Reproductive Endocrinology

LANDES

BIOSCIENCE

V ad e me c u m

Table of contents 1. The Menstrual Cycle

12. Reproductive Endocrinology Diagnostic Imaging

2. Puberty and Its Disorders

4. Dysfunctional Uterine Bleeding 5. Diagnosis and Management of Polycystic Ovary Syndrome 6. Obesity: Recognition and Treatment in Women 7. Hormonal Contraception

14. Surgical Treatment of Female Infertility 15. Ovulation Induction 16. Assisted Reproductive Technology 17. Alternative Medicine and Female Infertility 18. Male Infertility 19. Your Environment; Your Fertility—Is There a Link?

8. Endometriosis 9. Hyperprolactinemia 10. Premenstrual Syndrome 11. Treatment of the Menopausal Woman

Reproductive Endocrinology and Infertility

13. An Overview of Female Infertility

3. Amenorrhea

V ad eme c um

LANDES

BIOSCIENCE

LANDES

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V ad e me c u m Reproductive Endocrinology and Infertility

The Vademecum series includes subjects generally not covered in other handbook series, especially many technology-driven topics that reflect the increasing influence of technology in clinical medicine. The name chosen for this comprehensive medical handbook series is Vademecum, a Latin word that roughly means “to carry along”. In the Middle Ages, traveling clerics carried pocket-sized books, excerpts of the carefully transcribed canons, known as Vademecum. In the 19th century a medical publisher in Germany, Samuel Karger, called a series of portable medical books Vademecum.

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Vivian Lewis

v a d e m e c u m

Reproductive Endocrinology and Infertility Vivian Lewis, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Rochester School of Medicine and Dentistry Rochester, New York, U.S.A.

LANDES BIOSCIENCE

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VADEMECUM Reproductive Endocrinology and Infertility LANDES BIOSCIENCE Austin, Texas U.S.A. Copyright ©2007 Landes Bioscience All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all inquiries to the Publisher: Landes Bioscience, 1002 West Avenue, Austin, Texas 78701, U.S.A. Phone: 512/ 637 6050; FAX: 512/ 637 6079 ISBN: 978-1-57059-702-2 Cover artwork by Kristen Shumaker

Library of Congress Cataloging-in-Publication Data Reproductive endocrinology and infertility / [edited by] Vivian Lewis. p. ; cm. -- (Vademecum) Includes bibliographical references and index. ISBN-13: 978-1-57059-702-2 (alk. paper) 1. Endocrine gynecology . 2. Infertility, Female--Endocrine aspects. I. Lewis, Vivian, M.D. II. Series. [DNLM: 1. Genital Diseases, Female. 2. Endocrine System Diseases. 3. Infertility, Female. WP 140 R4247 2007] RG159.R452 2007 618.1--dc22 2007001376

While the authors, editors, sponsor and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Dedication I would like dedicate this book to my family whose love, support and patience have made it possible for me to pursue a career in academic medicine. My parents, Oswald Lewis and Vivian Lewis, encouraged and nurtured a love of learning. My brothers and sister were crucial in providing an intellectually stimulating environment as I grew up. My husband, Rustam Tahir, and sons, Darius and Jason, have been understanding and supportive while I put in the long hours necessary to complete this project. I am grateful to you all.

Contents Preface ......................................................................... xv Acknowledgements ..................................................... xvi

Part I: Reproductive Endocrinology 1. The Menstrual Cycle ...................................................... 3 John T. Queenan, Jr. GnRH .................................................................................................... 3 Follicular Phase ....................................................................................... 4 Luteal Phase ............................................................................................ 7 The Endometrium: Proliferative and Secretory Phases ............................ 8

2. Puberty and Its Disorders ............................................ 10 Adelina M. Emmi and Lawrence C. Layman Normal Puberty Physiology .................................................................. 10 Somatic Changes ............................................................................. 10 Endocrinology of Puberty ................................................................ 10 Abnormalities of Puberty ...................................................................... 12 Precocious Puberty .......................................................................... 12 Delayed Puberty .............................................................................. 15

3. Amenorrhea ................................................................. 23 Michael Wittenberger and Alicia Armstrong Evaluation ............................................................................................. 23 Eugonadism, Uterus Present ............................................................ 25 Hypogonadism (Prior Estrogen Exposure), Uterus Present ......................................................................... 25 Eugonadism, Uterus Absent ............................................................ 28 Hypogonadism, Uterus Present ....................................................... 29 Diagnoses ............................................................................................. 29 Eugonadotropic Amenorrhea (Normal FSH and LH) ............................................................ 29 Hypogonadotropic Amenorrhea ...................................................... 32 Hypergonadotropic Amenorrhea ..................................................... 33 Treatment ............................................................................................. 34

4. Dysfunctional Uterine Bleeding ................................... 36 William R. Phipps Differential Diagnosis and Mechanisms of Bleeding ............................. 37 History ................................................................................................. 39 Physical Examination ............................................................................ 40 Laboratory, Imaging and Other Diagnostic Studies ............................... 40 Treatment ............................................................................................. 43

5. Diagnosis and Management of Polycystic Ovary Syndrome .......................................................... 47 Kathleen M. Hoeger Diagnosis .............................................................................................. 47 Epidemiology ........................................................................................ 47 Clinical Features ................................................................................... 47 Pathophysiology .................................................................................... 48 Endocrine Evaluation ............................................................................ 49 Impact of Obesity ................................................................................. 50 Metabolic Complications ...................................................................... 51 Treatment Options ............................................................................... 51 Oral Contraceptives and Progestins ................................................. 53 Anti-Androgens ............................................................................... 53 Insulin Sensitizing Agents ................................................................ 54 Lifestyle Modification ...................................................................... 54

6. Obesity: Recognition and Treatment in Women .......... 56 Erin E. Flaherty and Richard S. Legro Assessment ............................................................................................ 57 Metabolic Syndrome ....................................................................... 57 Treatment ............................................................................................. 58 Diet and Exercise ............................................................................. 58 Pharmacotherapy ............................................................................. 58 Categories of Weight Loss Drugs ..................................................... 59 Other Medications and Herbal Supplements ................................... 60 Surgery ................................................................................................. 61

7. Hormonal Contraception ............................................ 65 Sarah Prager and Jody Steinauer Background .......................................................................................... 65 Assessing Evidence about Contraception ............................................... 65 Combination Hormonal Contraception ............................................... 67 Combination Oral Contraception ................................................... 67 Extended Use Combined Oral Contraception ................................. 70 Transdermal Contraceptive System .................................................. 72 Combined Contraceptive Vaginal Ring ........................................... 73 Injectable Combined Hormonal Contraception .............................. 74 Progestin Only Contraceptive Methods ................................................ 74 Progestin Only Pills ......................................................................... 74 Progestin Only Intramuscular Injection ........................................... 76 Implantable Progestin Contraception .............................................. 77 Levonorgestrel Intrauterine System ....................................................... 78 Emergency Contraception .................................................................... 79

8. Endometriosis .............................................................. 84 Sireesha Reddy Definition and Epidemiology ............................................................... 84 Pathogenesis .......................................................................................... 84 Diagnosis .............................................................................................. 84 Medical Treatment ................................................................................ 85 Oral Contraceptives ......................................................................... 85 Progestins ........................................................................................ 86 Gonadotropin Releasing Hormone Analogs ..................................... 86 New Therapies ................................................................................ 87 Surgical Treatment ................................................................................ 87

9. Hyperprolactinemia ..................................................... 89 Ghassan Haddad and Michael A. Thomas Biochemistry ......................................................................................... 89 Etiology ................................................................................................ 89 Physiologic ...................................................................................... 89 Pharmacologic ................................................................................. 90 Pathologic ....................................................................................... 91 Prolactinomas ....................................................................................... 91 Evaluation ............................................................................................. 92 Galactorrhea ......................................................................................... 92 Treatment ............................................................................................. 93 Observation ..................................................................................... 93 Medical Treatment ........................................................................... 93 Surgery ............................................................................................ 94 Radiotherapy ................................................................................... 94 Pregnancy Considerations ..................................................................... 94

10. Premenstrual Syndrome ............................................... 96 Stephanie A.M. Giannandrea, Linda H. Chaudron and Tana A. Grady-Weliky Risk Factors .......................................................................................... 96 Clinical Symptoms and History ............................................................ 97 Differential Diagnosis ........................................................................... 98 Etiology ................................................................................................ 99 Treatment ............................................................................................. 99 Lifestyle Interventions ................................................................... 100 Nutritional, Vitamin and Alternative/Complementary Treatment Strategies .............................................................. 100 Psychoeducation ............................................................................ 101 Cognitive Behavioral Therapy (CBT) ............................................ 101 Pharmacologic Interventions ............................................................... 101 Antidepressants .............................................................................. 101 Anxiolytics ..................................................................................... 104 Hormonal Treatments ................................................................... 104

11. Treatment of the Menopausal Woman ....................... 107 Ghassan Haddad and Daniel B. Williams The Menopause .................................................................................. 107 The Transition ............................................................................... 107 Symptoms of Menopause .................................................................... 108 Vasomotor Symptoms ................................................................... 108 Regimens for Hormone Replacement ................................................. 109 Alternative Treatments for Hot Flashes .......................................... 110 Alternative Medicine ..................................................................... 111 Genitourinary ..................................................................................... 112 Local Therapy (Vaginal or Topical Administration) ....................... 112 Osteoporosis ....................................................................................... 113 Pathophysiology ............................................................................ 113 Risk Factors and Diagnosis ............................................................ 113 Cardiovascular Disease ........................................................................ 115 HERS Study and Secondary Prevention of Cardiovascular Disease ...................................................... 116 WHI Study and Primary Prevention of Cardiovascular Disease ..... 116 Alzheimer’s Disease ............................................................................. 116 Risks of Homone Replacement ........................................................... 117 Estrogen Replacement Therapy and Breast Cancer ........................ 117 Estrogen Replacement Therapy and Endometrial Cancer .............. 117 Venous Thromboembolic Events ................................................... 117 Benefits of Hormone Replacement ..................................................... 118

12. Reproductive Endocrinology Diagnostic Imaging ..... 120 Peter Klatsky and Victor Y. Fujimoto Principles of Ultrasound and Magnetic Resonance Imaging (MRI) ..... 120 Ambiguous Genitalia .......................................................................... 120 Amenorrhea ........................................................................................ 121 Secondary Amenorrhea .................................................................. 125 Infertility ............................................................................................ 126 Anatomic and Tubal Factor Infertility ............................................ 126 MR-Hysterosalpingography ........................................................... 135 Recurrent Pregnancy Loss ................................................................... 135 Ovulatory Disorders ...................................................................... 136 Diminished Ovarian Reserve ......................................................... 137 Endometriosis ..................................................................................... 139 Fibroids .............................................................................................. 141

Part II: Infertility 13. An Overview of Female Infertility .............................. 145 Sandra L. Torrente and Valerie Montgomery Rice Overview ............................................................................................ 145 Ovulatory Disorders ...................................................................... 146

Tubal Disorders .................................................................................. 149 Treatment ...................................................................................... 150 Endometriosis ............................................................................... 150 Uterine Disorders .......................................................................... 150 Cervical Disorders ......................................................................... 150 Unexplained Infertility .................................................................. 151

14. Surgical Treatment of Female Infertility .................... 153 Mohammed Al-Sunaidi and Togas Tulandi Diagnostic Laparoscopy ...................................................................... 153 Laparoscopy Promoting Fertility ......................................................... 154 Adhesiolysis ................................................................................... 154 Treatment of Endometriosis .......................................................... 154 Treatment of Distal Tubal Occlusion ............................................. 156 Treatment of Proximal Tubal Occlusion ......................................... 158 Treatment of Mid-Tubal Occlusion ............................................... 159 Laparoscopic Treatment of Polycystic Ovary Syndrome (PCOS) ... 159 Hysteroscopy in Infertility .................................................................. 161 Diagnostic Hysteroscopy ............................................................... 161 Operative Hysteroscopy ................................................................. 162

15. Ovulation Induction .................................................. 165 Jon C. Havelock and Karen D. Bradshaw Testing Prior to Ovulation Induction .................................................. 165 Ovulation Induction Monitoring ........................................................ 167 Complications of Ovulation Induction ............................................... 167 Multiple Pregnancy ....................................................................... 167 Ovarian Hyperstimulation Syndrome (OHSS) .............................. 168 Methods of Ovulation Induction ........................................................ 168 Weight Loss ................................................................................... 168 Clomiphene Citrate ....................................................................... 168 Metformin ..................................................................................... 170 Aromatase Inhibitors ..................................................................... 170 Laparoscopic Ovarian Diathermy .................................................. 171 Glucocorticoids ............................................................................. 171 Pulsatile Gonadotropin Releasing Hormone .................................. 171 Dopamine Agonists ....................................................................... 171 Gonadotropins for Ovulation Induction ............................................. 172 Background ................................................................................... 172 Follicular Maturation with hCG—The Terminal Act in Ovulation Induction ......................................................... 173 Gonadotropin Ovulation Induction in PCOS ............................... 174 Ovulation in Hypogonadotropic Hypogonadism ........................... 175 Gonadotropins in Controlled Ovarian Hyperstimulation (COH) ...................................................... 176 COH with Gonadotropins in in Vitro Fertilization (IVF) ............. 176

16. Assisted Reproductive Technology ............................. 178 Tiffany Von Wald and Kim Thornton Definitions ......................................................................................... 178 Infertility History and Evaluation ....................................................... 179 Indications for ART ............................................................................ 181 Tubal Disease ................................................................................ 182 Endometriosis ............................................................................... 182 Male Factor Infertility ................................................................... 183 Ovulatory Disorders ...................................................................... 183 Unexplained Infertility .................................................................. 184 Diminished Ovarian Reserve ......................................................... 184 Other Indications for ART ............................................................ 184 Success Rates ...................................................................................... 184 Complications .................................................................................... 185 Multiple Gestation ........................................................................ 185 Ovarian Hyperstimulation Syndrome (OHSS) .............................. 186 Ectopic Pregnancy ......................................................................... 186 Other Risks ................................................................................... 187 Fetal Risks ..................................................................................... 187

17. Alternative Medicine and Female Infertility ............... 189 Hey-Joo Kang, Pak Chung and Raymond Chang Acupuncture ....................................................................................... 189 Herbal Treatments .............................................................................. 191 Vitamins and Dietary Supplements ..................................................... 191 Mind/Body Techniques ....................................................................... 192

18. Male Infertility ........................................................... 194 Stephanya Shear and Jeanne O’Brien Epidemiology ...................................................................................... 194 Physiology .......................................................................................... 194 Differential Diagnosis ......................................................................... 195 Evaluation ........................................................................................... 196 History and Physical ...................................................................... 196 Laboratory Studies ......................................................................... 197 Radiologic Studies ......................................................................... 198 Management ....................................................................................... 199 Post Evaluation—Follow Up Care ................................................. 199 Other Surgical and Medical Treatments for Infertility .................... 200

19. Your Environment; Your Fertility—Is There a Link? .. 201 Shanna H. Swan The Environment and Reproductive Factors in the Male .................... 202 The Environment and Reproductive Factors in the Female ................. 203 Factors That May Alter a Couples’ Fertility ......................................... 208 Web-Based Resources .......................................................................... 209

Index .......................................................................... 213

Editor Vivian Lewis, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Rochester School of Medicine and Dentistry Rochester, New York, U.S.A.

Contributors Mohammed Al-Sunaidi, M.D.

Linda H. Chaudron, M.D., M.S.

Department of Obstetrics and Gynecology McGill University Montreal, Quebec, Canada

Departments of Psychiatry, Pediatrics, and Obstetrics and Gynecology University of Rochester Medical Center Rochester, New York, U.S.A.

Chapter 14

Alicia Armstrong, M.D. Reproductive Biology and Medicine Branch National Institute of Child Health and Human Development Bethesda, Maryland, U.S.A. Chapter 3

Karen D. Bradshaw, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Texas Southwestern Medical Center Dallas, Texas, U.S.A. Chapter 15

Raymond Chang, M.D. Department of Internal Medicine Institute of East-West Medicine New York, New York, U.S.A. Chapter 17

Chapter 10

Pak Chung, M.D. Department of Obstetrics and Gynecology Center for Reproductive Medicine and Fertility Weill Medical College of Cornell University New York, New York, U.S.A. Chapter 17

Adelina M. Emmi, M.D. Section of Reproductive Endocrinology, Infertility and Genetics Department of Obstetrics and Gynecology Medical College of Georgia Augusta, Georgia, U.S.A. Chapter 2

Erin E. Flaherty, D.O.

Kathleen M. Hoeger, M.D.

Department of Obstetrics and Gynecology Pennsylvania State University College of Medicine Hershey, Pennsylvania, U.S.A.

Department of Obstetrics and Gynecology University of Rochester Medical Center Rochester, New York, U.S.A.

Chapter 6

Chapter 5

Victor Y. Fujimoto, M.D.

Hey-Joo Kang, M.D.

Department of Obstetrics, Gynecology and Reproductive Sciences UCSF Women’s Health, Mount Zion San Francisco, California, U.S.A.

Center for Reproductive Medicine and Fertility Weill Medical College of Cornell University New York, New York, U.S.A.

Chapter 12

Stephanie A.M. Giannandrea, B.A. University of Rochester Medical Center Rochester, New York, U.S.A. Chapter 10

Tana A. Grady-Weliky, M.D. Department of Psychiatry University of Rochester School of Medicine and Dentistry Rochester, New York, U.S.A. Chapter 10

Ghassan Haddad, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Cincinnati College of Medicine Cincinnati, Ohio, U.S.A. Chapters 9, 11

Jon C. Havelock, M.D. Pacific Centre for Reproductive Medicine

Burnaby, BC, Canada Chapter 15

Chapter 17

Peter Klatsky, M.D. Department of Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco San Francisco, California, U.S.A. Chapter 12

Lawrence C. Layman, M.D. Neurodevelopmental Biology Program Institute of Molecular Medicine and Genetics Medical College of Georgia Augusta, Georgia, U.S.A. Chapter 2

Richard S. Legro, M.D. Department of Obstetrics and Gynecology Pennsylvania State University College of Medicine Hershey, Pennsylvania, U.S.A. Chapter 6

Jeanne O’Brien, M.D.

