority of cases MRI will suffice for diagnosis of the presence of a lesion and definition of the extent of that lesion. Furthermore, much greater inherent safety and ease of performance of MRI, and the availability of magnetic resonance angiography, emphasize that MRI is the primary procedure for pituitary imaging, well worth any added expense compared to CT. A few patients may not tolerate the confined space in the MRI magnet, and in a few patients MRI findings may indicate a need for CT. There are a number of contradictions to MRI, including cardiac pacemakers and the presence of intracranial aneurysm clips. However, the vast majority of patients will be well served by MRI as the primary procedure for pituitary evaluation. REFERENCES 1 Taveras JM, Wood EH, eds. Diagnostic Neuroradiology. Baltimore: Williams and Wilkins, 1964. 2 DiChiro G, Nelson KB. The volume of the sella turcica. Am J Roentgenol 1962;87:989–1008. 3 Turski P, Newton TH, Horten BH. Sellar contour: anatomic-polytomographic correlation. Am J Roentgenol 1981;137:213–216. 4 Wortzman G, Rewcastle NB. Tomographic abnormalities simulating pituitary microadenomas. AJNR 1982;3:505–512. 5 Bartynski W, Lin L. Dynamic and conventional spin-echo MR of the pituitary microlesions. AJNR 1997;18:965–972. 6 Wolpert SM, Osborne M, Anderson M et al. The bright pituitary gland—a normal MR appearance in infancy. AJNR 1988;9:1–3. 7 Miki Y, Asato R, Okumura R et al. Anterior pituitary gland in pregnancy: hyperintensity at MR. Radiology 1993;187(1):229–232. 8 Caruso RD, Rosenbaum AE, Sherry RG et al. Pituitary gland. Variable signal intensities on MRI. A pictorial essay. Clinical Imaging 1998;22(5):327–332. 9 Daniels DL, Pojunas KW, Kilgore DP et al. MR of the diaphragma sellae. AJNR 1986;7:765–769. 10 Matsumoto K, Uchino A, Kato A et al. CT and MRI of sellar spine with upward extension of the pituitary gland: case report. European Radiology 1997;7(2):287–288. 11 Ryals B, Brown D, Levin S. Duplication of the pituitary gland as shown by MR. AJNR 1993;14:137–139. 12 Kucharczyk J, Kucharczyk W, Berry I et al. Histochemical characterization and functional significance of the hyperintense signal on MR images of the posterior pituitary. AJNR 1988;9:1079–1083. 13 Mark LP, Haughton VM. The posterior pituitary bright spot; a perspective. AJNR 1990;11:701–702. 14 Kucharczyk W, Lenkinski RE, Kucharczyk J, Henkelman RM. The effect of phospholipid vesicle on the NMR relaxation of water: an explanation for the MR appearance of the neurohypophysis? AJNR 1990;11:693–700.

Chapter 20 15 Colombo N, Berry I, Kucharczyk J et al. Posterior pituitary gland: appearance on MR images in normal and pathologic states. Radiology 1987;165:481–485. 16 Fujisawa I, Nishimura K, Asato R et al. Posterior lobe of the pituitary in diabetes insipidus: MR findings. J Comput Assist Tomogr 1987;11:221–225. 17 Brooks BS, Gammal TE, Allison JD, Hoffman WH. Frequency and variation of the posterior pituitary bright signal on MR images. AJNR 1989;10:943–948. 18 el Gammal T, Brooks BS, Hoffman WH. MR imaging of the ectopic bright signal of posterior pituitary regeneration. AJNR 1989;10:323–328. 19 Halimi P, Sigal R, Doyon D et al. Post-traumatic diabetes insipidus: MR demonstration of pituitary stalk rupture. J Comput Assist Tomogr 1988;12:135–137. 20 Hamilton J, Chitayat D, Blaser S et al. Familial growth hormone deficiency associated with MRI abnormalities. American Journal of Medical Genetics 1998;80(2):128–132. 21 Kandemir N, Cila A, Besim A, Yordam N. Magnetic resonance imaging (MRI) findings in isolated growth hormone deficiency. Turkish Journal of Pediatrics 1998;40(3):385–392. 22 Kornreich L, Horev G, Lazar L et al. MR findings in growth hormone deficiency: correlation with severity of hypopituitarism. AJNR 1998;19: 1495–1499. 23 Leger J, Velasquez A, Garel C et al. Thickened pituitary stalk on magnetic resonance imaging in children with central diabetes insipidus. Journal of Clinical Endocrinology and Metabolism 1999;84(6):1954–1960. 24 Colao A, Lastoria S, Ferone D et al. The pituitary uptake of (111)In-DTPA-DPhe1-octreotide in normal pituitary and in pituitary adenomas. Journal of Endocrinological Investigation 1999;22(3):176–183. 25 Wolpert SM. The radiology of pituitary adenomas. Endocrinology and Metabolism Clinic 1987;16:553–584. 26 Chen JC, Kucharczyk M. Hypothalamic—pituitary region: magnetic resonance imaging. Clin Endocrinol Metb 1989;3:73–87. 27 Gonzalez JG, Elizondo G, Saldivar D et al. Pituitary gland growth during normal pregnancy: an in vivo study using magnetic resonance imaging. Am J Med 1988;85:217–220. 28 Peyster RG, Adler LP, Viscarello RR et al. CT of the normal pituitary gland. Neuroradiology 1986;28:161–165. 29 Wiener SN, Rzeszotarski MS, Droege RT et al. Measurement of pituitary gland height with MR imaging. AJNR 1985;6:717–722. 30 Roppolo HMN, Latchaw RE, Meyer JD, Curtin HD. 1. Normal pituitary gland. Macroscopic anatomy—CT correlation. AJNR 1983;4:927–935. 31 Wolpert SM, Molitch ME, Goldman JA, Wood JB. Size, shape and appearance of the normal female pituitary gland. Am J Roentgenol 1984;143:377–381. 32 Swartz JD, Russell KB, Basile BA et al. High resolution computed tomographic appearance of intrasellar contents in women of childbearing years. Radiology 1983;147:115–117. 33 Tsunoda A, Okuda O, Sato K. MR height of the pituitary gland as a function of age and sex: especially physiological hypertrophy in adolescence and in climacterium. AJNR 1997;18:551–554. 34 Terano T, Seya A, Tamura Y et al. Characteristics of the pituitary gland in elderly subjects from magnetic resonance images: relationship to pituitary hormone secretion. Clinical Endocrinology 1996;45(3):273–279. 35 Kelly WM, Kucharczyk W, Kucharczyk J et al. Posterior pituitary ectopia: an MR feature of pituitary dwarfism. AJNR 1988;9:453–460. 36 Burrow GN, Wortzman G, Rewcastle NB et al. Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. N Engl J Med 1981;304:156–158. 37 Parent AD, Bebin J, Smith RR. Incidental pituitary adenomas. J Neurosurg 1981;54:228–231. 38 Martin MC, Schrlock ED, Jaffe RB. Prolactin-secreting pituitary adenomas. West J Med 1983;139:663–672. 39 Podlas H. Diagnosis of pituitary microadenomas by computed tomography. Medicamundi 1981;26:20–22. 40 Chambers EF, Turski PA, La Masters D, Newton TH. Region of low density in the contrast-enhanced pituitary gland: normal and pathologic processes. Radiology 1982;144:109–113. 41 Davis PC, Hoffman JC Jr, Malko JA et al. Gadolinium DTPA and MR imaging of pituitary adenoma: a preliminary report. AJNR 1987;8:817–823. 42 Davis PC, Hoffman JC Jr, Tindall GT, Braun IF. CT-surgical correlation in pituitary adenomas: evaluation in 113 patients. AJNR 1985;6:711–716. 43 Marcovitz S, Wee R, Chan J, Hardy J. Diagnostic accuracy of preoperative CT scanning of pituitary somatotropin adenomas. AJNR 1988;9:19–22. 44 Marcovitz S, Wee R, Chan J, Hardy J. Diagnostic accuracy of preoperative CT scanning of pituitary prolactinomas. AJNR 1988;9:13–17. 45 Davis PC, Hoffman JC Jr, Spencer T et al. MR imaging of pituitary adenoma: MR, CT, clinical and surgical correlation. AJNR 1987;8:107–112.

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46 Nichols DA, Laws ER Jr, Houser OW, Abboud CF. Comparison of magnetic resonance imaging and computed tomography in the preoperative evaluation of pituitary adenomas. Neurosurgery 1988;22:380–385. 47 Pojunas KW, Daniels DL, Williams AL, Haughton VM. MR imaging of prolactin-secreting microadenomas. AJNR 1986;7:209–213. 48 Kucharczyk W, Davis DO, Kelly WM et al. Pituitary adenomas: high-resolution of MR imaging at 1.5T. Radiology 1986;161:761–765. 49 Dwyer AJ, Frank JA, Doppman JL et al. Pituitary adenomas in patients with Cushing disease: initial experience with Gd-DTPA-enhanced MR imaging. Radiology 1987;163:421–426. 50 Kulkarni MV, Lee KF, McArdle CB et al. 1.5T MR imaging of pituitary microadenomas: technical considerations and CT correlation. AJNR 1988; 9:5–11. 51 Doppman JL, Frank JA, Dwyer AJ et al. Gadolinium DTPA enhanced MR imaging of ACTH-secreting microadenomas of the pituitary gland. J Comput Assist Tomogr 1988;12:728–735. 52 MacPherson P, Hadley DM, Teasdale E, Teasdale G. Pituitary microadenomas: does gadolinium enhance their demonstration? AJNR 1989;31:293–298. 53 Steiner E, Imhof H, Kuosp E. Gd-DTPA enhanced high resolution MR imaging of pituitary adenoma. Radiographics 1989;9:587–598. 54 Stein AL, Levenick MN, Kletzky OA. Computed tomography versus magnetic resonance for the evaluation of suspected pituitary adenomas. Obstet Gynecol 1989;73:996–999. 55 Newton DR, Dillon WP, Norman D et al. Gd-DTPA-enhanced MR imaging of pituitary adenomas. AJNR 1989;10:949–954. 56 Peck WN, Dillon WP, Norman D et al. High-resolution MR imaging of microadenomas at 1.5T: experience with Cushing disease. AJNR 1988;9: 1085–1091. 57 Marcovitz S, Wee R, Chan J, Hardy J. The diagnostic accuracy of pre-operative CT scanning in the evaluation of pituitary ACTH-secreting adenomas. AJNR 1987;8:641–644. 58 Davis PC, Hoffman JC Jr, Ralko JA et al. Gadolinium-DTPA and MR imaging of pituitary adenoma: a preliminary report. AJNR 1987;8:817–823. 59 Davis PC, Hoffman JC Jr, Tindall GT, Braun IF. Prolactin-secreting pituitary microadenomas: inaccuracy of high-resolution CT imaging. AJNR 1984;5: 721–726. 60 Yousem DM, Arrington JA, Zinreich SJ et al. Pituitary adenomas: possible role of bromocriptine in intratumoral hemorrhage. Radiology 1989;170:239–243. 61 Cannavo S, Curto L, Lania A et al. Unusual MRI finding of multiple adenomas in the pituitary gland: a case report and review of the literature. Magnetic Resonance Imaging 1999;17(4):633–636. 62 Chandler WF, Schteingart PE, Lyod RV et al. Surgical treatment of Cushing’s disease. J Neurosurg 1987;66:204–208. 63 Tabarin A, Laurent F, Catargi B et al. Comparative evaluation of conventional and dynamic magnetic resonance imaging of the pituitary gland for the diagnosis of Cushing’s disease. Clinical Endocrinology 1998;49(3):285–286. 64 Scotti G, Yu CY, Dillon WP et al. MR imaging of cavernous sinus involvement by pituitary adenomas. Am J Roentgenol 1988;151:799–806. 65 Young SC, Grossman RI, Goldberg HI et al. MR of vascular encasement in parasellar masses: comparison with angiography and CT. AJNR 1988;9:35–38. 66 Kaufman B, Kaufman BA, Arafah BM et al. Large pituitary gland adenomas evaluated with magnetic resonance imaging. Neurosurgery 1987;21:540–546. 67 Teng MMH, Huang C, Chang T. The pituitary mass after transsphenoidal hypophysectomy. AJNR 1988;9:23–26. 68 Cukiert A, Andrioli M, Goldman J et al. Cavernous sinus invasion by pituitary macroadenomas. Neuroradiological, clinical and surgical correlation. Arquivos de Neuro-Psiquiatria 1998;56(1):107–110. 69 Vasile M, Marsot-Dupuch K, Kujas M et al. Idiopathic granulomatous hypophysitis: clinical and imaging features. Neuroradiology 1997;39(1):7–11. 70 Ahmadi J, Meyers GC, Segall H et al. Lymphocytic Adenohypophysitis: contrastenhanced MR imaging in five cases. Radiology 1995;195(1):30–34. 71 Hwang SL, Howng SL. Pituitary abscess: CT and MRI findings. Journal of Formosan Medical Association 1996;95(3):267–269. 72 Ostrov SG, Quencer RM, Hoffman JC et al. Hemorrhage within pituitary adenomas: how often associated with pituitary apoplexy syndrome? AJNR 1989;10:503–510. 73 Benshoff ER, Katz BH. Ectopia of the posterior pituitary gland as a normal variant: assessment with MR imaging. AJNR 1990;11:709–712. 74 Gudinchet F, Burnelle F, Baith MO et al. MR imaging of the posterior hypophysis in children. Am J Roentgenol 1989;153:351–354. 75 Nemoto Y, Inoue Y, Fukuda T et al. MR appearances of Rathke’s cleft cysts. Neuroradiology 1988;30:155–159. 76 Kucharczyk W, Peck WW, Kelly WM et al. Rathke cleft cysts: CT, MR imaging and pathologic features. Radiology 1987;165:491–495.

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77 Roux FY, Lonstans JP, Monsaingeon V, Meder JF. Symptomatic Rathke’s cleft cysts; clinical and therapeutic data. Neurochirurgia 1988;31:18–20. 78 Pusey E, Kortman KE, Flannigan BD et al. MR of craniopharyngiomas; tumor delineation and characterization. Am J Roentgenol 1987;149:383–388. 79 Freeman MP, Kessler RM, Allen JH, Price AC. Craniopharyngioma; CT and MR imaging in nine cases. J Comput Assist Tomogr 1987;11:810–814. 80 Sorva R, Askinen JA, Heiskanen O. Craniopharyngioma in children and adults. Correlation between radiological and clinical manifestations. Acta Neurochir 1987;89:3–9. 81 Hayashi Y, Hamada Y, Oki H, Yamashita J. Pituitary stalk meningioma: case report. Neuroradiology 1997;39(5):351–353. 82 Pedersen H, Gjervis F, Klinken L. Malignancy criteria in computed tomography of primary supratentorial tumors in infancy and childhood. Neuroradiology 1989;31:24–28. 83 Nakagawa Y, Matsumoto K, Fukami T, Takase K. Exploration of the pituitary stalk and gland by high-resolution computed tomography. Neuroradiology 1984;26:473–478. 84 Ishikawa S, Furuse M, Saito T et al. Empty sella in control subjects and patients with hypopituitarism. Endocrinol Jpn 1988;35:665–674. 85 Newton TH, Potts DG, eds. Radiology of the Skull and Brain. St Louis: CV Mosby Company, 1971. 86 Gharib H, Frey HM, Laws ER Jr et al. Coexistent primary empty sella syndrome and hyperprolactinemia. Report of 11 cases. Arch Intern Med 1983;143:1383–1386.

87 Kaufman B, Tomsak RL, Kaufman BA. Herniation of the suprasellar visual system and third ventricle into empty sellae: morphologic and clinical considerations. Am J Roentgenol 1989;152:597–608. 88 Pollock SC, Brombery BS. Visual loss in a patient with primary empty sella. Case report. Arch Ophthalmol 1987;105:1487–1488. 89 Bursgtyn EM, Lavyne MH, Aisen M. Empty sella syndrome with intrasellar herniation of the optic chiasm. AJNR 1983;4:167–168. 90 Haughton VM, Rosenbaum AE, Williams AL, Drager B. Recognizing the empty sella by CT: the infundibulum sign. AJNR 1980;1:527–529. 91 Young WF Jr, Ospina LF, Wesolowski D, Touma A. The primary empty sella syndrome: diagnosis with metrizamide cisternography. JAMA 1981;246: 2611–2612. 92 Pompili A, Iachetti M, Riccio A, Squillaci S. Computed tomographic cisternography with iopamidol in the diagnosis of primary empty sella. Surg Neurol 1985;24:16–22. 93 Kuuliala I, Katevub K, Ketonen L. Metrizamide cisternography with hypocycloid and computed tomography in sellar and suprasellar lesions. Clin Radiol 1981;32:403–407. 94 Nichols DA, Laws ER Jr, Hauser OW, Abboud CF. Comparison of magnetic resonance imaging and computed tomography in the preoperative evaluation of pituitary adenoma. Neurosurgery 1988;22:380–385.

C h a p t e r

21 Neuro-ophthalmologic Evaluation of Pituitary Disorders Anthony C. Arnold

The anterior visual pathway and its associated cranial nerves, located immediately adjacent to the pituitary fossa, are particularly vulnerable to compression by space-occupying lesions of the gland; visual disturbance may be the presenting complaint or the first sign of recurrence of tumor after therapy. Neuro-ophthalmologic assessment plays a critical role in tumor detection, in pretreatment evaluation of visual status, and in posttreatment monitoring for progressive visual loss from recurrent tumor or sequelae of therapy. ANATOMIC CONSIDERATIONS Understanding the neuro-ophthalmologic manifestations of pituitary tumors requires a clear visualization of the anatomy of the parasellar region. The pituitary gland lies within the sella turcica of the sphenoid bone (Fig. 21.1a), covered by a fold of dura mater, the diaphragma sellae, which transmits the infundibulum via an opening centrally. The thickness of the diaphragma and the size of its central fenestration may relate to the ease with which tumors of the gland extend superiorly. The cavernous sinuses form the lateral walls of the sella; within them lie segments of the oculomotor, trochlear, and abducens nerves, along with the ophthalmic and maxillary portions of the trigeminal (Fig. 21.2a). Lateral expansion of pituitary masses (Fig. 21.2b) may compress these structures in their intracavernous course. Posterior to the sella, the two abducens nerves ascend the clivus en route to the cavernous sinus; expansion of tumor in this direction may affect these nerves as well. The optic chiasm and the intracranial portion of the optic nerves lie above the gland (Fig. 21.1a), within the basal (suprasellar) cistern of the subarachnoid space. The anterior cerebral and anterior communicating arteries pass in front of the chiasm/nerve complex and the internal carotid arteries are immediately lateral, while the third ventricle abuts it

posteriorly and superiorly. The relation of the ventricle to the posterior chiasm is of critical importance when expanding tumor causes flow obstruction, as the distended ventricle may directly compress visual fibers [1]. There is anatomic variability in the position of the chiasm in relation to the pituitary fossa, both in the superoinferior and in the anteroposterior planes. It is not normally in contact with the diaphragma sellae, usually lying up to 10 mm. above it (Fig. 21.1a), angled approximately 45 degrees upward posteriorly. This separation between normal pituitary gland and chiasm requires that intrasellar masses demonstrate significant suprasellar extension before compression of the visual pathway will occur (Fig. 21.1b). The chiasm most commonly (80%) overlies the sella turcica directly (Fig. 21.1c), less frequently being more anteriorly placed at the tuberculum sellae (“prefixed chiasm”), or more posteriorly over the dorsum sellae (“postfixed chiasm”) [2]. The optic tracts may be more vulnerable to tumor in the former configuration, the intracranial optic nerves in the latter. The chiasm is composed of more than two million axons, which represent the cumulative projections from the ganglion cells of the two retinas [3]. Its retinotopic organization (Fig. 21.3) is such that fibers originating from the nasal halves of each retina (53%) decussate in the chiasm, leading to the contralateral optic tract, while those from the temporal halves (47%) proceed ipsilaterally [4]. Superior and inferior retinal fibers tend to remain segregated in the corresponding portions of the chiasm. Projections from ganglion cells originating centrally in the retina (macular fibers) account for up to 90% of chiasmal axons; those that cross tend to do so in the central and posterior portion of the chiasm. An additional feature of chiasmal/optic nerve anatomy has recently been disputed. In the early 1900s, Wilbrand described a unique feature of the optic 687

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(a)

(b)

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FIGURE 21.1. Relation of the pituitary gland to the chiasm. (a) The intracranial optic nerve/chiasmal complex lies up to 10 mm above the diaphragma sellae (C represents anterior clinoid process, D dorsum, of the sella turcica). (b) Saggital section from MR scan of patient with massive pituitary tumor; suprasellar extension has elevated and distorted the chiasm (arrow). (c) Anatomic variations in the anteroposterior position of the chiasm. (a) and (c) from Miller [3].

nerve/anterior chiasm junction, in which some of the peripheral (extramacular) crossing fibers originating in each inferonasal retina loop anteriorly (the knee of Wilbrand) into the proximal portion of the contralateral optic nerve before proceeding posteriorly into the chiasm (Fig. 21.3). Horton, on the basis of primate and human studies of this anatomic region, concludes that the feature described by Wilbrand was an artifact induced by chiasmal shrinkage after atrophy of fibers from the enucleated eye in the specimens studied; there is no looping of fibers anteriorly in normal live primates. The reader is referred to Dr. Horton’s treatise for further detail [5].

Patterns of visual loss from compression of the anterior visual pathway are dependent on this organization, although the exact mechanism of damage to fibers from tumor is not clear. Direct compression alone appears inadequate to explain the types of loss which emerge; it would seem that pressure on the chiasm from below would cause superior altitudinal defects in both nasal and temporal quadrants if the entire inferior chiasm were compressed. Theories of vascular compromise and of preferential stretching of the median bar of the chiasm from suprasellar expansion have been invoked to explain the selective effects on crossing fibers, but data is as yet inconclusive [5–8].

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(a)

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FIGURE 21.2. (a) Relation of the pituitary gland to the cavernous sinuses. The intracavernous portions of cranial nerves 3, 4, 5, and 6 are vulnerable to compression by laterally expanding tumor. From Melen [21]. (b) Coronal section of MR scan, demonstrating lateral extension of tumor into the cavernous sinus (arrow).

SYMPTOMS

Visual Loss As our methods of diagnosis of pituitary tumors, both by radioimmunoassay and neuroradiologic techniques, have become more sophisticated, the frequency of visual loss in these patients has been steadily declining. Reported incidence of visual loss from tumor has decreased from virtually 100% in Henderson’s 1939 review of Cushing’s series [9], to 86% (1955) [10], 70% (1973) [11], 31% (1976) [12], and 9% (1983) [13]. Endocrine dysfunction has become the most common presenting complaint [14]; indeed, those patients with acromegaly, galactorrhea–amenorrhea syndrome, or Cushing's syndrome are least likely to present with visual complaints, since their hormonal imbalance creates systemic symptoms while the tumors are still relatively small. However, visual loss of unexplained etiology continues to be a significant problem among patients harboring tumor; it is the most common ophthalmologic presenting complaint.

Patients frequently describe visual loss as “dimness,” or “fogginess,” and may be able to localize the defect to the impaired field; others report only nonspecific complaints of poor vision, bumping into objects, or the sensation of objects “jumping into” or disappearing from their field of vision. Reading may be impaired, the patient noting that parts of the printed line are difficult to locate. Occasionally, a tumor will be detected when a visual examination is abnormal, the patient having been visually asymptomatic. The visual loss may be unilateral or bilateral, but is often quite asymmetric; involvement of one eye may precede that of the fellow eye by some time. The temporal fields are preferentially affected, although central visual loss is a frequent accompaniment and may be the only manifestation of tumor. The loss is typically insidious, with slow, inexorable progression, often over years, the rule. It is not unusual for patients with this clinical course to be misdiagnosed as “chronic optic neuritis,” nutritional “amblyopia,” or low tension glaucoma. A pattern of remitting/recurring visual loss, which may correspond to varying steroid dosage, occa-

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FIGURE 21.4. “Hemifield slide” phenomenon, illustrating slippage of the hemifields according to pre-existing horizontal or vertical phoria. From Kirkham [16]. FIGURE 21.3. Retinotopic organization of chiasmal and optic nerve fibers. Semidecussation of fibers results in crossing of nasal fibers to the opposite optic tract, while temporal fibers proceed ipsilaterally. Depiction of peripheral inferonasal fibers looping anteriorly into the contralateral optic nerve (knee of Wilbrand, large arrow) has recently been disputed by Horton. From Melen [21].

sionally causes diagnostic confusion with optic neuritis [15]. Rarely, sudden loss of vision may occur, due either to rapid tumor expansion (from infarction or hemorrhage) or simply the new onset of central fiber involvement.

Diplopia Diplopia is an uncommon symptom in pituitary tumors, usually resulting from lateral expansion of the mass into the cavernous sinus, with compression of the 3rd, 4th, or 6th cranial nerves producing ocular misalignment. It is most often present in association with the visual loss of chiasmal or optic nerve compression from a relatively large tumor, only rarely as the initial sign. The double images may be separated either vertically, horizontally, or obliquely, and may be present in the primary position of gaze or solely when the eyes are deviated. The patient may demonstrate an abnormal head posture in order to maintain the eyes in a position that enables fusion of the two images. Diplopia may also be the result of the so-called “hemifield slide phenomenon” (Fig. 21.4), in which, due to

bitemporal hemianopia, the nasal hemifields, which under normal binocular conditions each have a physiologic linkage to the temporal hemifield of the contralateral eye, are left “free floating” [16]. Since the stimulus to fusion of the corresponding hemifields is inadequate, binocularity cannot be maintained. Thus, any preexisting phoria, horizontal or vertical, may decompensate into an overt esotropia, exotropia, or hypertropia, with resultant diplopia within the remaining fields. Apparent gaps in the visual field may also result from this “slippage,” when esotropia creates a horizontal separation of the remaining nasal fields. This phenomenon should be suspected in patients with the appropriate field loss who complain of diplopia but do not demonstrate cranial nerve palsy.

Other Visual Sensory Abnormalities Patients with bitemporal hemianopia occasionally complain of impaired depth perception which is unrelated to ocular misalignment and the consequent loss of binocularity. The difficulty in judging distance may be manifest by inability to thread a needle or perform other detailed near visual tasks. This phenomenon has been attributed to so-called “postfixation blindness” [16], an overlapping of the temporal field defects during convergence on a visual target, which produces an anterior-posterior triangular region of visual loss just ahead of fixation, into which objects of regard may seem to disappear (Fig. 21.5).

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Neuro-ophthalmologic Evaluation of Pituitary Disorders Table 21.1. pituitary tumors

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Neuro-ophthalmologic manifestations of

Visual field defects Bitemporal hemianopia Amaurosis with contralateral temporal hemianopia Monocular temporal hemianopia “Junctional” scotoma Monocular central scotomas: central, paracentral, cecocentral, arcuate, altitudinal Monocular generalized depression Bitemporal hemianopic scotomas Homonymous hemianopia Visual acuity loss Snellen Contrast sensitivity Color vision Visual evoked potential Pupillary abnormality Impaired light reactivity Light–near dissociation Afferent pupillary defect Optic atrophy Primary Secondary Excavated “Band” or “bowtie” Papilledema Cranial nerve abnormality Ocular motor (oculomotor, trochlear, abducens) Sensory (trigeminal, divisions 1, 2) See saw nystagmus Miscellaneous “Hemifield slide” “Postfixation blindness” Visual hallucinations

EXAMINATION FIGURE 21.5. Postfixation blindness resulting from complete bitemporal field loss. The triangular region just beyond fixation is blind due to overlap of nonseeing temporal fields. From Kirkham [16].

Rarely, patients with pituitary adenomas experience visual hallucinations [17,18]. They may be formed (complex), consisting of actual figures, such as people or familiar objects, or unformed (simple), consisting only of light flashes. They have a variable relation to degree of visual loss, occurring with or without blindness and resolving with or without visual improvement. Their origin is probably multifactoral, related to compression of cerebral peduncle (peduncular hallucinosis), temporal lobe, or in some cases simply to blindness.

Clinical findings in patients with pituitary tumors are listed in Table 21.1 [18–12,19–22].

Visual Field Defects Because the nasal (crossing) fibers within the chiasm carry visual information from the temporal portions of the visual field, the most common form of field defect resulting from pituitary tumors is bitemporal loss. As the tumor extends to the underside of the chiasm, the inferior fibers are typically affected first, resulting in impairment of function in the superior temporal portions of the visual fields (Fig. 21.6). Continued growth typically produces a clockwise progression of field loss in the right eye, and a counterclockwise progression in the left, with eventual extension to the nasal quadrants. With the decreasing incidence of visual involve-

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FIGURE 21.6. tumor.

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Goldmann quantitative perimetry demonstrating bilateral superotemporal field depression in a patient with pituitary

ment by tumors, the frequency of bitemporal impairment is proportionately diminishing (5.5% in Anderson’s 1983 report [13]), but it accounts for some 45–61% of the overall number of patients with field deficits [11–13]. Asymmetric involvement at the time of presentation is the rule; roughly 12% of field cuts present with amaurosis in one eye and a temporal defect in the other (Fig. 21.7a) [11–13]. Less commonly (7% of field defects), the temporal deficit may be purely unilateral (Fig. 21.7b) [11–13]. Presenting patterns of visual field loss in patients with macroadenomas have been summarized by Poon et al. [23]. Even at the earliest stage of loss, the defects tend to marginate at the vertical midline of the field (Fig. 21.8). Indeed, this is the single most important feature allowing differentiation of bitemporal loss from other causes, including congenital optic disc anomalies (tilted discs, others), bilateral retinal disease (retinitis pigmentosa, retinal detachment), ptosis with secondary superotemporal field defect, and enlarged blind spots or cecocentral scotomas from optic nerve disorders (nutritional or toxic optic neuropathy, papilledema) [24]. In these disorders, the field deficits tend to be either isolated within the temporal fields away from the midline or to overlap it significantly. However, although the rule of vertical midline limitation is generally accurate, it must be applied with caution: Younge [25] has reported that chiasmal compression will rarely result in extension of a temporal defect up to 10 degrees into the superonasal quadrant. We have seen this phenomenon more frequently with the increased use of automated quantitative perimetry. The severity of visual loss is quite variable, with either relative or absolute field defects involving the peripheral or central fields, or both. The degree of visual loss may be cor-

related with chiasmal displacement documented on MR imaging [26]. In this respect, it is important to note that, as the majority of the chiasmal fibers are macular in origin, (serving central, though not necessarily fixational, vision), in over 95% of cases which develop field loss, the central 30 degrees will be affected [27,28] (See Appendix 1 pp. 703–704). Visual acuity, however, may remain normal, even though the degree of field loss is severe. Pure chiasmal damage may produce field deficits that extend down the entire vertical midline, splitting fixation, but sparing enough fibers subserving the foveal region to enable detailed fine vision in the remaining parafoveal field. If tumor growth extends anteriorly, or if the chiasm is postfixed, compression of one or both optic nerves may occur. Involvement of the proximal optic nerve at its union with the anterior chiasm produces the so-called “junctional syndrome” [4,14]. In this instance, visual field deficits typical of ipsilateral optic nerve involvement, (central scotoma, cecocentral scotoma, diffuse depression, with associated visual acuity loss) are associated with superotemporal impairment in the contralateral eye (Fig. 21.9). While Horton’s recent anatomic work [5] has cast doubt on a causal role for the “knee of Wilbrand” in this clinical presentation, suggesting rather that there is simply compression of both optic nerve and chiasm by an anterior tumor, the fact remains that this pattern of visual field defects effectively localizes to the chiasm/optic nerve junction. Clinicoradiologic correlation in such a case was recently documented by Karanjia and Jacobson [29]. This anterior chiasmal syndrome occasionally results in delayed diagnosis of pituitary tumors because the most prominent field defect, the central scotoma, may appear to

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(a)

(b)

FIGURE 21.7. Automated perimetry grayscale representation of central 30 degrees of visual fields (see Appendix 1), depicting asymmetric chiasmal involvement. (a) The right eye is totally blind, while the left demonstrates complete temporal hemianopia. (b) Unilateral hemianopic defect in left eye from pituitary adenoma. Minor superior depression in right eye is due to ptosis.

represent an isolated ipsilateral optic neuropathy. This may be particularly true when, as infrequently occurs, the visual loss is relatively rapid, and the patient is presumed to have optic neuritis. Since the involvement of the chiasmal fibers may be minor, resulting in only minimal field loss in the outer edges of the 30-degree field contralaterally, chiasmal

compression may not be suspected. It is thus critical for patients presenting with apparently isolated unilateral central scotoma to undergo careful evaluation of the contralateral superotemporal field, especially in cases where the clinical course is atypical for optic neuritis, i.e. absence of pain with eye movements, slowly progressive course, or recurrence of

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FIGURE 21.8. Classic bitemporal hemianopic defects, illustrating demarcation along the vertical midline. A minor degree of overlap to the nasal field (arrow) is commonly seen.

FIGURE 21.9.

“Junctional” syndrome. Right eye shows central scotoma, while left eye shows subtle superotemporal depression.

visual loss after steroid withdrawal. Even so, purely monocular central scotoma, cecocentral scotoma, or generalized depression may rarely result from extremely asymmetric expansion of tumor [30,31]; in these cases, the clinical course may be the only clue to the true nature of the process.

It is also essential to realize that anterior chiasmal and/or optic nerve compression may produce defects that even more closely mimic other optic neuropathies. Both unilateral and bilateral arcuate scotomas which cross the vertical midline and do not demonstrate bitemporal hemianopic

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(a)

(b)

FIGURE 21.10. Anterior chiasm/optic nerve compression. (a) Central visual fields demonstrating superior arcuate defect on the right, with central scotoma on the left. (b) Tangent screen perimetry, illustrating hemianopic temporal arcuate scotoma in right eye.

characteristics have been reported [32]; these may be indistinguishable from the visual field defects of glaucoma, optic nerve head drusen, ischemic retinal and optic nerve disease, and others (Fig. 21.10a). Hemianopic temporal arcuate scotoma [33], which, if accurately documented by perimetry, is by itself pathognomonic of anterior/central chiasmal dysfunction, is also rarely seen (Fig. 21.10b). Both reflect

continued arcuate organization of the nerve fibers well into the intracranial optic nerves and anterior chiasm, as proposed by Hoyt [4]. If the tumor extends posteriorly, or if the chiasm is prefixed, compression of the posterior crossing fibers and/or the optic tracts may occur. Involvement of the posterior fibers may selectively impair vision in the central portion of

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FIGURE 21.11. Goldmann perimetry showing bitemporal hemianopic scotomas with demarcation along the vertical midline.

FIGURE 21.12. Incongruous left homonymous hemianopic defect, with minor superimposed involvement of the right temporal field from a pituitary tumor compressing the right optic tract and posterior chiasm.

the temporal fields, giving rise to bitemporal hemianopic scotomas (Fig. 21.11) [14,34]. This is a relatively unusual presentation (4–6% of field defects [11–13]); although the clinical picture may resemble bilateral optic neuropathy, careful perimetry will reveal the characteristic vertical midline restriction of the scotomas. Visual acuity is typically normal. Compression of the optic tract produces incongruous homonymous field loss (Fig. 21.12) as a part of the optic tract syndrome [35,36], which may also include contralateral band optic atrophy and afferent pupillary defect (see below). In practice, posterior lesions may involve both chiasm and tract fibers, resulting in combined temporal hemianopic scotomas, peripheral temporal loss, and homonymous defects. In some cases, the only remaining field may be a unilateral nasal sector.

A discussion of the various techniques of visual field testing is presented in Appendix 1.

Visual Acuity Loss As with visual symptomatology and objective visual field deficits described above, the reported incidence of visual acuity loss in patients with pituitary tumors has decreased over the years, a figure of 4% was given in 1983 [13]. Visual acuity is typically normal in the presence of hemianopic defects from pure chiasmal or optic tract compression. Even complete pure bitemporal hemifield loss only splits fixation, allowing 20/15 acuity in the remaining nasal half of the central region, even though overall visual function is quite abnormal. It is the anterior extension of tumor to involve

Chapter 21

the optic nerves which results in damage to fibers serving central (fixational) vision. Even in this circumstance, visual acuity may be variably affected, ranging from 20/15 to no light perception (NLP), dependent upon the degree to which the portion of the visual fields involving central fixation are involved. Small central scotomas may produce profound visual acuity loss with relatively little peripheral impairment. Central visual function is most often tested using the Snellen chart, which tests the ability to discriminate black/white interfaces subtending increasingly small visual angles at standard distances from the eye. In subtle cases of optic neuropathy, contrast sensitivity testing, in which not only the size (visual angle subtended), but also the intensity of the contrast between black and white components of visual stimuli may be varied, may better identify acuity loss. This technique has been found to better quantify minimal optic nerve dysfunction persisting after optic neuritis [37], and is felt to be a more sensitive indicator of visuosensory impairment. Likewise, color discrimination loss, particularly in the red-green spectrum tested by the pseudoisochromatic (PIP) plates, may precede measurable acuity loss from anterior visual pathway damage. This characteristic is particularly useful in distinguishing acuity loss of optic nerve from that of retinal (macular) origin; in optic neuropathy, color vision loss is proportionately significantly worse than acuity loss, while in retinal disease, acuity and color loss correspond in severity. The visual evoked response (VER) is a manifestation of macular function, and as such is abnormal in the presence of decreased acuity, although it is not specific for visual pathway compression [38]. It is a more sensitive indicator of dysfunction, but its lack of specificity limits its usefulness. It has been reported as a method of monitoring intraoperative function of the visual pathway during pituitary surgery [39], but its value in clinical management is unproven.