Stephanya Shear, M.D.

Department of Urology University of Rochester Medical Center Rochester, New York, U.S.A.

Department of Urology University of Rochester Medical Center Rochester, New York, U.S.A.

Chapter 18

Chapter 18

William R. Phipps, M.D.

Jody Steinauer, M.D., M.A.S.

Department of Obstetrics and Gynecology University of Rochester Rochester, New York, U.S.A.

Department of Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco San Francisco, California, U.S.A.

Chapter 4

Sarah Prager, M.D. Department of Obstetrics and Gynecology University of Washington Seattle Washington, U.S.A. Chapter 7

John T. Queenan, Jr, M.D. Department of Obstetrics and Gynecology University of Rochester Medical Center Rochester, New York, U.S.A. Chapter 1

Sireesha Reddy, M.D. Department of Obstetrics and Gynecology University of Rochester Medical Center Rochester, New York, U.S.A. Chapter 8

Valerie Montgomery Rice, M.D. Department of Obstetrics and Gynecology School of Medicine Meharry Medical College Nashville, Tennessee, U.S.A. Chapter 13

Chapter 7

Shanna H. Swan, Ph.D. Department of Obstetrics and Gynecology University of Rochester School of Medicine and Dentistry Rochester, New York, U.S.A. Chapter 19

Michael A. Thomas, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Cincinnati College of Medicine Cincinnati, Ohio, U.S.A. Chapter 9

Kim Thornton, M.D. Division of Reproductive Endocrinology and Infertility Beth Israel Deaconess Medical Center and Boston IVF Harvard Medical School Waltham, Massachusetts, U.S.A. Chapter 16

Sandra L. Torrente, M.D.

Daniel B. Williams, M.D.

Department of Obstetrics and Gynecology School of Medicine Meharry Medical College Nashville, Tennessee, U.S.A.

Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Cincinnati College of Medicine Cincinnati, Ohio, U.S.A.

Chapter 13

Togas Tulandi, M.D. Department of Obstetrics and Gynecology McGill University Montreal, Quebec, Canada Chapter 14

Tiffany Von Wald, M.D. Division of Reproductive Endocrinology and Infertility Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts, U.S.A. Chapter 16

Chapter 11

Michael Wittenberger, M.D. National Institute of Child Health and Human Development Bethesda, Maryland, U.S.A. Chapter 3

Preface Reproductive Endocrinology and Infertility provides an overview of the most frequently encountered clinical challenges faced by medical students and residents. Part I begins with chapters on reproductive hormonal physiology and development to provide a basis for understanding the management of the most common reproductive clinical problems that confront obstetrician-gynecologists and other practitioners in women’s health. Several of the chapters, including obesity, premenstrual syndrome, menopause and imaging, provide a cross-disciplinary approach to endocrine related problems common among reproductive aged women. Part II includes chapters on the evaluation of infertility, as well as surgical and medical approaches to treating infertility in men and women. The chapter on alternative medicine provides a basis for understanding the increasingly popular use of therapies such as acupuncture and herbal treatments. The last chapter discusses the influence of environmental factors on fertility, an important field that is often ignored in the traditional approach to infertility. This text is meant to be used as a portable reference with readily accessible information including a summary of key points in each chapter. All of the contributors are involved in residency training programs and understand the kinds of patient management questions that are encountered in a busy practice. Our goal with this book is to provide information that will support solid patient management and hopefully pique the appetite to learn more. Vivian Lewis, M.D.

Acknowledgements I wish to extend many thanks to all of the contributors for their hard work. I am especially grateful to the authors who are current or recent trainees as their perspective is closest to the main target audience for this book. I would also like to thank Ron Landes and the staff at Landes Publication for their help and responsiveness. Finally, Anne Tedrow’s organizational skills were invaluable in helping to compile the submissions of the 33 authors featured in this volume.

Part I Reproductive Endocrinology

Chapter 1

The Menstrual Cycle John T. Queenan, Jr. Once a month the human endometrium exhibits a well-orchestrated, repeating cycle of proliferation, differentiation, death and renewal. Remarkably, the same cells programmed to slough within two weeks in the absence of a blastocyst are also able to nurture a gestation, if present, for 40 weeks. For implantation to occur, synchronization between the age of the embryo and the developmental stage of the endometrium is an absolute requirement. When functioning properly, the hypothalamic-pituitary-ovarian axis will coordinate the recruitment and selection of a dominant follicle while ordering endometrial preparation. Reproductive cycles begin at puberty as the hypothalamic pulse generator is activated and GnRH is secreted. Menstrual cycles are the most irregular during the 2 years after menarche and during the 3 years before menopause. Once a cyclic pattern is established, the menstrual cycle serves as a highly sensitive indicator of an intact hypothalamic pituitary ovarian (H-P-O) axis. To the clinician, the monthly cycle of endometrial degeneration and regeneration provides confirmation that the infertile patient has ovulatory cycles. Hypothalamic secretion of GnRH guides pituitary secretion of FSH and LH. The hypothalamus receives an enormous variety of signals and information. The interplay between the follicle and the CNS depends upon the ability of estrogen to transmit messages of positive and negative feedback. There are highly sensitive regions within the hypothalamus where estrogen can elicit feedback. Progesterone also exerts profound negative feedback on the hypothalamus. CNS neurotransmitters can exert their influence independent of sex steroids. Norepinephrine is stimulatory whereas dopamine, B-endorphins and other opioid peptides are inhibitory to the release of GnRH. The convergence of signals within the hypothalamus culminates in a pattern of pulsatile GnRH secretion.

GnRH Gonadotropin releasing hormone (GnRH) is a 10 amino acid peptide that is synthesized in the neuronal bodies of the arcuate nucleus of the medial basal hypothalamus and transported to the median eminence by neuroendocrine cell terminals. GnRH effluxes into capillaries and is transported from the hypothalamus to the pituitary through the portal circulation. GnRH binds to its receptor on the cell surface of the gonadotrophs. There, it activates adenylate cyclase and stimulates gonadotropin release. GnRH can stimulate the synthesis and release of both FSH and LH from the same cell. The variation in pulse frequency alters the ratio of FSH to LH. GnRH is secreted in a pulsatile manner; the amplitude and frequency of secretion vary throughout the cycle. In cell culture, pulsatile, rhythmic activity is an intrinsic property of individual GnRH neurons. A single or small group of GnRH Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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neurons may initiate a pulse and entrain other participating cells resulting in a neuroendocrine cascade. In the hypothalamus, the population of these neurons is termed 1 the GnRH pulse generator. If the frequency of GnRH pulses increases, there will be slight dominance of FSH over LH. This small, incremental FSH rise in the early follicular phase is sufficient to elicit follicular recruitment. One pulse every hour is typical of the follicular phase while one pulse every 2-3 hours is typical of the luteal phase. Normal gonadotropin secretion requires pulsatile GnRH discharge within a critical frequency and amplitude. Adequate FSH levels and LH pulses at approximately 60-90 minutes stimulate the normal growth of ovarian follicles. A slower frequency results in anovulation and amenorrhea. Follicles do not develop when the LH pulses decline to intervals of less than 2-3 hours. High, prolonged GnRH exposure saturates the GnRH receptors causing anovulation by down-regulation of the GnRH receptor and abolition of the gonadotropin response.

Follicular Phase Although the process of menstruation represents the endpoint of a previous cycle of endometrial changes, the first day of menstruation is the most recognizable point and is usually taken to mark the first day of an idealized 28 day menstrual cycle. On cycle day 1 menstruation arrives and a new cycle begins. During the follicular phase an orderly sequence of events takes place that ensures that the proper number of follicles is ready for ovulation. Folliculogenesis is a process that is initiated well prior to the arrival of menstruation. Once a primary follicle leaves the resting state it will take 85 days, or three complete menstrual cycles, to reach the point of ovulation. The follicle destined to ovulate is recruited in the first few days of the third cycle. It will measure 1-2 mm on cycle day 1. The first morphological evidence of maturation is differentiation of the granulosa cell layer and enlargement of the oocyte. Follicular recruitment will be driven by FSH secretion that started at the end of the luteal phase in the previous cycle. The demise of the corpus luteum at the end of the preceding cycle results in an abrupt decline in levels of progesterone, estrogen, and inhibin. FSH secretion is suppressed in the luteal phase by negative feedback from estrogen and progesterone. The sharp decline in these factors abolishes the negative feedback and allows FSH to rise shortly before and during menses. The increase in FSH at the luteal-follicular transition is responsible for follicle recruitment and initiation of steroidogenesis. Ovarian follicles may be found in four conditions: resting, growing, preovulatory or atretic. Once follicles leave the resting state, there are only two possible outcomes—ovulation or atresia—with atresia accounting for more than 99%. The primary oocyte, formed in fetal life, persists in prophase of the first meiotic division until the time of ovulation. Oocytes are stored in primordial follicles and protected for later use. This nongrowing group of follicles is termed the resting pool. Within the primordial follicle, the oocyte is sequestered in an immuno-privileged site. There are several layers of protection. Granulosa cells secrete the zona pellucida inward placing a mucopolysaccharide layer around the oocyte. Numerous cytoplasmic processes of the granulosa cells penetrate the zona pellucida presumably for respiration and nutrient exchange. A basal lamina separates the granulosa cells from the theca cells. Inflammatory cells are found within the ovarian cortex and stroma; however the oocyte is shielded from the influence of infection or hormones while it lies behind this barrier.

The Menstrual Cycle

5

Oocytes residing in the resting pool are probably under inhibitory control from autocrine factors. It is well documented that when oocytes are removed from resting follicles, they can spontaneously undergo nuclear maturation in vitro. This suggests 1 a release from local inhibitory factors. Such a strategy makes sense, as the limited supply of female gametes would be protected from influences that would render them unsuitable for future cycles. Folliculogenesis is continuous throughout life. Each day a cohort of follicles reaches 2-5 mm size and is either available to be further recruited by FSH or will undergo atresia. Thus, a cohort is always ready and continuously available for a response to FSH. Even without gonadotropin stimulation, some primordial follicles will leave the resting pool and develop into preantral follicles. This process occurs during times of anovulation (i.e., childhood, pregnancy, and OCP use) as well as during ovulatory cycles. The initial steps of follicular growth are independent of stimulation by pituitary hormones. Therefore the rate is unaffected by changes in the circulating gonadotropin or sex steroid hormone levels. The absence of gonadotropin stimulation will not prolong the total lifespan of oocytes, nor will excessive gonadotropin stimulation prematurely exhaust the oocyte supply. Primordial follicles are continuously undergoing an initial phase of growth and development that, in the vast majority of circumstances, will end in atresia. The gross wastage of follicles may be the necessary consequence of maintaining a constant supply of gonadotropin-sensitive follicles throughout each day of a woman’s reproductive life. This general pattern is interrupted when a group of follicles responds to a rise in FSH at cycle start and is propelled to further growth. Once they leave the resting pool they will establish contact with the circulatory system. Under the influence of FSH, the number of granulosa cells increases. As the FSH concentration rises there is a concomitant rise in estradiol receptors within the granulosa cells. Increasing estradiol levels within the follicle stimulate mitotic activity and increase the sensitivity to FSH. One of the major actions of FSH is the induction of granulosa cell aromatase activity. Little or no estrogen can be produced by FSH unprimed granulosa cells. FSH induces its own receptors and also increases activin, inhibin, and LH receptors. Activin is a potent FSH stimulator that will account for more FSH than does GnRH. Once the follicle acquires LH receptors and aromatase activity, ovarian androgens produced by the theca will be converted to estradiol. High local concentrations of estradiol enhance the follicular response to LH by working synergistically with FSH to induce LH receptors. Ovarian steroidogenesis is usually LH dependent. Folliculogenesis is thought to occur in four phases: recruitment, selection, dominance and ovulation. Recruitment takes place during cycle days 2, 3, and 4. The term recruitment indicates a cohort of quasi-synchronous follicles has entered a gonadotropin-dependent rapid growth phase. Overt connection of the follicular apparatus to the peripheral blood stream is coincident with onset of gonadotropindependent follicular growth. By cycle day 5 both menstrual flow and follicular recruitment end. In women, spontaneous multiple ovulation is atypical. Selection refers to the reduction of the cohort size down to the species-specific ovulatory quota. The dominant follicle is selected early when it develops LH receptors. LH stimulates androgen production in the theca. The dominant follicle uses androgen as a substrate and further accelerates estrogen output. Fluid accumulates amid the granulosa cell mass. The antrum is formed as the oocyte is displaced to one side by this process. Follicles

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at this stage measure 4-6 mm from the secretion of mucopolysaccharides by the granulosa layer, and the transudation of plasma proteins from the newly acquired 1 theca layer. By day 6 rising levels of estrogen in the bloodstream begin to cause peripheral effects. Estrogen first induces the lining of the uterus to proliferate and later promotes the secretion of thin, watery cervical mucus. The follicle destined to become dominant secretes the greatest amount of estradiol, which, in turn, increases the density of FSH receptors on the granulosa cell membrane. Rising peripheral estradiol levels result in negative feedback on FSH secretion. This withdraws the stimulus to the smaller follicles that have fewer FSH receptors. The nondominant follicles cease development and then become atretic. Selection marks the time when the influence of a single follicle creates an environment in which only it can adequately mature and reach ovulation. Peripheral levels of estradiol rise significantly by day 7 shortly after the process of selection of the dominant follicle has occurred. LH receptors are present on theca cells at all stages of the cycle and on granulosa cells after the follicle matures. While directing a decline in FSH levels the midfollicular rise in estradiol exerts a positive influence on LH. During the late follicular phase LH levels rise steadily stimulating androgen production in the theca. Usually one follicle reaches maturity and is ovulated while the remainder undergo atresia before the point of ovulation. The primary purpose of the other follicles is to deliver androgen substrate. Aromatase activity is highest in the preovulatory follicle thereby maintaining a high concentration of estradiol and a low concentration of androstenedione. In contrast the other follicles are FSH and aromatase deficient with a resultant predominance of androstenedione. After having served the purpose of acting as an endocrine gland, these follicles ultimately undergo atresia. By Day 8 selection ends and maturation begins. Normally, only one ovary sponsors recruitment. Once a dominant follicle is present, the opposite ovary could be removed without effect on the ensuing ovulation. This means that there is unambiguous ovarian asymmetry once the dominant follicle has been selected. The dominant ovarian follicle is the sole follicle destined to ovulate and somehow it continues to thrive in a milieu that it has helped to make inhospitable to others within its cohort. As the level of circulating estradiol rises, the plasma FSH falls back to basal levels (through negative feedback). The follicle reaches a state of gonadotropin independence. It is now self-sustaining and could continue to mature under the influence of only interfollicular FSH and estradiol. At this point in the cycle, rising levels of estradiol have induced endometrial proliferation. The lining which started at 1 mm will grow to a thickness of 8-10 mm. Ovarian hormones produce cyclic changes in all other parts of the female reproductive system. In the proliferative phase rising levels of estrogen promote secretion of thin watery mucus that permits the passage of spermatozoa into the uterus around the time of ovulation. By Day 11 estradiol is near its peak, and the lining has grown to maximal thickness. The follicle is near mature size at 16-20 mm. The final steps of oocyte maturation steps are completed on day 12. Having risen rapidly, estrogen levels reach a peak 24-36 hours before ovulation. The LH surge is preceded by an accelerated increase in serum estradiol levels. At nearly all times in the menstrual cycle, estradiol exerts a negative feedback effect. However, when estrogen levels exceed a critical threshold for a period of 2-3 days a change in the functional capacity of the gonadotrope occurs. There is a marked increase in sensitivity to GnRH and large amounts of gonadotropins are releasable

The Menstrual Cycle

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from a reserve pool. Only at this time can an LH surge occur. The process of self-priming means the LH response to the second GnRH pulse is much greater than to the first. The rising progesterone levels seen at the late follicular phase fur- 1 ther augment the LH surge as well as initiating a small surge in FSH. The LH surge leads to resumption of oocyte maturation, luteinization of granulosa cells and the production of progesterone and prostaglandins. Shortly before ovulation the preovulatory follicle reaches a diameter of 20-25 mm. Elevation of a conical stigma on the surface of the protruding follicle precedes rupture. Proteolytic enzymes and prostaglandin participate in degradation of the follicular wall. The oocyte, zona pellucida and corona radiata will detach from the follicular wall and float in the antral fluid. As ovulation approaches, the blood supply to the ovary increases and the ligaments contract pulling the ovary closer to the fallopian tube. The late follicular increase in serum estradiol levels will elicit an abundance of clear fertile mucus secreted by the cervix. Prior to ovulation the oocyte enters telophase of the first meiotic division. Chromosomal reduction occurs by migration of one half of the oocyte chromosomes into the periphery of the cytoplasm. There the chromosomes are packaged into the first polar body and extruded from the cytoplasm. After expulsion of the first polar body the oocyte enters second meiotic division. It arrests at metaphase until fertilization occurs. Ovulation occurs 10-12 hours after the LH peak and 36 hours after the estradiol peak. The most reliable indicator for the timing of ovulation is the onset of the LH surge, which begins 28-32 hours before ovulation. When the mature follicle ruptures, the oocyte, zona pellucida, and corona radiata are expelled into the peritoneal cavity near the entrance to the tube. The second meiotic division of the oocyte is not completed until after penetration of the ovum by a spermatozoon.