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and normal pupil size typically seen with the chiasmal syndrome (impaired visual pathway transmission does not cause change in pupillary size). Unilateral, or bilateral but asymmetric, damage results in the so-called relative “afferent pupillary defect,” (APD) or “Marcus Gunn pupil.” This sign, elicited by the “swinging flashlight test,” is the classic neuro-ophthalmologic manifestation of optic nerve compromise [3]. It results from decreased direct pupillary light reaction when compared with its consensual response (that initiated by stimulation of the contralateral eye). Thus, during alternate light stimulation of each eye, when the stimulus is moved from the normal pupil to the abnormal, there is apparent dilation of the abnormal pupil in response to light. Details of testing are described in Appendix 2, pp. 704–706.

Optic Atrophy This sign of visual pathway damage may take one of four forms: (i) primary; (ii) secondary; (iii) excavated; or (iv) “band” or “bowtie.” Most commonly, atrophic changes are primary in type, with pallor of the optic disc, either temporally (from damage to the papillomacular bundle of retinal nerve fibers) or diffusely over the entire nerve head; the disc margins are sharply demarcated (Figs 21.13 and 21.14). Secondary atrophy, with gliotic tissue on the disc surface, blurring its margins, and along parapapillary vessels, occurs in the rare case in which superimposed papilledema has been present. The earliest ophthalmoscopically visible manifestation of optic atrophy may be so-called “nerve fiber layer dropout.” This sign, first described by Newman and Hoyt [40], is detectable before visible change in the color of the optic disc occurs, and is manifest by thinning of the inner layers of the retina. It is usually easiest to see in the region of the retina

Pupillary Abnormality Impaired pupillary constriction is a hallmark of faulty transmission along fibers of the anterior visual pathway. The abnormal pupil typically has a slow and limited degree of reactivity to light, while maintaining a normal near response. This form of pupillary dysfunction is commonly seen in cases of visual compromise from pituitary tumors, but it is often subtle, and observers not experienced in pupillary evaluation may not detect it. Pituitary tumors may produce either bilateral (from chiasmal compression) or unilateral (from optic nerve compression) deficits in pupillary function. When bilateral deficits are present and relatively symmetrical, “light–near dissociation” occurs, with pupils which are poorly reactive to light but normally reactive to near stimuli. This manifestation of bilateral optic pathway compression may be distinguished from the other common causes of light–near dissociation, including syphilis (Argyll–Robertson pupils), dorsal midbrain (Parinaud’s) syndrome and tonic pupils, by the associated impaired vision

FIGURE 21.13. Severe optic neuropathy. Optic disc shows characteristic diffuse primary optic atrophy in patient with longstanding visual pathway compression. Disc is pale, with sharp margins.

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FIGURE 21.14. Less severe optic neuropathy. (a) Moderate optic atrophy, in which the temporal disc (supplied by papillomacular fibers nasal to macula) demonstrates pallor. The normal glistening appearance of the retinal nerve fiber layer is absent in this region (between arrows). (b) Mild optic atrophy, in which nerve fiber layer is less severely affected. Note the darker, linear, so-called “rake” defects in nerve fiber layer of inferotemporal region (arrows).

adjacent to the superotemporal and inferotemporal retinal vessels as they arch above and below the macula; the nerve fiber layer is normally thickest here. When damage occurs, the normally opalescent and striated appearance of the nerve fiber layer develops darker, dull red streaks, (“rake defects”) as bundles of retinal nerve fibers drop out (Fig. 21.14a). As damage progresses, these defects widen, typically in the papillomacular region, creating broader regions in which the normal sheen of the inner retina is lost (Fig. 21.14b); the focal foveal ophthalmoscopic reflex may disappear as well. These abnormalities may be best appreciated using the red-free (green) illumination source on the direct ophthalmoscope. Optic atrophy with excavation (Fig. 21.15) occurs in a small percentage of compressive lesions of the anterior visual pathway [41]. In Kupersmith and Krohn’s review of some 250 cases of intracranial tumor compressing the anterior visual pathway [42], 16 demonstrated significantly increased cupping which caused diagnostic confusion with glaucoma. The patients demonstrated, however, several features which aid in distinguishing this form of optic atrophy from true glaucoma: (i) pallor of the disc outside the enlarged cup (in glaucomatous cupping, the temporal rim of nonexcavated disc tissue typically does not become pale); (ii) extensive loss of visual acuity in relation to the degree of cupping (in glaucoma, visual acuity is relatively spared); and (iii) predominantly temporal visual field defects (glaucomatous visual field defects often are nasal or arcuate in character). In rare cases, only the crossing fibers within the chiasm are affected by the tumor. In this situation, only the nerve

fibers originating in the nasal portion (nasal to the macula) of each retina are affected; loss of these fibers (the nasal radiating and the papillomacular fibers) creates a horizontal band of atrophy with relative sparing of the superior and inferior poles (Fig. 21.16) [43,44]. This pattern of band atrophy is a subtle finding which may be seen unilaterally in association with temporal fiber disc atrophy in the contralateral eye (from optic tract lesions [35,36]), and it rarely may be an isolated unilateral finding as the result of optic nerve head disease of other origin (i.e., ischemic, retinovascular, demyelinating); when it is seen bilaterally, however, chiasmal compression must be strongly considered. Finally, it is well established that the degree of visible optic nerve damage may not correlate well with visual function. In most of the major series, the frequency of optic atrophy is significantly lower than that of visual field deficits (2% compared with 9% in Anderson’s most recent review [13]). Particularly in very slowly progressive compression, severe loss of visual field and/or acuity may be accompanied by relatively minor visible atrophy of the nerve head. Indeed, atrophy may rarely be undetectable in the presence of pronounced visual impairment; it is not a requisite finding for the diagnosis of chiasmal compression.

Papilledema This sign is extremely rare in our increasingly sophisticated diagnostic environment. Elevated intracranial pressure from

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(b) FIGURE 21.15. Optic atrophy with excavation. (a) Disc of optic nerve compressed by tumor shows significant enlargement and excavation of the normal physiologic cup (arrows) in association with pallor extending to temporal disc margin. (b) Glaucomatous disc shows more prominent cup excavation, without pallor of the temporal disc margin.

(a)

(b)

FIGURE 21.16. (a) Band or “bowtie” atrophy of the optic disc; a horizontal band of relative disc pallor is visible across the center of the disc, with sparing of superior and inferior poles (arrows). (b) Diagram of nerve fiber distribution at the nerve head illustrates how loss of fibers (arrows) originating nasal to fovea results in band atrophy. Spared fibers (large arrows) originating temporal to fovea arch above and below macula to enter superior and inferior poles of disc.

pituitary tumor occurs when there is sufficient suprasellar extension to obstruct CSF flow by invasion or compression of the third ventricle, or when tumor is large enough to create a generalized mass effect. As noted above, chronic papilledema may produce secondary optic atrophy in

addition to the primary atrophy resulting from direct compression of the pathway by tumor. Papilledema from pituitary tumor almost invariably is associated with significant visual loss, and it connotes the presence of a large mass [21].

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Cranial Nerve Abnormalities Ophthalmoplegia is unusual in patients with pituitary tumor; two most recent series found 1–1.4% presenting with this sign [12,13]. It typically results from lateral extension of the tumor into the cavernous sinus, with invasion or compression of the intracavernous segments of cranial nerves 3, 4, or 6 [45]. Involvement of these structures usually indicates a large and/or aggressive tumor; it is more commonly seen in so-called “invasive” adenomas (those histologically benign macroadenomas which display aggressive, locally invasive growth characteristics) or in tumor metastatic to the sella [14,46,47]. It generally occurs in the presence of visual loss, only rarely being an isolated feature; indeed, the occurrence of rapidly progressive visual acuity and/or field loss associated with extraocular muscle cranial neuropathies should raise the question of sellar malignancy [48]. Unilateral palsy is the rule. The oculomotor nerve is the most commonly involved, probably due to its more vulnerable position within the sinus, and dysfunction may initially be intermittent [49]. Partial involvement is common, with ptosis [50] or single extraocular muscle paresis a frequent presentation. The pupil may be affected, with dilation and poor reactivity; however, pupillary sparing is common in cavernous sinus lesions, and confusion with other causes of pupil-sparing palsies, such as diabetes, may occur [51]. If the intracavernous sympathetic pupillary fibers are damaged as well as the parasympathetic, the pupil may be small and poorly reactive. The abducens and the trochlear nerves are affected less frequently. Other signs of cavernous sinus invasion by tumor include trigeminal neuropathy and proptosis [14]. Occasionally, the ophthalmic and maxillary branches of the trigeminal nerve suffer damage, with resultant facial numbness, pain, or dysesthesia; decreased corneal sensation may be the earliest detectable sign. Again, this finding is typically part of a constellation of cranial neuropathies. Proptosis is an extremely rare finding, resulting from the vascular stasis and orbital congestion produced by intracavernous tumor.

See-saw Nystagmus This rare eye movement disorder consists of slowly alternating (two to five cycles per second) elevation and intorsion of one eye concurrent with extorsion and depression of the other; this produces conjugate alternating clockwise and counterclockwise rotational movements of the eyes superimposed on the dissociated vertical movements [52–54]. Oscillopsia, the visual perception of movement of one’s environment, may be noted. The disorder had been reported in some 28 cases by 1982, most commonly associated with parasellar lesions expanding into the third ventricle. Although the exact mechanism of production of this entity is not known, approximately one-half of the cases demonstrated lesions involving the diencephalon, and most investigators feel that it results from damage within the

upper brainstem. Experimental studies of the interstitial nucleus of Cajal and adjacent structures, in both animals and humans, have strongly implicated this region. Although not pathognomonic for pituitary tumor, the presence of see-saw nystagmus, particularly in association with bitemporal hemianopsia, requires neuroradiologic evaluation. PITUITARY APOPLEXY This term has been used to describe both ischemic and hemorrhagic phenomena, occurring within either pituitary tumors or nontumorous glands, and producing effects which are either subclinical or catastrophic in degree [14,55,56]. From the neuro-ophthalmolgic standpoint, it is most important to consider those entities which produce acute swelling within tumorous glands, with resultant compression of parasellar structures. The first symptom typically is excruciating, frontal or retro-orbital headache, often associated with signs and symptoms of meningeal irritation; in severe cases, sudden loss of consciousness or cardiovascular collapse may occur. Within hours to days, development of the full-blown syndrome may include bilateral loss of vision, usually worse in the temporal visual field quadrants (from additional upward expansion of tumor with chiasmal/optic nerve compression), ophthalmoplegia, trigeminal neuropathy, and sympathoparesis (from lateral expansion into the cavernous sinus, with compression of cranial nerves 3, 4, 5, and 6, along with the sympathetics). Marked compression of the cavernous sinus may result in proptosis and periorbital edema from orbital congestion. Hormonal and electrolyte imbalance frequently are associated; remote CNS effects, such as cerebral ischemia from tumor compression of major vessels, occur rarely. With an acute onset of the characteristic constellation of signs, the clinical diagnosis is relatively straightforward [57–59]. The presence of a pituitary tumor on CT or MR imaging, with or without evidence of intratumoral hemorrhage, is confirmatory. Treatment is controversial; some authors suggest nonsurgical management in less severe cases, even in the presence of visual loss, if nonprogressive [56]. We feel that, in general, patients with significant visual loss, even if nonprogressive, should undergo surgical decompression as soon as possible after medical stabilization. NEURO-OPHTHALMOLOGIC MANAGEMENT Patients with known pituitary tumor but no encroachment on the visual pathways must be carefully followed for evidence of growth with early chiasmal/optic nerve compression. The frequency of visual evaluation, with visual acuity measurements, color vision testing, pupillary testing, fundus examination, and quantitative perimetry must be individualized, based on the size of the tumor and its relation to critical structures. Typically, however, patients with this category of tumor are evaluated yearly after an initial normal neuro-ophthalmologic examination.

Chapter 21

Patients with visual pathway compromise who have undergone treatment, involving transfrontal or transsphenoidal surgical decompression, medical therapy with bromocriptine, or irradiation, must be followed more closely. After surgical intervention, visual function typically improves within a period ranging from hours to a maximum of 3–4 months [24]. Prognosis for return of vision may be loosely predicted from the duration of symptoms, preoperative appearance of the fundus (degree of atrophy, NFL loss [60]) and level of preoperative visual function; however, recovery is quite variable. Recent series have reported postoperative improvement of visual acuity in 46–82% and visual fields in 67–92% of patients [11,61–69]. Surprising

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degrees of visual return may occur; we have followed a patient with preoperative vision of no light perception who recovered significant central acuity (20/70) after successful surgery (Fig. 21.17). Postoperative decrease in visual function occurs in approximately 1–2% of cases [61,69]. We recommend careful ophthalmologic examination, including visual acuity, visual fields, color vision screening, pupillary function, and optic discs during the first 2 or 3 months following surgery, and at 6 months and 1 year postoperatively. Thereafter, examinations may be performed yearly unless evidence of visual deterioration prompts more detailed evaluation. Neuroradiologic testing is usually scheduled at yearly intervals.

(a)

(b)

FIGURE 21.17. (a) Preoperative perimetry in patient with massive pituitary tumor demonstrates blindness in the left eye, with temporal depression extending to the nasal quadrants in the right. (b) Postoperative perimetry depicts marked improvement, particularly nasally, on the left, with near resolution of defect on the right.

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Visual loss in the postoperative period raises several concerns.

Postoperative Recurrence Of first priority in the postoperative neuro-ophthalmologic evaluation is the detection of recurrent tumor, as this is the most common cause of late visual deterioration; the visual loss may be its first manifestation. The rate of recurrence after surgery depends on a number of factors, including tumor type, initial size, and mode of therapy. In recent series, figures from 4% to 12% have been reported, the majority within 5 years [63,70,71]; the incidence is decreased with the use of postoperative irradiation in cases where complete excision is not possible. Although clinical ophthalmic examination is a sensitive indicator of tumor regrowth, it is less accurate when there is already significant visual loss and when recurrence does not affect the visual pathway; regular neuroradiologic [72] and endocrinologic studies are mandatory.

Radiation Neuropathy In those patients who have received irradiation, either as primary therapy or as an adjunct to surgery, the possibility of delayed radiation necrosis of the chiasm or optic nerves must be considered [73–78]; occurrence rates range from 1.4% to 3.0% in recent series [79–84]. This usually occurs some 1–2 years after treatment (ranging from several months to 15 years) and is characterized by acute onset of severe visual loss (total blindness is not uncommon), with clinical signs of optic nerve and/or chiasmal dysfunction. In our experience, the visual field defects are more often characteristic of optic nerve than of chiasmal involvement, but either may occur. The optic nerve heads may be swollen, but typically appear normal initially, becoming atrophic within 4–8 weeks. Radiation retinopathy, with signs of retinal vasoocclusive disease, such as hemorrhage, exudates, arteriolar narrowing, sheathing, and neovascularization, may rarely be present [85]. Sensitivity to radiation demonstrates significant interindividual variation, and appears also to be dependent upon both absolute dose delivered to tissue and upon rate of delivery. Therefore, no absolute values for pathologic dose levels have been established; however, radiation neuropathy has most often been associated with total dose of greater than 5000 rads, particularly if administered in fractions greater than 250 rads/day [78]. Diagnosis is based on the typically more rapid onset of symptoms when compared with tumor recurrence and on neuroradiologic findings, both in ruling out regrowth of neoplasm and in demonstrating demyelinated or atrophic tissue. MR scanning is most effective for this purpose, demonstrating enlargement and enhancement of the affected chiasm and optic nerves. Fat-suppression technique is essential for accurate assessment of the intraorbital optic nerves for radiation damage [86].

Radiotherapy may also result in ocular motor cranial nerve palsies [14]. As with primary involvement from tumor, the oculomotor nerve is most commonly affected, followed in frequency by the abducens and trochlear. Onset is typically within the first year after therapy; in contrast to the visual loss from radionecrosis of the chiasm and optic nerves, there is often significant improvement in cranial nerve function over months to years. Early reports emphasized the association with heavy particle techniques [87–89], but nerve damage occurs with conventional external beam radiation as well [14]. The effect seems to be dose related; the high incidence in reports of heavy particle therapy probably reflects the higher delivered dose of radiation in those cases. Heavy particle techniques are infrequently used today. Recent series indicate that, with external beam doses of under 5000 rad, cranial neuropathies are extremely rare [90–91].

Empty Sella Syndrome This entity is usually categorized as either primary or secondary. The primary form represents an idiopathic extension of the subarachnoid space into a remodeled sella, with flattening of the pituitary gland [92]. It is unrelated to prior therapy for tumor and almost never produces visual compromise. The secondary form results from loss of intrasellar tissue, usually due to surgery or irradiation, rarely from spontaneous involution of tumor [93], and may create distortion of the chiasm which results in progressive visual dysfunction [94–96]. Traction from arachnoidal adhesions may play a part in this process. Although visual pathway impairment from the secondary form is rare, this entity remains an important consideration in the differential diagnosis of posttherapy visual loss. Symptomatology typically begins months after treatment, is characteristic of optic nerve and/or chiasmal dysfunction, and is progressive over weeks to months. Herniation and distortion of the suprasellar visual system is well visualized by MR scanning [96]. Sellar exploration with lysis of adhesions, sometimes associated with packing of the sella for support of the chiasm, has been reported to reverse (or prevent) the visual loss from this syndrome [95]. Rarely, the fat packing routinely performed after tumor resection to prevent such chiasmal distortion produces a mass effect on the chiasm, with visual loss [97]. SPECIAL CONSIDERATIONS

Bromocriptine Therapy This dopamine agonist has been shown to be effective in suppressing both the hormonal and the visual complications of prolactinomas; its role in the therapy of nonsecreting and of growth hormone secreting tumors is less clear [98]. In a recent prospective study [99], tumor size was reduced by 50% or more in 64% of patients, with the other 36% demonstrating less pronounced shrinkage. In nonrandom-

Chapter 21

ized series of patients with visual loss from prolactinomas, 24 of 25 showed improvement in visual fields or acuity, often within 24–72 hours of onset of therapy [100–103] (intramuscular injection may produce even earlier results [14]). This was accompanied by reduced prolactin levels and later neuroradiologic documentation of decreased tumor size. Improvement in ocular motor cranial nerve dysfunction was also noted in several cases. From the neuro-ophthalmologic standpoint, however, two points require emphasis: 1 Bromocriptine therapy must be continued indefinitely; the drug is not tumoricidal, and attempts at withdrawal invariably result in recurrence [98]. Rapid onset of severe visual loss has been reported to occur after discontinuance of therapy [104]. Additionally, Kupersmith and associates [105] have described three cases of prolactinoma with continued visual loss during bromocriptine therapy, suggesting that tumors may have mixed cell populations, with components not suppressed by the drug. For these reasons, it is particularly important that careful monitoring of visual function be performed in medically treated patients. We recommend neuro-ophthalmologic evaluation at 3–6 month intervals during the first year of therapy. 2 Pituitary apoplexy (see above) has been reported following the onset of therapy in an acromegalic [106]. Although a causal relation has not been proven, bromocriptine could cause tumor necrosis by its cell shrinkage effects. Awareness of the potential for this extremely rare occurrence during treatment will lead to appropriate early diagnostic and therapeutic measures.

Pregnancy The normal pituitary gland is known to enlarge during pregnancy, but it is difficult to conceive of extension sufficient to approach the anterior visual pathway. Adenomatous tissue, on the other hand, may produce visual loss as a result of growth during pregnancy, which later resolves as the tumor shrinks in the postpartum period [14,107–111]. This has been an infrequent occurrence in the past, as the hormonal effects of tumor often prevented conception. With the use of bromocriptine, though, normalization of hormone levels in the presence of existing tumor has made it more common [112]. Visual complications from pituitary tumors during pregnancy are still relatively unusual. Kupersmith et al. reported that none of 57 patients with microadenomas less than 1 cm in height developed visual loss, even in multiple pregnancies, although six of eight with macroadenomas suffered some degree of visual loss [113]. Because the incidence of permanent damage is so low, and the impairment that does occur is quite often reversible after delivery [14], we feel that it is reasonable to follow patients with known

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microadenoma without visual loss at 2 month intervals through delivery, and those with macroadenoma without visual loss more closely, determined by the clinical course. Treatment for those patients who demonstrate visual loss must be individualized based on time course and severity of loss, tumor size and type, and stage of pregnancy. Careful neuro-ophthalmologic testing, in conjunction with neuroradiologic studies where indicated, provides a sensitive indicator of the need for intervention. In general, when visual loss develops in the early stages of pregnancy, we recommend nonsurgical management of prolactinomas and those nonsecreting tumors with minimal, nonprogressive visual deficits. For patients with severe and/or progressive visual loss from a nonsecreting tumor, surgical decompression, usually transsphenoidally, is our treatment of choice. Later in the course of pregnancy, we advocate a nonsurgical approach unless visual loss is severe or rapidly progressive. Observation, with induction of labor at the earliest possible time, is most often elected for either prolactin-secreting or nonsecreting tumors, although bromocriptine may be considered for the former. Definitive therapy may be indicated postpartum in many cases, as the risk of visual loss from adenoma probably increases during subsequent pregnancies. A rare condition, termed lymphocytic adenohypophysitis, may occur during pregnancy and may mimic pituitary tumor, with suprasellar extension, mass effect on the anterior visual pathway, and visual loss typical of chiasmal/optic nerve compression [114]. It is characterized by dense lymphocytic infiltration of the gland, with hypopituitarism, possibly the result of an autoimmune disorder. Surgical decompression is indicated for cases with visual loss, and has been effective for visual recovery in numerous reports. Corticosteroid therapy is often attempted as a first line alternative in suspected cases without visual loss, though effectiveness has varied [115–118]. APPENDIX 1: TECHNIQUES OF VISUAL FIELD TESTING Several techniques are available for clinical evaluation of the fields, ranging from gross confrontation testing to detailed quantitative perimetry, and including such methods as Amsler grid testing, red desaturation testing, tangent screen, Goldmann perimetry, and automated perimetry. Detailed discussion of each technique is beyond the scope of this text; however, it is useful for the clinician to be aware of the practical considerations of each form of field analysis. Confrontation testing has the advantages of brevity, simplicity, and flexibility. It may be performed almost anywhere, without special equipment, and it may be the most appropriate test for patients who are unable to cooperate for detailed perimetry. Examiners must keep in mind, however, that it is only a screening test and that more subtle defects, particularly small scotomas, will escape detection. Even so, a large percentage of patients with visual loss from pituitary tumors will be detected by this method.

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In it, the examiner faces the patient at a distance of about 1 meter, with the patient fixating the examiner’s nose. Each eye is tested individually, using static presentation of varying numbers of fingers in each quadrant at approximately 20 degrees from central fixation. If fingers cannot be accurately counted, hand presentation or light stimulus is performed in each quadrant. Slow, inconsistent, or missed responses in the temporal regions compared with the nasal are highly suggestive of chiasmal compression. A variation of the test based on the extreme sensitivity of red stimuli in detecting early damage to the visual pathway involves presenting a large red object in each quadrant, paying particular attention to differences in color intensity and brightness when compared across the vertical midline; “dullness” or decreased color in the temporal quadrants is a highly sensitive indicator of chiasmal compression. Care must be taken to avoid presentation of stimuli within the normal blind spot, approximately 15 degrees temporal to fixation and just below the horizontal meridian, as it will result in false positive results; this may be avoided by presenting stimuli well above and below the horizontal midline. The Amsler grid is a useful office or bedside tool for evaluating subtle central defects in the fields. It utilizes a grid pattern tested at reading distance (0.33 meter), each square thus subtending 1 degree of visual field, with a total field of 20 degrees being tested. While fixating the central point, the patient is asked specifically to look for “blank spaces” or “distorted areas” within the field of vision, and to outline the abnormal areas on the chart. The patient thus maps out his or her own field deficit, and may be highly accurate. The test is particularly valuable for subtle central or paracentral defects which may be missed by other methods. Although tangent screen testing has largely been supplanted by perimetry, it retains the advantages of simplicity and sensitivity in the detection of small central defects. Since it is performed at 1 meter from the patient, rather than the 0.33 meter used in must perimetry, scotomas appear three times as large as those on perimeters, and are thus more easily distinguished by the examiner. The tangent screen is limited to evaluation of the central 30 degrees of the field. However, in recent studies, less than 3% of visual field deficits were limited exclusively to the peripheral region (more than 30 degrees from fixation) [27,28]. These reports included patients with glaucoma, in which peripheral defects are prominent; in patients with compression of the chiasm, with its predominantly macular content, the screening value of central fields is probably higher. Goldmann perimetry has been the benchmark for quantitative field analysis in recent years. It allows greater standardization and reproducibility, along with the ability to evaluate visual sensitivity in the peripheral field as well as the central. However, as noted above, since the entire representation of the field is smaller at its shorter working distance, the central 30 degrees of the field (and any defects within it) is compressed, making it more difficult to detect

small central and paracentral scotomas. Furthermore, the central 2 degrees of the field must be evaluated as an optional addition to standard testing; if this is not specifically requested, small central defects may be missed. These limitations aside, Goldmann perimetry remains an excellent method of identifying and following field loss. Automated quantitative perimetry involves testing of the visual field by the static method. It is highly accurate and may be more sensitive than kinetic techniques; comparison to Goldmann perimetry shows little difference in effectiveness, though the two techniques may complement each other. It has become the standard method of testing in most ophthalmologic centers. Although peripheral fields may be tested, the central 30 region is the usual initial focus. At approximately 75 points within this area, visual threshold is measured and given a numerical representation (Fig. 21.18a). This information is then displayed graphically by means of computer interpolation, producing the so-called “grayscale” image, which highlights abnormal regions of the field in a more familiar form (Fig. 21.18b). The following practical considerations apply: 1 Not every point in the “grayscale” printout has been tested. The actual 75 test points are usually about 6 degrees apart, and small scotomas that lie between these points may be missed. A program for evaluation of the central 10–15 degrees, with approximately 2 degree resolution, may be requested. 2 The periphery of both the central 30 degree and the full field tests are more sensitive to testing error, and false defects are commonly seen. 3 Certain patients, particularly the elderly or ill, do not adapt well to this form of testing; as in all visual field analysis, clinical correlation is essential, and simpler techniques may produce more valuable results. The value of colored visual stimuli for quantitative testing has been debated for many years [119]. The use of red stimuli may detect subtle visual field defects before any abnormality is seen with corresponding white light sources. Whether this is due to specific damage to red-sensitive visual elements by compression or simply to the fact that red stimuli are less intense than white, and thus enable testing of smaller isopters which detect more subtle loss, has not been definitively determined. However, with the ability of modern quantitative perimeters to vary white stimulus intensity down to minimal levels, colored stimuli are rarely used. APPENDIX 2: TESTING FOR THE AFFERENT PUPILLARY DEFECT The neural pathway for pupillary light reactivity originates in the retina and proceeds posteriorly along the optic nerve to the midbrain pupillomotor center, from which impulses

Chapter 21

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(a)

(b)

FIGURE 21.18. Automated quantitative static perimetry. (a) Numerical individual point sensitivity values of central 30 degrees of each eye. Actual test results (large arrows) are compared with age-adjusted normal population data to produce the total deviation table (small arrows), which highlights abnormalities (corresponding graphic representations are below). Sensitivity values are decreased in the temporal fields bilaterally. (b) “Grayscale” computerized interpolation of data in same patient; darker regions indicate areas of decreased sensitivity in the temporal fields.

are generated to both pupils along the efferent pathway, resulting in both a direct (ipsilateral) response and a consensual (contralateral) response. Impaired transmission along one side relative to the other thus results in bilateral impairment of the light response when that abnormal side is

stimulated, and bilaterally normal light responses when the contralateral side is stimulated. The APD is a result of this asymmetry. When a light stimulus is presented to the less damaged eye, the impulse for pupillary constriction is relatively strong for both eyes.

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Thus, when the stimulus is moved to the opposite (more damaged) eye, the stimulus for constriction is weaker, and the pupil in this more abnormal eye appears to dilate as the stimulus is presented to it. Then, when the stimulus is returned to the better eye, the pupil, which has previously been receiving weaker impulses from the contralateral eye, begins to receive a stronger input, and an additional constriction is noted. Testing for the APD is a critical step in the evaluation for anterior visual pathway compression, and should be performed in every instance. Several practical clinical points are pertinent: 1 The patient should be seated in a moderately darkened room (pupil reactivity is easier to assess when its size is relatively large). 2 The patient should fixate a distant target during the testing (preventing an unwanted near response with resultant miosis unrelated to light stimulus). 3 The stimulus should be a bright, focal light source (a dim or variable light may introduce inconsistent responses). 4 The light stimulus should be alternately presented to the eyes, remaining at each for approximately 1–2 seconds to allow the pupil to equilibrate, then quickly moving to the opposite eye (if no equilibration is allowed, the initial reaction of the pupil will be inconsistent). 5 Attention must be paid to the absolute degree of reactivity on each side (to detect bilateral, symmetrically sluggish pupils) and to the relative degree of reactivity (to detect asymmetrically sluggish pupils).

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Chapter 21 45 Neetens A, Selosse P. Oculomotor anomalies in sellar and parasellar pathology. Ophthalmologica 1977;175:80–104. 46 Max MB, Deck MDF, Rottenberg DA. Pituitary metastasis: incidence in cancer patients and clinical differentiation from pituitary adenoma. Neurology 1981;31:998–1002. 47 Neetens A, Mahler K, Bultinck J, Martin JJ. Sellar metastatic disease. Neuroophthalmology 1982;2:255–265. 48 Juneau P, Schoene WC, Black P. Malignant tumors in the pituitary gland. Arch Neurol 1992;49:555–558. 49 Wykes WN. Prolactinoma presenting with intermittent third nerve palsy. Br J Ophthalmol 1986;70:706–707. 50 Small KW, Buckley EG. Recurrent blepharoptosis secondary to a pituitary tumor. Am J Ophthalmol 1988;106:760–761. 51 Saul RF, Hilliker JK. Third nerve palsy: the presenting sign of a pituitary adenoma in five patients and the only neurological sign in four patients. J Clin Neuro-Ophthalmol 1985;5:185–193. 52 Daroff RB. See-saw nystagmus. Neurology 1967;15:874–877. 53 Fien JM, Willaims RDB. See-saw nystagmus. J Neurol Neurosurg Psychiat 1969;32:202–207. 54 Williams IM, Dickinson P, Ramsay RJ, Thomas L. See-saw nystagmus. Austral J Ophthalmol 1982;10:19–25. 55 Cardoso ER, Peterson EW. Pituitary apoplexy: a review. Neurosurgery 1984; 14:363–373. 56 Reid RL, Quigley ME, Yen SSC. Pituitary apoplexy. A review. Arch Neurol 1985;42:712–719. 57 McFadzean RM, Doyle D, Rampling R et al. Pituitary apoplexy and its effect on vision. Neurosurgery 1991;29:669–675. 58 Bills DC, Meyer FB, Laws ER et al. A retrospective analysis of pituitary apoplexy. Neurosurgery 1993;33:602–609. 59 Milazzo S, Toussaint P, Proust F et al. Ophthalmologic aspects of pituitary apoplexy. Eur J Ophthalmol 1996;6:69–73. 60 Lundstrom M, Frisen L. Atrophy of optic nerve fibers in compression of the chiasm–prognostic implications. Acta Ophthalmologica 1977;55(2):208–216. 61 Wilson CB, Dempsey LC. Transsphenoidal microsurgical removal of 250 pituitary adenomas. J Neurosurg 1978;48:13–22. 62 Ciric I, Mikhael M, Stafford T et al. Transsphenoidal microsurgery of pituitary macroadenomas with longterm followup results. J Neurosurg 1983;59:395–401. 63 Sherwen PJ, Patterson WJ, Griesdale DE. Transseptal, transsphenoidal surgery: a subjective and objective analysis of results. J Otolaryngol 1986;15:155–160. 64 Trautmann JC, Laws ER Jr. Visual status after transsphenoidal surgery at the Mayo Clinic, 1971–1982. Am J Ophthalmol 1983;96:200–208. 65 Lennerstrand G. Visual recovery after treatment for pituitary adenoma. Acta Ophthalmol 1983;61:1104–1117. 66 Cohen AR, Cooper PR, Kupersmith MJ et al. Visual recovery after transsphenoidal removal of pituitary adenomas. Neurosurgery 1985;17:446–452. 67 Peter M, De Tribolet N. Visual outcome after transsphenoidal surgery for pituitary adenomas. Br J Neurosurg 1995;9:151–157. 68 Powell M. Recovery of vision following transsphenoidal surgery for pituitary adenomas. Br J Neurosurg 1995;9:367–373. 69 Ciric I, Ragin A, Baumgartner C et al. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 1997;40:225–237. 70 Symon L, Logue V, Mohanty S. Recurrence of pituitary adenomas after transcranial operation. J Neurol Neurosurg Psychiatr 1982;45:780–785. 71 Thomson JA, Teasdale GM, Gordon D et al. Treatment of presumed prolactinoma by transsphenoidal operation: early and late results. Br Med J 1985;291:1550–1553. 72 Davis PC, Hoffman JC, Spencer JT Jr et al. MR imaging of pituitary adenoma: CT, clinical, and surgical correlation. ANJR 1987;8:107–112. 73 Schatz NJ, Lichtenstein S, Corbett JJ. Delayed radiation necrosis of the optic nerves and chiasm. In: Smith JL, Glaser JS, eds. Symposium of the University of Miami and Bascom Palmer Eye Institute, Vol 8. St Louis: CV Mosby Co, 1975: 131–139. 74 Harris JR, Levene MB. Visual complications following irradiation for pituitary adenomas and craniopharyngiomas. Radiology 1976;120:167–171. 75 Atkinson AB, Allen IV, Gordon DS et al. Progressive visual failure in acromegaly following external pituitary irradiation. Clin Endocrinol 1979;10:469–479. 76 Brown GC, Shields JA, Sanborn G et al. Radiation optic neuropathy. Ophthalmology 1982;89:1489–1493. 77 Hammer HM. Optic chiasmal radionecrosis. Trans Ophthal Soc UK 1983;103:208–211. 78 Kline LB, Kim JY, Ceballos R. Radiation optic neuropathy. Ophthalmology 1985;92:1118–1126.