Luteal Phase Fertilization takes place within the ampullary portion of the tube. Over the next two to three days the ovum remains unattached within the lumen as it is propelled toward the endometrial cavity by the ciliary action of the tubal epithelium. Movement of the ovum down the tube is aided by a current of fluid propelled by the action of the ciliated epithelium lining the tube. There is also propulsion from the gentle peristaltic action of the longitudinal and circular smooth muscle layers of the tube. The cervical mucus becomes highly viscid after ovulation and forms a plug that inhibits ascending entry of microorganisms from the vagina. The cervix functions to admit spermatozoa to the upper genital tract at a time when fertilization is opportune, but at other times, including pregnancy, to protect the normally sterile uterus and upper tract from bacterial invasion. These cyclic changes form the basis for the “natural’ forms of contraception that identify “the fertile period.” Immediately following ovulation, the ruptured follicle collapses, leaving behind a collapsed cyst lined by a thick layer of granulosa cells. It usually fills with a blood clot and redistends. With a sufficient number of LH receptors on the granulosa cells, LH acts directly on the granulosa cells to cause luteinization (formation of the corpus luteum) and the production of progesterone. The granulosa cells enlarge and increase their lipid content. Penetration of the basement membrane by blood vessels provides the LDL cholesterol that serves as the substrate for corpus luteum (CL) progesterone production. Large deposits of cholesterol arise from circulating lipoproteins (i.e., the yellow color) and support the high quantities of progesterone production. The blood clot and luteinized thecal and granulosa layers are invaded by capillaries to form a rich vascular network. The thecal layer acquires a blood supply that it did not contain

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during the entire follicular phase. This facilitates the massive progesterone secretion. The corpus luteum is the most active steroidogenic tissue in humans, but in the ab1 sence of pregnancy it has a finite lifespan of 12-16 days. After ovulation the GnRH pulse generator is slowed for the luteal phase. LH, FSH and estradiol levels fall but some LH is essential to maintain CL function. The accumulation of LH receptors during the follicular phase sets the stage for the extent of luteinization and the functional capacity of the corpus luteum. Normal luteal function requires optimal preovulatory follicular development and continued tonic LH stimulation. A defective luteal phase can contribute to infertility and early pregnancy wastage. Maintenance of the corpus luteum is normally dependent on pulsatile gonadotropin secretion, but endogenous (from a pregnancy) or exogenous hCG can serve the same purpose. The onset of the LH surge (28-32 h prior to ovulation) is the most reliable clinical indicator for the timing of ovulation. Progesterone is thermogenic so core body temperature rises by about 0.6˚F until 2 days before the next period in nonconception cycles. If implantation does not occur, LH and FSH return to basal levels and their receptor numbers are reduced leading to a marked decline in the progesterone and estradiol synthesis. Without the continued stimulus of LH, the corpus luteum cannot be maintained and 12-14 days after ovulation it regresses to form the functionless corpus albicans. Regression of the corpus luteum appears to involve the luteolytic action of its own estrogen production, mediated by an alteration in local prostaglandin production. Initiation of a new cycle is dependent on regression of the corpus luteum. Reactivation of the GnRH system results from the withdrawal of the inhibitory effects of corpus luteum steroids and inhibin. Released from the negative feedback effects, the GnRH pulses begin to accelerate leading to a rise in FSH levels that occurs two days before the onset of menses.

The Endometrium: Proliferative and Secretory Phases After menses the endometrium consists of simple tubular glands set within a vascular, cellular stroma. During the proliferative phase of the menstrual cycle, the glands are small, straight and round when seen in cross section. The endometrium is the primary target (organ) for ovarian steroids. Under the influence of estrogen, the glands multiply and their epithelium becomes taller and pseudostratified, during the follicular phase of the cycle. After ovulation, the onset of the secretory phase is signaled by the appearance of subnuclear vacuoles of glycogen which are evident in the endometrial glands by day 16. These start to migrate toward the lumen by day 17 although the majority are still subnuclear. By day 19 glycogen vacuoles are being extruded from the luminal edge of the cell. Meanwhile, after 2-3 days of tubal transport, the embryo enters the uterine cavity on day 17. It will not attach to the uterine epithelium for 2 to 3 days. On day 18-19, it hatches from the zona pellucida in preparation for attachment. There is a narrow window of receptivity to blastocyst implantation that corresponds to the period between cycle days 20 and 24 in a 28 day cycle. Peak levels of progesterone are seen at 8-9 days after ovulation, which approximates the time of implantation of the embryo. At that time, the endometrium has sufficient depth, vascularity, and nutritional richness to sustain placentation. While the endometrium is acquiring its receptivity, the embryo is acquiring its invasiveness. On day 21 the embryo attaches to the uterine epithelium. The peak of interglandular glycogen secretion coincides with the time of implantation of the free

The Menstrual Cycle

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blastocyst. Day 22 marks the peak in estradiol and progesterone levels for the luteal phase. The embryo has initiated invasion into the lining. A portion of the cytotrophoblast population differentiates into a syncytiotrophoblast that synthesizes large 1 amounts of hCG. HCG serves to “rescue” the corpus luteum and maintains luteal function with secretion of progesterone until placental steroidogenesis is established. By midsecretory phase, progesterone is abundant and intraglandular glycogen secretion reaches a peak. Stromal edema and spiral artery development reach a peak on day 22 or 23 in response to progesterone. Decidualization is seen as nuclei enlarge, and cytoplasm becomes very eosinophilic. It begins as a periarteriolar blush of cuffing around the spiral arterioles on day 23. By day 24 the embryo has completely penetrated the endometrial lining and by Day 25 syncytiotrophoblast cells are secreting HCG in amounts that stimulate the corpus luteum to continue to produce progesterone. The wave of decidualization proliferates and will reach a state of confluence by day 26. Decidualization occurs only when the endometrium is sequentially exposed to estrogenic priming followed by progesterone stimulation. Without embryo implantation, decreasing steroid levels lead to increased coiling and constriction of the spiral arteries which supply the upper 2/3 of the functional endometrium. The decreased blood flow to the functional portion of the endometrium furthers the process of ischemia and degradation. Fibrin thrombi begin to occupy endometrial capillaries of premenstrual endometrium. Obstructed vessels lead to increases in hydrostatic pressure. By day 28, the endometrium contains tortuous glands that are fragmented. The stroma consists of dark necrotic fragments. Free hemorrhage is present throughout the tissue. Menstrual bleeding is controlled by vasoconstriction of the ruptured basal arteries in the denuded basal layer. The basalis layer remains intact after menstruation and a new lining is regenerated from this layer. Within 2 days of the onset of menses the surface epithelium begins to regenerate under the influence of estrogen and continues this process while the endometrium is still shedding.

Key Points Events from hypothalamus, pituitary ovary and uterus are integrated via the interaction among GnRH, gonadotropins, HCG and the sex steroids. Embryonic implantation is the culmination of a highly complex sequence of tightly regulated events. Estrogen and progesterone have a central role in directing the changes that facilitate implantation. Embryo quality and endometrial development are the two main determinants of successful nidation. The HPO axis is structured to enable these two determinants to function synchronously. In the absence of pregnancy, the cycle is programmed to slough the endometrium and begin anew.

Suggested Reading 1. Queenan Jr JT, Fazleabas A. Embryo-uterine interactions during implantation. In: Seibel MM, ed. Infertility: A Comprehensive Text. Stamford: Appleton and Lange, 1997:671-685. 2. Mutter GL, Ferenczy A. Anatomy and histology of the uterine corpus. In: Kurman RJ, ed. Blaustein’s Pathology of the Female Genital Tract. 5th ed. New York City: Springer-Verlag, 2002:383-420. 3. Bulun SE, Adashi EY. The physiology and pathology of the female reproductive axis. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. Philadelphia: WB Saunders, 2003:587-663. 4. Clement PB. Anatomy and histology of the ovary. In: Kurman RJ, ed. Blaustein’s Pathology of the Female Genital Tract. 5th ed. New York City: Springer-Verlag, 2002:649-674.

Chapter 2

Puberty and Its Disorders Adelina M. Emmi and Lawrence C. Layman

Normal Puberty Physiology Somatic Changes Normal puberty is a progression of events in both girls and boys that is generally complete in 3-4 years. In females, thelarche (breast buds) is usually the first sign of estrogen production and occurs at an average age of 10.5 years, while pubarche (pubic hair growth) generally occurs about 6 months later. In 10-20% of girls, pubarche is the first event. These are estimates; thelarche varies slightly among different racial groups (white: 10.4 years; black: 9.5 years; Mexican/American: 9.8 years). Tanner Stages are used to classify the stages of puberty in both boys and girls (Table 2.1). Tanner Stage 1 is prepubertal, while Stage 5 is the fully mature adult status. Peak growth rate for girls generally is seen at Tanner Stage 3 breast development. Adrenarche is the result of adrenal androgen production (androstenedione, DHEA, and particularly DHEAS), which begins prior to changes in gonadotropin secretion at 6-8 years of age and continues through the mid-teens. During female puberty, growth in height occurs at a rate of 4-5 cm/year in early puberty. As estrogen production increases, growth hormone increases, resulting in increased IGF-1 and IGFBP-3, which mediates skeletal growth. Maximal growth velocity occurs in girls at age 12 and usually results in about a 9 cm increase in height. Menarche (initiation of menses) occurs on the downward arm of the growth curve at a median age of 12.5 years (white: 12.6 years; black: 12.15 years; Mexican/ American: 12.3 years). A variety of additional factors affect pubertal onset, such as weight, stress, and extreme physical activity. Some authors have noted a younger age of onset of breast development and possibly menarche in African-American girls that may be attributable to a greater BMI. In boys the initial pubertal event is testicular growth, which begins at about 10.5 years of age. When the testes exceed 2.5 cm in any dimension, the onset of puberty is approaching. Pubarche frequently starts simultaneously with testicular development. Axillary hair growth occurs at about the time of peak height velocity (about age 14 years in boys and 12 in girls) (Table 2.2).

Endocrinology of Puberty The GnRH pulse generator is the principal regulator of puberty through its control of pituitary gonadotropins and is active early in life. As a result, gonadotropin levels change throughout fetal development, childhood, puberty and adulthood. Gonadotropins begin to rise at 10 weeks gestation, peak at

Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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Table 2.1. Tanner staging in females with approximate ages in parentheses Tanner Stages Stage 1 (prepubertal) Stage 2 Stage 3

Stage 4 Stage 5

Breast nipple elevation only

Pubic Hair no pubic hair

breast budding (9.5)

sparse growth, most on labia majora (10.5) coarser, spread to mons (11.5)

increases in gland tissue, no separation of breast from areola (11) areola forms separate mound from breast (12) areola recedes to single breast contour (14)

adult type-limited growth (12) adult type-extends to medial thigh (13.5)

mid-gestation and decline at term because of negative feedback from placental steroids. At birth, there is a withdrawal of gestational steroids, which leads to a rise in FSH and LH with a subsequent decline which is sex specific. Girls tend to have a higher FSH to LH ratio at all times compared to boys, and their gonadotropin levels decline over a 2 to 4 year period. This early neonatal gonadotropin elevation may be significant enough to cause estradiol production and transient breast development in girls or result in testosterone production in boys. Thereafter, gonadotropin levels decline over about a 6-month period in boys. During childhood gonadotropins remain low in both sexes until puberty. Typically, prepubertal gonadotropins tend to exhibit a ratio of LH/FSH that is less than one. Gonadotropins begin to rise by age 9 years, first FSH, then LH. These increases are a reflection of the increasing pulse frequency of GnRH from the pulse generator. The exact central inhibitor of GnRH until this age is unclear. Slower GnRH pulse frequency tends to lead to the preferential secretion of FSH, while faster pulse frequency favors LH secretion. Initially LH pulses are nocturnal, but then become apparent throughout the day and result in gonadal steroid production. Maturation of the hypothalamic-pituitary-gonadal (H-P-G) axis with positive and negative feedback by gonadal steroids and inhibition by inhibin occurs around midpuberty and culminates in menstruation. However, a fully mature H-P-G axis in the female is usually operative within the first two years of menarche with regular ovulatory cycles.

Table 2.2. Usual order of pubertal events in males and females Females Thelarche Pubarche Maximal growth velocity Menarche Adult pubic hair Adult breast

Males Testicular growth Pubarche Maximal growth velocity

2

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In boys, two Sertoli cell proteins, inhibin B and antimullerian hormone (AMH)/ mullerian inhibiting substance (MIS), are produced in the early neonatal period. Inhibin B (human males have minimal inhibin A) increases soon after birth and 2 peaks at 4-12 months of age, declines to low levels by ages 3-9, and then increases again with the onset of puberty (at lower levels than the neonate). AMH/MIS is evident in the first month of life and peaks about 6 months of age, drops during childhood, and becomes very low with puberty, probably secondary to increased testosterone inhibition. These hormones are useful markers of testicular function in early childhood.

Abnormalities of Puberty Precocious Puberty Definitions and Etiology Precocious puberty is defined as the onset of puberty before the age of 8 in girls and age 9 in boys. These ages are 2.5 standard deviations below the mean age of puberty in North American children. This disorder is five times more common in girls than boys. It is classified as either central (GnRH-dependent) or peripheral (GnRH-independent) depending on whether the inciting event has activated the H-P-G axis. In central precocious puberty (CPP), activation of the hypothalamicpituitary axis occurs, leading to premature sexual development that typically follows the normal pattern of puberty except that it is early. In peripheral precocious puberty (PPP), steroid production is independent of activation of the central axis, as is the case in gonadal or adrenal tumors or McCune-Albright syndrome. Precocious puberty is often idiopathic, especially in girls, however, a work-up is indicated in order to rule out significant pathology. If left untreated, final adult height will be compromised because of steroid-induced premature closure of the epiphyses. These children have normal reproductive function and do not appear to be at risk for premature menopause. Psychosocial issues should also be addressed because other aspects of development correspond with chronological age. In addition, more benign variants, premature thelarche and premature pubarche, may also occur.

Diagnosis of Precocious Puberty Precocious puberty may result in a decrease of final adult height; so arresting the growth is an important objective. The history and physical exam are extremely important as are growth charts. A skeletal film of the hand for bone age is very important in assessing the severity of the disorder and need for treatment (Fig. 2.1). Premature thelarche may occur in girls 1-2 years old because of the GnRH pulse generator activity. Normally, this will not result in advanced growth and the bone age is consistent with chronologic age. No treatment is necessary, even though some girls may have follicular activity on ultrasound. Premature adrenarche without other signs of puberty is also a benign process, and if the bone age is normal, these patients can be followed expectantly. Patients with premature adrenarche tend to be taller and heavier than other children their age. These patients may be at risk for polycystic ovary syndrome in the future. If they have hirsutism, serum levels of total testosterone, DHEAS, and 17-hydroxyprogesterone may be indicated. If markedly elevated androgens are present or there is evidence of virilization, adrenal or ovarian neoplasms and congenital adrenal hyperplasia should be excluded as in peripheral precocious puberty (Fig. 2.1).

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2

Figure 2.1. An algorithm that can be used as a guide in the diagnosis of precocious puberty (PP). T, testosterone; DHEAS, dehydroepiandrosterone sulfate; 17OHP, 17-hydroxyprogesterone; US, ultrasound; MAS, McCune-Albright syndrome.

For children who develop breasts and have pubic hair suggesting precocious puberty, the history and physical examination including height, weight, Tanner staging, signs of virilization and estrogenization, thyroid exam, and a thorough neurological exam should be performed. A bone age will demonstrate accelerated growth compared to chronological age (for example, if the bone age for a 5-year old is 8 years). A CT or MRI is usually necessary to exclude a CNS tumor in patients with central or peripheral precocious puberty. In particular, patients with precocious puberty who have a rapid course of progression or who have CNS signs should have an MRI of the brain to exclude a tumor. A “GnRH stimulation test” is useful to determine if CPP or PPP is present. A LH response greater than FSH response indicates a central cause, while a primarily FSH response suggests a peripheral, or GnRH-independent cause. Since native GnRH is not available for these tests, a GnRH-agonist such as leuprolide acetate can be used at a dose of 20 μg/kg S.Q. FSH and LH levels should be drawn at baseline (before agonist administration) and every 15 minutes for 1 hour thereafter. If the LH/FSH ratio exceeds 1 or the maximum level of LH exceeds ~7 mIU/mL (cutoff value should be determined for your own lab), then the etiology is central (mediated through the H-P-G axis). It has also been suggested that if an immunofluorometric LH assay is used, a single unstimulated LH value >0.6 mIU/mL may eliminate the need for a “GnRH stimulation test” (remember there is lab variability and this cutoff level should be determined in your lab). Ovarian volume may also be increased in patients with CPP.

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In patients who do not have evidence of a central cause, ovarian ultrasound or adrenal CT may be helpful to evaluate the presence of a neoplasm. For boys, testicular palpation may indicate a mass needing biopsy. Thyroid studies (TSH and 2 total T4), prolactin, estradiol, DHEAS, testosterone, estradiol, and hCG levels should be considered.

Causes and Treatment of Precocious Puberty Central Precocious Puberty A number of factors can activate the hypothalamic production of GnRH, leading to stimulation of pituitary gonadotrophs and gonadal steroid production. Tumors can impinge on inhibitory neurons causing increased secretion of GnRH. A suspected malignancy should be followed by biopsy for identification. Benign tumors, such as hamartomas (hyperplastic malformations of the tuber cinerum which elaborate GnRH), can be successfully treated with GnRH agonist therapy. Long standing hypothyroidism can cause central precocity (usually associated with retarded bone age). Treatment will curtail symptoms. A careful history may illicit a previous history of an infectious process (i.e., meningitis), trauma, radiation, or developmental abnormalities (hydrocephalus). Ectopic gonadotropin production by tumors accounts for less than 0.5% of the causes of central precocity. The most common of these tumors include chorioepithelioma, dysgerminoma, and hepatoblastomas. Therapy is directed toward arresting further sexual development and skeletal growth. GnRH agonist therapy has become the standard for children with central precocious puberty. The depot form of leuprolide acetate is given at a dose of 300 μg/kg every four weeks. Be aware that 7.5 mg or more may be necessary for treatment in some children rather than the standard 3.75 mg dose. Therapy with leuprolide is continued until an age agreed upon by the patient, family, and the physician, usually 11-12 years of age. Adequate suppression of the H-P-G axis should be assessed by drawing an LH level by a standard GnRH agonist test or by a single LH value 2 hours after a dose of GnRH agonist. The maximal LH should be suppressed to less than 2-5 mIU/mL depending upon the assay used, although most suggest <2 mIU/mL. Follow-up visits should be scheduled every 3 months to assess growth velocity and every 6 months to assess Tanner staging and bone-age at least initially, and then less often. Peripheral Precocious Puberty Peripheral precocity can be caused by a number of disorders. A careful history will eliminate rare iatrogenic causes such as hormone containing lotions or meat from animals fed steroids. Gonadal neoplasms occur in about 10% of both boys and girls diagnosed with precocious puberty. The most common cause of precocity from gonadal estrogen production in girls is a follicular cyst. Careful follow up (including ultrasound to document ovarian size) and observation is appropriate. Surgery should be avoided because it might lead to an unnecessary oophorectomy. The most common malignant tumor that causes peripheral precocity is the granulosa-theca cell tumor, although these are very rare. They are almost always unilateral and diagnosed at an early stage,. In boys, tumors that produce hCG can cause precocious puberty. Treatment is usually surgical, and if malignant, adjuvant therapy may be indicated. Hepatoblastomas and hepatomas usually present with bilateral testicular enlargement and have a poor prognosis.

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Mc Cune-Albright syndrome is associated with precocity and is five times more common in girls than in boys. The diagnosis is made with the findings of café-au-lait spots, precocious puberty and polyostotic fibrous dysplasia. The order of pubertal development is sometimes completely haphazard. Skeletal fractures may occur in 2 the regions of polyostotic fibrous dysplasia because fibrous tissue replaces normal bone. The femur and skull are the most frequent fracture sites. The risk of fractures usually does not persist into adulthood. Hearing loss may occur if there is involvement of the temporal bone. McCune-Albright syndrome is caused by a somatic cell mutation of the Gsα gene, which encodes for a G-protein. Abnormal activation of other organs utilizing cAMP can occur so these patients should be screened for hypercortisolism, hyperthyroidism, and growth hormone excess. Testolactone, an aromatase inhibitor, at a dose of 20-40 mg/kg/day in four divided doses has been used successfully. Newer aromatase inhibitors have been used as well, but there is much more experience with testolactone. Adult height is not compromised and these adults have normal reproductive function. An important cause of PPP in boys is familial male precocious puberty (FMPP), previously known as testotoxicosis. This often presents at age 2-3 and occurs via an activating mutation of the luteinizing hormone receptor (LHR) gene that results in increased testosterone production without an increase in the LH ligand. These patients have prepubertal levels of gonadotropins, but adult-sized testes and adult levels of testosterone. It is inherited in an autosomal dominant mode, but interestingly, does not affect females. This can be treated by ketoconazole, a P450 cytochrome inhibitor of adrenal and gonadal steroidogenesis at doses of 400-600 mg/day. Liver enzymes must be followed to avoid hepatotoxicity. Antiandrogens such as flutamide may be added, but may also be hepatotoxic. Less common causes of peripheral precocious puberty include adrenal tumors (virilizing in boys; feminizing in girls), such as adrenal adenomas and cancer. Adrenal cancer has a poor prognosis.

Delayed Puberty Diagnosis Delayed puberty is defined as no signs of puberty by age 14 in boys. In girls, it is defined as either the absence of thelarche by age 13 or menarche by age 15. These are 2.5 standard deviations above the mean for North American children. In boys, delayed puberty signifies that there is a hypogonadal state. In girls, the differential diagnosis is complex and may include a hypogonadal state, anatomic abnormalities, such as absence or obstruction of the outflow tract, and certain disorders with ongoing estrogen production most commonly polycystic ovary syndrome (PCOS). An algorithm is shown in Figure 2.2. Note that the evaluation and diagnostic categories are similar for males with the exception of an obstructed genital tract. All patients with delayed puberty should have a TSH, total T4 (more robust assay than the problematic free T4), and serum prolactin, and detailed psychosocial history. Hypothyroidism (central, rather than primary) hyperprolactinemia, and hypothalamic disorders (eating disorders/stress/exercise) may occur in patients who are eugonadal or hypogonadal depending upon the duration of the process. A careful history and physical exam of the patient with delayed puberty are extremely important to ascertain if there are any initial signs of puberty and estrogen production. If there are no signs of breast development, the patient clearly has

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2

Figure 2.2. An algorithm that can be used as a guide in the diagnosis of delayed puberty. AIS, androgen insensitivity syndrome.

hypogonadism. If she has breast development, she has evidence of at least previous estrogen production, but her estrogen status must be determined at the time of presentation (she could now be hypogonadal). One of two tests is recommended: a vaginal maturation index or a progestin challenge test. Estradiol levels are not very helpful since it may be difficult to discriminate between low and low-normal. A vaginal smear (or vaginal maturation index) can be performed using a Q-tip to swab the vagina. The swab is gently rolled onto a slide and set with Urine Sedi-Stain or another quick prep stain. The ratio of parabasal, intermediate, and superficial (P/I/S) cells is reported, usually in that sequence. A predominance of parabasal cells (such as 70/30/0) indicates that the patient is probably hypogonadal (hypoestrogenic). If there are superficial cells present (as in 0/30/70), the patient is probably making estrogen or is eugonadal. The second screening test for the eugonadal state is the progestin challenge test. It is usually performed by administering medroxyprogesterone acetate 10 mg for 5-10 days (after a negative pregnancy test, if the patient has normal breast development). If the patient is hypogonadal, she may spot, but will not have a menstrual bleed after the medication is completed. This test can be repeated if negative the first time. The progestin challenge test does not need to be performed in patients with no breast development or who have a vaginal smear indicating no estrogen production (predominant parabasal cells).

Hypogonadism If hypogonadism is suspected on the basis of physical exam (Tanner 1 breasts), vaginal maturation index, or negative progestin withdrawal, serum gonadotropins

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should be obtained. If elevated, they should be repeated in several weeks for confirmation because of the pulsatile secretion of gonadotropins. When gonadotropins are persistently elevated, gonadal failure, also known as hypergonadotropic hypogonadism, is present. A karyotype should be performed in all children with elevated 2 gonadotropins to rule out a chromosomal abnormality (see below). If gonadotropins are low or normal (in the face of hypogonadism), the patient has hypogonadotropic hypogonadism due to hypothalamic or pituitary disease. Since sex steroids are necessary for growth, performing a bone age should be considered in hypogonadal patients. These patients can have delayed bone age compared to chronological age. They do not usually have a bone age beyond 11-12 years, however, if bone age is markedly delayed, growth hormone deficiency and/or hypothyroidism should be strongly considered.

Hypergonadotropic Hypogonadism Females Patients with hypergonadotropic hypogonadism will either have a normal female karyotype (46,XX), a normal male karyotype of 46,XY (Swyer syndrome) or an abnormal karyotype. About half of females with gonadal failure and amenorrhea will have an abnormal karyotype as compared to only 10-15% of boys with delayed puberty due to hypergonadotropic hypogonadism. In females with a chromosome abnormality, about half are found to have a 45,X cell line and the remainder possess a 45,X cell line plus a second mosaic cell line. The second cell line can be a 46,XX, 47,XXX, 46,XY, 46,X, i(Xq) or a number of structural abnormalities of the X chromosome including deletions. Turner stigmata may or may not be present. The most common feature is short stature (usually <5 feet), while absent puberty occurs in 90-95%. Cardiac anomalies (coarctation, dilated aortic root, bicuspid aortic valve) occur in ~50% of patients and renal anomalies in 30%. Therefore, patients should be evaluated for these abnormalities with a cardiac echo and an IVP or renal ultrasound. A cardiac echo has been suggested to be performed every three years for the rest of her life since patients may develop a dilated aortic root that is prone to rupture. It should also be kept in mind that about 10% of patients with a 45,X cell line will have some menstrual function, even if short-lived. It is therefore wise to karyotype all women who develop hypergonadotropic hypogonadism with short stature (<5’3”). Patients who have 45,X/46,XY karyotype can have a phenotype that ranges from completely absent sexual development to normal appearing male external genitalia depending on whether streak gonads or testes are present. Girls with a 46,XY cell line are at increased risk of developing gonadal tumors, such as gonadoblastomas or germ cell tumors like dysgerminomas. These tumors occur in about 15% of patients with a 45,X/46,XY cell line and in 20-25% of those with a pure 46,XY cell line (Swyer syndrome or 46,XY gonadal dysgenesis), and therefore, removal of the gonads is indicated when the diagnosis is made. Most patients with gonadal dysgenesis and a Y cell line, including Swyer syndrome, are phenotypic females with normal vagina, uterus, and cervix since their nonfunctioning testes (streak gonads) do not make AMH/MIS. They are not short as are the patients with a 45,X cell line. Regular follow up of patients with ovarian failure due to gonadal dysgenesis should also include thyroid studies, as there is an increased risk of developing disease.

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Women with hypergonadotropic hypogonadism and normal female chromosomes (46, XX) are phenotypic females with or without breast development. They can present with completely absent puberty (sexual infantilism), or with secondary 2 sexual development and amenorrhea, or they may have normal sexual development and abbreviated reproductive capacity. This disorder is termed 46,XX gonadal dysgenesis, premature ovarian failure, or hypergonadotropic amenorrhea. These patients have normal female internal and external genitalia as well as normal female height. Autoimmune disorders are present in about 20% of these patients, most frequently hypothyroidism and Addison’s disease. It is therefore reasonable to obtain a TSH, T4 and 8 AM cortisol level. The cortisol level should be 17-20 μg/dL to rule out Addison’s disease, and should be followed up with an ACTH stimulation test if low. A serum calcium, phosphorus and antinuclear antibody are also reasonable, although autoimmune parathyroid disease is less common. Premature ovarian failure can be associated with a number of genetic abnormalities. It is therefore important to get a good genetic history. Fragile X syndrome carrier status may be observed in ~3-4% of women with sporadic 46,XX ovarian failure, but in up to 10-15% of patients if two or more women in the family are affected with gonadal failure. It is reasonable to determine if there is a family history of mental retardation, which increases the likelihood for Fragile X syndrome. Fragile X syndrome may be tested by DNA (not cytogenetics) for the permutation allele. Although a patient with ovarian failure is unlikely to get pregnant spontaneously, there could be a risk for other family members to have a child with Fragile X syndrome. In patients with hypergonadotropic hypogonadism who do not have breast development, a pelvic exam should be performed to determine if a vagina is present (Fig. 2.2). Rarely, 17-hydroxylase deficiency (17-OHase) may be observed in females (who will have a uterus/vagina) or in males (who will have a blind vaginal pouch). It is a wise precaution to draw an 8 AM cortisol to exclude adrenal failure secondary to 17-OHase deficiency. Also, rare inactivating mutations in the LHR gene should be considered in a patient with gonadal failure, no breast development, and no vagina. Treatment of Gonadal Failure Estrogen can be used to initiate breast development in these patients. Unopposed conjugated estrogens are usually administered in a dose of 0.3 mg/day for a few months and then increased to 0.625, 0.9, then 1.25 mg/day until breast development is adequate. Initial low dose administration may allow for a more normal looking breast with early treatment. Low doses of ethinyl estradiol can be used beginning at 1 μg/day and gradually increased. Alternatively, estradiol 0.5 mg may be started and increased by 0.5 mg increments. Once breast development is achieved, progestins should be added. Medroxyprogesterone acetate 5-10 mg/day for 10-12 days/month is added for endometrial protection. The patient can then be switched to oral contraceptives. Pregnancy is extremely unlikely in these patients even with ovulation induction or estrogen withdrawal. The chances are not zero since ovarian function may wax or wane in those with a 46,XX karyotype. In vitro fertilization with oocyte donation allows many of these patients the chance to reproduce. Care must be taken in patients with a 45,X cell line because their risk of death due to aortic rupture in pregnancy is 1-2%. For patients with a 45,X cell line, treatment with recombinant growth hormone may also be considered. Although there is significant cost associated with its use, some evidence indicates that height gains of 2-3 inches may occur with long term treatment.

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Males The most common karyotype of males with gonadal failure is a normal 46,XY. However, 10-15% may have a 47,XXY (Klinefelter syndrome) or 46,XX karyotype (sex-reversed male). Patients with a 47,XXY karyotype are usually in the 50th per- 2 centile for normal male height and eunuchoid due to lack of epiphyseal closure (decreased upper to lower body ratio). Puberty is often initiated, but the tempo is disrupted and they become hypogonadal. The most consistent finding in this syndrome is testicular fibrosis which leads to azoospermia in >95% of pure 47,XXY males. If mosacism is present, about half of these males will have azoospermia. Gynecomastia occurs in about one-third to one-half of patients and frequently does not respond to hormonal therapy. Medical care should include evaluation for diabetes mellitus, breast cancer, leukemias, lymphomas, and germ cell tumors. Males with a 46,XX karyotype have a normal male phenotype since they have the sex determining region of the Y chromosome (SRY) initially, but they commonly develop gonadal failure and are azoospermic. Treatment for males with hypergonadotropic hypogonadism (regardless of karyotype) is comprised of replacing androgens to induce secondary sexual characteristics and normal sexual function and to prevent osteoporosis. When diagnosed in the newborn period, treatment with testosterone cypionate 25 mg IM is given several times to induce penile growth. If treatment is initiated at puberty, testosterone enanthate 50-100 mg IM should be given every 2-4 weeks. The usual adult dose for maintenance is 200 mg administered every two weeks. Topical testosterone gel or patches can also be utilized. Similar to females with gonadal failure, fertility is highly unlikely and donor insemination generally offers the best chance for pregnancy. In some circumstances, if a testicular biopsy or epididymal aspiration demonstrates mature sperm, IVF with ICSI may be an option.

Hypogonadotropic Hypogonadism When the patient is hypogonadal (absent breast development, without an estrogen withdrawal bleed, or a negative progestin challenge) and serum gonadotropins are low or normal (“normal” is inappropriate given the hypogonadism), the diagnosis is hypogonadotropic hypogonadism (HH). An MRI of the brain is necessary to exclude a pituitary tumor, most commonly a prolactinoma or craniopharygioma. If a tumor is present, it is usually treated medically (dopamine agonist for a prolactinoma), but surgery may be required for a craniopharyngioma, which may be malignant. If a tumor is not present, the cause is generally hypothalamic by exclusion. Although it is possible to perform a triple test (insulin induced hypoglycemia, GnRH, and TRH stimulation and check baseline and hormone levels every 15 minutes for 1-2 hours—TSH, prolactin, cortisol, LH, FSH, and GH), the cost is great and the yield is very low except in patients who have extreme short stature, which could suggest pituitary failure. If the patient has a height below the 5th percentile, particularly if there is a family history of pituitary failure, then combined pituitary hormone deficiency (CPHD) should be considered. Genetic counseling and testing for mutations in genes such as PIT1, PROP1, HESX1, or LHX3 should be considered. In the absence of a tumor, strong consideration must be given to the history and physical exam with particular attention to BMI, eating and exercise patterns, and stress. Eating disorders such as anorexia nervosa or bulimia must be sought because of the significant morbidity and mortality. A history of extreme exercise such as

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prolonged running or ballet must also be elicited, as should a history of stress. Morning cortisol levels are elevated in patients with eating disorders, and reverse T3 levels may be elevated (preferential conversion of T4 to rT3 instead of the more active 2 T3). Correction of the underlying problem with an increase in weight, reducing the exercise, or trying to relieve the stress will often lead to menstruation. For patients with hypogonadotropic hypogonadism who have no pituitary tumor and are of normal weight, two diagnoses must be considered. They may have constitutional delay of puberty (CDP) if they initiate puberty spontaneously before age 17 in girls and age 18 in boys (CDP is more common in boys). If they are older than 17 for girls and 18 for boys, the diagnosis is idiopathic or isolated hypogonadotropic hypogonadism (IHH). A history should be sought for anosmia/ hyposmia, midline facial defects, associated neurologic deficits such as synkinesia (tested by raising both arms for example when asked to raise one-corticospinal tract abnormality), hearing loss, or visual abnormalities. When IHH is combined with anosmia/hyposmia, the patient has Kallmann syndrome. Mutations in the KAL1 gene on the X chromosome account for about 5-10% of the causes in males (not females since it is X-linked recessive). Males with mutations in the KAL1 gene may also have unilateral renal agenesis (50% in one series), which should be tested. Mutations in the FGFR1 (KAL2) gene occur in about 10% of patients (male and female) with Kallmann syndrome. This autosomal dominant form of Kallmann syndrome can lead to individuals with mutations who are not affected (reduced penetrance), which can complicate the diagnosis. Midline facial defects and dental agenesis may occur in patients with FGFR1 mutations. For patients with normosmia, mutations in the gonadotrophin releasing hormone receptor (GNRHR) comprise approximately 5-10% of the cases and are inherited in an autosomal recessive fashion. Although mutations in other genes have been reported, they are thought to be rare. Testing for deletions of KAL1 may be performed commercially, but testing FGFR1 and GNRHR are generally performed only by research laboratories. Treatment for patients with hypogonadotropic hypogonadism involves administration of estrogen for girls (testosterone for boys) as described above. In contrast to patients with gonadal failure, patients with IHH can be given S.Q. FSH and LH (see ovulation induction chapter) for ovulation induction in females and cycle fecundity is similar for age-matched fertile women. For men who have testes larger than prepubertal size (≥4 mL by Prader orhidometer), 2000-3000 IU of hCG may be given S.Q. three times/weekly. If there is little or no response, recombinant FSH 150 IU may be added to this regimen. Most males will have evidence of spermatogenesis and fertility although it may take 6-12 months and their semen analysis parameters are often lower than what would be considered normal.