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79 Fisher BJ, Gaspar LE, Noone B. Radiation therapy of pituitary adenoma: delayed sequelae. Radiology 1993;187:843–846. 80 Brada M, Rajan B, Traish D et al. The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Clin Endocrinol 1993;38:571–578. 81 Hughes MN, Llamas KJ, Yelland ME et al. Pituitary adenomas: long-term results for radiotherapy alone and post-operative radiotherapy. Int J Radiat Oncol Biol Phys 1993;27:1035–1043. 82 Zierhut D, Flentje M, Adolph J et al. External radiotherapy of pituitary adenomas. Int J Radiat Oncol Biol Phys 1995;33:307–314. 83 McCord MW, Buatti JM, Fennell EM et al. Radiotherapy for pituitary adenoma: long-term outcome and sequelae. Int J Radiat Oncol Biol Phys 1997;39:437–444. 84 Colao A, Cebone G, Cappabianca P et al. Effect of surgery and radiotherapy on visual and endocrine function in nonfunctioning pituitary adenomas. J Endocrinol Invest 1998;21:284–290. 85 Bagan SM, Hollenhorst RW. Radiation retinopathy after irradiation of intracranial lesions. Am J Ophthalmol 1979;88:694–697. 86 Guy J, Mancuso A, Beck R et al. Radiation-induced optic neuropathy: a magnetic resonance imaging study. J Neurosurg 1991;74:426–432. 87 Dawson DM, Dingman JF. Hazards of proton-beam pituitary irradiation. NEJM 1970;282:1434. 88 Braunstein GD, Loriaux DL. Proton-beam therapy. NEJM 1971;284:332–333. 89 Price J, Wei WC, Chong CYL. Cranial nerve damage in patients after alpha (heavy)-particle radiation to the pituitary. Trans Am Acad Ophthalmol Otolaryngol 1979;86:1161–1170. 90 Rush SC, Newall J. Pituitary adenoma: the efficacy of radiotherapy as the sole treatment. Int J Rad Oncol Biol Phys 1989;17:165–169. 91 Rush SC, Kupersmith MJ, Lerch I et al. Neuro-ophthalmological assessment of vision before and after radiation therapy alone for pituitary macroadenomas. J Neurosurg 1990;72:594–599. 92 Jordan RM, Kendall JW, Kerber CW. The primary empty sella syndrome. AM J Med 1977;62:569–580. 93 Robinson DB, Michaels RD. Empty sella resulting from the spontaneous resolution of a pituitary macroadenoma. Arch Intern Med 1992;152:1920–1923. 94 Olson DR, Guiot G, Derome P. The symptomatic empty sella. J Neurosurg 1972;37:533–537. 95 Welch K, Stears JC. Chiasmapexy for the correction of traction on the optic nerves and chiasm associated with their descent into an empty sella turcica. J Neurosurg 1971;35:760–764. 96 Kaufman B, Tomsak RL, Kaufman BA et al. Herniation of the suprasellar visual system and third ventricle into empty sellae: morphologic and clinical considerations. AJNR 1989;10:65–76. 97 Slavin ML, Lam BL, Decker RE et al. Chiasmal compression from fat packing after transsphenoidal resection of intrasellar tumor in two patients. Am J Ophthalmol 1993;115:368–371. 98 Barrow DL, Tindall GT. Pituitary adenomas: an update on their management with an emphasis on the role of bromocriptine. J Clin Neuro-ophthalmol 1983;3:229–237. 99 Molitch ME, Elton RL, Blackwell RE et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 1985;60:698–705. 100 Grimson BS, Bowman ZI. Rapid decompression of anterior intracranial visual pathways with bromocriptine. Arch Ophthalmol 1983;101:604–606. 101 Moster ML, Savino PJ, Schatz NJ et al. Visual function in prolactinoma patients treated with bromocriptine. Ophthalmology 1985;92:1332–1341. 102 Lesser RL, Zheutlin JD, Boghen D et al. Visual function improvement in patients with macroprolactinomas treated with bromocriptine. Am J Ophthalmol 1990;109:535–543. 103 Mbanya J-CN, Mendelow AD, Crawford PJ et al. Rapid resolution of visual abnormalities with medical therapy alone in patients with large prolactinomas. Br J Neurosurg 1993;7:519–527. 104 Clark JDA, Wheatley T, Edwards OM. Rapid enlargement of nonfunctioning pituitary tumor following withdrawal of bromocriptine. J Neurol Neurosurg Psychiatr 1985;48:287. 105 Kupersmith MJ, Frohman L, Kleinberg D et al. Escape from bromocriptine. Ann Neurol 1985;18:142. 106 Alhajje A, Lambert M, Crabbe J. Pituitary apoplexy in an acromegalic patient during bromocriptine therapy: case report. J Neurosurg 1985;63:288–292. 107 Mills DW, Willis NR, Visual field defects in pregnancy. Canad J Ophthalmol 1970;5:16–21. 108 Magyar DM, Marshall JR. Pituitary tumors and pregnancy. Am J Obstet Gynecol 1978;132:739–751.

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109 Mills RP, Harris AB, Heinrichs L, Burry KA. Pituitary tumor made symptomatic during hormone therapy and induced pregnancy. Ann Ophthalmol 1979;11:1672–1676. 110 Mashima Y, Kigasawa K, Oguchi Y, Fujino T. Visual evoked potential analysis of pituitary adenoma: exacerbation of pituitary adenoma during pregnancy. Folia Ophthalmol Jpn 1985;36:291–296. 111 Fujimoto M, Yoshino E, Mizukawa N, Hirakawa K. Spontaneous reduction in size of prolactin-producing adenoma after delivery: Case report. J Neurosurg 1985;63:973–974. 112 Molitch ME. Pregnancy and the hyperprolactinemic woman. N Engl J Med 1985;312:1364–1370. 113 Kupersmith MJ, Rosenberg CR, Kleinberg D. Visual loss in pregnant women with pituitary adenomas. Ann Intern Med 1994;121:473–477.

114 Meichner RH, Riggio S, Manz HJ, Earll JM. Lymphocytic adenohypophysitis causing pituitary mass. Neurology 1987;37:158–161. 115 Stelmach M, O’Day J. Rapid change in visual fields associated with suprasellar lymphocytic hypophysitis. J Clin Neuro-Ophthalmol 1991;11:19–24. 116 Nishioka H, Ito H, Miki T et al. A case of lymphocytic hypophysitis with massive fibrosis and the role of surgical intervention. Surg Neurol 1994;42:74–78. 117 Thodou E, Asa SL, Kontogeorgos G et al. Lymphocytic hypophysitis: Clinicopathological findings. J Clin Endocrinol Metab 1995;80:2302–2311. 118 Kerrison JB, Lee AG. Acute loss of vision during pregnancy due to a suprasellar mass. Surv Ophthalmol 1997;41:402–408. 119 Mindel JS, Safir A, Schare PW. Visual field testing with red targets. Arch Ophthalmol 1983;101:927–929.

C h a p t e r

22 Evaluation of Normal Pituitary Function Gillian L. Booth Afshan Zahedi Shereen Ezzat

INTRODUCTION The assessment of normal adenohypophyseal hormone reserve has been facilitated by the availability of specific and sensitive assays of anterior pituitary peptides as well as synthetic hypothalamic releasing hormones including thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), and more recently corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GHRH). Investigations to elucidate the degree of pituitary function are an important component of the overall assessment of hypothalamic–pituitary disorders, and greatly enhance the information gained through clinical evaluation. The aim of this chapter is to summarize the procedures involved in the diagnostic evaluation of the pituitary. Emphasis has been placed on interpretation of normal responses in individuals with intact hypothalamic–pituitary function. Where possible, evidence describing the performance characteristics of each test ( for example, sensitivity and specificity) is reviewed. Hence, the utility of each procedure based on the ability to discriminate between normal and impaired hypothalamic–pituitary function is discussed. ASSESSMENT OF ANTERIOR PITUITARY FUNCTION CORTICOTROPH (ACTH) ASSESSMENT

Basal Plasma Cortisol In general, basal cortisol levels are of little value in discriminating between individuals with normal verses impaired hypothalamic–pituitary–adrenal (HPA) function (Table

22.1). Basal levels over 550 nmol/L virtually exclude adrenal insufficiency [1]. Although there is some evidence that morning cortisol values in the range of 300–500 nmol/L [2,3] predict normal corticotroph function, values as high as 450 nmol/L can occur in the presence of HPA axis impairment [4]. In the setting of severe acute illness, such as major surgery [5] or septic shock [6], cortisol levels usually exceed 1000 nmol/L, but do not correlate with other indicators of illness severity [6]. Hence, no clear threshold for a normal response to severe illness has been established. Although highly suggestive, very low basal cortisol concentrations are not specific for HPA axis dysfuntion; levels under 150 nmol/L have a specificity ranging from 50–100% [7,8], and a sensitivity of only 39–87% [7–9]. Factors that influence cortisol-binding globulin (CBG) levels may also confound the interpretation of serum cortisol. High estrogen states lead to an elevated serum cortisol by increasing CBG concentrations. Conversely, serum cortisol is reduced in the setting of cirrhosis, hyperthyroidism and other conditions that lower CBG levels. DYNAMIC TESTING

Insulin Tolerance Test The insulin tolerance test (ITT) is widely regarded as the gold standard for evaluating the integrity of the HPA axis. Results of insulin-induced hypoglycemia are reproducible, and correlate well with other tests of HPA function [10] and clinical outcomes [7]. The test is performed in the morning after an overnight fast. Rapid-acting insulin (usually 0.1–0.15 U/kg) is given intravenously with the aim of lowering blood glucose levels to less than 2.2 nmol/L (Table 22.2). Higher doses are required for insulin-resistant individuals, such as patients with acromegaly, who may require up to 0.3 U/kg or more. Among larger series, as 709

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Table 22.1.

Normal basal hormome values

Test

Source

Per ml or dl

SI units

Adrenocorticotropic hormone (ACTH)

Plasma

20–100 pg/ml

4.4–22.2 pmol/L

Antidiuretic hormone (ADH)

Plasma

2–12 pg/ml (>290 mosm/kg)

1.85–11.1 pmol/L

C-peptide insulin

Serum: Fasting

0.5–3.0 ng/mL

0.5–3.0 mg/L

Calcitonin

Plasma: Male Female

<91 pg/mL <71 pg/mL

<24.5 pmol/L <19.2 pmol/L

Catecholamines

Cortisol

Follicle-stimulating hormone (FSH)

Plasma: Norepinephrine Epinephrine Dopamine Urine: Norepinephrine Epinephrine Dopamine

110–410 pg/mL <50 pg/ml <30 pg/ml

0.7–2.4 nmol/L <0.27 nmol/L <0.19 nmol/L

15–56 mg/24 h <15 mg/24 h 100–440 mg/24 h

88.6–331 nmol/24 h <82 nmol/24 h 625–2750 nmol/24 h

Plasma a.m. p.m. Urine

5–20 mg/dl 2.5–10 mg/dl 25–95 ng/mgCr

0.14–0.55 mmol/l 0.07–0.28 mmol/l 78–297 mmol/molCr

Serum: Male Female

2–17 mIU/L 4–20 mIU/L

2–17 IU/L 4–20 IU/L

Gastrin

Serum

<200 pg/ml

<52 pmol/L

Glucagon

Plasma

50–200 pg/ml

14–57 pmol/L

Growth hormone (GH)

Serum: Child Adults Urine

<10 ng/ml <5 ng/ml 0.4–1.5 ng/gCr

<465 pmol/L <232 pmol/L

17-OH-corticosteroids (17-OHCS)

Urine Male: Female:

3–15 mg/24 h 2–12 mg/24 h

8.3–41.4 mmol/24 h 5.5–33 mmol/24 h (3–7 mg/g Cr) (0.9–2.2 mmol/molCr)

17-Ketosteroids

Urine: 0–8 yrs: 8 yr–puberty: Adult male: Adult female:

0–1 mg/24 h 1–10 mg/24 h 9–22 mg/24 h 5–15 mg/24 h

0–3.5 nmol/24 h 3.5–35 nmol/24 h 31–76 nmol/24 h 17–52 nmol/24 h

Luteinizing hormone

Serum: Male Female –premenopause

4–18 IU/l 5–25 mIU/ml 5–25 IU/l 30–200 mIU/ml 30–200 IU/l

–postmenopause Metanephrine

Urine

many as one-fifth (5–20%) of patients required more than one dose of insulin to achieve adequate hypoglycemia [2,11,12]. Symptoms, such as sweating (63%), hunger (50%), palpitations (51%), and tremors (31%) are common follow-

0.3–0.9 mg/24 h

1.5–4.5 nmol/24 h

ing administration of insulin [13]. Venous samples are collected at 0, 15, 30, 45, 60, 90, and 120 minutes for measurement of glucose, adrenocorticotropic hormone (ACTH), cortisol, and growth hormone (GH). A glu-

Chapter 22 Table 22.1.

Evaluation of Normal Pituitary Function

Continued

Test

Source

Per ml or dl

Osmolality

Serum Urine

285–293 mosmol/kg 300–900 mosm/kg

Pancreatic polypeptide (PP)

Plasma

<350 pg/ml

<86 pmol/L

Parathyroid hormone (intact assay)

Serum

11–54 pg/ml

1.2–5.6 pmol/l

Prolactin (PRL)

Serum: Male –newborn –child –adult Female –newborn –child –adult

141–189 ng/ml 4–8 ng/ml <15 ng/ml

6.4–8.6 nmol/l 0.18–0.36 nmol/l <0.7 nmol/l

141–189 ng/ml 4–8 ng/ml <20 ng/ml

6.4–8.6 nmol/l 0.18–0.36 nmol/l <0.9 nmol/l

14–56 ng/ml 13–81 ng/ml 29–108 ng/ml 102–182 ng/ml 98–319 ng/ml 136–293 ng/ml 43–178 ng/ml

0.1–0.4 nmol/l 0.1–0.6 nmol/l 0.2–0.8 nmol/l 0.7–1.3 nmol/l 0.7–2.3 nmol/l 1.0–2.1 nmol/l 0.3–1.3 nmol/l

14–60 ng/ml 19–97 ng/ml 34–137 ng/ml 104–374 ng/ml 192–347 ng/ml 132–305 ng/ml 24–153 ng/ml

0.1–0.4 nmol/l 0.1–0.7 nmol/l 0.2–1 nmol/l 0.7–2.7 nmol/l 1.4–2.5 nmol/l 0.9–2.2 nmol/l 0.2–1.1 nmol/l

Somatomedin C (insulin-like growth factor-I)

Testosterone (total)

Plasma Male 0–3 3–6 6–10 10–13 13–16 16–18 >18 Female (years) 0–3 3–6 6–10 10–13 13–16 16–18 >18

SI units

Serum: Male –prepubertal –pubertal –adult Female –prepubertal –pubertal –adult

8–14 ng/dl 84–180 ng/dl 300–1000

0.28–0.49 nmol/l 2.91–6.24 nmol/l 10.4–34.7 nmol/l

5–13 ng/dl 9–24 ng/dl 30–70 ng/dl

0.17–0.45 nmol/l 0.31–0.83 nmol/l 1.04–2.43 nmol/l

Serum: Adult male Adult female

80–280 pg/ml 3–13 pg/ml

69.3–970.9 nmol/l 10.4–45.1 nmol/l

Thyroid stimulating hormone (TSH)

Serum

0.4–4.8 mU/ml

0.4–4.8 mU/l

Vanillylmandelic acid (VMA)

Urine (24 h) Newborn Infant Child Adolescent Adult

<1 mg/d <2 mg/d 1–3 mg/d 1–5 mg/d 2–7 mg/d

<5.8 nmol/d <11.7 nmol/d 5.8–17.6 nmol/d 5.8–17.6 nmol/d 11.8–41.2 nmol/d

Testosterone (free)

711

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Diagnostic Procedures

Table 22.2.

Dynamic tests for assessment of anterior pituitary function

Test

Dose

Normal response

Side effects

ACTH 1 Insulin tolerance test

0.1–0.15 U/kg IV

peak C ≥ 500 nmol/L

Sweating, palpitation, tremor

2 Metyrapone test

30 mg/kg po at 23:00

peak 11–DOC ≥ 115 –200 nmol/L peak C < 270 nmol/L

Nausea, insomnia

3 CRH stimulation test

100 mg IV (ovine/human)

peak ACTH ≥ 2–4 X ≠ peak C ≥ 550 nmol/L OR ≠ ≥ 280 nmol/L

flushing

4 ACTH stimulation test

250 mg IV or IM

peak C ≥ 500–550 nmol/L

Rare

1 mg IV or IM

peak C ≥ 500 nmol/L

Rare

TSH TRH stimulation

200–500 mg IV

peak TSH ≥ 2.5 X ≠ OR ≠ ≥ 5–6 mU/L (F) ≠ ≥ 2–3 mU/L (M)

Flushing, nausea, urge to micturate

PRL TRH stimulation

200–500 mg IV

PRL ≠ ≥ 2.5 fold

Flushing, nausea, urge to micturate

100 mg IV

LH ≠ ≥ 2–3 X FSH ≠ ≥ 1.5–2 X*

Rare

50–100 mg po bid ¥ 5 d

Day 10–14: LH ≠ ≥ 2 X (F) FSH ≠ ≥ 1.5–2 X (F) LH ≠ ≥ 50–250% (M) FSH ≠ ≥ 30–200% (M)

0.1–0.15 U/kg

GH ≥ 3–10 ng/ml

Sweating, palpitation, tremor

2 Clonidine stimulation test

0.15 mg/m2 po

GH ≥ 5–10 ng/ml

Mild Ø BP drowsiness

3 L-arginine

0.5 g/kg (max 30 g) IV over 30–120 min

GH ≥ 5–10 ng/ml

Nausea

4 L-dopa

10 mg/kg po (max 500 mg)

GH ≥ 5–10 ng/ml

Nausea

5 Glucagon

0.03 mg/kg (max 1 mg)

GH ≥ 5–10 ng/ml

6 GHRH

1–5 mg/kg

GH ≥ 5 ng/ml

LH/FSH 1 GnRH stimulation test 2 Clomiphene

GH 1 Insulin tolerance test

Flushing

* Responses are frequent flat in normal individuals C = serum Cortisol

cometer is essential to provide immediate feedback regarding the level of hypoglycemia. After hypoglycemia is achieved, patients are provided with an oral glucose load and light meal.

consciousness occurs in less than 3% of tests [3,11]. Regardless, intravenous dextrose and hydrocortisone must be available in the event of severe, persistent hypoglycemia. Normal Response

Contraindications

Contraindications to the ITT include cardiac or cerebrovascular disease, epilepsy, pregnancy, and extremes of age. Severe adverse effects are rare; for example, transient loss of

From reports in the literature, the threshold for defining a normal peak cortisol level varies between 500 and 580 nmol/L (18–21 mg/dl). Older fluorimetric assays are reported to have a 20–30% positive bias, hence a previous

Chapter 22

cut-off value of 580 nmol/L correlates to a levels of approximately 500 nmol/L using current radioimmunoassays [14]. Raising the threshold above this level does not appear to improve test performance [3]. Using only a rise in cortisol of greater than 195 nmol/L and/or doubling from baseline to define a normal response leads to high rates of false-positive and false-negative results [12]. Since no other test of HPA axis function can outperform the ITT, sensitivity and specificity can not be determined.

Metyrapone Test The metyrapone stimulation test, previously a mainstay in evaluation of HPA axis reserve, yields results that are highly concordant with ITT (sensitivity 80–90%; specificity 80–100%) [10,15]. The theory behind the test involves blockage of the 11-hydroxylase step in the cortisol pathway, leading to reduced serum cortisol, increased secretion of pituitary ACTH, and a concomitant rise in the precursor 11-deoxycortisol (11-DOC). Older protocols were laborintensive and costly, because of the need for hospitalization and multiple 24-hour urine collection. However, the short metyrapone test requires only a single oral dose of metyrapone at 23:00 or midnight (30 mg/kg or 2–3 g) with measurement of serum 11-DOC and cortisol the following morning (Table 22.2) [16]. Adverse Events

Side effects include nausea, mental clouding, and insomnia [10,15]. Normal Response

Depending on the study, a normal response is described as a rise of 11-DOC to a peak of greater than 115–200 nmol/L (7–12 mg/dl) [10,15–17]. Failure to adequately suppress plasma cortisol (<270 nmol/L or 10 mg/dl) leads to falsely low 11-DOC levels [16]. For example, phenytoin causes enhanced metabolism of metyrapone, leading to inadequate enzymatic blockade and false-positive

Table 22.3. testing

Drug effects on pharmacological pituitary

Agent

Interference

Glucocorticoids

Impaired TSH response to TRH Impaired LH response to GnRH Impaired GH response to hypoglycemia

Estrogens

Accelerated metyrapone catabolism Increased corticosteroid-binding globulin

Phenytoin

Increased metyrapone and dexamethasone catabolism

Narcotics

Increased PRL Impaired GH/cortisol response to hypoglycemia

Ethanol

Increased PRL Inadequate dexamethasone-mediated cortisol suppression Impaired cortisol response to hypoglycemia

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results (Table 22.3). Peak ACTH levels are greater than 200 ng/L (45 pmol/L) in the majority of normal individuals [18]. However, ACTH responses correlate poorly with peak cortisol levels induced by hypoglycemia [19], and thus may not be the best parameter to follow.

Corticotrophin-releasing Hormone (CRH) Stimulation The CRH stimulation test involves the administration of ovine or human CRH (100 mg IV) and subsequent measurement of cortisol and ACTH at time 0, 15, 30, 45, 60, 90, and 120 minutes (Table 22.2). Adverse Events

Transient mild flushing is common following CRH administration [20–22]. Normal Response

Maximal ACTH responses are between two and four fold greater than baseline [22], and peak at 30 minutes [9]. Peak cortisol responses following CRH stimulation occur later (60 minutes) [9], and correlate with those observed during insulin tolerance testing [9,22]. For serum cortisol, a peak level over 550 nmol/L or an increment greater than 280 nmol/L (10 mg/dl) can be anticipated in normal individuals (sensitivity of 28–100%, specificity of 83–90%) [22]. Patient characteristics, such as obesity [20] do not appear to influence the response to CRH.

ACTH Stimulation Test The rapid ACTH test has gained acceptance in the evaluation of adrenal insufficiency, largely because it is quick to administer and has a high sensitivity for detecting primary adrenal failure. However, its utility in the diagnosis of central HPA axis dysfunction has been challenged. Traditional doses of tetracosactrin (Synacthen) or 1–24 ACTH (Cortrosyn) of 250 mg (IV or IM) are considered supraphysiologic, and thus may result in a normal adrenal response, even in the face of HPA insufficiency. The identification of patients with partial ACTH deficiency (e.g. chronic corticosteroid use) is particularly problematic [23,24]. In a large retrospective review by Hurel et al. [4] the standard ACTH stimulation test identified only one-third of patients with central adrenal insufficiency, leading to an unacceptably high false-negative rate. Reported sensitivities vary dramatically from 10% to 100% [8,11,13,24–29,30–34], however, the specificity is significantly higher (80–100%) [4,8,11,26–32,33,34]. Cortisol levels at 30 minutes correlate well with peak responses on ITT [35] and levels continue to rise until 60 minutes [35]. Results are not influenced by the time of day or prior treatment with low-dose dexamethasone [35]. Normal Response

The threshold for a normal response is considered to be 500 or 550 nmol/L (Table 22.2). Again, using a 200 nmol/L

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increment or doubling of baseline values as a criterion for passing the test may be misleading. Several authors have described an inverse relationship between basal cortisol values and the incremental response to ACTH stimulation [36,37]. Hence, patients with baseline levels over 550 nmol/L (representing normal HPA function) are least likely to demonstrate a 200 nmol/L rise during the test.

Low-dose ACTH Test A newer, low-dose ACTH-stimulation test, using 1 mg of synacten (IM or IV) is rapidly gaining favor over the standard 250 mg dose for identifying patients with central adrenal insufficiency (Table 22.2). Plasma cortisol levels at 30 minutes are maximal at doses as low as 0.5 mg and correlate highly with peak levels observed during insulin-induced hypoglycemia [35] and high dose ACTH stimulation [35]. Levels decline between 30 and 60 minutes, thus the 30 minute level is used for diagnostic purposes [35,38]. In most series, a threshold greater than 500 nmol/L was associated with a sensitivity approaching 100% [11,13,31,32,34] and a specificity of 80–100% [8,11,32–34]; although in one study [8] the sensitivity was only 71% with a specificity of 93%. When evaluating discordant results of standard and low-dose testing, the low-dose method is more frequently correct [34,35]. Because of the possibility of falsely low test results, any positive test (failure to respond appropriately) needs to be corroborated using a standard test of corticotroph function, such as the ITT. Thus, ACTH stimulation is a useful screening tool to rule out central ACTH deficiency. Side effects are rare with low doses of ACTH. THYROTROPIN (TSH) ASSESSMENT

Basal Thyroid Function Tests A normal serum TSH level (sTSH) does not rule out pituitary dysfunction (see Table 22.1 for normal ranges) [39– 41]. Central hypothyroidism appears to be associated with secretion of TSH that has reduced biological activity but retained immunoreactivity. Hence, the diagnosis of hypothalamic–pituitary–thyroid (HPT) insufficiency rests on the demonstration of a low or paradoxically normal sTSH in the face of low circulating thyroxine (T4) and an appropriate clinical picture. Severe nonthyroidal illness mimics the biochemical profile of central hypothyroidism, however, it is associated with low free triiodothyronine (T3), elevated reverse T3 levels and is reversible with resolution of the acute illness [42]. The specificity of TSH measurements has improved over the years due to the emergence of newer TSH immunoradiometric assays (third and fourth generation), capable of discriminating between an abnormally low TSH level and the lower end of the normal range [41]. However, sTSH is not a valid endpoint for assessing the integrity of the HPT axis in patients with hypothalamic or pituitary disorders, as normal TSH levels do not predict TSH reserve [43].

Thyrotropin-releasing Hormone (TRH) Stimulation Test The purpose of the TRH stimulation test is to assess thyrotroph and lactotroph function. This test may be performed on its own, or more commonly in conjunction with gonadotropin-releasing hormone stimulation and insulininduced hypoglycemia, known collectively as a triple bolus test, for assessment of overall pituitary function. Synthetic TRH (protirelin, Relefact TRH, 200–500 mg) is administered as an intravenous bolus (Table 22.2). Venous blood samples are collected for sTSH at baseline and 0, 20, and 60 minutes following TRH administration (as part of the triple bolus test, sampling times may vary depending on the timing of other samples). Fasting and bed rest prior to or during the test are unnecessary, but an empty bladder is advisable. Because the circadian rhythm of sTSH secretion leads to a greater sTSH response to TRH in the late afternoon and evening, this test should be performed in the morning. Caffeine and theophylline may enhance the activity of TRH, and patients should avoid these substances 12 hours prior to the test. Adverse Events

Mild adverse effects may occur with TRH administration; most commonly nausea (17%), flushing (24%), malaise (15%) and the urge to micturate, due to stimulation of smooth muscle in the genitourinary and gastrointestinal tracts (38%) [40,44,45]. Other side effects include light-headedness, headache, and dry mouth. When present, these symptoms occur shortly after TRH injection and last only a few minutes. Blood pressure may rise transiently during the first 30 minutes, and very rare cases of pituitary [46] and myocardial infarction have been reported following TRH administration. Normal Response

Peak sTSH levels usually occur between 20 and 30 minutes following TRH injection, and are similar for doses between 100 and 800 mg [44,45]. Failure of levels to decline by 60 minutes or a delayed peak (60–120 minutes) is reported to favor the presence of a hypothalamic rather than pituitary abnormality [47]. However, this finding is not specific, as patients with isolated intrasellar lesions may also demonstrate a delayed or prolonged peak [40,48]. Peak sTSH levels vary greatly across the physiological range, with higher baseline levels associated with a markedly greater response to TRH. In contrast, the fold response in TSH remains relatively constant across the normal range, with a minimum of at least 2.5-fold (and up to 23-fold) in normal individuals [49]. Most studies define a normal response based on the incremental rise in sTSH. Pr menopausal women have greater responses to TRH stimulation due to higher estrogen levels [50], while there is an age-related decline in TSH response in men over 40 [48,51,52]. Thus, a rise of sTSH of at least 5–6 mU/L is considered a normal response in women and young men, however the threshold is frequently lowered to approxi-

Chapter 22

mately 2–3.5 mU/L in men over 40 [40,43,48,49]. The absolute peak demonstrates tremendous interindividual, but less intraindividual variation; thus the test is highly reproducible for a given individual. An enhanced response is observed in cases of primary hypothyroidism, in which the absolute rise is exaggerated and prolonged [44,45,49]. Impaired responses are seen in patients with pituitary thyrotroph deficiency, and primary hyperthyroidism (overt or compensated) [44,51,53]. Baseline thyroid function indices and the clinical presentation can easily discriminate between the two syndromes. False positives can occur in the presence of a normal HPT axis. Approximately 9–10% of normal individuals exhibit a blunted response to TRH [53,54], however, this rises to as high as 30% or more in the elderly population [55,56]. Occasionally impaired responses are observed in the setting of a severe nonthyroidal illness, and in patients suffering from renal failure [57,58] and alcoholism [59]. Excess cortisol (either endogenous or exogenous) [60,61] and certain medications, such as dopamine agonists can suppress the pituitary–thyroid axis [42,62]. PROLACTIN (PRL) ASSESSMENT

Basal Levels Prolactin is the pituitary hormone that is least sensitive to local damage. Limited PRL reserve may, therefore, be a measure of the severity of pituitary damage. Newer assays use a two-site immunometric method, resulting in a more accurate assessment of circulating levels. Normal reference ranges differ by sex, with females having somewhat higher levels (4.0–25 mg/L) than males (0.5–19 mg/L) (Table 22.1).

TRH Stimulation Test The TRH stimulation test is carried out as described above (Table 22.2). Peak PRL levels are higher in women than in men, however the relative increase is similar between the two groups. Normal Response

A normal PRL response consists of a 2.5 fold rise in baseline values [63] between 15 and 30 minutes after TRH administration [64,65]. Using this criteria, Le Moli et al. [64] found that 24% of normal subjects have a blunted response. Responses are more variable with advanced age. Among elderly individuals, peak levels may become more delayed, however, mean increments tend to be similar [66]. An impaired response to TRH stimulation in conjunction with low-normal baseline levels occurs in the setting of severe anterior pituitary insufficiency. In contrast, the majority of patients with prolactinomas demonstrate a blunted response, however, basal levels are elevated [67,68]. Impaired TSH responses are not specific to prolactinomas, but can occur in patients with hypothalamic or other sources of hyperprolactinemia [68,69].

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GROWTH HORMONE (GH) ASSESSMENT

Circulating GH Basal Levels

Diminished GH reserve is one of the earliest signs of pituitary insufficiency. Because of the episodic nature of GH secretion and the limitations of conventional radioimmunoassays, normal individuals commonly have low or undetectable levels for large portions of the day (Table 22.1) [70]. Thus, a single GH measurement is of limited value in the assessment of somatotroph function. Moreover basal GH levels are unable to predict performance on dynamic testing [71,72]. One approach to bypass this limitation has been the measurement of mean overnight or 24-hour integrated serum GH concentrations (IGHC). However, this methodology is expensive, and time-consuming due to the need for frequent sampling (every 10–20 minutes). Mean GH levels decline 14% for each decade of adult life [73], despite intact pituitary reserve [72]. Reference ranges for 24-hour IGHC must be age and sex-adjusted [74], and individual levels are influenced by a host of other factors, such as food intake, nutritional status, body mass index, and physical activity [70,75,76]. Although more sensitive assays (immunoradiometric, ELISA and chemiluminescent assays) display less overlap between growth hormone deficient (GHD) individuals and controls [76,77], the diagnostic utility of IGHC falls far short of stimulation testing for identifying individuals with pathologically low GH levels [72,78–80].

Insulin-like Growth Factor I (IGF-I) Serum IGF-I levels reflect the cumulative daily exposure to GH and thus can serve as a surrogate marker for abnormal GH production. Normal ranges are age-dependent; levels peak during puberty [81] and decline progressively by 7–13% with each decade (Table 22.1) [75]. Thus, many elderly subjects have low circulating IGF-I concentrations. Levels are also reduced in the setting of malnutrition, hepatic disease, thyroid disease, diabetes, and renal failure [75]. Thus, while IGF-I levels are significantly lower in GHD individuals, there is considerable overlap between normal and GHD individuals, both in the adult [70,72,82] and pediatric populations [78,83,84]. In fact children with short stature tend to have lower IGF-I levels than their normally-growing counterparts, despite intact GH secretion [78,83,85]. Measurement of free IGF-I levels appears to have a greater specificity and positive predictive value [81].

Insulin-like Growth Factor I Binding Protein-3 (IGFBP-3) IGFBP-3 is a GH-dependent protein that binds IGF-I in the circulation. IGFBP-3 measurements are influenced by many of the same factors that determine IGF-I levels [75]. Similarly, IGFBP-3 levels can not reliably discriminate between

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normal and GHD adults [76]. In one study, as many as twothirds of patients with GHD had normal IGFBP-3 levels [70]. In children, IGFBP-3 may have a greater sensitivity and specificity than IGF-I for the diagnosis of GHD; in one large study these values were 97% and 95%, respectively [86]. In particular, IGFBP-3 appears to be more informative than IGF-I in young children with GHD [87]. PROVOCATIVE TESTING

Physiological Tests Physiologic tests may be useful as an initial screening procedure to rule out GH deficiency. Physical exercise (15– 20 minutes on a treadmill) acts as a stimulus for GH secretion and the sensitivity of this test is estimated to be in the range of 100%, depending on the threshold used (10–15 ng/ml) [88–90]. However, a normal response can be expected in only 75–95% of healthy children [88–90]. Similar GH responses occur during the first 60–90 minutes of sleep [91–93]. However, sleep-induced rises in GH are also blunted or absent in up to one-third of normal children [92]. Moreover, the need for performance in a hospital setting renders the test impractical for routine testing.

Pharmacological Tests By convention, an impaired GH response must be demonstrated on two provocative tests before a diagnosis of GH deficiency can be made (Table 22.2). The exception is the individual who has a structural lesion and concomitant pituitary hormone insufficiency. In children, a diagnosis of GHD is frequently sought during the investigation of short stature. In this context, the results of biochemical testing must be interpreted in light of other parameters, such as height velocity (Figs 22.1 and 22.2) and skeletal age. Unfortunately, there are no clear guidelines regarding the appropriate threshold for defining a normal response, but most studies use a GH level of greater than 3–10 ng/ml; with lower levels reserved for diagnosing GH deficiency in adults [75]. Some tests have a greater propensity towards falsepositive results, as can occur in the setting of obesity [94], cortisol excess [95], hypogonadism [96], chronic diseases such as rheumatoid arthritis [97], chronic renal failure [98], and depression [99], and certain medications [100]. All tests should be performed in the fasting state to avoid suppression of GH release caused by postprandial hyperglycemia.

Insulin-induced Hypoglycemia The insulin tolerance test (ITT) is considered the gold standard for the diagnosis of GHD in adults [75], and provides a concomitant assessment of the HPA axis. The ITT is generally not recommended for use in young children because of the potential harm of inducing hypoglycemia in this population [101]. The test is carried out in a similar manner to that detailed above and the same contraindications apply.

FIGURE 22.1. Standards of (a) height and (b) height velocity for North American boys. From Tanner [133].

Chapter 22

FIGURE 22.2.

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Standards of (a) height and (b) height velocity for North American girls. From Tanner [133].

Normal Response

Maximal responses are observed between 20 and 30 minutes, and are greater than those observed during other conventional forms of testing [102]. In young healthy adults, GH levels frequently exceed 20 ng/ml (40 mU/L) in response to insulin-induced hypoglycemia [102]. In general, GH responses peak during puberty [103] and decline with advanced age [104]. Hoffman et al. [70] found that a threshold of 3–5 ng/ml on ITT had a diagnostic accuracy of 100% for discriminating between adults with GH and coexisting pituitary hormone deficiency and matched controls [70]. False-positive results (failure to respond) are observed in up to 10–15% of normal individuals, primarily among the elderly.

Clonidine Clonidine stimulation is a safe and reliable method of assessing somatotroph function in children. The test involves providing an oral dose of clonidine (0.15 mg or 150 mg/m2), with measurement of GH at time 0 and every 30 minutes for 90–120 minutes. Peak responses occur between 60 and 120 minutes [71]. From the pediatric literature, falsepositive rates appear to be quite low (usually less than 10–15%) [71,105,106]. In adults, clonidine-stimulation appears to be less reliable than other standard tests of GH

reserve [76,102]. Mild reductions in systolic blood pressure, (5–10 mm Hg) and serum cortisol have been reported to occur following administration of oral clonidine [71,107]. These effects appear to be dose-independent, but are rarely symptomatic [107].

Arginine Intravenous L-arginine is administered (0.5 g/kg, maximum 30 g) over a 30–120 minute time period following an overnight fast. Measurements for serum GH are undertaken at time 0 and every 30 minutes for 2 hours. Thresholds that define a normal response are similar to those used in the ITT. Up to one-third of normal individuals do not respond to arginine [102,106,108]. Although GH responsiveness to arginine remains fairly stable with increased age, peak levels are highly variable. Thus, there is considerable overlap of responses to arginine among healthy elderly individuals and those with established GHD. Addition of insulin (0.1– 0.12 IU/kg) 60 minutes following arginine administrations greatly improves the accuracy of the test by diminishing the number of false-positives [109].

L-dopa L-dopa is given by mouth at a dose of 10 mg/kg (maximum 500 mg). Serum GH is measured on an hourly basis for 2–

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3 hours, with peak levels occurring between 60 and 90 minutes in the majority of cases. Approximately 5–20% of normal individuals have an impaired response [92,110]. Variations in the protocol, such as using L-dopa for 2 days prior to testing, appear to improve test responses. Nausea is a common side effect, occurring in up to one-third of subjects [109,110].

Glucagon Glucagon stimulation is widely used in adults to assess GH and HPA reserve when a contraindication to the ITT exists. Glucagon is administered in a dose of 0.03 mg/kg (maximum 1.0 mg) intramuscularly or subcutaneously, following which samples for GH are obtained on an hourly basis for 3 hours. In adults, glucagon-stimulation results in lower peak responses than insulin-induced hypoglycemia, but greater levels than observed during arginine or clonidine stimulation [102]. Approximately 10–20% of normal individuals demonstrate an impaired response [102].

Combinations of Test Agents Attempts to improve the diagnostic utility of these investigations have led to the development of newer tests using a combination of stimulatory agents. Various combinations, such as L-dopa with arginine [111], ITT [112], or propanolol [113], and the sequential arginine-insulin tolerance test [92,113,114] appear to have greater specificity than each test individually. Furthermore, pretreatment with a 4-month course of gonadal steroids may enhance the response to stimulation testing in children with constitutional delay, thereby allowing their differentiation from children with true GH deficiency [115].