Eugonadism (in Females) If breast development is normal and amenorrhea is present, the exam will determine if there is an outflow tract obstruction. The exam may identify an anatomic abnormality, such as absence of the uterus and vagina with either complete androgen insensitivity syndrome (CAIS) or mullerian aplasia (Mayer-Rokitansky-Kuster-Hauser syndrome) or obstruction of the outflow tract. A karyotype will serve to distinguish CAIS (46,XY) vs mullerian aplasia (46,XX), as will a testosterone (normal male levels in CAIS and normal female levels in mullerian aplasia). However, this is often not necessary. CAIS patients usually have absent pubic hair because of an X-linked recessive mutation in the androgen receptor gene, while females with mullerian aplasia are

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normal appearing females and should have pubic hair, since the defect involves uterine, renal, vaginal, and skeletal development. Remember that about 1/3 of women with mullerian aplasia will have unilateral renal agenesis and may have skeletal spinal fusion defects (Klippel Fiel syndrome) and need some form of evaluation for this. 2 Treatment is usually successfully accomplished with progressive vaginal dilation initiated when the patient is sexually mature and interested in intercourse (usually later teenage years or early 20s). Typically, lubricated, increasing sized vaginal dilators are used for 20-30 minutes/day over a period of 3-6 months until achievement of the final desired vaginal depth and size. Surgical creation of a neovagina, such as the McIndoe procedure, may also be utilized, but patients should understand that wearing a vaginal mold for 6-9 months postoperatively may still be necessary. Other obstructive causes such as a transverse vaginal septum or imperforate hymen will present as cyclic, worsening pelvic pain since uterine contents collect in the vagina (hematocolpos) and in the uterus (hematometra). These disorders present urgently or emergently. If an imperforate hymen is present, a hymenectomy may be performed, which is a relatively straightforward procedure in which the hymen is excised. A transverse vaginal septum presents a much more challenging operative procedure since the septum may be much thicker and higher in the vagina than appreciated; however, the septum must be opened and removed. A vaginal mold is also necessary postoperatively with this procedure. If no outflow obstruction is observed in a eugonadal patient and thyroid studies and prolactin are normal, the patient very likely has polycystic ovary syndrome (PCOS) as the cause of amenorrhea. These patients are at risk for diabetes and endometrial hyperplasia so treatment with oral contraceptives or acyclic progesterone, such as medroxyprogesterone acetate, if pregnancy is not desired. Ovulation induction is indicated for attempting pregnancy.

Key Points 1. The onset of puberty should occur over a three to four year period, with the usual first sign of puberty being breast budding (thelarche). 2. Sexual development prior to the age of 8 years in girls and 9 years in boys is considered early, and mandates an evaluation. It is often idiopathic and is five times more common in girls than boys. 3. Precocious puberty can be classified as being central (activation of the hypothalamic-pituitary-gonadal axis), which may be treated with GnRH agonists, or peripheral, which will not respond to GnRH agonists. If precocious puberty is not treated, final adult height may be compromised. 4. Delayed puberty is defined as absent puberty by age 14 in boys (no testicular development). For girls, no thelarche by age 13 or no menarche by age 15 is considered delayed. 5. All patients with delayed puberty should have a TSH, T4, prolactin, and girls should have a test for the presence of estrogen (a progestin withdrawal test or vaginal maturation index). 6. If a delayed puberty patient has evidence of estrogen, a pelvic exam will distinguish if there is an outflow tract abnormality vs. polycystic ovary syndrome. 7. In hypoestrogenic girls with delayed puberty, it is necessary to obtain FSH and LH levels. If gonadotropins are elevated, ovarian failure is present and a karyotype is warranted to exclude the presence of a Y chromosome. If gonadotropins are low or normal, a central (hypothalamic or pituitary) etiology is present, and an MRI is necessary to exclude a tumor.

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Suggested Reading 2

1. Grumbach MM. The neuroendocrinology of human puberty revisited. Horm Res 2002; 57(Suppl 2):2-14. 2. Grumbach MM. A window of opportunity: The diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metab 2005; 90(5):3122-7. 3. Hayes FJ, Crowley Jr WF. Gonadotropin pulsations across development. Horm Res 1998; 49(3-4):163-8. 4. Layman LC, Reindollar RH. Diagnosis and treatment of pubertal disorders. Adolesc Med 1994; 5(1):37-56. 5. Layman LC. Genetics of human hypogonadotropic hypogonadism. Am J Med Genet 1999; 89(4):240-8. 6. Layman LC. Mutations in human gonadotropin genes and their physiologic significance in puberty and reproduction. Fertil Steril 1999; 71(2):201-18. 7. Layman LC. Human gene mutations causing infertility. J Med Genet 2002; 39(3):153-61. 8. Lee PA. The effects of manipulation of puberty on growth. Horm Res 2003; 60(Suppl 1):60-7. 9. Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development: A study of 252 patients. Am J Obstet Gynecol 1981; 140(4):371-80. 10. Reiter EO, Lee PA. Delayed puberty. Adolesc Med 2002; 13(1):101-18, (vii). 11. Sun SS, Schubert CM, Chumlea WC et al. National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics 2002; 110(5):911-9.

Chapter 3

Amenorrhea Michael Wittenberger and Alicia Armstrong

Introduction Amenorrhea is a common gynecologic complaint that generates consternation in patients and clinicians alike. Patients are concerned because cyclic menstrual periods are considered to be a sign of health, and conversely, the absence of menstrual periods are a sign of disease. Additionally, the broad differential diagnosis, perceived complexity of the work up and the ramifications of the diagnoses often intimidate clinicians. The purpose of this chapter is to provide a framework to systematically evaluate and treat primary and secondary amenorrhea. Many clinicians consider primary and secondary amenorrhea to be the same diagnosis. Although there is a great deal of overlap, a subset of patients with primary amenorrhea differ markedly from those with secondary amenorrhea relative to the possibility of restoration of menses and conception. Traditionally, primary amenorrhea is defined as no menarche by 14 years of age in the absence of secondary sexual characteristics or absence of menses by 16 years of age in the presence of normal growth and secondary sexual characteristics. This definition has remained unchanged despite a shift towards earlier menarche. Secondary amenorrhea occurs in a woman with prior menses, and represents the absence of menses for a duration equal to at least three of her previous cycle intervals or six months. These definitions provide an initial framework to identify amenorrhea; however, the timelines described should not be strictly adhered to particularly in the presence of anatomic abnormalities and obvious pathology.

Evaluation Using the patient’s history and physical exam to guide the ordering of additional tests, the evaluation of amenorrhea can be both time efficient and cost effective. One such diagnostic approach is depicted in Figures 3.1-3.5. This management algorithm classifies patients by physical evidence of estrogen secretion and the absence of a Y chromosome. Because steroidogenesis is one of the basic functions of the intact gonad, the absence of breast development strongly suggests hypoestrogenemia; and therefore, hypogonadism. However, the presence of breasts does not confirm normal estrogen levels or eugonadism. Breast development is only a marker for past exposure to estrogen. To obtain information on a patient’s current estrogen status, it is necessary to evaluate the patient’s reproductive organs. Upon speculum examination of the patient’s vagina and cervix, a well-estrogenized vagina is characterized by pink, moist mucosa with multiple rugations and the presence of mucous discharge from the cervix. The presence of superficial cells on vaginal cytology is also characteristic of the well-estrogenized state. Conversely, thin, pale appearing vaginal mucosa without cervical discharge Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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Figure 3.1. Evaluation of amenorrhea.

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is suggestive of hypoestrogenism and hypogonadism. In addition to assisting in classifying the patient as eugonadal (normal serum estrogen) versus hypogonadal (hypoestrogenic), examination of the reproductive organs allows many anatomical abnormalities to be discovered, and specifically, perhaps most importantly, the presence of a uterus can be documented. These two features: hypogonadism ver- 3 sus eugonadism and presence or absence of a uterus will provide the direction for subsequent tests.

Eugonadism, Uterus Present Amenorrheic patients with evidence of estrogen production and an intact uterus require further evaluation to determine the etiology of their amenorrhea (Fig. 3.2). Pregnancy, even in a patient with primary infertility, always needs to be considered and eliminated as an etiology of amenorrhea. Thyroid disorders and hyperprolactinemia are common disorders associated with amenorrhea, therefore thyroid stimulating hormone and prolactin levels should be assessed. It is useful to perform a progestin challenge test in these individuals to assess the amount of estrogen production and the competency of the uterine outflow tract. A progestin challenge test takes advantage of endogenous estradiol and usually causes withdrawal bleeding within 2 to 7 days after cessation of progestins. Multiple formulations of progestins can be used (Table 3.1), and any amount of bleeding is considered a positive test. Lack of withdrawal bleeding should be further evaluated with another progestin challenge test after providing additional estrogen priming (1.25 mg conjugated estrogens or 2 mg estradiol for 21 days). Failure to bleed after this regimen may occur in several situations. First, when there is a lack of functional endometrium or an outflow tract obstruction. Alternatively, the patient may have elevated serum androgen levels that resulted in decidualization of the endometrial lining. In some instances withdrawal bleeding can occur in the presence of gonadal failure. Patients with vasomotor symptoms and a positive withdrawal bleed should have their follicle stimulating hormone (FSH) level assessed.

Hypogonadism (Prior Estrogen Exposure), Uterus Present Patients with vasomotor symptoms may be transitioning to our next class of amenorrheic patients—those with previous estrogen exposure and intact uteri who present with hypogonadism (Fig. 3.3). Measurement of serum FSH is critical in this group of patients to determine whether the deficiency in estrogen is secondary to a central versus a peripheral abnormality (e.g., hypothalamus and pituitary versus ovary). Low FSH levels indicate central dysregulation. A normal FSH level in the presence of hypoestrogenemia is also abnormal and should be interpreted as a possible central cause of amenorrhea. These patients have increased amounts of sialic acid in the carbohydrate portion of the FSH molecule rendering it biologically inactive. Antibodies in the immunoassay are still able to recognize the

Table 3.1. Progestin challenge test Parenteral 200 mg progesterone in oil Oral micronized progesterone 300 mg qhs for 5 days Oral medroxyprogesterone acetate 10 mg for 5 days

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Figure 3.2. Eugonadism with uterus.

3

Figure 3.3. Hypogonadism with uterus present and prior estrogen exposure.

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3

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Table 3.2. Gonadotropin levels

3

Normal adult female levels Ovulatory peak levels Hypogonadotropic state Hypergonadotropic state

FSH 5-20 IU/L twice basal <5 IU/L >20 IU/L

LH 5-20 IU/L twice basal <5 IU/L >40 IU/L

Adapted from: Speroff L, Fritz MA, eds. Clinical Gynecologic Endocrinology and Infertility, 7th ed. Lippincott Williams & Wilkins, 2004.

molecules, indicating that immunoreactivity does not always equal bioactivity. Since there are many possible etiologies associated with hypogonadotropic amenorrhea, information from the patient’s history and physical should be used to direct further tests. Multiple endocrinopathies, CNS tumors, systemic illnesses, excessive exercise and eating disorders should all be considered and the appropriate endocrine screening tests and imaging studies ordered. For patients with elevated FSH levels (hypergonadotropic amenorrhea) who are less than 30 years old, a karyotype should be ordered because of the higher likelihood of finding a chromosomal abnormality. If a normal karyotype is discovered, a transvaginal ultrasound may be helpful in further differentiating between the remaining patients. If an abnormal karyotype is discovered an ultrasound may identify the presence of testicular tissue.

Eugonadism, Uterus Absent Eugonadal patients who do not have evidence of a cervix on examination (Fig. 3.4) should undergo imaging studies for confirmation. If an absent uterus is confirmed, a karyotype should be obtained to rule out the presence of a Y chromosome. Testosterone levels are often useful in the differential diagnosis of patients with a 46 XY karyotype.

Figure 3.4. Eugonadism without a uterus.

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Table 3.3. Causes of primary amenorrhea Cause Ovarian failure Congenital absence of the uterus and vagina GnRH deficiency Constitutional delay of puberty

Frequency 48.5% 16.2% 8.3% 6.0%

Adapted from: Timmreck LS, Reindollar RH. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am 2003; 30:287-302.

Hypogonadism, Uterus Present Patients with a uterus without any evidence of prior estrogen exposure (Fig. 3.5) require a work up similar to those patients with evidence of prior estrogen exposure (Fig. 3.3). However, since they are presenting with primary amenorrhea, several additional diagnoses, discussed in the next section, need to be considered.

Diagnoses To summarize, the evaluation of primary or secondary amenorrhea leads to a differential diagnosis that includes both eugonadal and hypogonadal states. Hypogonadism can be further classified by FSH levels: hypogonadotropic (low FSH) and hypergonadotropic (high FSH) hypogonadism. Tables 3.3 and 3.4 summarize common causes of both primary and secondary amenorrhea.

Eugonadotropic Amenorrhea (Normal FSH and LH) Eugonadal amenorrhea covers a spectrum of disorders ranging from common to extremely rare conditions. Polycystic ovary syndrome (PCOS), a very common gynecologic condition, can lead to both primary and secondary amenorrhea. It is characterized by oligo-ovulation or anovulation, clinical or biochemical evidence of

Table 3.4. Causes of secondary amenorrhea Cause Anovulation Ovarian Failure

– abnormal karyotype – normal karyotype Hypothalamic suppression Weight loss/anorexia Prolactinoma Asherman’s syndrome Hypothyroidism

Frequency 28% 0.5% 10% 10% 10% 7.5% 7% 1%

Adapted from: Reindollar RH, Novak M, Tho SP et al. Adult-onset amenorrhea: A study of 262 patients. Am J Obstet Gynecol 1986; 155:531-543.

3

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Figure 3.5. Hypogonadism with a uterus.

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hyperandrogenemia, and polycystic appearing ovaries. According to the 2003 Rotterdam criteria, two out of three of these features must be present for this diagnosis. In addition to amenorrhea, patients with PCOS frequently have problems with infertility and insulin resistance. They are also at increased risk for developing metabolic syndrome, endometrial hyperplasia and endometrial cancer. 3 In addition to PCOS, several anatomic abnormalities can result in amenorrhea in the presence of normal estradiol levels. Congenital absence of the uterus and vagina, also known as Mayer-Rokitansky-Kuster-Hauser syndrome, is an example of eugonadal amenorrhea. Failure of the undifferentiated mullerian system to fuse properly results in varying degrees of uterine and vaginal agenesis in these women. Patients often have a short vaginal pouch or absent vagina. The uterus and fallopian tubes are frequently absent or if present consist of small uterine remnants attached to normal fallopian tubes and ovaries. Thirty percent of these patients have renal anomalies such as unilateral renal agenesis and twelve percent have skeletal anomalies. Because ovarian function is normal, ovarian steroidogenesis is intact, puberty is normal, but menstruation fails to occur. Other less common congenital anomalies resulting in amenorrhea include: absence of the endometrial cavity or endometrium, cervical atresia, transverse vaginal septum and imperforate hymen. Absence of the endometrium is exceedingly rare. Cervical atresia may present as hematometria or hematoperitoneum. Patients with transverse septae, resulting from failure of the lower third of the vagina to canalize, may present with hematocolpos and urinary frequency. A vaginal septum may be associated with abnormalities of the fallopian tubes or unilateral absence of the ovary and fallopian tube. Imperforate hymen may be distinguished from a transverse vaginal septum by physical examination. Patients with an imperforate hymen will demonstrate distention of the introitus by the hematocolpos when they perform a valsalva maneuver. Asherman’s syndrome, an acquired cause of amenorrhea, results from partial or complete destruction of the endometrium, often as a complication of a surgical procedure. Asherman’s syndrome, or uterine synechiae, may result from overzealous postpartum curettage, uterine surgery (cesarean section, metroplasty or myomectomy), uterine artery embolization, and infection. Rare infectious causes of Asherman’s syndrome include tuberculosis and uterine schistosomiasis. Various types of male pseudo-hermaphrodism can cause primary amenorrhea. The most common of these conditions, androgen insensitivity syndrome (AIS) occurs when an abnormal androgen receptor fails to initiate a signal in response to testosterone due to mutations in either the androgen binding or DNA binding sites. In its classical form, patients have a 46 XY karyotype and testes which produce both testosterone and Mullerian inhibitory substance (MIS). MIS causes regression of the Mullerian system and the absence of internal female genitalia. These individuals are unable to respond to testosterone with masculinization of the external genitalia and the default, an external female phenotype and formation of a short vaginal pouch, is seen in these patients. At puberty, peripheral aromatase converts testosterone to estradiol and breast development ensues. These patients also have very little pubic hair and are usually tall due to the presence of the Y chromosome. Partially descended testicles may result in the finding of bilateral inguinal hernias in childhood. In addition to the classical form of AIS, incomplete androgen insensitivity may present with amenorrhea; however, these phenotypic females may undergo varying degrees of virilization with puberty. Another form of male pseudo-hermaphrodism is caused by a deficiency in 17-ketoreductase. Instead of a defect in the androgen receptor, these patients have

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impaired testosterone production and present with clinical findings that are similar to incomplete androgen insensitivity. Hypogonadism comprises the remainder of the causes of amenorrhea. Hypogonadism may result when defects occur at the level of the hypothalamus and pituitary 3 or at the level of the ovary. Evaluation of gonadotropin levels can readily distinguish between the two. Hypogonadotropic hypogonadism represents a central nervous system abnormality and hypergonadotropic hypogonadism is indicative of a process occurring in the ovary. The first of these, hypogonadotropic hypogonadism, may be subdivided into the following categories: congenital abnormalities, acquired lesions, endocrinopathies, systemic illnesses, maladaptive behaviors, constitutional delay of puberty, and idiopathic hypothalamic hypogonadism.