Growth Hormone-releasing Hormone (GHRH) The discovery of growth hormone-releasing hormone (GHRH1-40, GHRH1-44, or GHRH1-29) from human pancreatic tumor cells brought a new method of GH assessment and a potential therapeutic agent to the forefront. Since that time, novel growth hormone releasing peptides (GRP-2, GRP-6, and hexarelin) have been developed that have greater potency and longer half-lives. The GHRH test involves administration of intravenous GHRH (1–5 mg/kg) with venous samples for GH obtained at time 0, 15, 30, 45, 60, 90, and 120 minutes. Peak GH responses in normal individuals are greater, but more variable following GHRH than during conventional tests of GH reserve. Maximal responses, occurring between 15 and 90 minutes after GHRH average between 20 and 30 ng/ml [116–118], and occasionally exceed 50–60 ng/ml [116–119]. Virtually all patients with intact somatotroph function achieve a peak GH level of greater than 5 ng/ml [116–119]. Responses are somewhat higher in women than in men and diminish with increasing age [116] and obesity [120,121]. Use of a GRP

alone [122] or a combination of GHRH and pyridostigmine [121] or GRP [122] leads to normal responses in obese subjects. The latter combination is associated with marked elevations of GH in normal individuals (up to 190 ng/ml). It has been proposed, however, that a peak GH of >15 ng/ml folowing the combined GRP/GHRH test can safely and reliably distinguish true adult GH deficiency from other clinical conditions [122a]. Adverse Events

Transient facial flushing is experienced by the majority of adults and some children within the first few minutes of GHRH administration and tends to resolve within 5–10 minutes [116,123]. Normal Response

The interpretation of this test is problematic, because of a large degree of overlap in responses of normal and growth hormone deficient individuals. In children, a threshold of 5 ng/ml has a sensitivity of only 22–57%, but a very high specificity [116–119,124]. In fact, children who are labeled GH-deficient by virtue of impaired responses on conventional testing (usually less than 5 ng/ml) may respond briskly to GHRH. In one large multicentered study, almost onefifth of children with GHD had a stimulated GH level over 15 ng/ml (30 mU/L) following GHRH [124]. Intact responses may occur in the setting of hypothalamic disease and in individuals with partial GH deficiency. The latter finding may explain why patients with a previous diagnosis of idiopathic GHD were more likely to respond than those with anatomic lesions. Performance characteristics appear to be more favorable for adults with severe GHD; reported sensitivities range from 75% to 100%, with a specificity of 100% for a threshold of 3–5 ng/ml [116,123]. One group found that by raising the threshold to 16.5 ng/ml and administering arginine in conjunction of GHRH the sensitivity improved to 100% [125], however, normal controls were not studied simultaneously. GONADOTROPIN (LH AND FSH) ASSESSMENT

Basal Levels Reference ranges for basal levels of LH and FSH are age and sex-dependent (Table 22.1). Moreover, levels vary throughout childhood, being very low in the prepubertal period and rising with the onset of puberty [126]. Premenopausal women experience fluctuations in gonadotropin levels during different parts of the reproductive cycle [127]. In postmenopausal women, a fall in serum estrogen results in loss of negative feedback to gonadotrophs, hence serum LH and FSH levels rise accordingly. Elevations in gonadotropin levels may precede the development of menopause by several years [128]. Although on average, serum testosterone levels (total, free and bioavailable) decline in elderly men [129], most older males retain serum testosterone within the normal range [130]. The binding of

Chapter 22

Evaluation of Normal Pituitary Function

(a)

719

(b)

FIGURE 22.3. Diagrammatic representation of sequence of phases of pubertal development in boys (a) and girls (b). Numbers inside bars represent Tanner stages of genital and pubic hair development. From Tanner [133].

(b)

(a) FIGURE 22.4. Tanner pubic hair stages for females (a) and males (b). Stage 1: no pubic hair. Stage 2: sparse growth of hair mainly along the labia or base of penis. Stage 3: darker, coarser hair spreading over the junction of the pubis. Stage 4: adult type hair with involvement of the medial aspect of the thigh. Stage 5: adult in quantity and distribution. From Tanner [133].

testosterone to serum globulins becomes more avid with advanced age [130], and may result in lower levels of free hormone [131]. Serum LH and FSH levels may be somewhat higher, pointing to a primary defect at the gonadal level [129,130,132]. Any process that lowers sex hormone binding globulin levels will lower total testosterone (obesity, hyperthyroidism or low protein states). Individuals with hypothalamic–pituitary–gonadal insufficiency have low or inappropriately normal LH, and FSH levels in the presence of reduced serum estradiol or testosterone. For children, gonadotropin levels should be interpreted in relation to pubertal development (Tanner staging) [133] (Figs 22.3 to 22.6).

DYNAMIC TESTING

Gonadotropin Releasing Hormone (GnRH) Stimulation Test To rule out central causes of hypogonadism, GnRH testing may be performed, either alone or in combination with other components of the triple bolus test. In this test, GnRH (Relefact) is administered intravenously at a dose of 100 mg and venous samples taken at time 0, 20, and 60 minutes (as part of the triple bolus test, sampling times may be changed depending on the timing of other samples). There are no contraindications to the test and side effects are rarely reported (Table 22.2).

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FIGURE 22.5. Tanner stages of male genital maturity. Stage 1: preadolescent penis, scrotum, and testes as in earlier childhood. Stage 2: slight scrotal enlargement. Stage 3: slight penile enlargement. Stage 4: further enlargement of scrotum and penis with darkening of scrotal skin. Stage 5: adult size. From Tanner [133].

FIGURE 22.6. Tanner stages of female breast development. Stage 1: preadolescent. Stage 2: elevation of breast papilla and areolar enlargement. Stage 3: further elevation and enlargement without separation of breast contours. Stage 4: areola and papilla project above and beyond contour. Stage 5: adult stage. From Tanner [133].

Chapter 22 Normal Response

Normal responses to GnRH stimulation consist of a rise in LH of two- to threefold and a rise in FSH of up to twofold [65,131,134–136]. However, a flat FSH response is not uncommon in normal individuals [137]. LH responses peak earlier than FSH responses (20–30 minutes verses 60 minutes) [65]. In premenopausal women, responses are lowest in the early portion of the follicular phase [127,137]. Furthermore, multiple tests should be performed at the same phase of the menstrual cycle if comparisons between studies are to be made. Older males experience a lesser increment in LH and FSH in response to GnRH [138], however, the majority continue to have at least a twofold rise in LH [131]. Furthermore, the time to peak response may be delayed (towards 60 minutes) in the older age range [138]. Because the responses of patients with hypothalamic and pituitary disorders is heterogeneous, the test is unable to accurately discern between the two sites. Blunted responses are characteristic of central hypogonadism [136,139]. False-positives may also occur in association with anorexia nervosa [140], chronic disease [141], and corticosteroid use [142]. Prepubertal children experience lower responses. During the early stages of puberty, FSH responses (three- to fourfold) exceed those of LH (twofold) [143], but become more characteristic of the adult pattern as puberty progresses [135,144]. An exaggerated response may occur in the setting of hypergonadotropic (primary) hypogonadism [145].

Clomiphene Stimulation Test Clomiphene is a partial estrogen agonist that blocks estrogen receptors in the hypothalamus and pituitary, leading to a concomitant rise in LH and FSH. Clomiphene is administered at a dose of 50–100 mg twice daily (2 mg/kg/d) for 5–7 days (7–10 days in men) (Table 22.2). In women, LH levels rise in the first 7 days, however a secondary peak is evident between day 9 and 14 [146]. A normal response is characterized by a 100% rise in LH levels over the baseline [146], and a 50% rise in FSH levels between day 10 and 14 [147]. For men, peak levels occur around day 10, and responses range from a 50% to 250% increase in LH and a 30–200% rise in FSH [148]. False-positives occur in the setting of anorexia nervosa [149], and noncompliance. A stimulated progesterone level of greater than 4–5 ng/ml at day 21 suggests that ovulation has occurred. ASSESSMENT OF POSTERIOR PITUITARY FUNCTION

Baseline Measurements Under normal circumstances, plasma sodium and osmolality are strictly maintained within specific ranges (sodium: 136–143 mmol/L; osmolality: 285–293 mosm/kg) under the control of thirst-, vasopressin-, and renal-dependent mech-

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anisms. Plasma sodium and osmolality may be normal or only modestly elevated in individuals who suffer from diabetes insipidus because of compensatory intake of large quantities of fluid. The latter requires an intact thirst mechanism. Alternatively, individuals who have primary polydipsia, in whom high urinary volumes are driven solely by excessive water intake, have normal to low serum osmolality. With an appropriate history, the presence of concomitant hypernatremia (more than 145 mmol/L), hyperosmolality (more than 300 mosm/kg), and a urinary osmolality that is not maximally concentrated is highly suggestive of diabetes insipidus (DI). In such cases, a trial of 1-desamino8-D-arginine vasopressin (DDAVP) should supercede further testing.

Water Deprivation Test The water deprivation test (WDT) is a cornerstone in the investigation of polyuric states (Table 22.4). The test involves assessing the response of plasma and urinary osmolality to progressive dehydration. Water is allowed ad lib overnight, then the test is started in the morning after a light breakfast. However, a longer period of water restriction (overnight) is preferred in mild cases, in order to elicit a sufficient response. Avoidance of tea, coffee, alcohol, and smoking after midnight is recommended. Individuals already on treatment with DDAVP are advised to omit their bedtime dose on the night before testing. Baseline plasma and urine osmolality, blood pressure and weight are measured at time 0, then, along with urinary output, are assessed every 2 hours for the duration of the test. The WDT can be performed in most patients, given that sufficient vigilance is practiced in order to avoid severe dehydration. Particular care is required in very young children and the test is contraindicated in infants. Fluids are withheld until the change in urinary osmolality is less than 30 mosm/kg for three consecutive hours. Alternately, the test is stopped if more than 3–5% of body weight is lost, indicating significant dehydration. Normal Response

Progressive concentration of the urine to greater than 750 mosm/kg [150–153] and a decline in urinary flow (less than 0.5 ml/min) constitutes a normal response, whereas most patients with diabetes insipidus (of any etiology) maintain their urinary osmolality (Uosm) under 300 mosm/kg [150,151]. Plasma osmolality reaches 300 mosmol/L in individuals with diabetes insipidus, while the ratio of urinary to plasma osmolality remains under 1.5 in patients with moderately severe forms of the disorder [154]. False-positives may occur in individuals with primary polydipsia (Uosm 300–750); following a prolonged exposure to dilute urine the capacity of the renal medulla to concentrate is compromised. This same phenomenon occurs in patients with any form of polyuria, which may explain the occurrence of

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Table 22.4.

Dynamic tests for assessment of posterior pituitary function

Test

Dose

Vasopressin Water deprivation test

2 mg sc/IM (0.1 mg/kg)

DDAVP

Urine osmolaity (mmol/kg)

1200

800

400

0 LD

2

4

6

Plasma AVP (pmol/l)

FIGURE 22.7. Relationship between urine osmolality and plasma arginine vasopressin (AVP) following fluid deprivation. From Baylis [151].

submaximal urinary concentration in patients with central DI in response to exogenous DDAVP. Furthermore, elderly individuals exhibit lower degrees of concentration, resulting in lower urinary to plasma osmolality than in younger subjects [155]. False-negatives may occur in patients with partial central or nephrogenic diabetes insipidus, who are able to mount an intermediate response to fluid restriction (Uosm 300–750). Polyuric states can be further differentiated by measuring plasma vasopressin (vp) levels at the end of the dehydration period. Established nomograms describing the relationship between plasma or urine osmolality and plasma vasopressin serve as a standard for comparison (Fig. 22.7) [150]. These measurements appear to improve the diagnostic accuracy of the test [150]. Patients with central diabetes

Normal response

Side effects

Normals: Uosm > 750 mosm/kg DI: Uosm < 300 mosm/kg

Thirst Lightheadedness

Normals: No change from above Central DI: Uosm > 750 mosm/kg OR Plasma/Uosm > 1.5 Equivocal: Uosm 300–750 Nephrogenic DI: Uosm < 300

–

insipidus have vp levels that are inappropriately low for the degree of osmolality. Once the maximal urinary concentration is attained, desmopressin (DDAVP, 2 mg (0.1 mg/kg in children to a maximum of 4 mg) or aqueous vasopressin (pitressin, 5 IU) is administered subcutaneously or intramuscularly. Normal individuals do not exhibit further urinary concentration following DDAVP. The diagnosis of central diabetes insipidus lies on the demonstration of inadequate urinary concentration during the first portion of the test, but a significant rise in urinary osmolality in response to DDAVP (more than 700–750 mosm/kg). In contrast, patients with nephrogenic diabetes insipidus are unable to respond to DDAVP (urinary osmolality remains under 300 mosm/kg). Results are considered equivocal if urine osmolality is between 300 and 750 mosm/kg after dehydration and the response to DDAVP is suboptimal or low (less than 750 mosm/kg). In a study by Zerbe et al. [150], no patient with central DI demonstrated adequate urinary concentration following DDAVP, according to these guidelines. However, only patients with severe central DI responded with a marked rise in urinary osmolality (five- to 16-fold). Reducing the threshold for a final urinary osmolality to 450 mosm/kg or using a urinary to serum osmolality of greater than 1.5 may lead to less false-positive test results [154].

Hypertonic Saline Test Below a specific threshold of plasma osmolality (usually 280 mosm/kg) [156], vp secretion is maximally suppressed. Above the level, vp concentrations rise in a linear fashion. The purpose of this test is to examine this relationship in response to an osmolar load, usually in patients who have equivocal findings on WDT [150,157]. The test involves the administration of hypertonic saline (5% saline at 0.05– 0.06 ml/kg of body weight per minute) for up to 3 hours

Chapter 22

Evaluation of Normal Pituitary Function

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Plasma AVP (pmol/l)

20

10

LD 280

300

320

Plasma osmolality (mmol/kg)

FIGURE 22.8. Relationship between plasma arginine vasopressin (AVP) and plasma osmolality following administration of hypertonic saline. The shaded area represents a normal response; patients with central diabetes insipidus show subnormal responses (hatched area). From Baylis [151].

or the development of: (i) plasma osmolality of 300 mosm/ kg; or (ii) intractable thirst. Patients are advised to remain supine for 30 minutes prior and throughout the duration of the test and fluid intake is not permitted. Apart from avoidance of alcohol and tobacco, no special preparation is required. The test is rarely used in children and never in children under 5 years of age [151]. Blood pressure, thirst, plasma electrolytes, osmolality, and vp levels are assessed every 20–30 minutes, while urinary electrolytes, osmolality, and urinary output are monitored on an hourly basis. Adverse Events

Side effects are relatively uncommon in adults (nausea, headache) [158], and elevations in blood pressure are in the range of 5–6 mmHg [156]. Normal Response

Nomograms defining a normal relationship between serum osmolality and vp have been established for interpretation of test results (Fig. 22.8) [151]. Consistently undetectable levels of plasma vp in the presence of hyperosmolality (approximately 300 mosm/kg) indicates the presence of central DI [150,158,159]. Individuals who demonstrate detectable but low levels of vp are described as having partial central DI. In contrast, individuals with either primary polydipsia or nephrogenic DI will have normal levels of vp for a given level of osmolality. The latter two groups can be further differentiated by their response to dehydration or DDAVP administration.

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24 Kane KF, Emery P, Sheppard MC, Stewart PM. Assessing the hypothalamo–pituitary–adrenal axis inpatients on long-term glucocorticoid therapy: the short synacthen versus the insulin tolerance test. Quarterly J Med 1995;88:263–267. 25 Ammari F, Issa BG, Millward E, Scanlon MF. A comparison between short ACTH and insulin stress tests for assessing hypothalamo–pituitary–adrenal function. Clin Endocrinol (Oxf.) 1996;44:473–476. 26 Bangar V, Clayton RN. How reliable is the short synacthen test for the investigation of the hypothalamic–pituitary–adrenal axis? Eur J Endocrinol 1998;139:580–583. 27 Cunningham SK, Moore A, McKenna J. Normal cortisol response to corticotropin in patients with secondary adrenal failure. Arch Intern Med 1983;143:2276–2279. 28 Stewart PM, Corrie J, Seckl JR et al. A rational approach for assessing the hypothalamo–pituitary–adrenal axis. The Lancet 1988;1:1208–1210. 29 Jackson RS, Carter GD, Wise PH, Alaghband-Zadeh J. Comparison of paired short synacthen and insulin tolerance tests soon after pituitary surgery. Ann Clin Biochem 1994;31:46–49. 30 Orme SM, Peacey SR, Barth JH, Belchetz PE. Comparison of tests of stressreleased cortisol secretion in pituitary disease. Clin Endocrinol (Oxf.) 1996;45:135–140. 31 Weintrob N, Sprecher E, Josefsbert Z et al. Standard and low-dose short adrenocorticotropin test compared with insulin-induced hypoglycemia for assessment of the hypothalamic–pituitary–adrenal axis in children with idiopathic multiple pituitary hormone deficiencies. J Clin Endocrinol Metab 1998;83:88–92. 32 Tordjman K, Jaffe A, Grazas N et al. The role of the low dose (1 mg) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 1995;80:1301–1305. 33 Shankar RR, Jakacki RI, Haider A et al. Testing the hypothalamic–pituitary–adrenal axis in survivors of childhood brain and skullbased tumors. J Clin Endocrinol Metab 1997;82:1995–1998. 34 Talwar V, Lodha S, Dash RJ. Assessing the hypothalamo–pituitary–adrenocortical axis using physiological doses of adrenocorticotropic hormone. Quarterly J Med 1998;91:285–290. 35 Rasmuson S, Olsson T, Hägg E. A low dose ACTH test to assess the function of the hypothalamic–pituitary–adrenal axis. Clin Endocrinol (Oxf.) 1996; 44:151–156. 36 May ME, Carey RM. Rapid adrenocorticotropic hormone test in practice. Am J Med 1985;79:679–683. 37 Kukreja SC, Williams GA. Corticotrophin stimulation test: inverse correlation between basal serum cortisol and its response to corticotropin. Acta Endocrinol (Copenh.) 1981;97:522–524. 38 Dickstein G, Shechner C, Nicholson WE et al. Adrenocorticotropin stimulation test: Effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773–778. 39 Holdaway IM, Evans MC. Sheehan A, Ibbertson HK. Low thyroxine levels in some hyperprolactinemic patients due to dopaminergic suppression of thyrotropin. J Clin Endocrinol Metab 1984;59:608–613. 40 Faglia G, Beck-Peccoz P, Ferrari C et al. Plasma thyrotropin response to thyrotropin-releasing hormone in patients with pituitary and hypothalamic disorders. J Clin Endocrinol Metab 1973;37:595–601. 41 Nicoloff JT, Spencer CA. The use and misuse of the sensitive thyrotropin assays. J Clin Endocrinol Metab 1990;71:553–558. 42 Kaptein EM, Kletzky OA, Spencer CA, Nicoloff JT. Effects of prolonged dopamine infusion on anterior pituitary function in normal males. J Clin Endocrinol Metab 1980;51:488–491. 43 Snyder PJ, Utiger RD. Response to thyrotropin releasing hormone (TRH) in normal man. J Clin Endocr 1972;34:380–385. 44 Faglia G, Beck-Peccoz P, Ambrosi B et al. The effects of a synthetic thyrotrophin releasing hormone (TRH) in normal and endocrinopathic subjects. Acta Endocrinol (Copenh.) 1972;71:209–225. 45 Haigler ED Jr, Pittman JA Jr, Hershman JM, Baugh CM. Direct evaluation of pituitary thyrotropin reserve utilizing synthetic thyrotropin releasing hormone. J Clin Endocr 1971;33:573–581. 46 Masago A, Ueda Y, Kanai H et al. Pituitary apoplexy after pituitary function test: A report of two cases and review of the literature. Surg Neurol 1995;43: 158–165. 47 Costom BH, Grumbach MM, Kaplan SL. Effect of thyrotropin-releasing factor on serum thyroid-stimulating hormone. An approach to distinguishing hypothalamic from pituitary forms of idiopathic hypopituitary dwarfism. J Clin Invest 1971;50:2219–2225. 48 Snyder PJ, Jacobs LS, Rabello MM et al. Diagnostic value of thyrotrophinreleasing hormone in pituitary and hypothalamic diseases. Assessment of

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thyrotrophin and prolactin secretion in 100 patients. Ann Intern Med 1974;81:751–757. Spencer CA, Schwarzbein D, Guttler RB et al. Thyrotropin (TSH)-releasing hormone stimulation test responses employing third and fourth generation TSH assays. J Clin Endocrinol Metab 1993;76:494–498. Rossmanith WG, Hohl B, Luttke B. Stimulated thyrotropin and prolactin secretion in lactating and non-lactating women. Gynecol Endocrinol 1995; 9:181–188. Sawin CT, Hershman JM. The TSH response to thyrotropin-releasing hormone (TRH) in young adult men: Intra-individual variation and relation to basal serum TSH and thyroid hormones. J Clin Endocrinol Metab 1976; 42:809–816. Erfurth EM, Nordén NE, Hedner P et al. Normal reference interval for thyrotropin response to thyroliberin: Dependence on age, sex, free thyroxine index, and basal concentrations of thyrotropin. Clin Chem 1984;302:196–199. Duntas L, Grab BM, Dominguez-Munoz JE et al. Evaluation of thyrotropin secretion before and after TRH by third generation chemiluminescent assay. Assessment of subclinical hyperthyroidism. Horm Metab Res 1993;25:430–433. Sawin CT, Geller A, Kaplan MM et al. Low serum thyrotropin (thyroidstimulating hormone) in older persons without hyperthyroidism. Arch Intern Med 1991;151:165–168. Kaiser FE. Variability of response to thyroid-releasing hormone in normal and elderly. Age and Ageing 1987;16:345–354. Impallomeni M, Yeo T, Rudd YT et al. Investigation of anterior pituitary function in elderly in-patients over the age of 75. Quarterly J Med 1987;63:505–515. Kaptein EM. Thyroid hormone metabolism and thyroid disease in chronic renal failure. Endocr Res 1996;17:45–63. Impallomeni M, Kaufman BM, Palmer AJ. Do acute diseases transiently impair anterior pituitary function in patients over the age of 75? A longitudinal study of the TRH test and basal gonadotrophin levels. Postgrad Med J 1994;70:86–91. Coiro V, Vescovi PP. Effect of pyridostigmine on the thyroid-stimulating hormone response to thyrotropin-releasing hormone in abstinent alcoholics. Alcoholism: Clin Exp Res 1997;21:1308–1311. Re RN, Kourides IA, Ridgway EC et al. The effect of glucocorticoid administration on human pituitary secretion of thyrotropin and prolactin. J Clin Endocrinol Metab 1976;43:338–346. Stratakis CA, Mastorakos G, Magiakou MA et al. Thyroid function in children with Cushing’s disease. J Pediatr 1997;131:905–909. Spencer C, Eigen A, Shen D et al. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem 1987;33:1391–1396. L’Hermite M, Vanhaelst L, Copinschi G et al. Prolactin release after injection of thyrotropin-releasing hormone in man. Lancet 1972;1:763–765. Le Moli R, Endert E, Fliers E et al. Establishment of reference values for endocrine tests II: Hyperprolactinemia. Netherlands J Med 1999;55:71–75. Sheldon WR Jr, DeBold CR, Evans WS et al. Rapid sequential intravenous administration of four hypothalamic releasing hormones as a combined anterior pituitary function test in normal subjects. J Clin Endocrinol Metab 1985;60:623–630. Jacobs LS, Snyder PJ, Utiger RD, Daughaday WH. Prolactin response to thyrotropin releasing hormone in normal subjects. J Clin Endocrinol Metab 1973;36:1069–1073. Assies J, Schellekens APM, Touber JL. The value of an intravenous TRH test for the diagnosis of tumoural prolactinaemia. Acta Endocrinol (Copenh.) 1980;94:439–449. Vance ML, Thorner MO. Prolactinomas. Endocrinol Metab Clin North Am 1987;16:731–753. Faglia G. The clinical impact of the thyrotropin-releasing hormone test. Thyroid 1998;8:903–908. Hoffman DM, O’Sullivan AJ, Baxter RC et al. Diagnosis of growth-hormone deficiency in adults. Lancet 1994;343:1064–1068. Laron Z, Gil-Ad I, Topper E et al. Low oral dose of Clonidine: An effect screening test for growth hormone deficiency. Acta Paediatr Scand 1982; 71:847–848. Toogood AA, O’Neill PA, Shalet SM. Beyond the somatopause: Growth hormone deficiency in adults over the age of 60 years. J Clin Endocrinol Metab 1996;81:460–465. Reutens AT, Hoffman DM, Leung K, Ho KKY. Age and relative obesity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab 1995;80:480–485.

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98 Ramirez G, O’Neill WM, Bloomer HA, Jubiz W. Abnormalities in the regulation of growth hormone in chronic renal failure. Arch Intern Med 1978;138:267–271. 99 Lesch KP, Laux G, Pfuller H et al. Growth hormone (GH) response to GH-releasing hormone in depression. J Clin Endocrinol Metab 1987;65: 1278–1281. 100 Abboud CF. Laboratory diagnosis of hypopituitarism. Mayo Clin Proc 1986;61:35–48. 101 Shah A, Stanhope R, Matthew D. Hazards of pharmacological tests of growth hormone secretion in childhood. Br Med J 1992;304:173–174. 102 Rahim A, Toogood AA, Shalet SM. The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endocrinol 1996;45:557–562. 103 Frasier SD, Hilburn JM, Smith FG Jr. Effect of adolescence on the serum growth hormone response to hypoglycemia. Journal of Pediatrics 1970; 77:465–467. 104 Muggeo M, Fedele D, Tiengo A et al. Human growth hormone and cortisol response to insulin stimulation in aging. J Gerontol 1975;30:546–551. 105 Lanes R, Recker B, Fort P, Lifshitz F. Low-dose oral clonidine. A simple and reliable growth hormone screening test for children. AJDC 1985;139: 87–88. 106 Slover RH, Klingensmith GJ, Gotlin RW, Radcliff J. A comparison of clonidine and standard provocative agents of growth hormone. AJDC 1984;138:314–317. 107 Lanes R, Hurtado E. Oral clonidine—an effective growth hormone-releasing agent in prepubertal subjects. J Pediatr 1982;100:710–714. 108 King JM, Price DA. Sleep-induced growth hormone release-evaluation of a simple test for clinical use. Arch Dis Child 1983;58:220–222. 109 Root AW, Russ RD. Effect of L-dihydroxyphenylalanine upon serum growth hormone concentrations in children and adolescents. J Pediatr 1972; 81:808–813. 110 Porter BA, Rosenfield RL, Lawrence AM. The Levodopa test of growth hormone reserve in children. AJDC 1973;126:589–592. 111 Weldon VV, Gupta SK, Klingensmith G et al. Evaluation of growth hormone release in children using arginine and L-dopa in combination. J Pediatr 1975;87:540–544. 112 Reiter EO, Root AW, Duckett GE. Sequential use of insulin and levodopa to provoke pituitary secretion of growth hormone. AJDC 1977;131:189–191. 113 Collu R, Brun G, Milsant F et al. Reevaluation of levedopa-propanolol as a test of growth hormone reserve in children. Pediatrics 1978;61:242–244. 114 Maghnie M, Strigazzi C, Tinelli C et al. Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab 1999;84:1324–1328. 115 Eakman GD, Dallas JS, Ponder SW, Keenan BS. The effects of testosterone and dihydrotestosterone on hypothalamic regulation of growth hormone secretion. J Clin Endocrinol Metab 1996;81:1217–1223. 116 Schriock EA, Lustig RH, Rosenthal SM et al. Effect of growth hormone (GH)-releasing hormone (GRH) on plasma GH in relation to magnitude and duration of GH deficiency in 26 children and adults with isolated GH deficiency or multiple pituitary hormone deficiencies: Evidence for hypothalamic GRH deficiency. J Clin Endocrinol Metab 1984;58:1043–1049. 117 Ghigo E, Mazza E, Imperiale E et al. Enhancement of cholinergic tone by pyridostigmine promotes both basal and growth hormone (GH)-releasing hormone-induced GH secretion in children of short stature. J Clin Endocrinol Metab 1987;65:452–456. 118 Takano K, Hizuka N, Shizume K et al. Plasma growth hormone (GH) response to GH-releasing factor in normal children with short stature and patients with pituitary dwarfism. J Clin Endocrinol Metab 1984;58:236–241. 119 Rogol AD, Blizzard RM, Johanson AJ et al. Growth hormone release in response to human pancreatic tumor growth hormone-releasing hormone-40 in children with short stature. J Clin Endocrinol Metab 1984;59:580–586. 120 Williams T, Berelowitz M, Joffe SN et al. Impaired growth hormone responses to growth hormone-releasing factor in obesity. A pituitary defect reversed with weight reduction. N Engl J Med 1984;311:1403–1407. 121 Cordido F, Casanueva FF, Dieguez C. Cholinergic receptor activation by pyridostigmine restores growth hormone (GH) responsiveness to GH-releasing hormone administration in obese subjects: Evidence for hypothalamic somatostatinergic participation in the blunted GH release of obesity. J Clin Endocrinol Metab 1989;68:290–394. 122 Cordido F, Penalva A, Dieguez C, Casanueva FF. Massive growth hormone (GH) discharge in obese subjects after the combined administration of GHreleasing hormone and GHRP-6: Evidence for a marked somatotroph secretory capability in obesity. J Clin Endocrinol Metab 1993;76:819–823.

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SECTION 5

Diagnostic Procedures

122a Popovic V, Leal A, Micic D et al. GH-releasing peptide-6 for diagnostic testing in GH-deficient adults. Lancet 2000;356:1137–1142. 123 Borges JLC, Blizzard RM, Gelato MC et al. Effects of human pancreatic tumour growth hormone releasing factor on growth hormone and somatomedin C levels in patients with idiopathic growth hormone deficiency. Lancet 1983;2:119–123. 124 Chatelain P, Alamercery Y, Blanchard J et al. Growth hormone (GH) response to a single intravenous injection of synthetic GH-releasing hormone in prepubertal children with growth failure. J Clin Endocrinol Metab 1987;65:387–394. 125 Aimaretti G, Corneli G, Razzore P et al. Comparison between insulininduced hypoglycemia and growth hormone (GH)-releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults. J Clin Endocrinol Metab 1998;83:1615–1618. 126 Neely EK, Hintz RL, Wilson DM et al. Normal ranges for immunochemiluminometric gonadotropin assays. J Pediatr 1995;127:40–46. 127 Aparicio NJ, Casas PR, Galimberti DM et al. Pituitary and ovarian response to acute stimulation with LHRH in normal and anovulatory women. Int J Fertil 1977;22:6–15. 128 Gow SM, Turner EI, Glasier A. The clinical biochemistry of the menopause and hormone replacement therapy. Ann Clin Biochem 1994;31:509–528. 129 Veldhuis JD, Urban RJ, Lizarralde G et al. Attenuation of luteinizing hormone secretory burst amplitude as a proximate basis for the hypoandrogenism of healthy aging in men. J Clin Endocrinol Metab 1992;75:707–713. 130 Harman SM, Tsitouras PD. Reproductive hormones in aging men. I. Measurement of sex steroids, basal luteinizing hormone, and leydig cell response to human chorionic gonadotropin. J Clin Endocrinol Metab 1980;51:35–40. 131 Snyder PJ, Reitano JF, Utiger RD. Serum LH and FSH responses to synthetic gonadotropin-releasing hormone in normal men. J Clin Endocrinol Metab 1975;41:938–945. 132 Kaufman JM, Giri M, Deslypere JM et al. Influence of age on the responsiveness of the gonadotrophs to luteinizing hormone-releasing hormone in males. J Clin Endocrinol Metab 1991;72:1255–1260. 133 Tanner JM, Davies PSW. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;107:317–329. 134 Wentz AC, Jones GS, Rocco L, Matthews RR. Gonadotropin response to luteinizing hormone releasing hormone administration in secondary amenorrhea and galactorrhea syndromes. Obstet Gynecol 1975;45:256–262. 135 Dunkel L, Perheentupa J, Virtanen M, Mäenpää J. GnRH and HCG tests are both necessary in differential diagnosis of male delayed puberty. AJDC 1985;139:494–498. 136 Mortimer CH, Besser GM, McNeilly AS et al. Luteinizing hormone and follicle stimulating hormone-releasing hormone test in patients with hypothalamic–pituitary–gonadal dysfunction. Br Med J 1973;73:73–77. 137 Wentz AC, Jones GS, Rocco L. Gonadotropin responses following luteinizing hormone releasing hormone administration in normal subjects. Obstet Gynecol 1975;45:239–246. 138 Harman SM, Tsitouras PD, Costa PT, Blackman MR. Reproductive hormones in aging men. II. Basal pituitary gonadotropins and gonadotropin responses to luteinizing hormone-releasing hormone. J Clin Endocrinol Metab 1982;54:547–551. 139 Borreman E, Wyman H, Rochefort JG, Van Campenhout J. The responses to synthetic luteinizing hormone-releasing hormone in patients with primary selective pituitary deficiency in gonadotropins. Am J Obstet Gynecol 1975;123:580–589. 140 Sherman BM, Halmi KA, Zamudio R. LH and FSH response to

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144

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147

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149

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151 152 153

154

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157 158

159

gonadotropin-releasing hormone in anorexia nervosa: Effect of nutritional rehabilitation. J Clin Endocrinol Metab 1975;41:135–142. Chryssicopoulos A, Koutsikos D, Kapetanaki A et al. Evaluation of the hypothalamic–pituitary axis in uremic males using dynamic tests. The possible role of testicular inhibin: a preliminary report. Renal Failure 1996;18:911–921. Sowers JR, Rice BF, Blanchard S. Effect of dexamethasone on luteinizing hormone and follicle stimulating hormone responses to LHRH and to colmiphene in the follicular phase of women with normal menstrual cycles. Horm Metab Res 1979;11:478–480. Dickerman Z, Prager-Lewin R, Laron Z. The plasma FSH and LH response to synthetic LH-RH in normal pre-pubertal and early pubertal girls—a re-evaluation. Acta Endocrinol (Copenh.) 1979;91:14–18. Oerter KE, Uriarte MM, Rose SR et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990; 71:1251–1258. Roth JC, Kelch RP, Kaplan SL, Grumbach MM. FSH and LH response to luteinizing hormone-releasing factor in prepubertal and pubertal children, adult males and patients with hypogonadotropic and hypergonadotropic hypogonadism. J Clin Endocrinol Metab 1972;35:926–930. Kjeld JM, Harsoulis P, Nader S et al. Hormonal responses to a first course of clomiphene citrate in women with amenorrhoea. Br J Obstet Gynaecol 1975;82:397–404. Kettel LM, Roseff SJ, Berga SL et al. Hypothalamic–pituitary–ovarian response to clomiphene citrate in women with polycystic ovary syndrome. Fertil Steril 1993;59:532–538. Tenover JS, Bremner WJ. The effects of normal aging on the response of the pituitary–gonadal axis to chronic clomiphene administration in men. J Andrology 1991;12:258–263. Wakeling A, Marshall JC, Beardwood CJ et al. The effects of clomiphene citrate on the hypothalamic–pituitary–gonadal axis in anorexia nervosa. Psychological Medicine 1976;6:371–380. Zerbe RL, Robertson GL. A comparison of plasma vasopressin measurements with a standard indirect test in the differential diagnosis of polyuria. N Engl J Med 1981;305:1539–1546. Baylis PH, Cheetham TD. Diabetes insipidus. Arch Dis Child 1998;79:84– 89. Rado JP. 1-desamino-8-D-arginine vasopressin (DDAVP) concentration test. Am J Med Sci 1978;275:43–52. Dunger DB, Secki JR, Grant DB et al. A short water deprivation test incorporating urinary arginine vasopressin estimations for the investigation of posterior pituitary function in children. Acta Endocrinol (Copenh.) 1998;117:13–18. Hendricks SA, Lippe B, Kaplan SA, Lee WNP. Differential diagnosis of diabetes insipidus: use of DDAVP to terminate the seven-hour water deprivation test. Journal of Pediatrics 1981;98:244–246. Li CH, Hsieh SM, Nagai I. The response of plasma arginine vasopressin to 14 h water deprivation in the elderly. Acta Endocrinol (Copenh.) 1984;105:314–317. Thompson CJ, Bland J, Burd J, Baylis PH. The osmotic thresholds for thirst and vasopressin release are similar in healthy man. Clinical Science 1986;71:651–656. Mohn A, Acerini CL, Cheetham TD et al. Hypertonic saline test for the investigation of posterior pituitary function. Arch Dis Child 1998;79:431–434. Milles JJ, Spruce B, Baylis PH. A comparison of diagnostic methods to differentiate diabetes insipidus from primary polyuria: a review of 21 patients. Acta Endocrinol (Copenh.) 1983;104:410–416. Rooke P, Baylis PH. A new sensitive radioimmunoassay for plasma arginine vasopressin. Journal of Immunoassay 1982;3:115–131.