Hypogonadotropic Amenorrhea The most common congenital cause of hypogonadotropic hypogonadism is Kallmann syndrome. Kallmann syndrome is characterized by isolated GnRH deficiency resulting in primary amenorrhea and sexual infantilism. Patients also have anosmia or hyposmia, midline facial defects and occasionally renal agenesis. Consistent with hyposmia/anosmia, imaging studies demonstrate absent or hypoplastic olfactory bulbs. It may be inherited in a X-linked and autosomal dominant or recessive fashion. The X-linked recessive gene (KAL gene) encodes for an adhesion protein. Lack of this protein prevents GnRH producing neurons from migrating to their normal position in the hypothalamus adjacent to the anterior pituitary. Other conditions leading to hypogonadotropic amenorrhea include: autosomal recessive GnRH receptor mutations, X-linked adrenal hypoplasia, mutations in the FSH β gene, and Prader-Willi and Laurence-Moon-Biedl syndromes. Acquired lesions in the CNS may also result in amenorrhea. Malignant and nonneoplastic intrasellar masses, such as nonfunctioning pituitary adenomas, craniopharyngiomas, cysts, fat deposits, tuberculosis, and sarcoidosis can lead to pituitary compression and hypogonadotropic amenorrhea. Nonfunctioning pituitary tumors comprise approximately 30-40% of all pituitary adenomas and may secrete biologically inactive FSH, α subunit, and rarely LH. Craniopharyngiomas usually develop between ages 6 to 14 years. These calcified-appearing tumors on radiological imaging may invade and destroy the pituitary and suprasellar regions. Lesions such as internal carotid aneurysms and obstruction of the aqueduct of Sylvius may produce hypogonadotropic amenorrhea. Other pituitary tumors may lead to endocrinopathies that secondarily lead to amenorrhea. Over 50% of pituitary tumors detected at autopsy secrete prolactin, which can inhibit pulsatile secretion of GnRH. Prolactinomas typically develop after puberty has started. Increased ovarian estrogen production leads to increased prolactin production via increased mRNA. About one third of patients with a prolactinoma present clinically with galactorrhea. Other endocrine tumors, such as Cushing’s syndrome and acromegaly usually produce amenorrhea prior to their full clinical expression. Deficiencies in hormones may also produce or accompany hypogonadotropic amenorrhea. Hypothyroidism is responsible for a small fraction of patients with amenorrhea, but is readily treatable and normal menstruation is quickly restored. Sheehan’s syndrome, pituitary insufficiency due to ischemia or infarction after an obstetric hemorrhage, is characterized by pan-hypopituitarism resulting in amenorrhea among other problems. In addition to congenital and acquired lesions of the CNS, all manners of stress may affect the hypothalamus and result in hypogonadotropic amenorrhea. Systemic

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illness such as poorly controlled diabetes, childhood rheumatoid arthritis and malabsorptive bowel disease may affect gonadotropin production and result in delayed menarche. Starvation as seen in eating disorders is a profound stress to the body. Anorexia nervosa usually presents after menarche and represents a significant life-threatening condition that may initially be noticed secondary to amenorrhea. 3 Neuropeptide Y, a peptide produced in the arcuate nucleus, normally stimulates feeding behavior; however, when elevated in anorexia nervosa, it inhibits GnRH secretion. Weight gain restores gonadotropin production, but normal menses do not always ensue. Similar to anorexia, extreme exercise especially prior to menarche may delay puberty. A reduction in body fat below a critical level and an increase in energy expenditure trigger a decrease in leptin levels. Lower leptin levels can suppress reproductive and thyroid functions and increase adrenal activity. Both patients with anorexia and exercise-induced amenorrhea have low FSH/LH and elevated cortisol and may be difficult to distinguish clinically. However, they differ subtly in other endocrine markers. Patients with anorexia have normal TSH and thyroxine (T4), but low T3 and elevated reverse T3; whereas, patients with exercise-induced amenorrhea have reductions in all thyroid hormones (T4, T3, rT3) and elevated growth hormone, testosterone, prolactin and endorphins. Another potential cause of delayed menarche associated with decreased FSH is constitutional delay of puberty. These girls usually present from families with similar histories of delayed menarche. They are shorter than their peers, and bone age lags behind their chronological age. If given GnRH, they will respond with a pubertal pattern of gonadotropin release (LH>FSH). When their bone age reaches 9 to 11 years, they usually spontaneously enter puberty. When all other identifiable causes of hypogonadotropic amenorrhea are ruled out, the remaining patients with low or normal gonadotropin levels, normal prolactin, and normal imaging studies are labeled as having idiopathic hypothalamic amenorrhea. However, many of these will have increased cortisol secretion and may represent another class of stress-induced amenorrhea.

Hypergonadotropic Amenorrhea In contrast to hypogonadotropic hypogonadism, hypergonadotropic hypogonadism is often the result of primary ovarian hypofunction. Hypergonadotropic amenorrhea includes a variety of clinical entities including: Turner’s syndrome, ovarian failure, and pseudo-ovarian failure. Turner’s syndrome results from a missing sex chromosome in all or a portion of the cells. The resulting karyotype, 45 X, indicates they have a single copy of an X chromosome (monosomy X). Absence of key ovarian genes on the other X chromosome results in premature loss of germ cells. During fetal life, Turner’s syndrome patients have a normal number of germ cells at midgestation; however, an accelerated loss of germ cells occurs thereafter. Due to this accelerated loss of follicles, less than 15% of women with Turner’s syndrome will enter spontaneous puberty. Furthermore, less than 5% will achieve a spontaneous pregnancy before developing ovarian failure. Mosaicism, in which all of the cell lines are not monosomy X, explains why some patients are able to initiate puberty and even achieve pregnancy. Approximately 5% of Turner’s syndrome patients have Y chromosome material that is evident on karyotyping. This number doubles when specific Y chromosome DNA probes are used in the evaluation. However, only mosaic Turner’s syndrome patients with the presence of a Y cell line on karyotype are at increased risk for gonadoblastoma.

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In addition to premature ovarian failure, other stigmata of Turner’s syndrome may be observed which include: cardiovascular abnormalities that may cause complications in pregnancy; wide spaced nipples (shield chest); renal anomalies (horseshoe kidney); high arched palate; low hairline; webbed neck; multiple pigmented nevi; 3 short fourth metacarpal digits; increased carrying angle of the arms; lymphedema; and short stature with height usually less than 63 inches/160 cm. Turner’s syndrome patients also have an increased prevalence of autoimmune disorders—Hashimoto’s thyroiditis and diabetes mellitus. Hypergonadotropic patients with a normal complement of chromosomes may develop amenorrhea secondary to, or as a transition to ovarian failure. Multiple causes of 46 XX ovarian failure have been elucidated. Acquired causes include: radiation; chemotherapy; and possibly infectious elements like childhood viruses. Autoimmune ovarian failure has been commonly described. Therefore, a careful look for other autoimmune disorders is imperative. Other autoimmune disorders include: Hashimoto’s thyroiditis; pernicious anemia; vitiligo; diabetes mellitus; hypoparathyroidism; and, importantly, adrenal insufficiency. Adrenal insufficiency is a potentially lethal condition that may present with subtle findings of hyperpigmentation, weakness, lethargy, anorexia, nausea, vomiting, and orthostatic hypotension. Genetic causes of ovarian failure include: mutations occurring in the POF1 and 2 regions of the X chromosome; expansion of CGG repeats between 55-200 in the FMR1 gene as seen in the Fragile X syndrome premutation; blepharosphimosis/ ptosis/epicanthus inversus syndrome; ataxia telangectasia; myotonic dystrophy; and galactosemia. Patients with 46 XY gonadal dysgenesis (Swyer syndrome) also have a normal, though unexpected, complement of chromosomes. They have mutations in or in proximity to the SRY gene that results in impaired testicular development. Streak gonads rather than normal testes form, MIS is not produced and normal internal female genitalia develop. In the absence of normal testosterone production, normal external female genitalia also develop. Because gonadal steroidogenesis is not normal, puberty and menses do not occur. The presence of a Y chromosome also places these patients at increased risk for germ cell tumors. Patients with resistant ovary syndrome (Savage syndrome) also have hypergonadotropic hypogonadism, but they have normal ovarian germ cell reserve as evidenced by normal antral follicle counts. Instead, they have FSH receptor gene mutations or post-receptor signaling defects. Since they do not have ovarian failure despite the absence of menses, they are termed pseudo-ovarian failure. Aromatase enzyme deficiencies, 17-hydroxylase gene mutations and LH receptor gene mutations may also present with elevated gonadotropins and normal ovarian germ cell reserve.

Treatment Once a diagnosis is established, appropriate treatment can be implemented. Treatment of these diverse disorders often requires consultation with other specialists. The treatment of primary and secondary amenorrhea may involve medical management, surgical management, and patient specific counseling. Medical management should be directed at treating the underlying condition, preventing undesirable complications, and addressing reproductive concerns. Patients with hypothyroidism or hyperprolactinemia are two groups of amenorrheic patients readily treated medically. Thyroid hormone replacement rapidly corrects amenorrhea associated with hypothyroidism. Likewise, prolactinomas are usually

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slow growing and respond well to dopamine agonists such as bromocriptine or cabergoline. Patients with PCOS have amenorrhea secondary to anovulation. Lack of luteal progesterone and unopposed estrogen places them at risk for endometrial hyperplasia and carcinoma. Therefore, cyclic progestin administration may be necessary to prevent these complications. Alternatively, ovulation induction may be 3 desirable if pregnancy is wanted. In addition, PCOS patients often have insulin resistance and are at risk for diabetes and metabolic syndrome. Beginning an insulin-sensitizing agent to potentially prevent these complications may be considered, but this recommendation is still under active investigation. All hypogonadal patients are by definition estrogen deficient and therefore subject to increased risk of premature osteopenia and osteoporosis. Again, treatment should be considered to prevent this unwarranted complication. Finally, many patients are concerned with reproductive options. For those patients with diagnoses amenable to potential conception, ovulation induction versus contraception should be offered. Other patients with ovarian failure or mullerian anomalies often require referral for assisted reproductive technologies in order to conceive. For those patients with diagnoses requiring surgical intervention, appropriate referral is imperative. Surgery is necessary to restore anatomy, remove tumors, or to prevent the malignant transformation of Y chromosome containing gonads. Uterine outflow tract abnormalities and Asherman’s syndrome should be corrected by an appropriately trained gynecologist or reproductive endocrinologist. Neurosurgical intervention may be required for other tumors of the CNS. Lastly, any patient diagnosed with a Y chromosome by karyotype requires a gonadectomy to prevent the development of germ cell tumors. In patients with AIS, the gonads are allowed to remain in situ until after puberty to facilitate more normal breast formation. Counseling is an important aspect of treatment of amenorrhea. Patients are often concerned that amenorrhea is a sign of a significant problem. Some patients are given information that may have devastating implications for their future fertility and self-identity and others may learn about some undesirable health effects associated with their diagnosis. Therefore, it is critical to provide supportive counseling and carefully discuss all the ramifications of the diagnosis. Finally, counseling may provide a primarily therapeutic role in treating anorexia and encouraging weight gain and exercise reduction.

Suggested Reading 1. Timmreck LS, Reindollar RH. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am 2003; 30:287-302. 2. Reindollar RH, Novak M, Tho SP et al. Adult-onset amenorrhea: A study of 262 patients. Am J Obstet Gynecol 1986; 155:531-543. 3. Apgar BS. Diagnosis and management of amenorrhea. Clinics in Family Medicine 2002. 4. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility, 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2004.

Chapter 4

Dysfunctional Uterine Bleeding William R. Phipps

Introduction Abnormal vaginal bleeding is a common complaint encountered by physicians. Such bleeding may be secondary to a wide array of specific underlying problems, but in many cases a diagnosis of dysfunctional uterine bleeding (DUB) is ultimately made. The term DUB refers to abnormal uterine bleeding that is not a consequence of structural or systemic disease. Usually DUB is related to anovulatory menstrual cycles, a condition specifically referred to here as anovulatory DUB. Women with ovulatory cycles may also have DUB, specifically referred to here as ovulatory DUB. Other terms used to describe abnormal bleeding patterns include oligomenorrhea and polymenorrhea, traditionally used to designate patterns of bleeding episodes with intervals greater than 35 and less than 24 days, respectively. The term menorrhagia refers to episodes of excessive flow and/or duration occurring at regular normal intervals, and metrorrhagia to such episodes occurring at irregular intervals. Still another term, used increasingly in recent years, is heavy menstrual bleeding, and is generally used to describe abnormal uterine bleeding on the basis of either anovulatory or ovulatory DUB. Any vaginal bleeding not occurring on the basis of regular ovulatory menstrual cycles can be considered abnormal, and thus the characteristics of normal menses as shown in Table 4.1 are pertinent. However, many women without clinically significant abnormalities have menstrual patterns that fall outside these norms, and naturally a patient is most likely to consult her physician when she detects a pattern that she considers abnormal for herself. In this same vein, a woman with a clinically significant abnormality may not recognize that anything is wrong. In any event, the decision to intervene should be governed by the individual circumstances present, and not the presence or absence of a specific pattern.

Table 4.1. Normal menses: Characteristics Menarche Interval Duration Amount of flow Menopause

Mean 12-13 years 28-30 days 4-6 days 30-45 ml 50-52 years

Normal Range 8-16 years 24-35 days 2-7 days 20-80 ml 40-60 years

Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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Differential Diagnosis and Mechanisms of Bleeding Table 4.2 lists a number of conditions that may present with abnormal vaginal bleeding. Although many if not most patients with abnormal bleeding will ultimately be diagnosed as having DUB, it is important that the other entities shown be

Table 4.2. Causes of abnormal vaginal bleeding Dysfunctional Uterine Bleeding Anovulatory DUB Ovulatory DUB Pregnancy-Related Bleeding Threatened, missed, or incomplete abortion Ectopic pregnancy Molar pregnancy Third trimester or puerperal bleeding Benign Anatomic Lesions Endometrial hyperplasia Uterine myoma(s) Adenomyosis Endometrial or endocervical polyp(s) Cervical or vaginal endometriosis Vaginal adenosis Müllerian anomalies associated with partial outflow obstruction Uterine arteriovenous malformation Cesarean delivery scar Malignancies Endometrial adenocarcinoma Uterine sarcoma Cervical or vaginal carcinoma Gestational trophoblastic neoplasia Disorders of Hemostasis Thrombocytopenia von Willebrand disease Other platelet disorders Factor deficiencies Anticoagulation therapy Severe hepatic disease Inflammatory Processes Endometritis, cervicitis Infectious or atrophic vaginitis Miscellaneous Pelvic lacerations/trauma Intrauterine device Intravaginal foreign body Drug-related (including hormonally active agents) Hypothyroidism Uterine sarcoidosis Modified from: Phipps WR. Abnormal vaginal bleeding. In: Leppert PC, Peipert JF, eds. Primary Care for Women, 2nd Ed. Philadelphia: Lippincott Williams & Wilkins, 2004:136.

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excluded with reasonable certainty prior to treatment. Accordingly, the diagnosis of either anovulatory or ovulatory DUB is one of exclusion. The pathophysiology and optimal treatment of anovulatory DUB are best understood by comparison to the bleeding that occurs as part of the normal menstrual cycle. In the follicular or proliferative phase of the cycle, estradiol produced by the enlarging dominant follicle causes endometrial glands and stroma to proliferate. 4 After ovulation, during the luteal or secretory phase, the corpus luteum produces large amounts of progesterone in addition to estrogen, resulting in secretory changes in the endometrium. In the absence of pregnancy and the secretion of human chorionic gonadotropin, regression of the corpus luteum is associated with the withdrawal of progesterone and estrogen. The result is a normal menses, an orderly and self-limited event that involves desquamation of the entire endometrium. The initiation of normal menstruation involves enzymatic degradation of the functional layer of the endometrium and associated breakdown of blood vessels. Subsequent hemostasis is provided first by normal coagulation mechanisms and then by arterial vasoconstriction and reepithelialization. The normal coagulation mechanisms include the formation of platelet plugs, involving von Willebrand factor (VWF), as well as thrombin-induced fibrin generation. Typically, clots are not passed because of endometrial fibrinolytic proteins that promote clot liquefaction. Unlike normal menstrual bleeding, anovulatory DUB involves exposure of the endometrium to estrogen unopposed by progesterone for relatively long time periods. This leads to abnormally high and structurally unstable endometrium. The tissue is delicate and undergoes essentially spontaneous breakdown with associated bleeding related to the presence of increased numbers of often dilated, irregular, and fragile venous capillaries. The process is not an orderly one, may go on more or less indefinitely, and involves different portions of the endometrium at different times. Additionally, clot passage may occur on the basis of an exhaustion of endometrial fibrinolytic proteins. Ovulatory DUB differs from anovulatory DUB in that ovulation occurs on a regular basis, and thus the abnormal bleeding usually has a regular pattern. The heavy nature of ovulatory DUB is thought in part to be a consequence of abnormal arachidonic acid metabolism on endometrial function with excess production of vasodilatory as opposed to vasoconstrictive prostaglandins. As well, women with ovulatory DUB have been shown to have abnormally increased levels of endometrial fibrinolysis. As for other causes of abnormal vaginal bleeding, pregnancy-related bleeding may occur in both abnormal and essentially normal pregnancies, and thus the possibility of pregnancy must always be considered prior to intervention. In particular it is important to make a diagnosis of an ectopic pregnancy as early as possible, allowing for early medical or surgical treatment. The abnormal bleeding that occurs vaginally during a tubal pregnancy is nearly always a consequence of endometrial shedding secondary to abnormal corpus luteum function. This bleeding often precedes pelvic pain symptoms which are generally a consequence of tubal rupture and/ or intrapelvic bleeding. The possibilities of a disorder of hemostasis or both benign and malignant anatomic lesions should also be considered in all patients presenting with abnormal vaginal bleeding. In particular platelet disorders often present as menorrhagia, especially in adolescents. In older patients, malignancies are relatively more common, and it is especially important to rule out endometrial hyperplasia

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and adenocarcinoma. In this same vein, cancer always needs to be ruled out in the presence of any bleeding that occurs in a postmenopausal woman who is not taking hormone replacement therapy. The mechanisms by which heavy abnormal bleeding occurs in conditions such as uterine myomas and endometrial cancer are not well understood, but in many cases large and fragile surface blood vessels are present, seemingly related to the release of angiogenic factors pro4 duced by the tumors themselves.

History A careful history is of course essential to the management of any patient presenting with abnormal bleeding. The date of onset of the presenting episode and her prior menstrual history need to be determined along with the presence of concomitant symptoms of any kind. Also important are the patient’s general obstetrical and gynecologic history, including her pregnancy and infertility history, prior pelvic surgeries, abnormalities noted on prior exams, Pap smear results, and contraceptive method. A history of any significant medical problems should be noted, and inquiries made about symptoms suggestive of endocrine and bleeding disorders and about family members having similar problems. The typical history in cases of anovulatory DUB is one of irregular episodes of often painless bleeding occurring in an unpredictable fashion with episodes ranging from a day of spotting to several weeks of continuous, heavy bleeding, often with passage of clots vaginally. Long periods of amenorrhea may or may not be interspersed among bleeding episodes. The cyclic symptoms of mittelschmerz and premenstrual molimina are absent. Patients particularly at risk include postmenarchal teenagers, women with polycystic ovarian syndrome or obesity-related ovulatory dysfunction, and perimenopausal women, up to 50% of whom report episodes of heavy abnormal bleeding. Women with ovulatory DUB in general present with menorrhagia. Monthly blood loss greater than 80 ml is considered abnormal and often associated with iron-deficiency anemia. As a practical matter, it is difficult to precisely quantify blood loss, and thus decisions about both investigating and treating a patient for menorrhagia largely hinge on her subjective complaints. If a more objective assessment is desired for whatever reason, however, the quantity of flow can be assessed by using a pictorial blood flow chart developed by Higham et al. Less accurately, the number of standard tampons or pads used by a patient during her menses can be counted, with each standard tampon or pad corresponding very roughly to 5 ml of blood loss. A history of mucocutaneous bleeding, such as epistaxis, gingival bleeding, or easy bruising, may suggest von Willebrand disease (VWD), idiopathic thrombocytopenia purpura, or another bleeding diathesis. In particular patients with VWD, the most common bleeding disorder of hemostasis, often have a history of excessive menstrual bleeding since menarche, postpartum hemorrhage, bleeding associated with surgery or dental procedures, or anemia. Von Willebrand disease is an autosomal-dominant condition with considerable molecular and clinical heterogeneity. It has an overall prevalence of about 1%, and in particular should be considered when an adolescent patient presents with abnormal uterine bleeding. The family history may not always be helpful, because of the variable penetrance associated with mild to moderate VWD (type 1), and because males especially may not be symptomatic. Of note, individuals with blood type O have on average 25% lower von Willebrand factor (VWF) levels, and on this basis many women have what can

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considered to be a relatively mild nongenetic form of VWD, as opposed to having an inherited mutation involving the von Willebrand protein gene. Furthermore, hypothyroidism can result in an acquired form of VWD, which resolves with thyroid replacement. The history will also often provide diagnostic clues when a benign or malignant anatomic lesion is the cause of abnormal bleeding. An enlarging submucosal myoma 4 in a patient with regular menstrual cycles will often present with a regular bleeding pattern associated with a gradually increasing amount and/or duration of bleeding over time, and perhaps increasing dysmenorrhea. Ovulatory women with bleeding from an endometrial or endocervical polyp may present with a pattern of erratic bleeding episodes essentially superimposed on a normal menstrual cycle pattern. Women with endometrial hyperplasia or adenocarcinoma will often have a long history of obvious anovulation and symptoms consistent with polycystic ovarian syndrome. It is also important to note that some women with conditions usually associated with menorrhagia, such as ovulatory DUB, a submucosal myoma, or a bleeding diathesis, may be oligo-ovulatory. Accordingly such women would be expected to present with irregular and heavy menses, mimicking the usual pattern encountered with anovulatory DUB. Other combinations of causes may also be present, and thus in general the identification of one cause should not necessarily preclude a search for others that may be contributing to an individual patient’s abnormal bleeding symptoms.

Physical Examination In cases of abnormal vaginal bleeding, a careful physical exam may reveal findings pointing towards a specific diagnosis. Obviously the patient’s vital signs are important, especially in the presence of acute or substantial bleeding, or when an abnormal pregnancy may be present, situations in which immediate surgical or medical intervention may be in order. The presence of a goiter may suggest hypothyroidism, and acne and hirsutism may suggest polycystic ovarian syndrome (PCOS), often associated with anovulatory DUB. The pelvic exam is particularly important. The vagina and cervix should be thoroughly inspected for lesions, and the amount of ongoing bleeding noted. Bimanual exam may reveal evidence for an intrauterine or ectopic pregnancy, uterine myomas or adenomyosis, a Müllerian anomaly with partial outflow obstruction, or an ongoing pelvic infection.

Laboratory, Imaging and Other Diagnostic Studies Decisions about what diagnostic studies should be performed in cases of abnormal vaginal bleeding need to be individualized. Table 4.3 provides a list of evaluative measures that should be considered, and most patients should at least have a complete blood cell count (CBC) that includes platelets if not done recently. In general, it is mandatory to rule out pregnancy with a serum or sensitive urine pregnancy test in anyone that could possibly be pregnant, regardless of contraceptive method or the specific bleeding pattern present. If pregnancy is not present, most premenopausal women should have their ovulatory status established. This may involve basal body temperature charting, serum progesterone determinations, or endometrial sampling. Given the high prevalence of autoimmune thyroid disease in women, the concentration of thyroid-stimulating hormone (TSH) should also be routinely assessed, even in the absence of more specific evidence for thyroid disease.

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Table 4.3. Diagnostic studies in cases of abnormal vaginal bleeding Study

Rationale, Comments

CBC

To assess for anemia and to rule out thrombocytopenic bleeding.

Iron profile (serum About two thirds of patients with menorrhagia are iron, total iron binding iron-deficient. capacity, ferritin) Serum or sensitive urine pregnancy test

Mandatory whenever the possibility of pregnancy is present.

Pictorial blood assessment charting

May be particularly useful in of ovulatory DUB when the diagnosis is unclear and for monitoring treatment results.

TSH

Women with hypothyroidism may have DUB on the basis of ovulatory dysfunction and acquired VWD.

Other endocrine studies

Progesterone levels may be used to assess for either regular or irregular ovulation. Other hormonal testing may be needed to delineate the nature of ovulatory dysfunction (e.g., PCOS, impending menopause, or hyperprolactinemia).

Ivy BT and/or PFA-100 closure time

Either test can be used to screen for platelet dysfunction. The PFA-100 closure time is more reproducible and is substantially more sensitive than the BT for VWD but is still often normal in mild cases of VWD.

PT, aPTT, VWF antigen, ristocedin cofactor assay of VWF, factor VIII

In cases of an inherited procoagulant deficiency, or bleeding due to chronic liver disease or vitamin K deficiency, the PT or aPTT is generally abnormal, but these tests frequently do not identify several common disorders of hemostasis. Patients with VWD generally have abnormal VWF antigen, ristocedin cofactor assay of VWF, and factor VIII results.

ABO typing

Individuals with blood type O have decreased VWF and factor VIII levels.

Transvaginal ultrasonography

In general, not reliable to exclude endometrial polyps or submucosal myomas in premenopausal women; endometrial thickness <5 mm in postmenopausal women makes endometrial cancer very unlikely.

Saline sonohysterogram

Sensitivity for detecting intracavitary lesions similar to that of hysteroscopy.

Hysterosalpingogram

Less sensitive for detection of intracavitary lesions than SSH or hysteroscopy, but may be warranted when a less common Müllerian anomaly is suspected or in infertilty patients when tubal status is also a concern.

Pelvic MRI

Particularly helpful when adenomyosis is suspected and other testing is nondiagnostic.

Hysteroscopy

Miniaturized instrumentation may allow for coupling of diagnostic and therapeutic procedures in the office setting.

Endometrial sampling

Critically important if concern about hyperplasia, adenocarcinoma, or endometritis.

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Especially younger patients should usually be assessed for the presence of disorders of hemostasis. When such a disorder is suspected, in addition to a CBC, testing should include a prothrombin time (PT), an activated partial thromboplastin time (aPTT), an Ivy bleeding time (BT) and/or platelet function analyzer-100 (PFA-100) closure time, as well as studies more specific for VWD, namely the ristocetin cofactor assay of VWF, quantification of VWF antigen, and a factor VIII assay. In this 4 context both the BT and the PFA-100 closure time serve to screen nonspecifically for platelet dysfunction, but these tests, especially the BT, have relatively poor sensitivity for VWD. Furthermore, even if the more specific tests to assess for VWD are done, its diagnosis can still be problematic as the results can be ambiguous. Consultation with a hematologist may be in order in such cases, as well as in cases with negative results but nonetheless a high level of suspicion for a bleeding diathesis. In both of these situations, additional testing, especially platelet aggregation and release studies, may be warranted, but the determination of what testing is appropriate is best left to the consulting hematologist. Particularly when there is a distinct possibility of an anatomic lesion, a variety of imaging studies may be of use, but again the specific studies warranted depend on the individual circumstances. Transvaginal ultrasonography may immediately reveal obvious lesions such as submucosal or intramural myomas, adenomyosis, or polyps, but especially in premenopausal women both polyps and myomas associated with cavity distortion are frequently missed. Thus in many cases the instillation of saline solution into the uterus coupled with real-time ultrasonography, or a saline sonohysterogram (SSH), should be performed. This allows for much better delineation of intracavitary mass lesions, with sensitivity very similar to that of hysteroscopy. Transvaginal ultrasonography by itself, however, can be particularly helpful in cases of younger obviously anovulatory patients when there is concern about the possibility of endometrial hyperplasia or adenocarcinoma. In such cases, a thicker endometrial lining (greater than 10-11 mm) as measured by ultrasound should lower the threshold for performing an endometrial biopsy. Transvaginal ultrasonography by itself is also useful in cases of postmenopausal bleeding in that an endometrial thickness measurement of less than 4-5 mm makes endometrial cancer very unlikely, thus obviating the need for an endometrial biopsy. Another option to evaluate the anatomy of the uterine cavity is of course the hysterosalpingogram (HSG), which has the additional benefit of assessing for tubal disease in cases of abnormal bleeding in which infertility is also an issue. However, the HSG has inferior sensitivity and specificity as compared to SSH for detecting intracavitary mass lesions and should not be done routinely in cases of abnormal bleeding. An exception is situations in which an unusual Müllerian anomaly is suspected, for example uterus didelphys in combination with an obstructed hemivagina in which partial outflow obstruction can occur and result in an abnormal bleeding pattern. Pelvic magnetic resonance imaging (MRI) may also occasionally be warranted, especially in cases in which other imaging studies are inconclusive and an unusual Müllerian anomaly or adenomyosis is suspected. Hysteroscopy is another diagnostic measure that should be considered early on, particularly if this can be done in an office setting using a flexible instrument with a small outer diameter. Hysteroscopy is better for assessing for focal lesions such as polyps or submucosal myomas than for diffuse lesions such as endometrial hyperplasia, but is still considered to be highly accurate for the detection of frank endometrial adenocarcinoma. One advantage of office hysteroscopy over SSH is the

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increasingly available option of performing directed biopsies or removing focal lesions such as small endometrial or endocervical polyps. When a tentative diagnosis of anovulatory DUB is made, the decision about whether or not to perform endometrial sampling depends primarily on the risk for endometrial hyperplasia or adenocarcinoma, two conditions that also occur as a consequence of chronic anovulation. Most women older than 35 and virtually all 4 women older than 40 who present with apparent anovulatory bleeding should undergo endometrial sampling, as should many younger women with a long history of anovulation, particularly if obesity, hyperinsulinemia, or a thick endometrial stripe by ultrasound is present. Such sampling can usually be accomplished easily in the office setting using a Pipelle endometrial suction curette or similar device. From a diagnostic standpoint, there is little if any place for traditional dilatation and curettage, except in conjunction with hysteroscopy.

Treatment Once a diagnosis of either anovulatory or ovulatory DUB is made, either tentatively or more definitively, treatment is tailored to the individual circumstances of the case. These include a host of factors, including the degree of ongoing bleeding and the presence or absence of hemodynamic stability, whether or not causes of bleeding other than DUB are also present, and future fertility considerations. The focus of the treatment modalities discussed here is those for DUB, but many of these same modalities may be indicated for other causes of abnormal bleeding. For example, many of the treatments effective in cases of ovulatory DUB can also be applied successfully in cases of VWD. For women with apparent anovulatory DUB, following initial diagnostic measures, the first goal of therapy is to stop the acute bleeding episode. This can nearly always be accomplished without surgical intervention. If uterine curettage is performed, this by itself does provide a substantial acute therapeutic effect, although in general there is no reason not to start medical therapy immediately after endometrial sampling of any kind. In most cases of anovulatory DUB, the bleeding can be stopped with the administration of a progestin. A typical progestin regimen is medroxyprogesterone acetate (MPA), 10-20 mg orally once daily for 10 days. This will usually stop the bleeding during the time it is being administered followed by more or less orderly withdrawal bleeding starting immediately after the MPA is discontinued. This sequence of events is similar to that of the secretory phase of the normal cycle. It is important to advise the patient at risk for pregnancy that occasionally ovulation will occur as a result of progestin administration and that she should expect to have bleeding after it has been stopped. Another therapeutic option useful in stopping acute anovulatory DUB involves oral contraceptives (OCs), each containing 30-35 μg of ethinyl estradiol and a progestin. A variety of regimens may be used, including, for example, having the patient take 2-4 pills daily for five days, which will often bring the bleeding to a halt within one or two days, followed by another 21 days of one pill daily, after which withdrawal bleeding can be expected. For the patient who has been bleeding heavily for a prolonged period of time, with little residual endometrial tissue, it may be best to initially use high-dose estrogen therapy, for example conjugated estrogens (Premarin), 25 mg by intravenous bolus every 4 hours for two or three doses. The immediate improvement with such therapy is due more to a pharmacologic effect of estrogen on small vessel hemostasis than to estrogen’s ability

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to cause proliferation and healing of endometrial tissue. Once the bleeding has stopped in response to such treatment, in general an OC regimen should be started. Patients diagnosed as having anovulatory DUB, but not responsive to the regimens outlined above, require additional evaluation. This may include endometrial sampling if not previously performed, SSH, or hysteroscopy. Once the acute episode of anovulatory DUB has been treated, attention is di4 rected towards the possible need for long-term treatment. For the patient who is usually ovulatory, for whom it is thought that the bleeding episode just treated is unlikely to recur, a period of observation may be all that is necessary. On the other hand, some form of chronic therapy is indicated for patients whose anovulatory state responsible for the DUB is unlikely to abate spontaneously. The goals of this long-term therapy, which must include a progestin component, are to prevent recurrences of the unpredictable bleeding episodes, prevent endometrial hyperplasia, and lower the patient’s risk for endometrial cancer. Iron supplementation should be started at this time, if indicated. Long-term treatment with OCs in the usual cyclic fashion is the best treatment for most patients with anovulatory DUB, although some patients may prefer extended-cycle OCs. Treatment with OCs is particularly useful for those women who occasionally undergo spontaneous ovulation and need birth control, as well as those with polycystic ovarian syndrome, because of amelioration of the associated hyperandrogenism. Patients who are not candidates for OC use may be treated with cyclic progestin treatment, for example, MPA, 10 mg orally once daily the first 10-14 days of each month, or even every second or third month. Anovulatory women with DUB who desire pregnancy should of course have an appropriate hormonal evaluation followed by initiation of ovulation induction therapy. Patients diagnosed as having ovulatory DUB can be treated successfully with several different regimens, both hormonal and nonhormonal in nature. These include OCs or a nonsteroidal anti-inflammatory drug (NSAID) regimen, such as ibuprofen, 400 mg orally every 6 hours, starting on cycle day 1 and continuing through cessation of menses. Both of these treatments not only decrease the amount of bleeding, but also address the often associated problem of dysmenorrhea. The mechanism by which NSAIDs work is not entirely clear, but appears to involve a disproportionate reduction in the uterine concentrations of vasodilatory prostaglandins as compared to that of the prostaglandin F2α, a potent vasoconstrictor. Another possible treatment modality for ovulatory DUB is an antifibrinolytic agent, such as epsilon aminocaproic acid. In particular, there is strong evidence that the antifibrinolytic agent tranexamic acid is very effective, but unfortunately this agent is not generally available in the United States. Still another option is danazol, for example, 200 mg orally daily. Most patients taking such a dose continue to experience regular menses, and androgenic side effects may be a problem. Furthermore, barrier contraception is needed if the patient is sexually active. An option for ovulatory DUB that may be underutilized in the United States is the Mirena levonorgestrel-releasing intrauterine system (LNG-IUS). The LNG-IUS is an intrauterine device designed to release 20 μg of the progestin levonorgestrel daily over a period of 5 years. Although only approved in this country as a birth control measure, many studies have shown the LNG-IUS to be highly effectively for ovulatory DUB, with large reductions (greater than 80%) of blood loss, and overall outcomes comparable to those achieved with endometrial ablation. The effects seen are primarily on the basis of local endometrial effects, as a substantial majority of

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ovulatory women using the LNG-IUS continue to ovulate regularly. Interestingly, despite continued ovulation, women with endometriosis and ovulatory DUB have reduced dysmenorrhea symptoms after LNG-IUS insertion. Furthermore, women with abnormal bleeding attributed to myomas also experience decreased bleeding after LNG-IUS insertion, and the device provides effective treatment for endometrial hyperplasia. For women with ovulatory DUB, the most common side effect is 4 breakthrough bleeding, and there is an increased risk of functional cyst formation. At times, patients with either anovulatory or ovulatory DUB have a consistently poor response to the long-term medical options described, or unacceptable side effects. In that situation, consideration may be given to treatment with a long-acting gonadotropin releasing hormone (GnRH) agonist, such as leuprolide acetate, to induce a menopause-like state. Long-term treatment with a GnRH agonist for most patients is problematic, however, because of the adverse effects on bone density as well as vasomotor symptoms. Thus in general, a patient with DUB failing to respond to the regimens described is best treated surgically, particularly if the patient is older and future fertility is not a concern. Long-term surgical options for DUB include hysterectomy and endometrial ablation. Both can be performed using several different approaches. Hysterectomy is clearly the most definitive treatment for DUB and can be done by laparotomy, laparoscopically, or vaginally, with the best approach for a given patient determined by the individual circumstances involved. The ovaries may be preserved. In general, hysterectomy is associated with more complications than ablation procedures but also higher long-term patient satisfaction rates and substantially lower rates of the need for repeat surgery. Furthermore women at increased risk for endometrial hyperplasia or adenocarcinoma are not good candidates for ablation. For many patients, however, despite the advantages of hysterectomy, endometrial ablation may be a better choice, particularly if the goal is not amenorrhea. This may be because of medical reasons, such as surgical risks for hysterectomy, or personal preference, such as the desire to avoid a more major surgery. Generally about 40% of women experience amenorrhea after ablation, and a similar proportion experience significantly reduced bleeding. There are now many options available for ablation, both hysteroscopic and nonhysteroscopic, as recently reviewed by Shirk. If a nonhysteroscopic approach is used, in general a diagnostic hysteroscopy should be done beforehand. This primarily has to do with not missing lesions such as carcinomas or submucosal myomas.