Index

Page numbers in italic indicate figures; those in bold indicate tables AAAS 59 abducens (cranial nerve VI) 668 compression 690, 700 pituitary apoplexy 700 radiation neuropathy 702 abscess, pituitary 36, 416 acetylcholine 142 achondroplasia 103 acid labile subunit (ALS) 91, 92 acidophil adenomas 410 acidophil stem cell 33 acidophils embryology 79 histologic staining 4 lactotrophs 23 mammosomatotrophs 24 oncocytes 32 somatotrophs 20 acquired immune deficiency syndrome (AIDS) see HIV infection/AIDS acromegaloidism 423, 425 acromegaly 331, 419–47 animal models 419–20 arthropathy 429 carbohydrate metabolism 97 cardiovascular complications 430 clinical features 411, 426, 428, 428–33, 429 presenting symptoms 428, 428 colonic polyps 432, 432 diabetes mellitus 97, 433 diagnosis 423, 424, 433–5, 434, 436 differential diagnosis 434–5 ectopic 423–6, 434–5 diagnostic investigations 423, 424 growth hormone production 331, 425, 435 growth hormone-releasing hormone (GHRH) production 331, 423–4 treatment 424–5 endocrine complications 433 familial 425, 426 fugitive 33 genetic syndromes 425–6, 426 growth hormone hypersecretion 331, 411, 412, 425, 426, 428, 435 response following surgery 422 secretion regulation 84

secretory patterns 422 serum levels 99, 433–4, 434, 434 urine levels 434 growth hormone-releasing hormone (GHRH) hypersecretion 10, 17, 423–4 secretory patterns 421–2 treatment 424–5 historical aspects 3, 419 hyperprolactinemia 139, 433 imaging techniques 435 incidence 419 insulin-like growth factor binding protein 1 (IGFBP-1) levels 92, 94, 433–4 insulin-like growth factor-I (IGF-I) levels 433, 434, 435 neuromuscular changes 431 outcome 431, 431, 433, 436, 447 growth hormone level relationship 436, 436 pathogenesis 420, 420–6, 421 pituitary adenomas 331, 411, 412, 412, 420 ectopic 435 mixed growth hormone-cell/-prolactin-cell 420–1 pure growth hormone-cell 21, 420–1 thyroid-stimulating hormone (TSH)-secreting 565 pituitary carcinoma 421 pituitary mass pressure effects 426 pregnancy 636 psychological changes 431 respiratory complications 430–1 skeletal features 428–9, 430 skin changes 430 somatotroph abnormalities 422–3 treatment 435–47 aims 435–7, 437, 443, 447 decision-making 443–5, 446, 446, 447 dopamine agonists 412, 440–3, 441, 442, 443, 444, 445 growth hormone receptor antagonists 443 radiotherapy 439, 440 surgery 412, 412, 437–9, 438, 439 tumors 431–3, 432 activin 234 adenohypophysial cell production 35 gonadotropin secretion regulation 234 Addisonian crisis 388 Addison’s disease (adrenal insufficiency) 531 corticotroph response 27

hyperpigmentation 52 adenohypophysis see anterior pituitary adenoid cystic carcinoma of lung 68 adenomas 36, 352, 410–13 classification 410 clinical presentation 410 ectopic 435 endocrine activity 37 evaluation 406–7 imaging investigations 673 macroadenomas 677–9, 678, 679 microadenomas 664, 665, 674–5, 675, 676 surgical treatment 410 adenosine prolactin secretion effects 141 thyroid-stimulating hormone (TSH) secretion effects 187 adipocytes adrenocorticotropin (ACTH) actions 59–60 growth hormone actions 97 insulin-like growth factor-I (IGF-I) actions 95 adipsic hypernatremia see hypernatremia/hypodipsia syndrome adrenal adenoma 513 growth hormone-releasing hormone (GHRH) secretion 423, 424 adrenal androgens adrenarche 58, 59 Cushing’s disease 509 diagnosis 523–4 synthesis 58–9 adrenal carcinoma 513 Cushing’s disease 511 adrenal gland adrenocorticotropin (ACTH) actions 58–9 cortical cell metabolism 58–9 Cushing’s disease 508–9, 510 imaging investigations 528–9 prolactin effects 147 steroidogenesis 58 stress/illness response 616 adrenal hyperplasia ACTH-independent bilateral macronodular 513–14 adrenocorticotropin (ACTH) actions 58 congenital 257, 330 Cushing’s disease 510–11 adrenal hypoplasia congenita/hypogonadotropic hypogonadism 354, 355

727

728

Index

adrenal insufficiency adrenocorticotropin (ACTH) levels 498 hyperprolactinemia 152 pitutary function 620 tertiary 333–4 thyroid-stimulating hormone (TSH) levels 188 adrenal rests 511 adrenalectomy 541 adrenarche 58, 59 adrenocortical nodular dysplasia, primary 513 adrenocorticotropin (ACTH) 45–68 adipocyte actions 59–60 adrenal gland actions 11, 58–9 steroidogenesis in Cushing’s disease 508–9 alcohol effects 642 assay 53 bilateral inferior petrosal sinus sampling 527–8, 536 Cushing’s disease diagnosis 522–3, 523, 524, 527–8, 536 pregnant patient 636 assessment tests 709–14 basophils secretion 4 biosynthesis 496–8 corticotroph adenoma secretion 28, 67, 499–505 corticotroph production 25, 27, 63 corticotropin-releasing hormone (CRH) actions 11 drug effects 644 extra-pituitary localization 47–8 extracerebral 48 hypothalamus 47, 48 mRNA expression 49 fetus/neonate 20, 45, 66 gene structure 48–9 melanocortin receptor activation 56, 57–8 opiate effects 645 oversecretion see Cushing’s disease pregnancy 632 proopiomelanocortin (POMC) precursor 49, 50, 52 pulsatile release 63 secretion abnormalities 67–8 secretion regulation 53, 53–6, 63–8, 498 negative feedback 63–4 puberty 66 second messengers 53, 54 stress/illness response 55, 616 adrenocorticotropin (ACTH) deficiency 61, 369–75 acquired 370–2 aldosterone secretion 374 brain irradiation effects 344, 344 clinical features 372–3 diagnostic tests 373–5, 374, 378, 379–80 basal serum cortisol 374–5 insulin-induced hypoglycemia test 375 metyrapone test 375 short ACTH stimulation test 375 etiology 370 genetic/familial disorders 369–70 glucocorticoid replacement therapy 382–4 acute deficiency management 384 advice for patients 383 perioperative 384 hypothalamic disease 333–4 adrenocorticotropin (ACTH) receptor (melanocortin 2 receptor; MC2R) 56, 57–8 adrenocorticotropin (ACTH) receptor defects familial glucocorticoid deficiency 370 triple A (Allgrove’s) syndrome 370 adrenocorticotropin (ACTH) resistance syndromes 370 adrenocorticotropin (ACTH) stimulation test 713–14 low-dose test 714 normal response 713–14 short test 375

adrenocorticotropin (ACTH)-secreting ectopic tumors 68 adrenocorticotropin (ACTH)-secreting pituitary adenomas 67–8, 410, 499–505 Nelson’s syndrome 413 prolactin secretion 466 see also corticotroph adenoma; Cushing’s disease adrenocorticotropin (ACTH)-secreting pituitary carcinoma 68 adult respiratory distress syndrome (ARDS) 57 afferent pupillary defect (Marcus Gunn pupil) 697 testing technique 704–6 African pygmies 90 age-related changes corticotroph neural lobe invasion 27, 27 gonadotropins 238–9, 239, 718 growth hormone 82, 103 hypothalamus 18 pituitary 18, 617 sex hormone-binding globulin 238 skeletal muscle atrophy 103 sleep 82 testosterone 238, 239, 239 agouti locus 61–3 lethal yellow mutation 61, 62 agouti-related protein (AGRP) 62–3 agouti-signaling protein (ASPI) 62 AHC mutations 354, 355 Ahumada–Argonz–del Castillo syndrome 455, 456 AIDS see HIV infection/AIDS akinetic mutism 329 alanzapine 647 alcohol effects 642–4 adrenocorticotropin (ACTH) 642 cortisol 532, 642 gonadotropins 619, 642–4 growth hormone 642 liver damage-related euthyroid sick syndrome 642 prolactin 644 thyroid-stimulating hormone (TSH) 642 vasopressin 318 alcohol-induced pseudo-Cushing’s syndrome 642 aldosterone secretion 374 Cushing’s disease 509 Allgrove (triple A) syndrome 59, 370 Allstrom Hallgren syndrome 356 a subunit of glycoprotein hormones 172, 176, 218 assay (free a subunits) 228 corticotroph adenoma secretion 505 expression in development 20, 172 gene structure/organization 221–2, 222 cAMP response element (CRE) 222 gonadotropin adenoma diagnosis 583, 584 mammosomatotroph expression 21 null cell expression 32 oncocyte expression 32 somatotroph expression 21 a-adrenergic drugs 318 17-a-hydroxylase 58, 226 a-melanocyte-stimulating hormone (a-MSH) 15, 497, 509 anti-inflammatory activities 57 extracerebral synthesis 48 melanocortin receptor activation 56, 57 pituitary carcinoma secretion 68 POMC gene structure 48 POMC precursor 49, 50, 52 processing 51, 53 prolactin secretion effects 141 a-methyldopa 150 alprazolam 646 Alstrom–Hallgren syndrome 336 amenorrhea adult hypogonadism 357 antipsychotic drug-related 647 exercise-related 251, 356 galactorrhea/hyperprolactinemia 146 gonadotropin adenoma 582 lactational 132, 251–2

postpill 252 primary 359–61 diagnostic tests 360–1 prolactinoma 468, 469 secondary 361 stress response 252, 356 thyroid-stimulating hormone (TSH)-secreting tumors 565 weight loss 356 Ames dwarf mouse 20, 37, 46 Prop-1 mutations 121, 173 amino acid ingestion 131 aminoglutethimide 543 amitriptyline 647 amoxapine 647 amphetamines 646 Amsler grid testing 703, 704 amygdalo–hypothalamic tract 6 amyloidosis 37, 616 anabolic steroids 356 analgesic response to stress/exercise 66 anaplastic astrocytoma 600 postradiotherapy tumors 605 androgen replacement therapy 384–6 pituitary effects 649–50 androgens 216 liver disease 619 obesity 254, 255, 618 polycystic ovary disease 254 precocious puberty 257 thyroid-stimulating hormone (TSH) effects 177, 180, 189, 562 anencephaly 26, 31, 36, 333, 349, 363 aneurysm imaging investigations 664 pituitary impingement 351 rupture 325 angiography 663, 664 angioma 36 angiotensin converting enzyme (ACE) inhibitors 150, 648 angiotensin II adenohypophysial cell production 34 adrenocorticotropin (ACTH) secretion response 55 prolactin secretion regulation 126, 127, 140 vasopressin release stimulation 289, 318 anorchia (vanishing testis syndrome) 237 anorexia 7 anorexia nervosa 327–8 growth hormone/insulin-like growth factor-I (IGF-I) levels 107 hypercortisolic state 532 hypogonadotropic hypogonadism 251, 258 hypothalamic dysfunction 328 management 384 neuroendocrine abnormalities 328 anosmia 16, 243, 332, 355, 359 olfactory testing 357 anosmin 16 anovulation 255 anterior hypothalamic nucleus 7 anterior hypothalamus gliosis 326 anterior lobe see pars distalis anterior pituitary 18–36 anatomy 18, 18–19 functional 20–36, 407 surgical 407 cytokines production 35 embryology 19–20 failure see hypopituitarism function evaluation 709–21 basal hormone values 710, 711 drug interactions 713 dynamic tests 712 growth factors production 35–6 histologic staining methods 3–4 hormones 350 hypothalamic peptides production 34

Index hypothalamic regulation 320–1 molecular determinants of cytodifferentiation 20 necrosis 351 nerve supply 19 pathology 36–7 hormone deficiency 36–7 hormone excess 37 mass effects see mass effects peptide hormones production 34 pregnancy-related enlargement 628 regulation feedback control 8–9, 9 hypothalamic releasing/inhibiting hormones 8, 9 temporal secretion patterns 10 vascular supply 3, 5, 19 antiandrogens 650 anticholinergic drugs 648 anticonvulsants 650 antidepressants 646–7 hyperprolactinemia 150, 647 antiestrogens 649 antihistamines 648–9 antihypertensives 648 hyperprolactinemia 150 antipsychotic drugs 149–50, 647 antithyroid drugs 568 antoneoplastic drugs 649 aortic arch stretch receptors 288 AP-1 175, 224 AP-2 124, 125 apathy 320, 329 aplasia, pituitary 36, 349, 363, 376 apolipoprotein B (ApoB) 97, 98 apomorphine 84, 648 apoplexy, pituitary 351, 406, 582, 703 clinical features 700 diagnosis 380–1 neuro-ophthalmological examination 700 treatment 384 appetite 12, 14, 48, 50 disorders 16 hypothalamic control 318, 320 APUD (amine precusror uptake and decarboxylation) system 19 AQP2 mutations 301 nephrogenic diabetes insipidus 283, 294, 296, 298, 299, 300 aquaporin-2 protein (AQP2) 298, 299 AQP2 gene mutations in nephrogenic diabetes insipidus 294, 296, 298, 299, 300 lithium therapy-related down regulation 300 arachidonate pathways 126 arachnoid cyst 342, 342, 350, 415, 594–5 surgical treatment 415 arachnoiditis 326 arcuate nucleus 7 dopamine 11, 187 growth hormone-releasing hormone (GHRH) 10, 10 proopiomelanocortin (POMC)-derived peptides 15 arginine stimulation, growth hormone assessment 100, 717 arginine vasopressin see vasopressin Argyll–Robertson pupil 697 aromatase 145, 226 arthritis 57 arthropathy 429 aseptic meningitis 594 athletes 356 long-term effects of running in males 252 menstrual disorders/hypogonadotropic hypogonadism 251, 252 atrial stretch receptors 288, 317 atropine 142, 316, 648 attention deficit disorder 646 autoimmune hypophysitis 363 autoimmune thyroiditis 203

automated perimetry 703, 704, 705 autonomic dysregulation 256 autonomic function 7, 320 AVP-NPII gene 280, 280 mutations in diabetes insipidus Brattleboro rats 281, 281 human autosomal dominant/autosomal recessive disease 281, 282, 283, 283–4 AVPR2 gene 293 mutations 294, 295, 301 classification 297 diversity 296–7 nephrogenic diabetes insipidus 283 Ayala’s disease 603, 604 7B2 52 corticotroph adenoma secretion 68, 505 ballet dancers 251 barbiturates 318, 530 Bardet–Biedl syndrome 333, 335–6 clinical features 336 basal anterior pituitary hormone values 710, 711 basal encephalocele 250, 363 basal follicle stimulating hormone (FSH) level 718–19 basal growth hormone level 715 basal luteinizing hormone (LH) level 718–19 basal plasma cortisol 374–5, 709 basal prolactin level 715 basophil adenomas 410, 499–501 basophils 79 corticotrophs 25, 45 gonadotrophs 29 histologic staining 4 thyrotrophs 28 Bay K8644 127 Beckwith–Wiedemann syndrome 600 behaviour, hypothalamic regulation 15, 320 behavioural abnormalities 329 benzodiazepines 646 beta blockers 318 pituitary effects 648 b subunit of of glycoprotein hormones 172, 218, 219 null cells 32 regions of similarity 219 variable regions 219 b-endorphin 11, 15, 497, 509, 510, 523, 645 assay 53 exercise response 56 extracerebral synthesis 48 mRNA expression 49 pituitary carcinoma secretion 68 POMC gene structure 48 POMC precursor 49, 50, 52 processing 51 11-b-hydroxylase 58 3-b-hydroxysteroid dehydrogenase 146, 226 17-b-hydroxysteroid dehydrogenase 146, 226 b-lipotropin (LPH) 496, 502, 509, 510, 523 pituitary carcinoma secretion 68 POMC gene structure 48 POMC precursor 49, 50, 52 b-melanocyte-stimulating hormone (b-MSH) 50, 497, 509, 513 POMC gene structure 48 bexarotene 650 bicoid-related homeobox genes 20, 46 Biemond syndrome 336 BIM 22015 57 binocularity defects 690 bleomycin 599 blood pressure 54, 288, 289 blood volume status regulation 317–18 blood–brain barrier 4, 5, 279, 667 anatomical basis 286 osmoreceptor relationships 286 body composition growth hormone actions 97, 98, 98

729

growth hormone therapy response 103, 105 measurement 105 polycystic ovary disease 254 body fat growth hormone actions 97, 98, 98 puberty onset 255 reproductive function relationship 234 female athletes 251 body mass puberty onset 255 regulation 60, 83 reproductive function linkage 234 bombesin 14 adenohypophysial cell production 34 corticotroph adenomas 505 prolactin secretion effects 141 thyroid-stimulating hormone (TSH) secretion effects 187 bone density Cushing’s disease 515, 518 growth hormone actions 98 growth hormone therapy response 105, 106 hyperprolactinemia 147 measurement 105 bone metabolism growth hormone actions 98 prolactin effects 147 bone morphogenetic protein 2 (BMP2) 121 corticotroph development 47 bone morphogenetic protein 4 (BMP4) 121 a subunit expression in embryo 172–3 corticotroph development 47 bone morphogenetic proteins, pituitary organogenesis 47, 172 bone tumors 605 bradykinin 141 brain irradiation 343 brain stem 6 Brattleboro rats 281, 281 breast development 143–4 milk production 144 parathyroid-like hormone production 144 prolactin actions 143–4 breast cancer 620 gonadotropin-releasing hormone agonist analogs 265 breast disease 619–20 bromazepam 646 bromocriptine 144, 145, 146, 331, 377, 379, 568, 619 acromegaly 440, 441 pregnant patient 636 Cushing’s disease 540 fetal effects 483, 483, 484–5 gonadotropin adenomas 589 impact on visual symptoms 702–3 long-acting preparation 480 prolactinoma 121, 475–8, 476, 477, 482, 485 radiotherapy combined treatment 474 surgery following 478–80, 479 side effects 480 brown tumor of hyperparathyroidism 605 bulimia 251 bupropion 647 burns 105 buspirone 648 butyrophenones 134, 149, 647 neuroleptic malignant syndrome 325 C-LIM 177 cabergoline acromegaly 440 fetal effects 483 prolactinoma 481, 482, 485 cachexia 7, 234 hypothalamic in adults 327 caffeine 646 calcitonin 141

730

Index

calcitonin gene-related peptide (CGRP) 14–15 adenohypophysial cell production 34 prolactin secretion effects 141 calcium channel blockers 648 prolactin secretion effects 127, 150, 151 calcium metabolism, prolactin effects 147 calcium response element 124 calcium signaling gonadotrophs 231 lactotrophs 124, 126–7 calpain I 47 calpain II 47 calpastatin 47 cAMP response element (CRE) a subunit of glycoprotein hormones gene 222 prolactin gene 124 cAMP response element-binding protein (CREB) 124, 222–3 cAMP signaling adrenocorticotropin (ACTH) regulation 54, 498 Leydig cells 224 prolactin gene transcription/secretion regulation 124, 125, 127 thyroid-stimulating hormone (TSH) subunit genes transcription stimulation 175, 180 vasopressin regulation 281 carbamazepine 650 carbidopa 135, 648 carbidopa-primed L-dopa test 461, 461 carbohydrate metabolism acromegaly 97 growth hormone actions 97 prolactin effects 147–8 carboplatin 415 carboxypeptidase E 51–2 carcinoid tumors adrenocorticotropin (ACTH) secretion 68 growth hormone-releasing hormone (GHRH) secretion 423, 424 treatment 424–5 carcinoma, pituitary 68, 352 Cushing’s disease 505 growth hormone secretion 421 imaging investigations 678, 679 metastatic spread 425 thyroid-stimulating hormone (TSH) secretion 563 cardiac failure 106 cardiovascular disease acromegaly 430 Cushing’s disease 515 growth hormone deficiency 98, 368 cardiovascular function, growth hormone actions 98–9 Carney complex 59, 425, 513, 615 carotid arteries 4, 407, 668 imaging 667, 671, 672 carotid sinus stretch receptors 288 cartilaginous tumors 597 castration gonadotroph changes 30, 31, 218 gonadotropin changes 231, 232 catabolic states, growth hormone therapy 105 catecholamines adrenocorticotropin (ACTH) secretion response 55 growth hormone release effects 84 stress response 55 thyroid-stimulating hormone (TSH) secretion regulation 187 cavernous hemangima 605 cavernous sinus compression 700 cavernous sinus meningioma 414 cavernous sinuses 19, 407, 687, 689 imaging 667, 670–1, 673 central nervous system tumors, precocious puberty 257 central pontine myelinolysis 306 central scotoma 692, 693, 694 cerebellar ataxia 250, 356

cerebral salt retention syndrome see hypernatremia/hypodipsia syndrome cerebrospinal fluid (CSF) pituitary compression 18 third ventricle 6 cerebrospinal fluid (CSF) rhinorrhea 582 cerebrovascular accident 351 Chiari–Frommel syndrome 455, 456 chlorgyline 647 chlorimipramine 646, 647 chlorpheniramine 648 chlorpromazine 149, 318, 331 chlorpropamide 650 cholecystokinin (CCK) adenohypophysial cell production 34 growth hormone release stimulation 84 hypothalamic functional anatomy 12–13 prolactin secretion effects 141 thyroid-stimulating hormone (TSH) secretion effects 187 vasopressin release regulation 290 cholesterol adrenal gland steroidogenesis 58, 508–9 growth hormone actions 97, 98 cholesterol side chain cleavage enzyme 58 cholinergic agonist drugs 648 chondrocytes growth hormone effects 95 insulin-like growth factor-I (IGF-I) actions 94, 95 chondroid chordoma 597 chondroma 597 imaging investigations 681 chondromyxoid fibroma 605 chondrosarcoma 597 chordoma 36, 415, 595–7 clinical features 596 imaging investigations 681 pathology 595–6, 596 treatment 415, 596 variants 596–7 choriocarcinoma 339, 416, 601, 602 precocious puberty 340 chorionic gonadotropin 216 a subunit 218 assay 257 b subunit 219 gene structure/organization 222, 223 deglycosylation for therapeutic gonadotropin inhibition 265 ectopic production 257 evolutionary aspects 220, 221 fetal reproductive system development 236 hypogonadotropic hypogonadism treatment 260, 260–1 pulsatile pituitary secretion 257 structure 218, 220 structure–activity relationships 219 thyroid-stimulating hormone (TSH) receptor binding 191 see also human chorionic gonadotropin (hCG) chorionic gonadotropin receptor see luteinizing hormone (LH)/chorionic gonadotropin receptor chorionic gonadotropin-secreting tumor, precocious puberty 257, 330, 340 choristoma adenohypophysial neuronal 17 hypothalamic 331, 423 choroid glioma of third ventricle 600–1 chromogranin A 47, 505 chromophobe adenomas 410 chromophobe cells histologic staining 4 null cells 32 chronic illness gonadotropin deficiency 356 growth hormone therapy 103 hypogonadotropic hypogonadism 357–8 cimetidine 141, 648

long-term endocrine effects 649 circadian rhythms 7, 12 adrenocorticotropin (ACTH) 64–5 corticotroph activity 498 corticotropin-releasing hormone (CRH) release 55 cortisol 64–5, 498 entrainment 320 fetal behaviour 66 24-h light–dark cycle 10, 498 hypothalamic control 320 hypothalamic disease 328–9 sleep-related hormone secretion 10 thyroid-stimulating hormone (TSH) release 184, 184–5 circumventricular organ osmoreceptors 286 cirrhosis 619 gonadotropin deficiency 356 hyperprolactinemia 151–2 insulin-like growth factor-I (IGF-I)/insulin-like growth factor-binding protein (IGFBP) levels 92 cisplatin 649 cleft lip and palate 333, 363 clinoid meningioma 414 clomiphene 387, 649 clomiphene test (gonadotropin stimulation test) 241, 721 clonality studies corticotroph adenoma 504–5 gonadotropin adenoma 580–1, 582 Langerhans cell histiocytosis 603 prolactinoma 464 clonidine 142, 648 growth hormone deficiency provocative testing 101, 717 clozapine 647 cocaine 645, 646 hyperprolactinemia 150 coccydiosis 351 codeine 645 cold receptors 318 colloid cyst 414 surgical treatment 414 third ventricle 342–3, 363 colonic polyps 432, 432 color vision loss 697 combined pituitary hormone deficiency (CPHD) congenital hypothyroidism 197 growth retardation 197 Lhx3 mutations 250–1 Pit-1 mutations 197 PROP-1 mutations 197, 198 communicating artery 5 compulsive water drinking 300, 301, 304 computerized tomography (CT) 663, 664–8, 665, 666, 667, 668 acromegaly 435 artefacts from dental devices 665, 665 bone detail 666–7 contrast agents 665–6 craniopharyngioma 581, 669 Cushing’s disease adrenal gland 528–9 pituitary 528, 528 Cushing’s syndrome 528–9 empty sella syndrome 684, 684 lens radiation exposure 666 magnetic resonance imaging (MRI) comparison 684 meningioma 681 normal anatomy 667–8 pituitary tumors 406 prolactinoma 470 Rathke’s cleft cyst 680, 680 technical factors 666 thyroid-stimulating hormone (TSH)-secreting tumors 567 confrontation testing 703–4

Index congenital adrenal hyperplasia 257, 330 conopressins 284 constitutional delay in puberty 357, 359 contrast agents 665–6 sensitivty testing 697 Cornelia de Lange syndrome 36, 601 corpora amylacea 18 corpus luteum 145 cortico–hypothalamic fibers 6 corticostatins 63 corticotroph 25–8, 45–8, 407 Addison’s disease response 27 adrenocorticotropin (ACTH) pulsatile release 63 anatomy 45 basophilic invasion (extension into posterior pituitary) 45, 47 ageing-related 27, 27 cholecystokinin (CCK) production 34 circadian rhythm of activity 498 corticotropin-releasing hormone (CRH) receptors 54 corticotropin-releasing hormone (CRH) response 11, 27 Crooke’s hyaline change 26–7, 27, 47 development 20, 26, 45, 79, 121 differentiation regulation 20, 45–7 electron microscopy 25–6, 26 galanin 47 GH transgenic animals 89 histologic staining 4 neurophysin 47 non-ACTH peptides 47 pars intermedia 25, 27, 45 proopiomelanocortin (POMC) peptides expression 25, 26, 27, 46, 47 precursor processing 52 vasopressin receptors 55 zona intermedia 47 corticotroph adenoma 28 7B2 secretion 68, 505 bombesin 505 chromogranin A 47, 505 clonality 504–5 Crook’s cells 67, 500 electron microsocopy 500, 500 excess adrenocorticotropin (ACTH) secretion 67, 499–505 galanin 47, 505 gastrin 67–8 histology 499–501, 500, 501 hypothalamic corticotropin-releasing hormone (CRH) suppression 501 imaging 528, 528–9, 529 mixed adenomas 505 pars intermedia 506 pharyngeal pituitary 45 prevalence 499 proopiomelanocortin (POMC) gene expression 501–3, 502 secretogranins 505 silent 28, 499, 502, 505–6 tumor growth 503–4 vasoactive intestinal peptide (VIP) 47 corticotroph hyperplasia Cushing’s disease 506, 507–8, 508 excess adrenocorticotropin (ACTH) secretion 67 corticotropin upstream transcription-binding element (CUTE) 20 corticotropin-like intermediate lobe peptide (CLIP) 497, 513 POMC gene structure 48 POMC precursor 49, 50 processing 52, 53 corticotropin-releasing hormone (CRH) 11 acute illness-related gonadotropin suppression 253 adrenocorticotropin (ACTH) secretion stimulation 53, 53, 54, 55–6, 64, 498 circadian rhythm 64, 65, 498 modulators of release 55–6

vasopressin synergism 56, 279, 498 corticotroph adenoma growth stimulation 504 corticotroph regulation 27, 498 ectopic/excess secretion 17 extracerebral distribution 11 extrahypothalamic distribution 11 fetal development 8 hypothalamic functional anatomy 11, 12, 321 proopiomelanocortin (POMC) expression regulation 49–50 suppression by corticotroph adenoma (Cushing’s disease) 501 corticotropin-releasing hormone (CRH) receptors 54 corticotrophs 498 gene defects 369 signaling 498 type 1 50, 54 type 2 54 corticotropin-releasing hormone (CRH) stimulation test 713 adverse events 713 Cushing’s disease 526–7, 527, 536 normal response 713 corticotropin-releasing hormone (CRH)-secreting tumor 331 Cushing’s syndrome 511–12 cortisol adrenocorticotropin (ACTH) secretion negative feedback 64 alcohol effects 642 basal plasma level 374–5, 709 breast development 143 circadian rhythm of secretion 64–5, 498 fetus/neonate 66 sleep–wake pattern relationship 65 exercise response 56 hyperreactive syndrome 513 hypoglycemia-related secretion 65 levels in Cushing’s disease daily production rate 521 plasma 519, 519 pregnant patient 635 saliva 519, 520 postprandial increase 65 pulsatile secretion 63 Cushing’s disease 517, 518 therapy 382 thyroid-stimulating hormone (TSH) circadian secretion pattern regulation 185 Cortosyn, iatrogenic Cushing’s syndrome 514 CQP 201–403 482 cranial nerves 668 examination 700 imaging 668 radiation neuropathy 702 craniopharyngioma 36, 324, 325, 326, 327, 328, 329, 331, 333, 334, 341–2, 352–3, 353, 356, 363, 413, 414, 597–9 adamantinomatous type 413 clinical features 341, 381, 413, 598 diagnosis 381–2 imaging investigations 664, 669, 680–1, 681 management 413 papillary type 413 pathology 597–8, 598 thyroid-stimulating hormone (TSH) deficiency 198 treatment 598–9 Creutzfeldt–Jakob disease 260, 390 CRG 279 Crooke’s change corticotrophs 26–7, 27, 28, 47 corticotroph adenoma 67, 500 Crytococcus neoformans 614 Cushing’s disease 331, 412–13, 496–546 adrenal gland steroidogenesis 508–9 non-ACTH proopiomelanocortin (POMC) peptide effects 509–10 adrenal hyperplasia 510–11

731

multinodular 510–11 simple diffuse 510 adrenal rests (accessory adrenocortical tissue) 511 adrenocortical carcinoma 511 adrenocorticotropin (ACTH) oversecretion 498–505 adrenal effects 508–10 Cushing’s hypothesis 498–9 demonstration 499 episodic pattern 499, 499 glucocorticoid negative feedback abnormalities 502–3, 503 mechanism 499, 502–3 tumor clonality effects 504–5 tumor growth 503–4 adrenocorticotropin (ACTH)-secreting adenoma 67, 499–505 ectopic tumors 68 clinical features 412, 514–17, 517, 534 children 517 corticotroph adenomas 331, 499–505 pars intermedia 506 pharyngeal pituitary 45 corticotroph function assessment ACTH reserve 526–7 baseline 524 dynamics 524–6 corticotroph hyperplasia 17, 506, 507–8, 508 cortisol pulsatile secretion 517, 518 course 518 Cushing’s syndrome differentiation 533–4 diagnosis 412, 516–28 imaging techniques 528, 528–9, 529, 536 initial work-up 518–19 intercurrent pathological states 530–1 pitfalls 529–34 routine laboratory tests 516 strategy 534–6, 535 ectopic ACTH syndrome differentiation 534 epidemiology 496 growth hormone levels 84, 85 historical aspects 514 hormonal evaluation 519–28, 535 adrenocortical androgen plasma levels 523–4 adrenocorticotropin (ACTH) plasma levels 522–3, 523, 524 bilateral inferior petrosal sinus sampling 527–8, 536 corticosteroid urine levels 519–20, 521 corticotropin-releasing hormone (CRH) test 526–7, 527, 536 cortisol daily production rate 521 cortisol plasma levels 519, 519 cortisol saliva levels 519, 520 drug interaction problems 529–30 high-dose dexamthasone suppression test 524–5 low-dose dexamthasone suppression test 521 LVP test 526 metyrapone test 525–6 non-ACTH proopiomelanocortin (POMC) peptide plasma levels 523, 524, 524 overnight 1 mg dexamthasone suppression test 521–2 overnight 8 mg dexamthasone suppression test 525 hyperpigmentation 52, 510, 516 hypothalamic corticotropin-releasing hormone (CRH) suppression 501 hypothalamic dysfunction 331, 506–7, 508 medical treatment 540, 541–4 mixed adenomas 505 multiple endocrine neoplasia type 1 506 pituitary carcinoma 68, 505 post-treatment adrenocorticotropin deficiency 372 pregnant women 517–18 proopiomelanocortin (POMC) peptide extraadrenal effects 510 radiotherapy 539–40 surgery 412–13, 413

732

Index

Cushing’s disease (cont.) adrenalectomy 541 pituitary 536–9, 537, 545–6 treatment 409, 536–44, 545–6 adrenal-directed 540–4 pituitary-directed 536–40 Cushing’s procedure 406, 408 Cushing’s syndrome 412 ACTH-independent ACTH receptor pathways activation 59 ACTH-independent bilateral macronodular adrenal hyperplasia 513–14 causes 496, 497, 511–14 corticotropin-releasing hormone (CRH)-secreting tumors 511–12 cortisol hyperreactive syndrome 513 Cushing’s disease differentiation 533–4 diagnosis 412, 535, 535 ectopic adrenocorticotropin (ACTH) secretion 68, 512–13 ACTH-secreting oat-cell lung carcinoma 68 diagnostic evaluation 524, 525 pancreatic islet tumors 68 pheochromocytoma 68 epidemiology 496, 497 gonadal tumors 514 growth cessation 364 hormonal evaluation 519–22 iatrogenic 514 post-treatment adrenocorticotropin deficiency 372 pregnancy 635–6 pituitary–adrenal function tests 635 premature labor 636 primary adrenocortical tumors 513 thyroid-stimulating hormone (TSH) levels 188 Cushing’s ulcers (neurogenic ulcers) 329–30 CV 205-504 589 cyclophosphamide 649 cyproheptadine 331, 540 cytokines acute illness-related gonadotropin suppression 253 adenohypophysial cell production 35 hypothalamic functional anatomy 15 hypothalamic-pituitary axis activation 66 prolactin secretion effects 148 thyroid-stimulating hormone (TSH) effects 189 cytomegalovirus 614 cytotoxic drugs 649 danazol 264 DAX-1 mutations, hypogonadotropic hypogonadism 245, 246, 355 dDAVP therapy 303–4 therapeutic trial 303 De Morsier syndrome see septo-optic dysplasia decidual prolactin 128–9 defecation 320 dehydration, diabetes insipidus differential diagnosis direct test 302–3 indirect test 301–2, 302, 302 delayed puberty 357–9 ballet dancers 251 Pit-1 gene mutations 362 depression 84 hypercortisolic states 531–2 dermoid cyst 350, 594 desferrioxamine 255 desipramine 646, 647 17,20-desmolase 66 developmental abnormalities 349 growth hormone deficiency 363 homeodomain transcritpion factor mutations 250–1 developmental cysts 350 dexamethasone 383, 568 dexamthasone suppression tests 636 Cushing’s disease high-dose 524–5 low-dose test 521, 529, 533, 535

overnight 1 mg 521–2, 529, 535 overnight 8 mg 525 pregnant patient 529 drug interaction problems 530 diabetes insipidus 16–17, 256, 321 central 292–4, 323–4 autosomal dominant forms 293, 324 autosomal recessive form (DIDMOAD; Wolfram’s syndrome) 293, 324 AVP-NPII gene mutations 281, 281, 282, 283, 283–4 Brattleboro rats 281, 281 clinical features 292 etiology 292, 292–3, 324, 324 hypernatremia/hypodipsia syndrome 293, 294, 324–5 idiopathic 324 imaging investigations 673 postoperative 409 postpartum 637 pregnancy 636–7 treatment 303–4 tumors 324, 603, 604, 614, 615 X-linked form 324 diagnostic testing 301–4 dDAVP therapeutic trial 303 direct test 302–3 urine osmolality after dehydration (indirect test) 301–2, 302, 302 differential diagnosis 301–3, 303 dipsogenic 301 gestational 292, 301, 637 nephrogenic 294 acquired 300, 300 AQP2 mutations 283, 294, 296, 298, 299, 300 AVPR2 mutations (X-linked form) 283, 294, 295, 296–7 clinical features 296 congenital 294, 295, 296–7, 298, 299, 300 early treatment 297–8 genetic testing 297 lithium actions 647 diabetes mellitus 37 acromegaly 97, 433 adrenocorticotropin (ACTH) deficiency 370 growth hormone levels 82, 107 insulin-like growth factor-I (IGF-I)/insulin-like growth factor-binding protein (IGFBP) levels 92, 94, 107 pituitary changes 618 pituitary infartion 351 diaphragma sellae 18, 19, 407, 687 imaging 671 diaphragma sellae meningioma 414 diazepam 646 DIDMOAD (Wolfram) syndrome 293, 324 diencephalic autonomic epilepsy (episodic/paroxysmal hypothermia) 326 diencephalic epilepsy 329 diencephalic glycosuria 328 diencephalic syndrome of infancy 323, 327, 327 diencephalon 8 digitoxin 650 dihydroergocriptine 482 dihydroergocristine 482 diltiazem 127, 648 diphenhydramine 648 diphenylhydantoin 318 diplopia 690 hemifield slide phenomenon 690, 690 dipsogenic diabetes insipidus 301 domperidone 134, 562, 647–8 dopamine fetal hypothalamus 8 growth hormone release effects 84 hypothalamus functional anatomy 10–11, 135, 321 lactotroph suppression 120 prolactin secretion inhibition 10–11, 126, 127, 133–5

somatotropin release-inhibiting factor (SRIF) release regulation 86 thyroid-stimulating hormone (TSH) secretion inhibition 187, 562 subunit gene transcription regulation 175, 177, 179–80 dopamine agonists 648 acromegaly 440–3, 441, 442, 443, 444, 445 side effects 443 effects in pregnancy/fetal effects 482, 483, 483, 484–5 lactotroph suppression response 24 prolactinoma 474, 475–82, 476, 477, 481, 485 preoperative treatment 478–80, 479 dopamine D2 receptor antagonists antipsychotic drugs 647 pituitary effects 647–8 knock out mouse studies 134 proopiomelanocortin (POMC) precursor processing 53 neuroleptic malignant syndrome 325 prolactin secretion inhibition 126, 134, 135 prolactinomas 464–5 thyrotroph 187 dopamine deficiency hyperprolactinemia 331 hypothalamic/hypophysial stalk lesions 16 prolactinoma pathogenesis 459, 461, 461 thyroid-stimulating hormone (TSH) levels 195 dorsal longitudinal fasiculus 7 dorsomedial nuclei 7 Down syndrome 601 drug-related pituitary changes 642–50, 643, 644 Dutch hunger winter 236, 237 dwarfism 16, 37 dynorphin (preproenkephalin B) 48 dysgenesis, pituitary 363 dysgerminoma 601 dysthermia 16, 256, 321, 325–6 dystopia, pituitary 36 eating disorders 256 ecchordosis physaliphora 595 ectopic adrenocorticotropin (ACTH) Cushing’s disease differentiation 534 Cushing’s syndrome 68, 512–13 ectopic growth hormone 423 ectopic growth hormone-releasing hormone (GHRH) 423 ectopic pituitary tissue 36, 349–50, 363, 592 ectopic prolactin 152 ectopic salivary gland tissue 592 ectrodactyly, ectodermal dysplasia-clefting (EEC) syndrome 363 efferent hypothalamic projections 7 electron microscopy 4 acidophil stem cells 33 corticotroph adenoma 500, 500 corticotrophs 25–6, 26 follicular cells of adenohypophysis 30 gonadotrophs 218 gonadotropin adenoma 580 lactotrophs 23, 23–4, 120 mammosomatotrophs 24–5, 25 null cells 32, 32 oncocytes 32, 33, 33 prolactinomas 465–6 somatotrophs 21, 21 thyrotroph adenoma 563 thyrotrophs 28, 28 emaciation, hypothalamic disease 321, 327 embryology 218 adenohypophysis 19–20 corticotrophs 45 gonadotropin-releasing hormone (GnRH) neuron migration into hypothalamus 217, 217–18 homeodomain transcription factor expression 46, 121, 218

Index hypophysial portal vessels 19, 45 hypothalamus 8 lactotrophs 121 posterior pituitary 8 somatotrophs 79–80 embryonal carcinoma 339, 416, 601 emotional behaviour 7, 329 hypothalamic regulation 320 emotional/psychological stress adrenocorticotropin (ACTH) secretion regulation 66 growth hormone secretion suppression 82 empty sella syndrome 18, 350, 351, 363, 594, 681–3 growth hormone neurosecretory dysfunction 102 imaging 683, 683–4, 684 posttherapy visual loss 702 enalapril 150, 648 encephalitis 326 endodermal sinus tumor (yolk sac tumor) 339, 416, 601 endogenous opioids 15, 25 endometriosis 264 endorphins 25 endoscopic surgery 416 gonadotroph adenomas 586 endothelin adenohypophysial cell production 36 prolactin secretion effects 141 energy balance 48, 63, 83, 318, 320 hypothalamic disease impact 326–8 reproductive axis linkage 234, 235, 236 enkephalins 645 environmental deprivation syndrome (psychosocial dwarfism) 337, 337, 363, 364 epidemic hemorrhagic fever 351 epidermal growth factor (EGF) 15 adenohypophysial cell production 35 prolactin gene transcription modification 123 epidermoid cyst 350, 416, 594 episodic/paroxysmal hypothermia (diencephalic autonomic epilepsy) 326 erythropoietin 650 essential hypernatremia see hypernatremia/hypodipsia syndrome estradiol gonadotropin secretion regulation 232–3 menstrual cycle 239, 240 obese men 254 estrogen breast development 143 gonadotroph response 30 gonadotropin secretion stimulation 232 influence on Cushing’s disease diagnosis 529 lactotroph development 121 lactotroph pregnancy/lactation-related hyperplasia 24 obesity-related metabolism 618 ovarian synthesis follicle stimulating hormone (FSH) actions 226 prolactin effects 145, 146 prolactin gene regulation 123, 124 thyroid-stimulating hormone (TSH) regulation 177, 180, 189, 562 estrogen receptors 20 lactotrophs 23 development 80 mammosomatotrophs 24 proopiomelanocortin (POMC) glycosylation 51 estrogen replacement therapy 390 female gonadotropin deficiency 386–7 growth hormone therapy dosage adjustment 104–5, 105 pituitary effects 649 prolactin levels 131 estrogen responsive element follicle stimulating hormone (FSH) b subunit 224 luteinizing hormone (LH) b subunit promoter 223 prolactin gene 123

estrogen-induced prolactinoma 466–7 etomidate 543 euthyroid hyperthyroxinemia 201, 201, 567–8 euthyroid sick syndrome 650 chronic renal failure 618 liver disease 618 alcohol-induced 642 starvation 620 thyroid-stimulating hormone (TSH) glycosylation 182 levels 203 evolutionary aspects glycoprotein hormones 220–1 oxytocin 284 vasopressin 284 exercise adrenocorticotropin (ACTH) response 65–6 amenorrhea 251, 356 analgesia 66 growth hormone secretion 82 hypercortisolic state 532 prolactin level response 133 extension locus 57 external genitalia development 236 external plexus 4, 19 extramedullary hematopoiesis 605 eye changes, acromegaly 431 false pregnancy (pseudocyesis) 337–8 familial glucocorticoid deficiency syndrome 59, 370 melanocortin 2 receptor (MC2R) mutations 59 familial glucocorticoid resistance 533 familial panhypopituitarism 333, 334 Fanconi’s anemia 363 fat/fat mouse 52 fear/anxiety 54, 320 feedback control, anterior pituitary hormones 8–9, 9 feeding behaviour 83, 318 inhibition 12–13 ‘feeding center’ (ventrolateral nucleus) 7, 320 fenclofenac 189 fenestrated capillaries 4, 5, 19 fenfluramine 138, 650 fentanyl 645 fertile eunuch syndrome 244, 247, 333, 355 fetus adrenocorticotropin (ACTH) 66 gonadotropin-releasing hormone (GnRH) 236 gonadotropins production 236 reproductive system development 236 growth hormone 82, 633 maternal Cushing’s syndrome-related risk 636 thyroid-stimulating hormone (TSH) 183 subunit gene expression 172–3 thyrotropin-releasing hormone (TRH) 183 thyroxine (T4) 183 triiodothyronine (T3) 183 fibroblast growth factor (FGF) 15, 31 adenohypophysial cell production 35 prolactin secretion effects 141 fibroblast growth factor 8 (FGF8) 121 corticotroph development 47 fibrocystic breast disease 619–20 fibroma 36 fight-or-flight reaction 320 finasteride 650 fluid volume, growth hormone actions 98 flumazenil 646 fluoxetine 138 fluoxymesterone 649 flutamide 650 fluvoxamine 647 follicle growth 226 follicle stimulating hormone (FSH) 216–65 age-related changes 238, 239, 617 a subunit 218 gene structure/organization 221–2 assay 226–9, 227

733

basal level measurement 718–19 bioassays 228 free a-subunit secretion 228 gonadotropin adenoma diagnosis 583, 584, 585 radioimmunoassay (RIA) 216, 227, 227 receptor-binding assay 228 two-site-directed immunoassays 227–8 b subunit gene gonadotropin-releasing hormone (GnRH) response 230–1 structure/organization 222, 223–4 b subunit mutations clinical features 355 hypogonadism 247, 248 biologic role 224, 224–6 female 226 male 224–6 childhood levels 237–8 commercial preparations 260 deficiency, PROP-1 mutations 197, 218, 250 evolutionary aspects 220–1 fetus 236 glycosylation 221 gonadotroph secretion 29, 218 gonadotropin-releasing hormone (GnRH) regulation 11, 230–1 gonadotropin-releasing hormone (GnRH) stimulation test 240–1 isoform microheterogeneity 229 male gonadotropin deficiency treatment 386 menstrual cycle 239, 240 pregnancy 630, 631 puberty 238 pulse pattern detection 241–2 reproductive system development 236 secretion regulation 229, 229–36 starvation (undernutrition) reponse 234 structure 218–20, 220 follicle stimulating hormone (FSH) receptor 217, 224, 225 activating mutations 248 gonadal tumors 248–9 inactivating mutations with hypogonadism 248 ovarian granulosa cells 226 therapeutic gonadotropin antagonists development 265 follicle stimulating hormone (FSH)-secreting tumor see gonadotropin adenoma follicular cells of adenohypophysis 30–1 folliculostellate cells of adenohypophysis 31 follistatins 234 gonadotroph expression 35 gonadotropin secretion regulation 234 food intake regulation 83 Forbes–Henneman–Griswold–Albright syndrome 455, 456 forebrain embryology 8 hypothalamic afferent neural pathways 6 Foster–Kennedy syndrome 342 Fröhlich syndrome 413 fugitive acromegaly 33 fungal infection 351, 614 Gagel’s granuloma 603, 604 galactorrhea 144 amenorrhea 146 men 146 prolactinoma 468, 469 galanin adenohypophysial cell production 34 corticotroph adenoma 47, 505 corticotrophs 47 extracerebral distribution 13 growth hormone release stimulation 84 hypothalamic functional anatomy 13 prolactin secretion effects 141 gamma knife stereotactic radiosurgery acromegaly 439

734

Index

gamma knife stereotactic radiosurgery (cont.) craniopharyngioma 599 Cushing’s disease 539 gonadotropin adenomas 588 meningioma 599 postoperative 409 prolactinoma 475 g1 POMC precursor 49, 50 g2 POMC precursor 49, 50 g3 POMC precursor 49, 50 g-aminobutyric acid (GABA) POMS transcription regulation 50 prolactin secretion inhibition 135–6 thyroid-stimulating hormone (TSH) secretion effects 187 g-lipotrophic hormone (LPH) 497, 502, 510, 523 POMC precursor 50 g-melanocyte-stimulating hormone (g-MSH; g melanotropin) 509 melanocortin receptor binding 57 POMC gene structure 48 POMC precursor 52 gangliocytoma 595 hypothalamic 17, 331, 423, 511 Gardner’s syndrome 432 gastrin 13 adenohypophysial cell production 34 corticotroph adenoma secretion 67–8 prolactin secretion effects 141 gastrin-releasing peptide (GRP) 14 adenohypophysial cell production 34 gastrointestinal neuropeptides anterior pituitary production 34 growth hormone release effects 84 gastrointestinal tract motility 320 GATA-2 b subunit gene promoter transactivation 174 thyrotroph differentiation 173 gelastic seizures 322, 329, 593 gender differences see sexual dimorphism generalized resistance to thyroid hormones (GRTH) 199 clinical features 201 management 201 thyroid receptor (TR) abnormalities 199–201, 200 germ cell tumors 339–40, 416, 601, 601–2 clinical features 602 pathology 601–2 pre-treatment biopsy 602 systemic metastasis 602 treatment 602 germinoma 339, 363, 416, 601 GH gene transcription regulation 86 transgenic animal studies 89–90 GH-1 mutation 362 Ghrelin growth hormone secretion regulation 80, 87–9, 89 hypothalamic actions 88–9 somatotroph adenoma receptors 422 structure 87 giant cell granuloma 36, 352 giant cell tumor 605 gigantism 17, 425–6 causes 426 growth hormone-secreting pituitary adenomas 411 mammosomatotroph hyperplasia 25 therapeutic options 426, 427 GL13 mutations 593 glioblastoma multiforme 600, 601 postradiotherapy tumors 605 glioma 36, 363, 599–601 choroid of third ventricle 600–1 hypothalamic 324, 331, 340, 340–1, 415, 423 imaging investigations 681 optic chiasm 340, 340–1, 415

optic nerve 325 optic pathway 566–600 pituitary 600 postradiotherapy tumors 605 treatment 600 glomangioma 605 glucagon brain functional anatomy 13–14 growth hormone release stimulation 84 growth hormone assessment 718 pancreatic secretion regulation 86 glucocorticoid receptor mutation 68 glucocorticoid response element 124 glucocorticoids abrupt cessation of therapy 371 adrenal gland steroidogenesis 58 Cushing’s disease 508–9 adrenocorticotropin (ACTH) deficiency treatment 382–4 acute deficiency management 384 advice for patients 383 perioperative therapy 384 adrenocorticotropin (ACTH) secretion inhibition 53, 56 abnormalities in Cushing’s disease 502–3, 503 negative feedback 63–4, 498 corticotropin-releasing hormone (CRH) release modulation 55, 64 excess corticotroph Crooke’s hyaline change 26–7, 27 functional hypercortisolic states 531, 531–3, 535 growth hormone deficiency 364 familial resistance 533 growth hormone secretion regulation 80, 81, 84–5 hypothalamic disease 333–4 iatrogenic Cushing’s syndrome 514 pituitary effects of therapy 650 prolactin gene transcription/secretion regulation 124, 125 proopiomelanocortin (POMC) expression inhibitory regulation 49–50 thyroid-stimulating hormone (TSH) secretion regulation 175, 180, 188, 562 vasopressin secretion inhibition 64 glucoreceptors, hypothalamic 320 glucose metabolism 14 glycoprotein hormones 216, 218, 220 a subunit 218 b subunit 218, 219 evolutionary aspects 220–1 heterodimer formation 218, 219 structure–activity relationships 219–20 subunit homologies 218 subunit structure 172 glycosylation follicle stimulating hormone (FSH) 221 luteinizing hormone (LH) 221 prolactin 128, 129 thyroid-stimulating hormone (TSH) 180–2, 181, 561 biological activity influence 183 regulation 182 glycyrrhetinic acid 530 goiter 565 Goldmann perimetry 471, 703, 704 gomitoli 4–5, 19 gonadal development 236 gonadal dysgenesis 359 gonadal failure, primary 357 gonadotroph 29–30, 216, 218, 407 activin/inhibin production 35 a subunit gene expression 176 angiotensin II production 34 castration-related changes 30, 31, 218 development 20, 79, 121 differentiation regulation 20 sexual dimorphism 20, 29

electron microscopy 29, 30, 218 follistatin expression 35 gonadotropin-releasing hormone (GnRH) stimulation 231 gonadotropins production 29, 218 histologic staining 4 morphology 218 precursor cells 218 SF-1 expression 29, 176 gonadotroph adenoma 30, 31, 256 oncocytes 32 SF-1 expression 30 see also gonadotropin adenoma gonadotropin adenoma 413, 575–89 a subunit secretion 576–7 clinical features 582, 582–3 gonadotropin excess symptoms 583 hormone deficiency symptoms 582 neurologic symptoms 582 clonality studies 580–1, 582 diagnosis 583–6 electron microscopy 580 etiology 580–2 follicle stimulating hormone b subunit secretion 576–7, 577 follicle stimulating hormone (FSH) secretion 575, 576 ovarian hyperstimulation 583, 583 hormonal evaluation 583–6, 584 men 583–4, 584 women 584–5, 585 imaging investigations 583 luteinizing hormone b subunit secretion 576–7, 577 luteinizing hormone (LH) secretion 575–6, 576 non-gonadotropic hormones secretion 577, 585–6 pathology 579–80, 580 pathophysiology 575 primary hypogonadism differentiation 585, 585 prolactin secretion 466 secretory product levels 575 basal secretion 575–7 in vitro studies 577–8, 578, 579 stimulated secretion 577 treatment 586, 586–9 medical 589 radiotherapy 588, 588–9 surgery 586–8, 587, 588 gonadotropin associated peptide (GAP) 135 gonadotropin deficiency 353–5 congenital hypogonadotropic hypogonadism 354–5 etiology 354 PROP 1 gene mutations 218, 362 treatment in female 386–8, 390 gonadotropin therapy 387–8 sex steroids 386–7 treatment in male 384–6, 390 aims 384 androgen replacement therapy 384–6 gonadotropin therapy 386 gonadotropin inhibitors 262–3 gonadotropin-releasing hormone (GnRH) 11–12 adenohypophysial cell production 34 development 8, 236 neuron migration into hypothalamus 217, 217–18 sexual dimorphism 29 energy balance–reproductive function linkage 234, 236 extrahypothalamic localization 12 gene mutations in hpg mouse 245–6 gonadotropin adenoma response 577 gonadotropin stimulation test 240–1, 719, 721 children 241 normal response 721 gonadotropins regulation, experimental models 257–9 hypersecretion disorders 17

Index hypothalamic functional anatomy 11–12 ovulatory LH surge 239 precocious puberty 17 prolactin secretion stimulation 140 pulsatile release 216, 259 defects 16 gonadotropin secretion regulation 229–31, 230 hypogonadotropic hypogonadism treatment 262, 386, 388 LH b subunit transcription induction 223 pulse generator pathology 217 gonadotropin-releasing hormone (GnRH) agonist analogs 216, 262, 263–5, 356, 589 mechanism of gonadotropin downregulation 263 side effects 264 structure–activity relationships 263 therapeutic applications 263–5 gonadotropin-releasing hormone (GnRH) antagonist analogs 262–3, 265, 589 deglycosylated glycoprotein hormones 265 gonadotropin receptor binding inhibitors 265 gonadotropin-releasing hormone (GnRH) deficiency 16 clinical features 355 developmental neuron migration disorders 218 gonadotropin-releasing hormone (GnRH) receptor mutations 245, 247, 354 gonadotropin-releasing hormone (GnRH)-secreting tumor 257 gonadotropins 216–65 age-related changes 238–9, 239, 617 alcohol effects 642–4 assay 226–9, 227 bioassays 228, 238 free a-subunit secretion 228 radioimmunoassay (RIA) 227, 238 receptor-binding assay 228 two-site-directed immunoassays 227–8, 238 assessment tests 240–2, 718–21 basal levels 718–19 clomiphene stimulation test 721 dynamic testing 719, 721 gonadotropin-releasing hormone (GnRH) stimulation test 240–1, 719, 721 childhood levels 237–8 drug effects 643 evolutionary aspects 220–1 gonadotroph production 29 gonadotropin-releasing hormone (GnRH) regulation, experimental models 257–9 historical aspects 216–17 hypogonadotropic hypogonadism treatment 260, 260–2 isoform microheterogeneity 229 menstrual cycle 239–40 opiate antagonist effects 645 opiate effects 645 pregnancy 630–1 prolactin level effects 144–5 puberty 238 pulse pattern detection 241–2 secretion disorders 242–57 hypergonadotropic 256–7, 257 hypogonadotropic 243–56 secretion regulation 229, 229–36 stress/illness response 252–3, 616 subunit genes 217 see also follicle stimulating hormone (FSH); luteinizing hormone (LH) gout 60 granular cell tumor 36, 595 granulomatous disease 36, 322, 326, 351–2, 363 granulomatous hypophysitis 415, 415 management 415 granulosa cell aromatase bioassay (GAB) 228 granulosa cell cytodifferentiation 226 Graves’ disease 191

grooming behaviour 63 growth growth hormone actions 94–6 insulin-like growth factor-I (IGF-I) actions 94 standard height/height velocity 716, 717 growth factors 15, 15 adenohypophysial cell production 35–6 growth failure/retardation combined pituitary hormone deficiency (CPHD) 197 Cushing’s disease 517 drug treatment of attention deficit disorder 646 growth hormone deficiency 364–5 growth hormone-releasing hormone (GHRH) deficiency 16 hypothalamic disease 333 Pit-1 gene mutations 362 prolactinoma 469 see also short stature growth hormone 79–108 acidophils secretion 4 stem cells 33 acromegaly diagnosis 433–4, 434, 434 pulsatile release 422 age-related changes 617 alcohol effects 642 assays 99–101 adult deficiency evaluation 103–4, 104 basal levels 715 childhood deficiency evaluation 99–101 24-hour integrated concentration 99 hypersecretion evaluation 99 urinary measurements 99 variability 101 breast development 143 cardiovascular actions 98–9 chondrocyte actions 10 circulating forms 81–2 clinical use see growth hormone therapy development 20, 82, 633 diabetes-related changes 618 drug effects 643 extrapituitary production 94 gene regulation 80–1 gene structure 79 glucocorticoid responsive elements 85 locus control region (LCR) 80 promotor 80 GH transgenic animals 89–90 growth-promoting actions 94–6, 96 in vitro 95 longitudinal bone growth 95 systemic administration response 95–6 hypersecretion 107, 107 insulin-like growth factor-I (IGF-I) relationship 93, 95 gene expression regulation 91 intracellular signaling 90, 91, 91 liver actions 10 liver disease 619 malnutrition-related changes 620 mammosomatotroph secretion 24, 120–1 metabolic actions 10, 96–9 acute indulin-like effects 97, 97 body composition 98 bone 98 carbohydrate metabolism 97 lipid metabolism 97–8 protein metabolism 97 muscle strength effects 98 obesity-related changes 617–18 paracrine action 94–9 peripheral actions 90–4 pregnancy 628, 632–3 pulsatile release 82, 82, 86, 87, 99, 422 renal clearance impairment 108 secretion abnormalities 107, 107–8 secretion regulation 81–4

735

autoregulation 87 exercise 82 feedback loops 87, 88 Ghrelin 87–9, 89 glucocorticoids 84–5 growth hormone secretogogues (GHS) 87–9 growth hormone-releasing hormone (GHRH) 10, 85, 86–7 hypothalamic hormones 84–9 insulin-like growth factor-I (IGF-I) feedback 86, 87, 88 leptin 83, 83–4 neurotransmitters/neuropeptides 84 nutritional/metabolic factors 82 somatotropin release-inhibiting factor (SRIF) 10, 85–7 thyroid hormone 85 sleep-related release 82 somatotroph adenomas 21 somatotroph production 10, 20, 21, 21 stress/illness response 82, 616 structure 81, 81 transgenic mouse studies 419–20 uremia-related changes 618 growth hormone assessment tests 715–18 basal growth hormone levels 99–100, 365, 715 insulin-like growth factor-I binding protein-3 (IGFBP-3) 367, 715–16 insulin-like growth factor-I (IGF-I) levels 99–100, 365–6, 715 provocative testing 100–1, 103–4, 716–18 adult growth hormone deficiency 103–4, 104, 369 arginine 717 chilhood growth hormone deficiency 365, 366–7 clonidine 717 insulin-induced hypoglycemia (insulin tolerance test) 100, 716–17 L-dopa 717–18 pharmacological tests 716 physiological tests 716 growth hormone binding protein (GHBP) 90 growth hormone deficiency 361–9, 592 adults 367–9 ageing-related skeletal muscle atrophy 103 cardiovascular risk 98, 368 causes 103, 103 clinical features 367–8, 368 diagnosis 368–9, 369 etiology 367 growth hormone provocative tests 103–4, 104, 369 indications/benefits of growth hormone therapy 104, 104 physical findings 103, 103 bone mass reduction 98 brain irradiation effects 344, 344, 363 children 362–7 acquired 363–4 clinical features 364–5 diagnosis 365, 365–7, 380 genetic/familial 333, 362–3 growth hormone provocative tests 365, 366–7 insulin-like growth factor binding protein 3 (IDFBP-3) levels 367 screening tests 365 serum growth hormone levels 365 serum insulin-like growth factors 365–6 urinary growth hormone levels 367 developmental pituitary disorders 363 diagnostic criteria 102 etiology 361–3, 362 familial panhypopituitarism 333 fat metabolism body fat mass/obesity 97 lipoprotein levels 97–8 GH-1 gene mutations 362 glucocorticoid excess 364

736

Index

growth hormone deficiency (cont.) growth hormone neurosecretory dysfunction 102 growth hormone-releasing hormone (GHRH) receptor mutations 362 hormonal evaluation/diagnosis see growth hormone assessment tests hypothalamic disease 333 hypothyroidism 363, 364 imaging investigations 672 insulin resistance 97 isolated deficiencies 37, 333 muscle strength reduction 98 Pit-1 gene mutations 197, 218, 250, 362 PROP 1 gene mutations 197, 218, 250, 362 treatment 389–91 associated hormonal deficiencies 390, 391 growth hormone therapy 102–3, 389, 390–1 long-term care 390 side effects 390 growth hormone neurosecretory dysfunction 102 growth hormone receptor (GHR) 90–1, 142, 143 antagonists, acromegaly 443 mutations 91 Laron syndrome 108 signaling pathway 90, 91, 91 structure 90 growth hormone resistance 362–3 growth hormone binding protein (GHBP) levels 90 Laron syndrome 363 growth hormone secretogogues (GHS) growth hormone secretion regulation 87–9 signaling pathway 88 somatotroph responses 88 growth hormone secretogogues (GHS) receptor 87 growth hormone therapy achondroplasia/hypochondroplasia 103 adults 103–7, 389 benefits/indications 104, 104, 105 complications 104, 105, 105, 107 dosage 104–5 treatment algorithm 106 AIDS-associated wasting syndrome 106 cardiac failure 106 catabolic states 105 children 102–3, 390–1 chronic disease 103 classic growth hormone deficiency 102 competitive sports use 106–7 contraindications 389 idiopathic short stature 102 low birth weight 102–3 monitoring 389 osteoporosis 105–6 ovulation induction 106 recombinant hGH 101–2, 390 Turner’s syndrome 102 wound healing 106 growth hormone-binding protein 81 growth hormone-producing adenoma 410, 411–12 see also acromegaly; somatotroph adenoma growth hormone-producing tumor animal models 419 transgenic mouse studies 419–20 preoperative evaluation 407 prolactin secretion 466 see also acromegaly growth hormone-releasing hormone (GHRH) 10 acromegaly abnormalities 421–2 extrapituitary tissue hypersecretion 423–4 hypothalamic hypersecretion 423 adenohypophysial cell production 34 deficiency 16 extracerebral distribution 10 fetal hypothalamus 8 growth hormone provocative testing 100, 718 adverse events 718 normal response 718

growth hormone secretion regulation 80, 85 desensitization 87 feedback loops 87, 88 somatostatin interaction 86–7 hypersecretion 107, 107 hypothalamus functional anatomy 10, 321 immunocytochemical localization 10, 10 placental production 633 prohormone 85 prolactin secretion stimulation 139, 139 structure 10, 85, 85 gut peptide homologies 85 transgenic mouse studies 419, 421–2 growth hormone-releasing hormone (GHRH) receptor 85 mutations, growth hormone deficiency 362 somatotroph adenomas 422 growth hormone-releasing hormone (GHRH)secreting tumor 10 acromegaly 331 somatotroph hyperplasia 22 gsp mutations 17, 422, 423 Gsx-1 mutations 250 gut endocrine cells somatostatin secretion 10 thyrotropin-releasing hormone (TRH) localization 11 gut peptide hormones 12, 13, 34 growth hormone-releasing hormone (GHRH) structural homologies 85 H1 antihistamines 648 H2 antihistamines 648–9 hallucinations 691 hamartoma, hypothalamic 17, 331, 338–9, 416, 423, 593 clinical features 338 management 416 precocious puberty 330–1, 338, 593 Hand–Schuller–Christian disease see Langerhans cell histiocytosis Hayek–Peake syndrome 325 head injury 37 growth hormone deficiency 363 hypopituitarism 350 pituitary infartion 351 headache, pituitary mass effects 36, 426, 467, 469 gonadotropin adenoma 582 prolactinoma, effects of pregnancy 484 thyroid-stimulating hormone (TSH)-secreting tumors 565 hemangioblastoma 605 hemangiopericytoma 605 hemochromatosis 37, 352, 613 hypothalamic hypogonadism 16, 255 hemorrhage adrenocorticotropin (ACTH) response 66 pituitary lesions 37, 351 hemosiderosis 352 heparin 650 heroin 645 Herring bodies 12, 13, 14 Hesx1 121, 218 see also Rpx HESX1 mutations 46, 217, 218, 220, 250 high density lipoprotein (HDL) 97, 98 hippocampal–hypothalamic tract 6 hirsutism 515 histamine 141–2 histiocytosis 322, 324, 325, 333, 343 histiocytosus X see Langerhans cell histiocytosis histologic staining methods 3–4 histoplasmosis 351 historical aspects 3 acromegaly 419 Cushing’s disease 514 gonadotropins 216–17 pituitary imaging 663–4 pituitary surgery 405–6

prolactin 119 HIV infection/AIDS 351, 614 gonadotropin suppression/testosterone levels 253, 356 wasting syndrome, growth hormone therapy 106 holoprosencephaly 333, 349, 363 homeodomain transcription factors 121, 218 anterior pituitary development 20 a subunit expression regulation 173 mutations 217, 218, 219, 220 pituitary developmental disorders 250–1 hormone-sensitive lipase 97 hpg (hypogonadotropic) mouse 245–7, 258, 259 human chorionic gonadotropin (hCG) gonadotropin deficiency treatment 386, 388 preparations 260 human menopausal gonadotropin (hMG) gonadotropin deficiency treatment 386, 388 preparations 260 hunger 7 hydergine 482 hydrocephalus 325, 410 pituitary infartion 351 hydrocortisone 382, 383, 384, 390, 391 21-hydroxylase cytochrome P-450 enzyme 58 5-hydroxytryptophan 138 hydroxyurea 414 hypergonadotropic disorders 256–7, 257 hypernatremia/hypodipsia syndrome (adipsic/essential hypernatremia; cerebral salt retention syndrome) 293, 294, 324–5 hyperparathyroidism, brown tumors 605 hyperphagia 318, 320 hypothalamic obesity 327 hyperpigmentation Cushing’s disease 52, 510, 516 Nelson’s syndrome 545 hyperprolactinemia 149–54 acromegaly 139, 433 adrenal insufficiency 152 amenorrhea 146 postpartum 132 bone mineral density 147 causes 149, 150 medications 149–50, 647, 648 cirrhosis 151–2 diagnostic tests 153–4, 154 differential diagnosis 470 ectopic prolactin secretion 152 galactorrhea 144, 146 gonadotropin deficiency/pulsatile release inhibition 145, 356 hypogonadotropic hypogonadism 255 hypothalamic disease 331–2 hypothalamic/hypophysial stalk lesions 16, 152–3, 153 hypothyroidism 152 idiopathic 153 insulin resistance 147 lymphocytic hypophysitis 37 men 146, 147 menstrual disorders 146 neurogenic 152 polycystic ovaries 146 prolactin-secreting microadenoma 331–2 renal disease 150–1, 151 reproductive system effects 145, 145, 146, 255 sexual dysfunction 146, 147, 331 short luteal phase 145, 146 suckling episode-related 132 treatment 384 see also prolactinoma hypersexual behaviour 329 hypersomnolence 328 hypertension acromegaly 430 Cushing’s disease 515 hyperthermia 323

Index hypothalamic disease 325–6 paroxysmal 326 hyperthyroidism Cushing’s disease diagnostic problems 530 hypothalamic pathology 17 pituitary resistance to thyroid hormones (PRTH) 199, 202, 202 pitutary function 620 secondary thyroid-stimulating hormone (TSH) deficiency 202 thyroid-stimulating hormone (TSH) levels 183, 194, 194 subclinical disease 203 thyroid-stimulating hormone (TSH) receptor mutations 191 thyroid-stimulating hormone (TSH)-secreting tumors 202, 202, 413, 561, 563, 565 thyrotrophs 28–9 hypertonic saline test 722–3, 723 adverse events 723 normal response 723 hypochondroplasia 103 hypoglycemia 318, 320 adrenocorticotropin (ACTH) response 65 insulin-induced growth hormone deficiency diagnosis (insulin tolerance test) 100, 104 growth hormone release response 82, 84 POMS transcription regulation 50 prolactin response 133 hypogonadotropic (hpg) mouse 245–7, 258, 259 hypogonadotropic hypogonadism 243–56, 321, 323 acquired 243, 243, 251–6, 356 hypothalamic lesions 332 adolescents 356–7, 359 adults 355, 357, 357 diagnostic approach 361 amenorrhea 361 anorexia nervosa 251 chronic renal failure 618 clinical features 356–7 congenital/idiopathic 243, 243–51, 258–9, 332–3, 354–5 anosmia 243, 332, 355 associated somatic abnormalities 243 b subunit gene mutations 247–8, 248, 249 DAX-1 mutations 245, 246 delayed puberty evaluation 357, 359 developmental neuron migration disorders 218 genetics 244–7, 245 gonadotrophs 218 gonadotropin adenoma differentiation 585, 585 gonadotropin pulsatile secretion 244, 244 gonadotropin receptor mutations 248–9 gonadotropin-releasing hormone (GnRH) pulse generator pathology 217 gonadotropin-releasing hormone (GnRH) receptor mutations 245, 247 gonadotropin-releasing hormone (GnRH) replacement 231, 232 gonadotropin-releasing hormone (GnRH) stimulation test 240 heterogeneity of presentation 244 KALIG-1 mutations 244, 245 reproductive system development 236 syndromic associations 249–50, 333 undescended testes 237 diagnostic tests 357, 360, 379 female 359 gonadotropin provocation tests 360 male 358 drug-related 252, 647 experimental models 258, 258–9 female athletes 251 fertile eunuch syndrome 333 functional 356 clinical evaluation 357–8 hpg mouse 245–7 hypophysial stalk lesions 16

hypothalamic 16, 256, 329 gonadotropin-releasing hormone (GnRH) pulsatile therapy 386, 388 obesity association 326–7 illness response 252–3, 616 iron overload 613 malnutrition 620 ob/ob mice 236 PROP 1 gene mutations 362 stress response 252 subventricular nucleus changes 7 treatment gonadotropins 260, 260–2 pulsatile gonadotropin-releasing hormone (GnRH) 262 hyponatremia 304 clinical features 306 treatment 306, 306 hypophagia 320 hypophysial portal circulation 3, 19, 320–1, 407 development 19, 45 direction of blood flow 5–6 vasopressin transport 279 hypophysial stalk lesions 16 hypophysitis 36, 351 management 415 hypopituitarism 36, 349–91 brain irradiation effects 343–4, 344, 350, 439, 474 clinical features 353–79 developmental disorders 349–50 diagnosis 379–82 etiology 349, 353 extrinsic extrasellar/parasellar disease 349 functional disorders 353 hypothalamic disorders (secondary pituitary disease) 16–17, 349 idiopathic 363, 380 inflammatory disorders 351–2 intrinsic (primary pituitary disease) 349 local mass pressure effects 468 neoplastic disorders 352–3, 380 postoperative 409, 438, 473 structural disorders 349–53 traumatic/posttraumatic 350, 363, 381 treatment 382–91 vascular disorders 350–1 hypoplasia, pituitary 36, 349, 363 hypothalamic disorders 15–18, 322 children 323 clinical features 256, 321–3 anatomic site of lesions 323, 323 Cushing’s disease 506–7, 508 hyperprolactinemia 16, 152–3, 153 infiltrative 343 pathophysiological principles 321–3 prolactinoma pathogenesis 459, 461, 461 thyroid-stimulating hormone (TSH) levels 195–6 hypothyroidism 195–6, 196, 196 hypothalamic factors 3, 321 releasing/inhibiting hormones 8, 9, 320–1 anterior pituitary regulation 8–9, 9 deficiency 16–17 excess 17–18 neuronal efferent inputs 9–10 thyroid-stimulating hormone (TSH) regulation 185–7 subunit gene transcription 175, 177, 179–80 hypothalamic hypogonadism see hypogonadotropic hypogonadism hypothalamic tumors 17, 338–43 growth hormone deficiency 363 hypothalamus 317–44 adrenocorticotropin (ACTH) expression 47, 48 age-related changes 18 anatomy 317, 318, 319 functional 10–15, 320–1 nuclei 5, 7–8, 317, 318, 318, 319 surgical 407

737

topographic 4, 5, 280 anterior pituitary function control 8–15, 320–1 hyperfunction disorders 330–2 hypofunction disorders 332–4 appetite control 318, 320 behaviour regulation 320 circadian rhythm control 320 cold receptors 318 embryology 8 gonadotropin-releasing hormone (GnRH) neuron migration from olfactory apparatus 217, 217–18 emotional expression regulation 320 functions 317–18, 320–1 glucoreceptors 320 historical aspects 3 hormones see hypothalamic factors memory processes regulation 320 nerve supply (afferent neural pathways) 6–7, 55 nucleoinfundibular pathways 7–8 osmoreceptors 317, 318 pathology see hypothalamic disorders proopiomelanocortin (POMC) expression 48 radiotherapy effects 343–4, 344 sleep–wake cycle regulation 320 syndromic disorders 334, 334–8 temperature regulation 318 vascular supply 4–5, 6, 407 visceral (autonomic) function regulation 320 warm receptors 318 water metabolism regulation 317–18 hypothermia 323 episodic/paroxysmal (diencephalic autonomic epilepsy) 326 hypothalamic disease 326 hypothyroidism adrenocorticotropin (ACTH) deficiency 370 central acquired 376–7 clinical features 377 combined pituitary hormone deficiency (CPHD) 197 congenital pituitary disorders 197–8, 375–6 diagnosic tests 373–4, 377, 377, 379 hypothalamic 16, 195–6, 196, 196, 198, 334, 376 Pit-1 mutations 197, 198 PROP-1 mutations 197, 198 thyroid-stimulating hormone (TSH) b subunit defects 180, 183, 197, 197, 386 thyroid-stimulating hormone (TSH) deficiency 197–8 thyroid-stimulating hormone (TSH) glycosylation 182 thyroid-stimulating hormone (TSH) receptor gene mutations 376 thyrotropin-releasing hormone (TRH) receptor gene mutations 375–6 differential diagnosis 377 free thyroxine (T4) levels 377 generalized resistance to thyroid hormones (GRTH) 199 gonadotropin deficiency 384 growth hormone deficiency 363, 364 hyperprolactinemia 133, 152 pituitary hyperplasia 562 pitutary function 620 somatotroph changes 21 thyroid-stimulating hormone (TSH) 183, 202, 377 assay 194, 194 circadian secretion pattern 184 glycosylation 183 subclinical disease 203 thyrotrophs 29, 29 hypoxia 318 ichthyosis, congenital 356 Id 20

738

Index

illness response adrenal function 616 adrenocorticotropin (ACTH) 616 gonadotropin suppression 252–3, 356, 616 growth hormone 616 prolactin 616 thyroid-stimulating hormone (TSH) 616 IM-9-P3 lymphoblastoid cell prolactin 129 imaging investigations 663–84 adrenal gland 528–9 corticotroph adenoma 528, 528–9, 529 gonadotropin adenoma 583 historical aspects 663–4 pituitary carcinoma 678, 679 posterior pituitary 672, 673 prolactinoma 470–1, 674 thyroid-stimulating hormone (TSH)-secreting tumors 566–7 imipramine 646, 647 immune system hypothalamic-pituitary axis interactions 66–7 prolactin effects 148–9 immunochemiluminometric assay (ICMA) gonadotropins 227–8, 238 prolactin 130 prolactinomas 455 thyroid-stimulating hormone (TSH) 565 immunocytochemistry 4 corticotroph adenoma 500, 501 vasopressin secretory pathway 279 immunofluorometric assay (IFMA) adrenocorticotropin (ACTH) 53 gonadotropins 227–8, 238 immunogold technique 4 immunoradiometric assay (IRMA) adrenocorticotropin (ACTH) 53 Cushing’s disease 502, 522–3 growth hormone 101 prolactin 130 prolactinomas 455 thyroid-stimulating hormone (TSH) 192–3, 193, 565 impotence 146, 147 incidentaloma index 410–11 in vitro fertilization 106 infarction, pituitary 350, 351 Sheenan’s syndrome 633 infections 351, 614 Cushing’s disease 515 inferior hypophysial arteries 5, 19 infertility 146, 147, 468 inflammatory disorders 36–7 hypopituitarism 351–2 infundibulum imaging 668, 672 vascular supply 4 inhibin A 233, 233 inhibin B 233, 233 inhibin-related peptides 233–4 inhibins 216, 233, 233 adenohypophysial cell production 35 gonadotropin secretion regulation 233–4 menstrual cycle 240 insect diuretic hormone 284 insomnia 328 insulin breast development 143 growth hormone secretion regulation 80, 81, 97 pancreatic secretion regulation 86 insulin resistance growth hormone deficiency 97 hyperprolactinemia 147 polycystic ovary disease 254 insulin tolerance test (insulin-induced hypoglycemia) 709–13 adrenocorticotropin (ACTH) deficiency 375 contraindications 711–12 growth hormone deficiency diagnosis 100, 716–17

adults 104 normal response 712–13, 717 insulin-like growth factor-binding protein 1 (IGFBP-1) 92, 94 acromegaly 433–4 insulin-like growth factor-binding protein 3 (IGFBP-3) 91, 92, 94, 95 growth hormone deficiency evaluation 100, 367, 369, 715–16 growth hormone therapy monitoring 389 insulin-like growth factor-binding protein-related proteins (IGFBP-rPs) 91 insulin-like growth factor-binding proteins (IGFBPs) 91–2, 94 role in growth regulation 96, 96 insulin-like growth factor-I (IGF-I) 10, 36 acromegaly 99, 420, 433, 434, 435 chronic renal failure 108 deficiency 107–8 fetal production 91 gene expression regulation 91 growth hormone deficiency evaluation 99–100, 103, 365–6, 368–9, 715 induction 90, 91, 93 metabolic actions mediation 96 secretion feedback regulation 80, 86, 87, 88 therapy monitoring 389 growth-promoting actions 94, 96 in vitro 95 longitudinal bone growth 95 systemic administration response 95–6 liver disease 619 malnutrition-related changes 620 placental production 633 structure 91, 92 synthesis 91 transgenic animal studies 420 GH 89 MTIGF-1 89 insulin-like growth factor-II (IGF-II) 91, 92 interferon-g 15 interleukin-1 (IL-1) 15, 66, 498 thyroid-stimulating hormone (TSH) effects 189 interleukin-1b (IL-1b) adrenocorticotropin (ACTH) secretion response 55 cerebral distribution/activities 15 interleukin-2 (IL-2) 67 interleukin-6 (IL-6) 15, 31, 66, 498 adenohypophysial cell production 35 adrenocorticotropin (ACTH) secretion response 55–6 thyroid-stimulating hormone (TSH) effects 189 interleukins 15 intermediate lobe see pars intermedia internal plexus see gomitoli interstitial cell-stimulating hormone (ICSH) see luteinizing hormone (LH) interstitial radiotherapy craniopharyngioma 599 Cushing’s disease 539–40 intracranial germ cell tumors 339–40 precocious puberty 340 intracranial pressure elevation 698–9 intrasellar gangliocytoma 331 intrasellar meningioma 414 iodinated contrast agents 666 iodine deficiency 203 iodine metabolism 191 ioxapine 325 iron overload 613 Jackson dwarf mouse 37 Pit-1 mutations 197 JAK2 143 JAK/STAT signaling adrenocorticotropin (ACTH) regulation 50, 53 growth hormone receptor (GHR) 90

prolactin receptor 143 jet lag 82 joining peptide 496, 502 POMC gene structure 48 proopiomelanocortin (POMC) precursor 49, 50, 52 C-terminal amidation 51 juvenile primary hyperthyroidism 192 KAL mutations 16, 332, 354, 355 KALIG-1 218 idiopathic hypogonadotropic hypogonadism 244, 245 Kallmann’s syndrome 16, 354, 354–5 anosmia 243, 332, 355 gonadotroph changes 30 see also hypogonadotropic hypogonadism, congenital/idiopathic keratinocytes 57 ketoconazole 409, 543, 650 kidney, prolactin effects 148 Kline–Levin syndrome 329 Klinefelter syndrome 601 Korean hemorrhagic fever 614 Korsakoff ’s psychosis 329 !Kung San of Botswana 236, 238 L-asparaginase 649 L-dopa 377, 379, 648 growth hormone release regulation 84 L-dopa stimulation test growth hormone assessment 100, 717–18 prolactinoma 461, 461 labetolol 648 labor 633, 645 lactation 633 central diabetes insipidus amelioration 636 inappropriate 144 lactotroph hyperplasia 24, 119 oxytocin gene transcription stimulation 281 pituitary hyperplasia 18 prolactin actions 144 prolactin levels 132, 132 suckling episode-related release 132 vasopressin gene transcription stimulation 281 lactational amenorrhea 132 sub-Saharan Africa 251–2 lactotroph 23–4, 407 calcium-mediated responses 124 development 20, 24, 79, 80, 121 differentiation regulation 20 dopamine actions 11 dopamine D2 receptors 135 electron microscopy 23, 23–4, 120 estrogen receptor a expression 23 estrogen response 124 GH transgenic animals 89 histology 4, 120 immunocytochemistry 23, 23 morphology 119–20 Pit-1 expression 23, 79, 121, 123 pregnancy/lactation-related hyperplasia 24, 124, 628 prolactin phosphorylation (granule prolactin kinase) 128 readily releasable/storage pools 129 secretion 23, 119, 120, 120 prolactinomas 461–2 suppression 24, 120 vasoactive intestinal peptide (VIP) production 35 lactotroph adenoma see prolactin-producing adenoma Langerhans cell histiocytosis 343, 352, 356, 363, 603, 603, 604, 614–15 clonality studies 603 histology 603 imaging investigations 681 lanreotide 412 acromegaly 442 somatostatin receptor (SSTR) binding 86

Index thyroid-stimulating hormone (TSH)-secreting tumors 569 Laron syndrome 363 growth hormone binding protein (GHBP) levels 90 insulin-like growth factor-I (IGF-I) deficiency 107–8 lateral nuclei 7 lateral preopetic area osmoreceptive cells 286 Laurence–Moon syndrome 333, 336 Laurence–Moon–Biedl syndrome 250, 356 lazy pituitary syndrome 363, 364 lean body mass, growth hormone actions 97, 98, 98 leiomyoma 605 leptin 60 energy balance–reproductive function linkage 234, 236 gene mutations 355 growth hormone secretion regulation 83, 83–4 puberty initiation 236 receptor mutations 354, 355 lergotrile 482 leukemia 602 hypothalamic infiltration 343 leukemia-inhibitory factor (LIF) 50 leukemia-inhibitory factor (LIF) receptor 50 Leydig cells 216 LH receptors 224 testosterone synthesis 224 Lhx3 20, 46, 121, 173, 176, 218 mutations 46 combined pituitary hormone deficiency 250–1 Lhx4 20, 218 libido reduction, hyperprolactinemia 146, 147 light–dark 24-h cycle 10 LIM homeobox gene expression 20, 121, 173, 176 linear accelerator (LINAC) radiotherapy gonadotropin adenomas 588 postoperative 409 prolactinoma 475 lipid metabolism 97–8 lipofuscin accumulation 18 lipolysis adrenocorticotropin (ACTH) actions 59–60, 510 growth hormone actions 97 lipotrophic hormone (LPH) actions 510 lipoproteins adrenocortical cell uptake 58 adrenocorticotropin (ACTH)-stimulated metabolism 58 growth hormone actions 97 lipotrophic hormone (LPH) corticotroph production 25 Cushing’s disease diagnosis 523, 524 lisuride 482 lithium 647 acquired diabetes insipidus 300 liver, growth hormone actions 10 liver disease pituitary changes 619 see also cirrhosis long portal vessels 5, 6, 19, 279 loral (trabecular) arteries 5, 19 low birth weight, growth hormone therapy 102–3 lower body negative pressure (hemorrhage simulation), adrenocorticotropin (ACTH) response 66 lung tumors, ectopic adrenocorticotropin (ACTH) secretion 68 luteinizing hormone (LH) 216–65 age-related changes 238, 239, 239, 617 a subunit 218, 219, 220 gene structure/organization 221–2 gonadotropin-releasing hormone (GnRH) response 230 synthesis 221 assay 226–9, 227, 718–19 bioassays 228 free a-subunit secretion 228

gonadotropin adenoma diagnosis 583, 584, 585 radioimmunoassay (RIA) 216, 227, 227 receptor-binding assay 228 two-site-directed immunoassays 227–8 b subunit 219 gene structure/organization 222, 223 gene transcription regulation 223, 230–1 gonadotropin-releasing hormone (GnRH) response 230–1 mutations causing hypogonadism 247–8, 249, 355 promoter estrogen responsive element 223 synthesis 221 biologic role 224, 224–6 female 226 male 224–6 childhood levels 237–8 commercial preparations 260 corticotroph adenoma secretion 505 evolutionary aspects 220–1 fetus 236 reproductive system development 236 testicular descent 236–7 gonadotroph secretion 29, 218 gonadotropin-releasing hormone (GnRH) regulation 11, 230–1 gonadotropin-releasing hormone (GnRH) stimulation test 240–1 isoform microheterogeneity 229 menstrual cycle 239, 240 ovulatory surge 239 obesity-related changes 618 pregnancy 630, 631 pulsatile release 231, 240 hyperprolactinemia inhibition 145 puberty 238 pulse pattern detection 241–2 secretion regulation 229, 229–36 starvation (undernutrition) reponse 234, 236 structure 218–20, 220 structure–activity relationships 219–20 subunit glycosylation 221 luteinizing hormone (LH) deficiency brain irradiation effects 344, 344 PROP-1 mutations 197, 218, 250 luteinizing hormone (LH)-secreting tumor see gonadotropin adenoma luteinizing hormone (LH)/chorionic gonadotropin receptor 217, 224, 225 activating mutations gonadal tumors 248–9 sexual precocity 248, 249 inactivating mutations with hypogonadism 248, 249 ovarian luteal cells 226 luteinizing hormone-releasing hormone (LHR) see gonadotropin-releasing hormone (GnRH) LVP test 526 17,20-lyase 58, 226 Lyme disease 614 lymphoblastoid cell prolactin 129, 148 lymphocytic hypophysitis 36–7, 351, 415, 415, 615, 634–5 adrenocorticotropin (ACTH) deficiency 370 diagnosis 381 hyerprolactinemia 37 hypothyroidism 376 management 415 pathogenesis 634 presentation in pregnancy/postpartum 634, 637, 703 prolactin deficiency 379 treatment 634–5 visual complications 703 lymphoma 602 McCune–Albright syndrome 17, 257, 264, 565 acromegaly 425, 435

739

adrenal cortex protein kinase A activation 59 gigantism 426 hypercortisolism 514 mammosomatotroph hyperplasia 25 precocious puberty 330 Maffuci syndrome 597 magnetic resonance angiography 406 magnetic resonance imaging (MRI) 663–4, 668–80, 669, 670, 671, 672, 673 acromegaly 435 computerized tomography (CT) comparison 684 craniopharyngioma 669, 681, 681 Cushing’s disease adrenal gland 528–9 pituitary 528, 529 Cushing’s syndrome 528–9 empty sella syndrome 684 gadolinium enhancement 675–7, 676 gonadotropin adenoma 583 hypothalamic disorders 322 intraoperative 416 meningioma 681 normal anatomy 670–2 pituitary carcinoma 678, 679 pituitary microadenomas 674–5 pituitary size/shape 674, 674 pituitary tumors 406 posterior pituitary 679–80 prolactinoma 470 Rathke’s cleft cyst 680, 680 technical factors 668–9 dynamic scanning 669–70 thyroid-stimulating hormone (TSH)-secreting tumors 567 magnocellular neurons 7, 12, 12, 13, 279 vasopressin synthesis/processing 279, 280, 317 male contraceptives 264–5 malnutrition growth hormone/insulin-like growth factor-I (IGF-I) levels 107 hypogonadotropic hypogonadism 620 pitutary function 620 see also obesity; undernutrition mamillary nuclei 8 mamillotegmental tract 7 mamillothalamic tract 7 mammary gland casein production assay 130 mammosomatotroph 22, 24–5, 120 development 20, 79 differentiation regulation 20 electron microscopy 24–5, 25 growth hormone secretion 120–1 hyperplasia 25 prolactin secretion 120–1 mammosomatotroph adenoma 25 acidophil stem cells 33 mammotroph see lactotroph Marcus Gunn pupil see afferent pupillary defect marijuana 252, 644–5 mass effects 36, 410 anatomic considerations 687–8 clinical features 426 germ cell tumors 602 gonadotrope dysfunction 256 gonadotropin adenoma 582 metastatic tumors 604 prolactinomas 467–8 effects of pregnancy 483–4 somatotroph adenomas 426 symptoms 689–91 thyroid-stimulating hormone (TSH)-secreting tumors 565 meclastine 648 meclofenamate 189 medial nuclei 7 median eminence 4, 6, 7 median forebrain bundle 6, 7 medroxyprogesterone acetate 387 megestrol acetate 372

740

Index

melanocortin 1 receptor (MC1R) 56, 57 melanocortin 2 receptor (MC2R) 56, 57–8 adipocytes 59, 60 familial glucocorticoid deficiency syndrome 59 mutations 59 skin cells 60 melanocortin 3 receptor (MC3R) 57, 60 melanocortin 4 receptor (MC4R) 57, 60–1, 63 melanocortin 5 receptor (MC5R) 57, 61 adipocytes 60 melanocortin receptors 56, 57–8 agouti protein antagonism 61–2 lethal yellow phenotype 62 agouti-related protein (AGRP) antagonism 63 behaviour mediation 63 cAMP second messenger 56 corticostatins antagonism 63 ligand specificity 57 melanocytes 57 melanoma 605 melatonin 141 melphalan 649 memory disorders 329 memory processes regulation 320 menarche body weight linkage 234 delay in ballet dancers 251 MENIN 425 meningioma 36, 342, 363, 599, 599 acromegaly association 432 clinical features 599 imaging investigations 664, 681, 683 intrasellar 414 parasellar 414 pathology 599 postradiotherapy tumors 605 suprasellar 414 treatment 414, 599 menopause 617, 718 prolactin levels 131 subventricular nucleus changes 7, 18 menstrual cycle 239–40 estradiol 239, 240 follicle stimulating hormone (FSH) 239, 240 inhibin 240 luteinizing hormone (LH) 239, 240 ovarian changes 239 progesterone 239, 240 prolactin 131 menstrual disorders female athletes 251 stress response 252 mesulergine 482 metabolic clearance rate (MCR) 130 metaclazepam 646 metastasis, germ cell tumors 602 metastatic tumors 36, 264, 353, 415, 603–4, 615 clinical features 604 imaging investigations 681 metastasis into pituitary adenoma 604 treatment 604 metergoline 482 methadone 645 methionine enkephalin (met-enkephalin) 15, 56 methyldopa 648 methylphenidate 646 methysergide 138 metoclopramide 134, 149, 377, 562, 647–8 metyrapone test 375, 525–6, 713 adverse events 713 normal response 713 metyrapone therapy 409, 543, 636 micturition 320 middle cerbral arteries 672 middle hypophysial arteries 5, 19 milk ejection 633 mixed adenoma–gangliocyoma 595 molecular probes 4 monoamine oxidase inhibitors 647

hyperprolactinemia 150 morphine 139, 645 motilin 84 mouse interstitial cell testosterone assay (MICT) 228 Msx1 176 mucopolysaccharidosis 37 multiple blood transfusions 613 multiple endocrine neoplasia (MEN) type I 352, 595, 615 acromegaly 425, 433 Cushing’s disease 506 prolactinomas 465 multiple endocrine neoplasia (MEN) type IIa (Sipple’s syndrome) 68, 615 multiple lentigenes syndrome 250, 356 multiple sclerosis 326, 327, 329, 330 mutiple myeloma 666 myopathy 431 myotonia dystrophica 379 N-terminal pro-opiomelanocortin peptide 496, 502, 509, 523 adrenal proliferation stimulation 58 assay 53 glycoslyation 500 mRNA expression in nonpituitary tissue 49 POMC gene structure 48 proopiomelanocortin (POMC) precursor 49, 50, 52 C-terminal amidation 51 nalfemene 645 naloxone 645 naloxone test (LH stimulation test) 241 nalrexone 645 narcolepsy 329 nasopharyngeal carcinoma 681 Nb2 Node rat lymphoma cell prolactin assay 130 nefazodone 647 Nelson’s syndrome 413, 505, 511, 518, 528, 544–5 adrenocorticotropin (ACTH)-secreting adenoma 67 definition 544 hyperpigmentation 52, 510, 545 management 413 medical treatment 540 prevalence 544 nephrogenic diabetes insipidus see diabetes insipidus nerve palsies 36 neuro-ophthalmologic evaluation 687–706 tumor monitoring 700–2 NeuroD/b2 20 corticotroph expression 46 corticotroph POMC expression 48 neurofibromatosis type 1 415 gliomas 599, 600 neurogenic (Cushing’s) ulcers 329–30 neuroleptic malignant syndrome 325 neuroleptics 647 hyperprolactinemia 149–50 neurologic syndromes 256 neuromedin 14 neuronavigation 416 neuropeptide Y (NPY) 14 adenohypophysial cell production 34–5 brain distribution 14 energy balance–reproductive function linkage 234, 236 leptin effects 83–4 neurophysin I 12 neurophysin II 12 neurophysins 285, 317 assay 292 corticotrophs 47 neuropsychiatric syndromes 256 neurosecretion 3 neurosurgical trauma 350 neurotensin 14 adenohypophysial cell production 35

brain distribution 14 growth hormone release stimulation 84 prolactin secretion effects 140–1 somatotrophin release-inhibiting factor release regulation 86 thyroid-stimulating hormone (TSH) secretion effects 187 nifedipine 127, 648 nimodipine 127 nizatidine 648, 649 Nkx2.1 (T/ebp; Tff1) null mutations 47 nociceptin (orphanin FQ) 139 non functioning pituitary adenomas 410–11 surgical treatment 411, 411 see also null cell adenomas nongerminomatous germ cell tumors 339, 416 nonscrotal patch 385 nonsteroidal anti-inflammatory agents (NSAIDs) 189 Noonan’s syndrome 102 norepinephrine growth hormone release effects 84 vasopressin release stimulation 285, 289 nortriptyline 647 nucleus intracalatus 8 null cell adenomas 36, 410 see also non functioning pituitary adenomas null cells 31–2 electron microscopy 32, 32 nutritional growth hormone release regulation 82 ob 234 leptin gene product 83 ob/ob mice 236, 259 obesity 7, 254–5, 321 agouti locus lethal yellow mutation 61, 62 Cushing’s disease 514, 516, 517 diagnostic problems 530 female reproductive function 254–5 weight reduction effects 255 gonadotropin deficiency 384 growth hormone release response 82, 83 hypothalamic 326 associated clinical findings 326–7 hyperphagia 327 male androgen levels 254 male gonadotropin-releasing hormone (GnRH) 254 melanocortin receptor defects 60, 61 pituitary function changes 617–18 obstructive lung disease 253 Oct-1 80 Oct-2 80 octreoscan 424, 425 octreotide 21, 94, 186, 412, 413 acromegaly 440–2, 441, 442, 443, 444, 445 pregnant patient 636 preoperative treatment 444–5 Cushing’s disease 540 gonadotropin adenomas 589 somatostatin receptor (SSTR) binding 86, 86 somatotroph adenoma response 22, 23 thyroid-stimulating hormone (TSH)-secreting tumors 568–9, 569, 570 octreotide stimulation test 566 oculomotor nerve (cranial nerve III) 668 compression 690, 700 pituitary apoplexy 700 imaging 668 radiation neuropathy 702 olfaction 7 testing 357 olfactory apparatus, fetal GnRH neuron migration into hypothalamus 217, 217–18 olfactory-genital dysplasia see hypogonadotropic hypogonadism, congenital/idiopathic Ollier disease 597 oncocytes 32–3 electron microscopy 32, 33, 33

Index oncocytoma 32, 36 op’DDD Cushing’s disease 529, 530, 541–3, 542 side effects 541 ophthalmoplegia 700 opioid antagonists 645–6 opioids 645 adrenocorticotropin (ACTH) secretion modulation 56 growth hormone release effects 84 hyperprolactinemia 150 prolactin secretion stimulation 138–9 thyroid-stimulating hormone (TSH) secretion regulation 187 vasopressin release regulation 289–90 optic atrophy 697, 697–8, 698, 699 optic chiasma 407, 668, 668–9 anatomic variability 668, 668 compression-related visual loss 692–5 imaging 668, 672, 673 radiation neuropathy 702 retinotopic organization 668, 690 optic chiasma glioma 340, 340–1, 415 optic nerve 668–9 compression 692, 695 junctional syndrome 692, 694 imaging 668 radiation neuropathy 702 retinotopic organization 668, 690 optic nerve glioma 325 optic nerve hypoplasia 363 optic pathway compression 694, 696 optic pathway gliomas 599–601 imaging investigations 681 optic sheath meningioma 414 optico-hypothalamic glioma 415 oral contraceptives Cushing’s disease diagnostic problems 529 prolactinoma relationship 458–9, 459 oral hypoglycemic drugs 650 Org2766 57 organ failure, growth hormone therapy 105 organum vasculosum of lamina terminalis (OVLT) 279 osmoreceptive cells 286 vascular supply 4 orgasmic dysfunction 146 orphanin FQ (nociceptin) 139 osmoreceptors 279, 317 blood–brain barrier 286 cell identification 286 central 285 circumventricular organ 286 extracerebral 285–6 hypothalamus 317, 318 signal transduction via stretch inactivated cationic channels 286, 287 osmoregulation 317–18 plasma osmolality/thirst/plasma sodium regulatory feedback system 301, 721 prolactin actions in lower animals 148 osmotic stimulation oxytocin gene transcription response 281 vasopressin gene transcription response 281 vasopressin secretion regulation 285–8 threshold for release 286–8, 287 osteoporosis, growth hormone therapy 105–6 ovarian tumors cortisol-secreting 514 gonadotropin receptor activating mutations 248–9 ovary follicle stimulating hormone (FSH) actions 226 gonadotropin adenoma hyperstimulation 583, 583 luteinizing hormone (LH) actions 226 menstrual cycle changes 239, 240 prolactin effects 145–6 steroid synthesis 226 ovulation induction 387

gonadotropin-releasing hormone agonist analogs 265 growth hormone therapy 106 obesity 255 oxytocin 7, 12 adrenocorticotropin (ACTH) secretion regulation 56 assay 292 axonal transport of precursors 285 evolutionary aspects 284 fetal hypothalamus 8 gene regulation 281 gene structure 280 historical aspects 3 labor 633 mediators of release 285 milk ejection 633 neurophysin I 285 opiate effects 645 postpartum period 633 pregnancy 628, 633 prolactin secretion stimulation 139–40 structure 284, 284, 284 synthesis 7, 12, 279 thyroid-stimulating hormone (TSH) responses 187 oxytocin deficiency 17 oxytocin receptors 290 P-LIM see Lhx3 pain perception 13, 14, 15, 48 paired-like homeobox genes 46 Pallister–Hall syndrome 339, 363, 593 pancreatic islet cells somatostatin secretion 10 thyrotropin-releasing hormone (TRH) localization 11 pancreatic islet tumors adrenocorticotropin (ACTH) secretion 68 growth hormone-releasing hormone (GHRH) secretion 423, 424 panhypopituitarism, familial 333, 334 papilledema 698–9 paraganglioma 36, 605 paraneoplastic syndromes 343 parasellar meningioma 414 parasellar region anatomy 687–8 parasympathetic nervous system 7, 320 parathyroid-like hormone 144 paraventricular nuclei 3, 7, 279 corticotropin-releasing hormone (CRH) 11, 55 dopamine 11 embryology 8 glucocorticoid receptors 56 magnocellular neurons 7, 279, 286, 317 osmoreceptive cells 286 oxytocin synthesis 7, 12 parvicellular neurons 7 prosomatostatin synthesis 86 thyrotropin-releasing hormone (TRH) 185 vascular supply 4 vasopressin synthesis/release 7, 11, 12, 13, 285, 286, 317 pargyline 647 Parinaud’s syndrome 697 Parkinson’s disease 326 paroxysmal hyperthermia 326 paroxysmal hypothermia (diencephalic autonomic epilepsy) 326 pars distalis (anterior lobe) 18, 407 pars glandularis see pars distalis pars infundibularis see pars tuberalis pars intermedia 18, 407 corticotroph adenoma 506 corticotrophs 25, 27 development 45 rodent/human differences 47 pars tuberalis 6, 18, 407 parvicellular neurons 7 vasopressin secretory pathway 279

741

penfluridol 127 penile erection 63 peptide growth factors 15, 15 peptide histidine isoleucine (PHI) growth hormone release stimulation 84 prolactin secretion stimulation 137–8 peptide histidine methionine (PHM) 137–8 peptidyl-a-hydroxyglycine a-amidating lyase (PAL) 51 peptidylglycine-a-amidating monooxygenase (PAM) 51 pergolide 480–1 pharyngeal pituitary 45, 363, 593 phenothiazines 134, 149, 647 neuroleptic malignant syndrome 325 phentolamine 648 phenytoin 530, 650 pheochromocytoma adrenocorticotropin (ACTH) secretion 68 growth hormone-releasing hormone (GHRH) secretion 424 phosphoinositide-protein kinase C pathway 126 physostigmine 648 pigeon crop prolactin assay 119, 130 pigmentation agouti locus 61 lethal yellow mutation 62 melanocortin 1 receptor (MC1R) activation 57 melanocortin receptor defects 61 see also hyperpigmentation pilocytic astrocytoma 600, 600 pimozide 127 pineal germinoma 324, 331 pineal nongerminomatous germ cell tumors 339 pineal tumors 17, 325 pinealoma 324 piperoxan 142 pirenzepine 142, 648 Pit-1 20, 79–80, 218 b subunit gene promoter binding 174, 175 expression during development 46, 121 growth hormone gene regulation 80, 81 lactotroph expression 23 mammosomatotroph expression 24 prolactin gene binding site 123 structure 123 thyrotroph expression 29, 173, 561 TSH b subunit gene transcription regulation 561 Pit-1 mutations 36, 173, 217, 218, 219, 220, 250, 465 combined pituitary hormone deficiency (CPHD) 197 congenital hypothyroidism/primary TSH deficiency 197, 198 growth hormone deficiency 37, 362 Jackson dwarf mouse 197 pituitary cell differentiation disorders 250 prolactin deficiency 362, 379 Snell dwarf mouse 197 thyroid-stimulating hormone (TSH) deficiency 362, 376 pituitary adenylate cyclase activating polypeptide (PACAP) 141 pituitary compression symptoms see mass effects pituitary function evaluation 709–23 pituitary glycoprotein hormone basal element (PGBE) 176 pituitary resistance to thyroid hormones (PRTH) 199, 200 clinical features 201–2 thyroid receptor (TR) abnormalities 199, 201 treatment 202 pituitary stalk 407 vascular supply 4, 5 pituitary stalk lesions hyperprolactinemia 16, 152–3 pituitary infartion 351

742

Index

pituitary tumors growth hormone deficiency 363 hypopituitarism 352, 380 pizotifen 138 placental a subunit gene expression 176 placental prolactin-like proteins 128 plain X-ray 663 pituitary tumors 406 plasma osmolality/thirst/plasma sodium regulatory feedback system 301, 721 plasmacytoma 602–3 platelet activating factor 141 pleasure center 320 pleurihormonal adenoma 67 Pneumocystis carinii 614 pneumoencephalography (PEG) 663 empty sella imaging 683–4 poikilothermia 326 poliomyelitis 326 polycystic ovary disease 618 androgen serum levels 254 body composition 254 genetic factors 254 gonadotropin secretion abnormalities 253–4 gonadotropin-releasing hormone agonist analogs 265 insulin resistance 254 prolactin levels 146 polydipsia 324 diabetes insipidus 16, 292, 296, 300 primary 300–1 diagnostic testing 301–4 polyglandular syndromes 615–16 polyposis coli 432 polyuria diabetes insipidus 16, 292, 294, 296, 300, 324 diagnostic testing 301–4 posterior pituitary function assessment 721–3, 722 differential diagnosis 293–4 pregnancy 301 primary polydipsia 300–1 POMC (proopiomelanocortin) 48 expression 496, 497 corticotroph adenoma (Cushing’s disease) 501–3, 502 tumor adrenocorticotropin (ACTH) secretion 512, 512–13 mutations 61, 62, 369, 370 polyadenylation 49 posttranslation modification defects 370 promoter 48 regulation 49–50 structure 48, 496 transcription/splicing 48–9, 49, 496 posterior hypothalamic nucleus 8 posterior pituitary 279–306, 407 anatomy 279, 280 surgical 407 embryology 8 function evaluation 721–3 basal measurements 721 dynamic tests 721–3, 722 hypertonic saline test 722–3 water deprivation tst 721–2 imaging 672, 673, 679–80 vascular supply 4–5, 6 posterior pituitary disorders 15–18 pregnancy 636–7 postfixation blindness 690, 691 postpartum alactogenesis 379 postpartum amenorrhea 132 postpartum hypopituitarism 7, 18 postpartum period central diabetes insipidus 637 oxytocin 633 prolactin 629, 629 thyroid-stimulating hormone (TSH) deficiency 376

postpartum pituitary necrosis see Sheehan’s syndrome postpill amenorrhea 252 postradiotherapy tumors 604–5 Pou 1 mutations 217 POU homeodomain transcription factors 121, 123, 173, 218 POUIFI protein 79, 80 Prader orchidometer 357 Prader–Willi syndrome 249–50, 333, 334–5, 355–6 clinical features 335 prazosin 648 precocious puberty 321, 322, 323, 330–1 causes 330, 330 ectopic gonadotropin-releasing hormone (GnRH) secretion 256 germ cell tumors 340, 602 gonadotropin adenoma 583 gonadotropin-dependent (true/central form) 257 gonadotropin-releasing hormone agonists 264 growth hormone neurosecretory dysfunction 102 hypothalamic hamartomas 330–1, 338, 593 hypothalamic lesions 17, 256 incomplete 330 juvenile primary hyperthyroidism 192 luteinizing hormone receptor activating mutations 248, 249 prednisone 382, 383 pregnancy 628–37 acromegaly 636 amenorrhea evaluation 360, 361 anatomical changes 628 Cushing’s disease 517–18 diagnostic difficulties 529 Cushing’s syndrome 635–6 pituitary–adrenal function tests 635 diabetes insipidus 301, 636–7 hormonal changes 628–33, 629 hypercortisolic state 532–3 lactotroph hyperplasia 24, 119, 124 lymphocytic hypophysitis 634–5, 637, 703 pituitary hyperplasia 18 polyuric states 301 prolactin serum levels 131, 131–2 prolactinoma 482–5 dopamine agonist effects 482, 483, 483 effects on tumor size 119–20, 483, 483–5, 484 management approach 485–6 subventricular nucleus changes 18 visual complications 703 premature adrenarche 58 prepro-AVP-NPII gene 279 prepro-OX-NPI gene 279 preproenkephalin A 48 preproenkephalin B (dynorphin) 48 progesterone biosynthesis, prolactin effects 145 breast development 143 gonadotropin secretion regulation 233 menstrual cycle 239, 240 prohormone convertase 1 (PC1) 51, 52 gene mutations 51 prohormone convertase 2 (PC2) 51, 52 7B2 protein association 52 prolactin 119–54 acidophil stem cells production 33 age-related changes 131, 617 alcohol effects 644 assay 119, 129–30 chemiluminometric (ICMA) 130 immunoradiometric (IRMA) 130 large prolactinomas 130, 455–6 mammary gland casein production 130 Nb2 Node rat lymphoma cell 130 pigeon crop 119, 130 radioimmunoassay (RIA) 129–30 assessment tests 715 basal levels 715 thyrotropin-releasing hormone (TRH) stimulation test 715

biosynthesis 127–9 cleavage products 127 glycosylation 128, 129 large molecular weight polymers 128 phosphorylation 128 posttranslational modification 127, 128 primary translation product 122, 127 brain irradiation effects 344, 344 breast disease 619, 620 corticotroph adenoma secretion 505 decidual 128–9 development 20, 24 drug effects 643 dopamine D2 receptor antagonists 647 ectopic secretion 152 excessive secretion see hyperprolactinemia gene 5¢ flanking region 122, 123 calcium response element 124 cAMP responsive element 124 chromosome location 122 estrogen-response element 123 glucocorticoid response element 124 Pit-1 binding site 123 regulation 124–7, 125 structure 122, 122 thyroid hormone response elements 123–4 tissue specific enhancers 123 historical aspects 119 knock out mouse studies 144–5, 146, 148, 149 lactation 132, 132 lactotroph readily releasable/storage pools 129 lactotroph secretion 23, 119–21, 120, 120 lymphoblastoid cell 129, 148 mammosomatotroph secretion 24, 120–1 menstrual cycle changes 131 metabolic clearance rate (MCR) 130 neuroendocrine regulation 133–42, 134 prolactin inhibitory factors (PIFs) 133, 133–6 prolactin-releasing factors (PRFs) 136–42 short loop feedback 142 obesity-related changes 618 opiate effects 645 physiologic actions 130–3, 142–9 adrenal cortex 147 bone metabolism 147 breast 143–4 carbohydrate metabolism 147–8 gonadotropin secretion 144–5 immune system 148–9 kidney 148 ovary 145–6 testes 146–7 placental variant 128 postpartum 629, 629 pregnancy 131, 131–2, 628–9, 629 production rate (PR) 130 prolactin receptor interaction 143, 143 pulsatile secretion 130–1, 131 amino acid ingestion response 131 sleep response 131 secondary/tertiary hypothyroidism differentiation 198 secretion dynamics in prolactinoma 462, 462–3, 463 secretion regulation angiotensin II 126, 127 arachidonate pathways 126 cAMP 125–6 dopamine 126, 127 estrogen 124 glucocorticoids 125 intracellular calcium 124, 126–7 phosphoinositide-protein kinase C pathway 126 thyroid hormones 125, 133 thyrotropin-releasing hormone (TRH) 11, 126, 127 vasoactive intestinal peptide (VIP) 12, 126 stress/illness response 132–3, 148, 150, 616

Index suckling response 630, 630 uremia-related changes 618 prolactin deficiency 149, 379, 391 acquired 379 congenital 379 diagnostic tests 379, 380 Pit-1 mutations 197, 218, 250, 362, 379 PROP-1 mutations 197, 218, 250, 362, 379 prolactin inhibitory factors (PIFs) 10–11, 133, 133–6 prolactin kinase 128 prolactin receptors 142–3, 143, 144 gene structure 142 knock out mouse studies 144–5, 147, 148, 149 prolactin-producing adenoma see prolactinoma prolactin-releasing factors (PRFs) 136–42 prolactinoma 410, 411, 455–86 adrenocorticotropin (ACTH)-secreting tumors 466 animal models 466–7 classification 455–6 clinical features 411, 455, 456, 468–71 children/adolescents 469–70, 470 men 469, 469 women 468, 468 clonality 464 estrogen-induced 466–7 fertility restoration 485 follicle stimulating hormone (FSH) secretion 466 frequency in autopsy studies 456, 457 galactorrhea 146 gonadotroph changes 30 grading 455, 456 growth hormone-secreting tumors 466 historical aspects 455 hyperprolactinemia differential diagnosis 470 imaging investigations 470–1, 674 microadenomas 331–2, 456–7, 457 management 482 observation 471 mixed growth hormone-cell/-prolactin-cell adenomas 420–1 multiple endocrine neoplasia type I 465 natural history 456–8, 458 oral contraceptive use relationship 458–9, 459 pathogenesis 459–65, 460 hypothalamic dopamine defect 459, 461, 461 lactotroph hyperplasia 461–2 pathology 465–6 pituitary mass pressure effects 467–8 pregnancy 482–5 effects on tumor size 119–20, 483, 483–5, 484 prolactin assays 130, 407 prolactin secretion dynamics 462, 462–3, 463 suppressed lactotrophs 24 thyroid-stimulating hormone (TSH) secretion 466 treatment 471–82 dopamine agonist therapy 121, 411, 475–82, 476, 477 indications 471 macro/microadenomas 482 radiotherapy 473–5, 474, 482 recurrence rates 473 surgery 411, 411, 412, 462, 462–3, 463, 463–4, 464, 471–3, 472, 473, 478–80, 479, 482 tumorigenic mutations 464, 464–5 see also hyperprolactinemia proopiomelanocortin (POMC) 48 corticotroph production 25, 26, 27 molecular aspects 46, 47 corticotropin-releasing hormone (CRH) actions 11 extracerebral synthesis 48, 53, 498 ectopic ACTH-secreting tumors 68 gene see POMC hypothalamic expression 48 precursor biosynthesis 50–3, 496 C-terminal amidation 51, 497 glycosylation 51, 497 N-terminal acetylation 51

product terminology 50 proteolytic enzymes 51–2 proteolytic processing 51–3, 496, 497 precursor domains 49, 50 sorting into secretory granules 52 proopiomelanocortin (POMC) CRH responsive element (PCRH-RE) 50 proopiomelanocortin (POMC) peptides 15 Cushing’s disease diagnosis 523, 524 differentiation from ectopic ACTH syndrome 524 PROP-1 20, 80, 121, 173, 218 expression during development 46 PROP-1 mutations 36, 46, 173, 217, 218, 219, 220, 465 combined pituitary hormone deficiency (CPHD) 197, 198 congenital hypothyroidism/primary TSH deficiency 197, 198 gonadotropin deficiency 362 growth hormone deficiency 362 hypogonadotropic hypogonadism 354, 355, 362 pituitary cell differentiation disorders 250 prolactin deficiency 362, 379 thyroid-stimulating hormone (TSH) deficiency 362, 376 propranolol 568, 648 growth hormone deficiency provocative testing 100 protein kinase A adrenocorticotropin (ACTH) regulation 53, 54 McCune-Albright syndrome 59 thyroid-stimulating hormone (TSH) actions 191 protein kinase C adrenocorticotropin (ACTH) regulation 53, 54 prolactin gene transcription regulation 124, 126, 127 thyroid-stimulating hormone (TSH) actions 191 protein metabolism, growth hormone actions 97 proton-beam radiotherapy acromegaly 439 Cushing’s disease 539 PrRP31 140 pseudocyesis (false pregnancy) 337–8 pseudohypoparathyroidism 356 type 1b 379 pseudoisochromatic plates 697 psychological morbidity acromegaly 431 Cushing’s disease 515–16 psychosocial dwarfism (environmental deprivation syndrome) 337, 337, 363, 364 PTTG 423, 465 Ptx 173 Ptx1 20, 61, 176 corticotroph expression 46 corticotroph POMC expression 48 PTX1/P-OTX 121 Ptx2 20 corticotroph expression 46 Ptx2a 250 Ptx2b 250 puberty adrenocorticotropin (ACTH) 66 body weight linkage 234 delayed ballet dancers 251 male 357–9 Pit-1 gene mutations 362 prolactinoma 469 development (Tanner staging) 719, 720 gonadotropins 238 growth hormone 82 leptin in initiation 236 obese girls 255 pulsatile release adrenocorticotropin (ACTH) 63 circadian rhythms 64 chorionic gonadotropin 257

743

gonadotropin pulse pattern detection 241–2 gonadotropin-releasing hormone (GnRH) 216, 259 gonadotropin secretion regulation 229–31, 230 LH b subunit transcription induction 223 growth hormone 82, 86, 87, 99 acromegaly 422 starvation response 82, 82 luteinizing hormone (LH) 231, 240 puberty 238 prolactin 130–1, 131 thyroid-stimulating hormone (TSH) 183–4, 184 pulse generator pathology 217 pupillary abnormalities 697 pyridostigmine 648 quetiapine 647 quinagolide 481 quipazine 138 radioimmunoassay (RIA) adrenocorticotropin (ACTH) 53 Cushing’s disease diagnosis 522 follicle stimulating hormone (FSH) 216, 227, 227, 238 growth hormone 101 luteinizing hormone (LH) 216, 227, 227, 238 neurophysins 292 oxytocin 292 prolactin 119, 129–30 prolactinomas 455 thyroid-stimulating hormone (TSH) 192, 561, 565 vasopressin 291 radiotherapy acromegaly 439, 440 chordoma 596 complications 439, 474–5, 589 growth hormone deficiency 363 ocular motor palsy 702 postradiotherapy tumors 604–5 visual loss 702 craniopharyngioma 599 Cushing’s disease 539–40 effects on hypothalamus 343–4, 344 effects on pituitary 350, 363, 381 germ cell tumors 416, 602 gonadotropin adenomas 588, 588–9 hypothalamic hypothyroidism 376 prolactinoma 473–5, 474, 482, 485 thyroid-stimulating hormone (TSH)-secreting tumors 568 see also gamma knife stereotactic radiosurgery; linear accelerator (LINAC) radiotherapy rage 7, 320, 329 raloxifene 649 ranitidine 141, 648, 649 rat interstitial cell testosterone assay (RICT) 228 Rathke’s cleft cyst 152, 350, 414, 593–4, 594 imaging investigations 680, 680 surgical treatment 414 Rathke’s cleft tumor 50 Rathke’s pouch 8, 18, 19, 20, 79, 121 a subunit gene expression 172 developmental abnormalities 349 absence 36 embryology 45, 47 homeobox gene expression 46, 121, 173 recombinant follicle stimulating hormone (rhFSH) 260 recombinant growth hormone (hGH) 101–2 clinical applications see growth hormone therapy recombinant thyrotropin (rhTSH) 203–4 clinical use 203 red desaturation testing 703, 704 relaxin 141 renal cell carcinoma 68 renal failure, chronic 666 Cushing’s disease diagnostic problems 530–1

744

Index

renal failure, chronic (cont.) gonadal dysfunction 255–6 gonadotropin suppression 253, 356 growth hormone clearance impairment 108 growth hormone therapy in children 103 hyperprolactinemia 150–1, 151 hypogonadotropic hypogonadism 618 insulin-like growth factor-I (IGF-I) levels 108 pituitary changes 618–19 prolactin metabolic clearance rate (MCR) 130 thyroid function changes 618 renal water handling 318 reproductive function chronic renal failure 255–6 energy balance linkage 234, 235, 236 female athletes 251 hyperprolactinemia 255 reserpine 150, 648 reticular activating system 320 retinohypothalamic tract 6, 320 reverse hemolytic plaque assay 4, 120, 120, 121 Rieger syndrome 250, 363 rifampicin 530 risperidol 150 Rpx 20, 47, 80, 121, 173 mutations 46 RU 486 530, 543–4, 544 Rud syndrome 250, 356 Russel syndrome 415 S-100 protein 31 salivary gland rests 592 sandostain 442 sarcoidosis 36, 322, 324, 325, 326, 343, 351–2, 356, 382, 605, 613–14 diagnosis 605 imaging investigations 613, 681 pituitary–hypothalamic dysfunction 613–14 steroid therapy 605, 614 sarcoma 36, 352 postradiotherapy tumors 605 satiety 7 satiety center 318 schwannomas 605 scrotal patch 385 secretin 141 secretogranins 505 see-saw nystagmus 700 selective serotonin reuptake inhibitors 150, 647 sella turcica 18, 687, 688 plain X-ray 663, 664 sellar non-pituitary tumors 592–605, 593 sellar thyroid follicular tumor, primary 605 seminoma 339, 601 septic shock 351 a-melanocyte-stimulating hormone (a-MSH) response 57 septo-optic dysplasia 46, 250, 324, 333, 334, 336–7, 363, 592 clinical features 336 serotonin prolactin secretion stimulation 138 thyroid-stimulating hormone (TSH) effects 187 Sertoli cell aromatase bioassay 228 Sertoli cells 226 FSH receptors 224 sex hormone-binding globulin ageing changes 238 obesity 254, 255 sexual behaviour 7, 11 sexual dimorphism adrenocorticotropin (ACTH) pulsatile release 63 brain differentiation 7 fetal gonadotropic hormones 8 fetal gonadotropin-releasing hormone (GnRH) 8, 29 gonadotroph development 20, 29 growth hormone secretion/tissue targeting 91 pituitary anatomy 18

sexual dysfunction gonadotropin adenomam 582 hyperprolactinemia 331 hypothalamic disorders 329 obesity 326 male gonadotropin deficiency treatment 384 prolactinoma 469 thyroid-stimulating hormone (TSH)-secreting tumors 565 sexual maturation 17 SF-1 expression 20 gonadotroph adenoma 30 gonadotrophs 29, 176 development 46 null cells 32 oncocytes 32 sham rage 320, 329 Shapiro’s syndrome 326, 329 Sheehan’s syndrome (postpartum pituitary necrosis) 37, 350–1, 379, 633–4, 637 clinical features 633 diagnosis 381, 634 treatment 634 Shh (Sonic hedgehog) 47 shivering 318 shock, pituitary infartion 351 short luteal phase 145 hyperprolactinemia 145, 146 short portal vessels 19, 279 short stature growth hormone binding protein (GHBP) levels 90 growth hormone receptor (GHR) mutations 91 growth hormone therapy in childhood 102 see also growth failure/retardation sickle cell disease 666 side-chain cleavage enzyme 226 signaling pathways adrenocorticotropin (ACTH) secretion 53, 54 growth hormone receptor (GHR) 90 growth hormone secretogogues (GHS) 88 melanocortin receptors 56, 57 prolactin gene transcription/secretion regulation 125, 125–6 somatostatin receptors (SSTRs) 86, 86, 186 thyroid-stimulating hormone (TSH) receptor 191 silent corticotroph adenoma 499, 502, 505–6 silent somatotroph adenoma 421 silent subtype III adenoma 33 single photon emission tomography (SPECT) 673 prolactinoma 471 thyroid-stimulating hormone (TSH)-secreting tumors 567 single upper central incisor 363 Sipple’s syndrome (multiple endocrine neoplasia type IIa) 68, 615 Six-3 121 skeletal disorders, acromegaly 428–9, 430 SKF 101926 290 skin changes acromegaly 430 Cushing’s disease 514, 515, 516, 518 skin melanocortin 2 receptors (MC2R) 60 skull X-ray 663 Cushing’s disease 528 pituitary tumors 406 sleep ageing-related changes 82 growth hormone release 82 in children/young adults 82 hormone secretion 10 hypothalamic lesion effects 256 prolactin secretion response 131, 131 thyroid-stimulating hormone (TSH) levels 184 sleep apnea 430–1 sleep center 320 sleep–wake cycle hypothalamic disease 328–9 hypothalamic regulation 320

small cell lung cancer adrenocorticotropin (ACTH) secretion 68 growth hormone-releasing hormone (GHRH) secretion 423, 424 smoking 644 snakebite 615 Snell dwarf mouse 37, 173 Pit-1 mutation 121, 173, 197 Snellen chart 697 sodium valproate 331, 650 Cushing’s disease 540 sodium/thirst/plasma osmolality regulatory feedback system 301 somatostatin 10, 186 extrahypothalamic distribution 10, 86 fetal hypothalamus 8 growth hormone secretion regulation 10, 80, 85–6 feedback loops 87, 88 growth hormone-releasing hormone (GHRH) interaction 86–7 hypothalamic release regulation 86 pancreatic insulin/glucagon secretion regulation 86 prohormone 86 prolactin secretion effects 141 SRIF-14 85, 86, 186 SRIF-28 85, 86, 186 structure 85–6, 86, 186 thyroid-stimulating hormone (TSH) secretion regulation 86, 186, 562 thyrotropin-releasing hormone (TRH) production inhibition 180 somatostatin analogs, acromegaly 440–3, 441, 442, 443, 444 long-acting analogs 442 somatostatin ligands (SRLs) see somatostatin analogs somatostatin receptor 1 (SSTR1) 86 somatostatin receptor 2 (SSTR2) 86, 186 octreotide actions 440, 441 somatostatin receptor 3 (SSTR3) 86 somatostatin receptor 4 (SSTR4) 86 somatostatin receptor 5 (SSTR5) 86, 186 octreotide actions 440 somatostatin receptors (SSTRs) 86, 87, 186 signaling pathway 86, 86, 186 somatotroph adenomas 422 somatotroph 20–4, 407 abnormalities in acromegaly 422–3 development 20, 79–80, 121 differentiation regulation 20 electron microscopy 21, 21 GH transgenic animals 89, 90 growth hormone production 10, 20, 21, 21, 81 growth hormone-releasing hormone (GHRH) response 22, 85 histologic staining 4 Pit-1 expression 20, 79, 121, 123 transformation 422–3 somatotroph adenoma 21–2 acromegaly 420–1 electron microscopy 22, 22 octreotide response 22, 23 pathogenesis 421 secretory substances 21–2 silent 421 surgery 437–9, 438 side effects 438–9 somatotroph hyperplasia 421 gigantism 426 somatotropin release-inhibiting factor (SRIF) see somatostatin somatotropin release-inhibiting hormone (SRIH) see somatostatin somnolence 321, 328, 329 Sotos’ syndrome (cerebral gigantism) 17 Sp1 80 sperm banking 386 spermatogenesis 216, 224

Index follicle stimulating hormone (FSH) actions 224, 225–6 gonadotropin deficiency treatment 384, 386 luteinizing hormone (LH) actions 224, 225–6 testosterone actions 224–5 intratesticular levels 226 sports use of growth hormone 106–7 standard height/height velocity 716, 717 Stat 1 143 Stat 3 143 Stat 5 143 STAT proteins growth hormone signaling 90, 91, 91 prolactin receptor signaling 143 steroidogenesis adrenal gland 58, 508–9 skin 60 steroidogenesis activator polypeptide (SAP) 508–9 steroidogenic acute regulatory protein (StAR) 58 luteinizing hormone (LH) regulation 226 mutations 58 steroidogenic factor see SF-1 stress 50 adrenal function 616 adrenocorticotropin (ACTH) response 65–6, 616 emotional/psychological stress 66 amenorrhea 356 analgesia 66 behavioural response via olfactory cues 61 catecholamines 55 corticotropin-releasing hormone (CRH) response 55 gonadotropins response 252–3, 616 growth hormone response 82, 616 hypercortisolic state 532 immune system modulation 67 local skin responses 60 menstrual disorders 252 athletes 252 prolactin response 132–3, 148, 150, 616 thyroid-stimulating hormone (TSH) response 616 stretching 63 stria terminalis 7 subcapsular artery 5 subfornical organ 279 osmoreceptive cells 286 vascular supply 4 substance P 14 adenohypophysial cell production 35 brain distribution 14 growth hormone release stimulation 84 prolactin secretion effects 141 somatostatin regulation 86 thyroid-stimulating hormone (TSH) secretion effects 187 subventricular nucleus 7 hypertrophic changes 18 magnocellular neurons 7 suckling parathyroid-like hormone mRNA production 144 postpartum amenorrhea 132 prolactin response 132, 144, 630, 630 thyrotropin-releasing hormone (TRH) response 136 sulpiride 149 sun-sensitivity 57 superior hypophysial arteries 4, 5, 19 suprachiasmatic nucleus 7, 320 circadian rhythm generation 64 supraoptic hypophysial tract 279 supraoptic nucleus 3, 7, 279 embryology 8 magnocellular neurons 7, 279, 286, 317 osmoreceptive cells 286 perinuclear zone 286 vascular supply 4 vasopressin synthesis/release 285, 286, 317 suprasellar arachnoid cyst 342 suprasellar germ cell tumors 339–40

clinical features 339 suprasellar germinoma 324, 325, 331, 333, 334 suprasellar meningioma 342, 414 suprasellar tumors 256 surgery 405–17 acromegaly 437–9, 438, 439 pregnant patient 636 chordoma 596 complications 409 craniopharyngioma 598–9 Cushing’s disease 536–9, 537, 545–6 Cushing’s procedure 406, 408 diagnostic procedures 406, 406–7 endoscopy 416 germ cell tumors 602 gonadotropin adenoma 586–8, 587, 588 complications 587–8, 588 historical aspects 405–6 intraoperative magnetic resonance imaging (MRI) 416 meningioma 599 neuronavigation 416 pituitary adenomas 410 postoperative visual function 701, 701–2 tumor recurrence 702 prolactinoma 463–4, 464, 471–3, 472, 473, 482, 485 complications 473 preoperative bromocriptine 478–80, 479 surgical anatomy 407 techniques 407, 407–9 thyroid-stimulating hormone (TSH)-secreting tumors 568 transcranial pterional (frontolateral) approach 408–9, 410 transnasal approach 405 transsphenoidal approach 406, 408, 408, 410, 437–8, 438 surgical trauma adrenocorticotropin (ACTH) response 66 growth hormone therapy 105 sweating 318 sympathetic nervous system 8, 320 syndrome of bioinactive growth hormone 362 syndrome of inappropriate antidiuretic hormone (SIADH) 17–18, 304–5, 305, 306, 325 associated disorders 304, 305, 325 cytotoxic drug-induced 649 syndrome of inappropriate thyroid-stimulating hormone (TSH) 567 syphilis 36, 322, 326, 351, 614, 697 systemic disorders 613–20, 614 T-1 cell line 174 tall stature 426 tamoxifen 649 tangent screen 703, 704 temazepam 646 temperature regulation 7, 8 disorders 16, 256, 321, 325–6 hypothalamic function 318 temporal hemianopic scotoma 695, 696 teratoma 339, 416, 601 terguride 482 testes gonadotropin responses 216 prolactin effects 146–7 testicular descent 236–7 testicular tumors cortisol-secreting 514 gonadotropin receptor activating mutations 248–9 testolactone 232 testosterone ageing changes 238, 239, 239, 718–19 biosynthesis 224 prolactin effects 146, 147 dietary restriction response 356 follicle stimulating hormone (FSH) effects 231–2 gonadotropin adenoma diagnosis 583

745

HIV infection 253 luteinizing hormone (LH) effects 224, 231, 232 obesity 254, 618 secretion regulation 217, 224, 231–2 spermatogenesis 224–5 intratesticular levels 226 thyroid-stimulating hormone (TSH) effects 189 b subunit response 175 testosterone therapy future development 386 gonadotropin deficiency 384–6 children 385 parenteral administration 385 safety 385 transdermal administration 385 pituitary effects 649–50 thalamus embryology 8 hypothalamic afferent neural pathways 6 thalassemia major 613 thioxanthenes 647 neuroleptic malignant syndrome 325 third ventricle 668 thirst 287–8, 289, 318, 324, 721 plasma sodium/osmolality regulatory feedback system 301 thrifty genotype 60 thymosin fraction 5 141 thyroglobulin 191 thyroid C cells 10 thyroid function tests 714 thyroid gland, thyroid-stimulating hormone (TSH) effects 172, 191, 192 thyroid hormone replacement therapy 388–9 chidhood 388, 391 growth hormone replacement combined therapy 390 hypothyroid coma 388–9 thyroid hormone resistance syndromes 199–202 generalized form (GRTH) 199 pituitary form (PRTH) 199 thyroid receptor (TR) abnormalities 199–200 thyroid hormone response elements 123–4 thyroid hormones prolactin gene transcription modification 123–4, 125 see also thyroxine (T4); triiodothyronine (T3) thyroid receptor (TR) see triiodothyronine (T3) receptor thyroid-stimulating hormone (TSH) 172–204, 561 actions 191–2 age-related changes 617 alcohol effects 642 a subunit 172, 218, 561 free subunit measurements 193–4 TSH receptor interactions 190 a subunit gene 172 cell specificity of expression 176–7 expression in embryo 172–3 expression regulation 177–8 promoter 176, 176 structure 175, 175–6 T3 response element 177 transcription 178, 179 translation 180, 181 assay 172, 192–5, 194, 202, 203 free subunit measurements 193–4 immunometric 192–3, 193 radioimmunoassay 192 thyroid-stimulating hormone (TSH)-secreting tumor diagnosis 565 assessment tests 714–15 basal thyroid function tests 714 thyrotropin-releasing hormone (TRH) stimulation test 194–5, 195, 714 b subunit 172, 561 free subunit measurements 193–4 TSH receptor interactions 190 b subunit gene 172

746

Index

thyroid-stimulating hormone (TSH) (cont.) defects in congenital hypothyroidism 197, 197 expression in embyo 173 expression regulation 174–5 mutations 180, 376 Pit-1 binding sites 175 Pit-1 regulation 561 promoter 174, 174 structure 173, 174 T3 receptor binding sites 175, 175 thyrotroph-specific expression 174 transcription 178, 179 translation 180, 181 TRH-response regions 175 biosynthesis 178–83 folding 172, 182 glycosylation 172, 180–2, 181, 183, 561 subunit combination 182–3 transcription 178–80 translation 180, 181 transport into secretory granules/vesicles 183 corticotroph adenoma secretion 505 drug effects 643 evolutionary aspects 220 extrathyroid actions 192 fetal levels 183 gonadotropin receptor cross-activation 192 iodine metabolism effects 191 neonatal levels 183 opiate effects 645 plasma half-life 183 pregnancy 631, 631 production disorders hypothalamic 195–6 pituitary 196–203 recombinant thyrotropin (rhTSH) 203–4 secretion 183–9 feedback control 185, 187–9 pattern 183–4, 184 regulation 86, 185, 185–7, 561–2 stress/illness response 616 structure 182, 182, 218, 220 subunit genes 172–8 ontogeny of expression 172–3 thyroid gland effects 172, 191 growth response 192 thyroid hormone synthesis stimulation 191–2 thyrotroph production 28, 28 hypothyroidism 29 thyrotropin-releasing hormone (TRH) regulation 11, 172 TSH receptor desensitization 192 TSH receptor interactions 190–1 thyroid-stimulating hormone (TSH) deficiency 196, 375–7, 379 acquired 198 clinical features 377 congenital 197–8 diagnostic tests 373–4, 377, 377, 379 free thyroxine (T4) 377 thyroid-stimulating hormone (TSH) serum level 377 etiology 375 Pit-1 mutations 197, 218, 250, 362, 376 PROP-1 mutations 197, 218, 250, 362, 376 secondary 202–3 differential diagnosis 203 thyroid hormone replacement therapy 388–9 thyroid-stimulating hormone (TSH) excess pituitary disorders thyroid hormone resistance syndromes 199–202 TSH-secreting pituitary tumor 198–9, 199 secondary 202–3 differential diagnosis 203 thyroid-stimulating hormone (TSH) receptor 189 chorionic gonadotropin binding 191 gene 189 mutations in central congenital hypothyroidism 376

signal transduction 191 structure 189–90, 190 thyroid-stimulating hormone (TSH) interactions 190–1 thyroid-stimulating hormone (TSH)-related desensitization 192 thyroid-stimulating hormone (TSH)-secreting tumors 182, 198–9, 199, 410, 413, 561–71 antithyroid drug therapy 568 carcinoma 563 characteristics 564 clinical features 413, 563, 565, 565 diagnosis 565–7 a subunit levels 566 dynamic tests 566 pituitary imaging 566–7 thyroid-stimulating hormone (TSH) assay 565–6 differential diagnosis 567–8, 568 follow-up/criteria for cure 569–70, 570 management 413 medical treatment 568–9, 570 pathogenesis 561–3 pathology 563 prolactin secretion 466 radiotherapy 568 surgery 568 see also thyrotroph adenoma thyrotroph 28–9, 183, 407 a subunit expression 176–7 b subunit specific expression 174 development 20, 79, 121, 561 differentiation regulation 20, 173, 173 dopamine D2 receptor 187 electron microscopy 28, 28 histologic staining 4 Pit-1 expression 79, 121, 123, 561 secretory granules/vesicles 183 somatostatin receptors (SSTRs) 186 thyroid-stimulating hormone (TSH) secretion 28, 28, 172, 183 thyrotropin-releasing hormone (TRH) actions 11 thyrotropin-releasing hormone (TRH) receptors 185 thyrotroph adenoma pathology 563 see also thyroid-stimulating hormone (TSH)secreting tumors thyrotroph embryonic factor (TEF) 20, 173 thyrotropin see thyroid-stimulating hormone (TSH) thyrotropin-releasing hormone (TRH) 11, 185, 321 adenohypophysial cell production 34 disorders 195 fetus 8, 183 gonadotropin adenoma response 577 growth hormone secretion stimulation 84 lactotroph stimulation 11, 120 prolactin gene transcription regulation 123 prolactin secretion regulation 126, 127, 136–7 thyroid-stimulating hormone (TSH) glycosylation regulation 182 thyroid-stimulating hormone (TSH) production stimulation 172, 177, 185–6, 561 a subunit gene expression 177, 179 b subunit gene expression 175, 179 diagnostic testing 186 thyroid-stimulating hormone (TSH) provocation test 194–5, 195 thyroid-stimulating hormone (TSH)-secreting adenoma pathogenesis 562 thyrotroph receptors 185 thyrotropin-releasing hormone (TRH) receptor mutations 562 central congenital hypothyroidism 375–6 thyrotropin-releasing hormone (TRH) stimulation test 196, 714 adverse events 714 gonadotropin adenoma diagnosis 583, 584, 584, 585, 585

normal response 714–15 prolactin assessment 715 secondary (pituitary) hypothyroidism 198 tertiary (hypothalamic) hypothyroidism 198 thyroid-stimulating hormone (TSH)-secreting tumor diagnosis 566 thyroxine (T4) 11, 172 breast development 143 conversion to triiodothyronine (T3) 562 fetal levels 183 hypothyroidism differential diagnosis 377 neonatal levels 183 thyroid hormone replacement therapy 388–9 thyroid-stimulating hormone (TSH) response 187–8, 191 thyroxine (T4) stimulation test 566 tissue culture 4 Titf1 218 Tolosa–Hunt syndrome 594 toluene 325 tomograms 664 toxic multinodular goiter 191 Toxoplasma gondii 614 Tpit corticotroph expression 46–7 corticotroph POMC expression 48, 61 TPIT mutations 61 trabecular (loral) arteries 5, 19 transdermal estrogen therapy 386, 387 transdermal testosterone administration 385 transforming growth factor-a (TGFa) 15, 35 transforming growth factor-b1 (TGFb1) 141 transgenic mouse studies growth hormone 89–90, 419–20 growth hormone-releasing hormone (GHRH) 419, 421–2 insulin-like growth factor-I (IGF-I) 89, 420 transient diabetes insipidus of pregnancy 637 transsphenoidal encephalocele 333 transsphenoidal surgery complications 587–8, 588 Cushing’s disease 539, 545 gonadotropin adenomas 586, 587, 588 prolactinoma 463–4, 464, 471 thyroid-stimulating hormone (TSH)-secreting tumors 568 trauma growth hormone therapy 105 hypopituitarism 350, 363, 381 tricyclic antidepressants 647 hyperprolactinemia 150 trigeminal nerve (cranial nerve V) 668 compression 700 pituitary apoplexy 700 imaging 668 triiodothyronine (T3) 11, 172 age-related changes 617 fetal levels 183 growth hormone secretion effects 80–1, 85 liver disease 619 neonatal levels 183 thyroid hormone replacement therapy 388–9 thyroid-stimulating hormone (TSH) a subunit gene expression regulation 177 b subunit gene expression regulation 174–5 glycosylation regulation 182 negative feedback control 187–8, 191, 562 subunit gene transcription inhibition 178, 178–9, 179 triiodothyronine (T3) receptors (TR) thyroid hormone resistance syndromes 199–200, 200 thyroid-stimulating hormone (TSH) b subunit gene binding sites 175, 175 thyroid-stimulating hormone (TSH) subunit gene transcription regulation 178, 179 TRa1 179, 200 TRa gene 199–200 TRb1 179, 200, 201

Index TRb2 179, 200 TRb gene 200 mutations in generalized resistance to thyroid hormones (GRTH) 200, 200–1 mutations in pituitary resistance to thyroid hormones (PRTH) 201 triiodothyronine (T3) stimulation test 566 triple A (Allgrove) syndrome 59, 370 trochlear nerve (cranial nerve IV) 668 compression 690, 700 pituitary apoplexy 700 imaging 668 radiation neuropathy 702 trophoblast-specific element (TSE) 176 trophoblastic tumors 257 Trovert 443 tryptophan hydroxylase 138 tuber cinereum 317 tuberculosis 36, 322, 326, 351, 614 tuberculum sellae meningioma 414 tuberoinfundibular dopamine (TIDA) pathway 135, 142 prolactinoma pathogenesis 461 animal model 466, 467 tuberoinfundibular GABAergic system 136 tuberoinfundibular tract 7, 320 tumor necrosis factor 15, 66 adrenocorticotropin (ACTH) response 55 thyroid-stimulating hormone (TSH) effects 189 tumors 409–10 classification 410 diagnostic procedures 406, 406–7 postoperative management hormone replacement 409 radiotherapy 409 recurrence 409 surgery see surgery Turner’s syndrome growth hormone neurosecretory dysfunction 102 growth hormone therapy 102 primary amenorrhea 359 unc-86 80 unclassified plurihormonal cells 33–4 undernutrition gonadotropin deficiency 234, 384 growth hormone release stimulation 82, 82 growth hormone/insulin-like growth factor-I (IGF-I) levels 107 insulin-like growth factor-I (IGF-I)/insulin-like growth factor-binding protein (IGFBP) levels 92 reproductive function impact 234 anorexia nervosa 251 delayed onset menses in ballet dancers 251 Dutch hunger winter 236, 237 !Kung San of Botswana 236, 238 lactational amenorrhea in sub-Saharan Africa 251–2 volunteer experiments 236 subventricular nucleus changes 7, 18 testosterone response 356 urinary 17-hydroxycorticosteroids Cushing’s disease 520, 521, 535 Cushing’s syndrome diagnosis in pregnancy 635 urine osmolality, diabetes insipidus differential diagnosis 301–2, 302, 302 urocortin 54 uterine fibroids 265 V1 receptor 55 second messenger system 54 V1b receptor 55

V2 receptor 55 second messenger system 54 Van Wyk–Grumbach syndrome 331 vanishing testis syndrome (anorchia) 237 vascular endothelial growth factor 31 vascular lesions 37 hypopituitarism 350–1 vasculitis 351 vasoactive intestinal peptide (VIP) 12 adenohypophysial cell production 35 corticotroph adenoma 47 growth hormone release stimulation 84 lactotroph stimulation 11 prolactin secretion stimulation 126, 137–8, 140 thyroid-stimulating hormone (TSH) effects 187 vasoconstriction 318 vasodilatation 318 vasopressin 7, 12 acute illness-related gonadotropin suppression 253 adrenocorticotropin (ACTH) secretion regulation 11, 12, 50, 53, 53, 54–6, 279, 498 corticotropin-releasing hormone (CRH) synergism 56, 279, 498 modulators of release 55–6 assay 291–2 axonal transport of precursors 285 drug effects 644 evolutionary aspects 284 fetal hypothalamus 8 gene expression in diabetes insipidus Brattleboro rats 281, 281 human autosomal dominant/autosomal recessive disease 281, 282, 283, 283–4 gene regulation 281 gene structure 280, 280 historical aspects 3 hormone precursor 280, 280 processing to active hormone 280, 281 hypothalamic functional anatomy 12, 12, 13 magnocellular neuron synthesis 7, 12, 13, 279, 317 neurophysin II 285 opiate effects 645 osmotic threshold for release 286–8, 287 platelet association 285 posterior pituitary function assessment hypertonic saline test 722–3, 723 water deprivation test 721–2, 722 pregnancy 633 prolactin secretion stimulation 139–40 secretion disorders 323–5 deficiency 16–17 excess 17–18 secretion regulation 64, 285, 285–90, 317 baroregulation 288 hormonal influences 289–90 osmotic stimuli 285–8, 301 structure 284, 284, 284 thyroid-stimulating hormone (TSH) secretion effects 187 variants in animal groups 284 vasopressin receptors 55, 290–1, 291 antagonists 290–1 second messengers 54, 498 vasopressin V1 receptor 498 vasopressin V1au receptor 290 vasopressin V1b protein kinase C 50 vasopressin V1b receptor 290 vasopressin V2 receptor 290 AVPR2 gene 293 mutations 294, 295, 296–87 renal collecting duct water permeability regulation 293–4 structure 295

747

vasotocin 284 ventrolateral nucleus (‘feeding center’) 7, 320 ventromedial nuclei 7 verapamil 127, 150, 151, 648 vinblastine 649 vincristine 415, 649 virilizing tumors 257 visual acuity assessment 406, 696–7 visual cortex 6 visual evoked potentials 697 visual fields assessment 691–6, 692, 693, 694, 695, 696 techniques 703–4 visual function monitoring 700–2 visual hallucinations 691 visual loss 406, 668 bromocriptine therapy impact 702–3 clinical features 689–90, 691 examination 691–700 cranial nerve abnormalities 700 optic atrophy 697, 697–8, 698, 699 papilledema 698–9 pupillary abnormality 697 see-saw nystagmus 700 visual acuity loss 696–7 visual field defects 691–6 gonadotropin adenoma 582 outcome following surgery 586–7, 587 incidence 689 pituitary adenoma presentation 410 pituitary apoplexy 700 pituitary mass effects 426, 467–8, 469, 582, 594 diagnosis 583 postoperative tumor recurrence 702 pregnancy 483–4, 703 prolactinoma 471, 483–4 radiation neuropathy 702 thyroid-stimulating hormone (TSH)-secreting tumors 565 visual field defects 36, 256, 410 Von Economo’s encephaltis 328 von Hippel–Lindau disease 605 wakefulness 320 wakefulness center 320 warm receptors 318 water deprivation test 721–2, 722 normal response 721–2 water intoxication 17 water metabolism hypothalamic disorders 323–5 hypothalamic regulation 317–18 Wegener’s granulomatosis 614 weight loss-related amenorrhea 356 Werner’s syndrome see multiple endocrine neoplasia type I Wernicke’s encephalopathy 326, 328, 329 whole-brain irradiation 343 Wnt4 121 Wnt5a a subunit expression regulation 172–3 corticotroph development 47 Wolff ’s syndrome 329 Wolfram (DIDMOAD) syndrome 293, 324 wound healing, growth hormone therapy 106 yawning 63 yohimbine 142, 648 yolk sac tumor (endodermal sinus tumor) 339, 601 Zollinger–Ellison syndrome 506 zona intermedia corticotrophs 47