Summary and Key Points 1. Many women with abnormal vaginal bleeding have either anovulatory or ovulatory DUB. The diagnosis of DUB is one of exclusion. 2. Diagnostic studies in cases of abnormal bleeding need to be tailored to the individual circumstances present. It is important to rule out pregnancy in any woman presenting with abnormal bleeding. The possibility of a disorder of hemostasis should also always be considered. 3. Transvaginal ultrasonography, SSH, hysteroscopy, and endometrial biopsy are all measures that should be considered early in the evaluation of a woman with abnormal uterine bleeding. 4. Most cases of DUB can be managed medically, both in the short and long run. Consideration should be given to placement of a LNG-IUS before surgical interventions such as hysterectomy or endometrial ablation.

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Suggested Reading

4

1. Breitkopf DM, Frederickson RA, Snyder RR. Detection of benign endometrial masses by endometrial stripe measurement in premenopausal women. Obstet Gynecol 2004; 104:120-5, [In this retropective study, premenopausal women with abnormal bleeding and intracavitary lesions often had endometrial thickness measurement less that 5 mm by ultrasound, highlighting the relatively poor sensitivity of transvaginal ultrasonography in such cases]. 2. Clark TJ. Outpatient hysteroscopy and ultrasonography in the management of endometrial disease. Curr Opin Obstet Gynecol 2004; 16:305-11, [This review provides a good discussion of the relative merits of transvaginal ultrasonography, SSH, and outpatient hysteroscopy in cases of abnormal uterine bleeding]. 3. Ferenczy A. Pathophysiology of endometrial bleeding. Maturitas 2003; 45:1-14, [This review of the mechanisms involved in abnormal uterine bleeding focuses on the underlying histology]. 4. Hatasaka H. The evaluation of abnormal uterine bleeding. Clin Obstet Gynecol 2005; 48:258-73, [This review presents a well balanced approach to evaluating women with abnormal uterine bleeding]. 5. Higham JM, O’Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990; 97:734-9, [This paper describes a relatively simple and objective pictorial chart method for quantifying menstrual blood loss]. 6. Hurskainen R, Paavonen J. Levonorgestrel-releasing intrauterine system in the treatment of heavy menstrual bleeding. Curr Opin Obstet Gynecol 2004; 16:487-90, [This review provides a short but useful overview on the use of the LNG-IUS in cases of abnormal uterine bleeding]. 7. Kouides PA. von Willebrand disease and other disorders of hemostasis in the patient with menorrhagia. Women’s Health 2005; 1:231-44, [Perhaps 10 or 15% of all women who present with abnormal uterine bleeding have VWD. This review helps the clinician understand what should be done when VWD is either suspected or diagnosed]. 8. Lethaby A, Shepperd S, Cooke I et al. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; CD000329, [This Cochrane review compared hysterectomy to endometrial ablation for the management of heavy menstrual bleeding]. 9. Marsh F, Duffy S. The technique and overview of flexible hysteroscopy. Obstet Gynecol Clin North Am 2004; 31:655-68, [This paper provides a useful overview of the use of office flexible hysteroscopy in cases of abnormal uterine bleeding]. 10. Shirk GJ. Minimally invasive surgery for ablation of the endometrium. Clin Obstet Gynecol 2005; 48:325-36, [This review provides the clinician with an update in the rapidly changing area of endometrial ablation techniques]. 11. Speroff L, Fritz MA. Regulation of the menstrual cycle. Clinical Gynecologic Endocrinology and Infertility. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:187-231, [This chapter in the latest version of a classic textbook provides the reader with a good understanding of the normal menstrual cycle, allowing for an informed approach to the patient whose cycle is not normal]. 12. Speroff L, Fritz MA. Dysfunctional uterine bleeding. Clinical Gynecologic Endocrinology and Infertility. 7th ed. Philadelphia: Lippincott Williams and Wilkins, 2005:547-71, [This chapter provides a broad and updated overview of all aspects of DUB].

Chapter 5

Diagnosis and Management of Polycystic Ovary Syndrome Kathleen M. Hoeger

Diagnosis Polycystic ovary syndrome (PCOS) is a heterogeneous condition associated with irregular menstrual cycles and androgen excess. Additional terminologies used to describe the syndrome include Stein-Leventhal syndrome, named for the authors of the first published description in 1935, or sclerocystic ovarian disease. An international consensus conference has proposed that the syndrome can be diagnosed if at least two of the following features are present: irregular or absent ovulation, elevated androgens or clinical androgen excess, and polycystic ovaries on ultrasound (Fig. 5.1). The finding of polycystic ovaries on ultrasound is neither solely diagnostic nor necessary for diagnosis of PCOS. Additionally, the syndrome can only be diagnosed after exclusion of other medical conditions. Differential diagnosis of PCOS includes nonclassic adrenal hyperplasia due to 21-hydroxylase deficiency, Cushing’s syndrome, hyperprolactinemia, hypothyroidism, acromegaly or virilization due to an adrenal or ovarian neoplasm. The history alone may serve to distinguish the features of PCOS which is often perimenarchal in onset. However, a panel of endocrine tests is generally indicated to fully exclude the other causes of anovulation and/or hirsutism (see Endocrine Evaluation).

Epidemiology The prevalence of PCOS varies by ethnic group and geographic area studied. However, the best population based studies suggest the prevalence is approximately 6-7% in reproductive aged women. As such it is recognized as one of the most common endocrine disorders in women and the most frequent cause of ovulatory dysfunction. In women presenting with hirsutism approximately 74% will be found to have PCOS. There is evidence that PCOS is a heritable condition. So far there have been unsuccessful attempts to define a specific gene mutation, but studies of the sisters of PCOS women suggest an autosomal dominant pattern with approximately 50% of sisters demonstrating features of PCOS. Current understanding is that this is a multi-genetic disorder.

Clinical Features The key physical features of PCOS are listed in Table 5.1. In general the diagnosis of PCOS is based on clinical history. Typically women with PCOS present with irregular, infrequent menses or amenorrhea. This is typically present at menarche with onset of irregular menses from the outset, or delayed onset of menarche. Less Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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Table 5.1. Physical features of PCOS Hyperandrogenism Acne Alopecia

5

Male pattern hair growth (Hirsutism)

Locations: Chin Sideburn Upper lip Chest/peri-areolar Lower abdomen Inner thighs Sacral

Insulin Resistance (associated but not required for diagnosis) Acanthosis nigricans

Darkening of skin on back of neck/ underarms

Central adiposity

Increased waist circumference compared to hip

Skin tags

typical is onset of menstrual irregularity at a later age. It is now recognized however that the condition of PCOS can exist in women with regular menses. The most distinctive feature is that of clinical androgen excess. Hirsutism is usually present and can range from mild to severe. Usually hair growth is present on the face and chin as well as the lower abdomen. It is also not uncommon to see frontal hair loss and thinning of scalp hair. Acanthosis nigricans, a dark thickening of the skin, is often present. It can be found at the base of the neck, the axilla and under the breast. Acne is also often present from adolescence but by itself may not be a distinguishing feature of PCOS.

Pathophysiology No single etiologic factor fully explains all the features of PCOS. Excess androgen production is primarily from the ovary. Increased testosterone production by theca cells of polycystic ovaries has been demonstrated. Increased LH secretion by the pituitary gland is consistently demonstrated. It is not clear if this is a primary defect in the GnRH pulse generator or if this is a secondary phenomena. Increased LH stimulation to the theca cells drives increased androgen production. It is also recognized that women with PCOS, independent of body weight, demonstrate insulin resistance. When carefully studied, most women with PCOS demonstrate hyperinsulinemia. Increased insulin resistance is associated with worsening of the clinical manifestations of PCOS. Insulin acts, along with increased LH secretion, to enhance androgen production from the ovary. Insulin also inhibits hepatic production of sex-hormone binding globulin (SHBG). SHBG is the principle binding protein for testosterone, and decreased SHBG results in increases in the proportion of unbound or free testosterone.

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Table 5.2. Endocrine evaluation for PCOS Hyperandrogenism Total testosterone SHBG or free testosterone

Free testosterone assays are highly variable and often have poor reproducibility depending on lab. Free androgen index (FAI) can be calculated with SHBG-total testosterone/SHBG (both in nmol/L).

DHEAS 17-hydroxyprogesterone

ACTH stimulation test for value >2 ng/mL.

24 hour urinary free cortisol

If Cushing’s disease suspected.

2 hour oral glucose tolerance test

Screen for glucose intolerance or diabetes. Use a 75 gm glucose load with a fasting and 2 hour glucose.

Oligo-Amenorrhea TSH Prolactin FSH LH

LH is usually higher than FSH in PCOS, but this is not always seen particularly in the obese patient.

Imaging Studies Pelvic ultrasound

Not necessary for diagnosis but can be confirmatory. If very elevated testosterone, can screen for ovarian tumor.

Adrenal imaging

If very elevated adrenal androgens.

Endocrine Evaluation As PCOS is diagnosed after exclusion of other endocrine disorders, a work-up to assess for these other conditions is indicated. Table 5.2 summarizes the primary endocrine evaluation. Key to the differential diagnosis is to rule out late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. This disorder mimics PCOS as it also presents at menarche and is associated with hyperandrogenism. Unlike PCOS the increased androgens in congenital adrenal hyperplasia are primarily from adrenal origin. A morning blood sample for 17-hydroxyprogesterone is a good screening test for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Samples should be drawn in the follicular phase if the patient is cycling. Generally levels less than 2 ng/mL are not consistent with late onset 21-hydroxylase deficiency. Borderline values should be followed by an ACTH stimulation test. Androgen evaluation should include a serum total testosterone and DHEAS. Hormonal assays for free testosterone are highly variable with poor reproducibility. Perhaps a better way to estimate free testosterone is to use SHBG to calculate a free testosterone index (ratio of total testosterone to SHBG—both measured in nmol/L, also called free androgen index [FAI]).

5

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5

Figure 5.1. Ultrasound of polycystic ovary. Note increased numbers of follicles in peripheral pattern and hyperechoic stroma.

This has been shown to be more reliable as a screen for free hormone. In general values of FAI that are greater than 4.0 are suggestive of androgen excess although there is a large overlap in the normal range. Menstrual irregularity should prompt evaluation of TSH and prolactin. For menstrual irregularity or amenorrhea in the absence of hirsutism, an FSH value can be helpful to eliminate premature ovarian failure as a cause. Although typically LH levels are higher than FSH in PCOS, the ratio of LH to FSH is not diagnostic of PCOS. LH secretion is modified by obesity which is a common finding in PCOS. Imaging studies are indicated for extremely high values of testosterone (>200 ng/ dL) or DHEAS (>2 times the upper limits of the assay) to assess for ovarian or adrenal virilizing neoplasm; however these conditions are exceedingly rare. Usually the clinical picture suggesting tumors is one of rapid onset of androgen excess and virilization. Cushing’s syndrome is also a rare cause of androgen excess. The clinical picture in this case would likely include hypertension, abdominal striae and easy bruising. Round facial appearance with facial plethora, buffalo hump fat distribution, and centripetal obesity are also features of the syndrome. Ovarian ultrasound to assess for polycystic morphology of the ovaries is neither necessary nor conclusive for diagnosis, but can be confirmatory if the clinical picture is supportive (see Fig. 5.1).

Impact of Obesity It is generally recognized that obesity, although not a defining feature of the syndrome, is highly prevalent in PCOS. Most studies in the United States report higher incidences of obesity (upward of 50%) than those of other countries. There is variable ethnic distribution of obesity in PCOS as well.

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Obesity is overall highly prevalent in most developed countries, and the rate of obesity is growing rapidly. Insulin resistance, a feature seen independently of body weight in PCOS, is almost universally noted with obesity. As noted previously, insulin resistance, in association with obesity, will worsen the clinical presentation of PCOS. Numerous studies demonstrate worse androgen profile and more severe menstrual disturbances in obese subjects with PCOS compared to their lean counterparts. Response to treatment may also be adversely impacted by obesity.

Metabolic Complications Although PCOS often presents in the early reproductive years, it is now recognized that the consequences of PCOS extend beyond the reproductive axis and the reproductive years. Women with PCOS appear to be at substantial risk of developing diabetes and cardiovascular disease. Several studies indicate that the risk of metabolic syndrome in PCOS is approximately 50% in young adulthood. Metabolic syndrome is a constellation of metabolic risk factors that increase the risk of cardiovascular events 2-fold. For women, these include increased abdominal waist circumference (>88 cm), elevated triglycerides (≥ 150 mg/dL), reduced HDL (<50 mg/ dL), elevated blood pressure (≥ 130 mm Hg systolic or ≥ 85 mm Hg diastolic or drug treatment for hypertension), and elevated fasting glucose (≥ 100 mg/dL). Many women with PCOS develop impaired glucose tolerance or frank diabetes. In studies of obese women with PCOS 30-40% will have previously undiagnosed impaired glucose tolerance and as many as 10% will have frank type 2 diabetes. This increased risk of impaired glucose tolerance and diabetes is also seen in young adolescent women with PCOS who are obese. Therefore assessment of women with diagnosis of PCOS should include an assessment of glucose tolerance. This is best accomplished through the use of an oral glucose tolerance test. Vascular endothelial dysfunction has been described in women of all ages with PCOS and appears to be associated with insulin resistance. Hypertension may develop during the reproductive years although this has not been consistently demonstrated. Coronary artery calcification and increased carotid intima media thickness has also been shown to be significantly more prevalent in women with PCOS compared to control women. Several recent studies have associated obstructive sleep apnea with insulin resistance. Increased BMI alone did not show the same association. The prevalence of sleep apnea in women with PCOS is higher than in non-PCOS women and may be linked primarily to increased insulin resistance. Given the prevalence of increased metabolic abnormalities in women with PCOS, careful attention to assessment of the metabolic state is recommended. This includes assessment of glucose tolerance and lipid profiles even in young women with PCOS particularly if they are obese. Inquiry into symptoms of sleep apnea is also recommended.

Treatment Options Many women present to their physician for management of symptoms of androgen excess and/or menstrual irregularity. In general medical treatment is designed to lower serum androgens and thereby improve symptoms. There are several pharmaceutical agents that are used for PCOS although there is no specific FDA-approved medication for the treatment of PCOS. Table 5.3 summarizes the main clinical treatments in PCOS.

5

Endometrial stabilization and induces secretory changes Reduces 17-hydroxylase Inhibits DHT binding to receptor Blocks action of DHT on receptor Inhibits 5-α reductase Inhibits ornithine decarboxylase Reduces hepatic glucose output Decreases insulin levels Improves skeletal and hepatic insulin sensitivity

Cyclic progestins

Spironolactone

Flutamide

Finasteride

Eflornithine hydrochloride

Metformin

Pioglitazone/ Rosiglitazone

Presumed Mechanism of Action Decreases LH secretion Suppresses ovarian testosterone production Increases SHBG

Improved ovulatory rates Effective insulin sensitizer

Improved ovulatory rates Improved menstrual cycles Decreased androgens

Topical cream that slows rate of facial hair growth

Reduced hirsutism

Reduced hirsutism

Reduced acne Reduced hirsutism

Induction of menses

Impact Cyclic menses Reduced serum testosterone Improved acne/hirsutism

Possible weight gain Pregnancy category C

Gastrointestinal side effects common

Does not prevent new hair growth Does not impact androgens

No impact on alopecia Possible teratogen

Hepatocellular dysfunction Possible teratogen

Menstrual irregularity Pregnancy Category C

No androgenic improvements

Possible Disadvantages Possible adverse impact on lipids Hypertension Increased coagulability Variable progestin component with variable androgen impact

5

Treatment Combination oral contraceptives

Table 5.3. Treatment options for PCOS

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Oral Contraceptives and Progestins One first line agent that is used for the control of menstrual irregularity is also the predominant treatment for androgen suppression. Use of combination oral contraceptives will significantly reduce circulating free testosterone. Oral contraceptives contain ethinyl estradiol which will suppress LH secretion from the pituitary and decrease LH-driven production of testosterone from the ovary. Additionally, estrogenic compounds increase SHBG production in the liver which will reduce the 5 circulating component of free testosterone. The progestin component of the oral contraceptive will also contribute to LH suppression. The type of progestin varies in different combination oral contraceptives. Progestins can have variable androgenic activity as they are derived from an androgenic base. Drosperinone, an analog of spironolactone with unique anti-androgenic activity, also has progestin activity and is now available in an oral contraceptive. At this time, it has not yet been studied for its effects to reduce androgenic symptoms more than other oral contraceptive formulations, but it is a promising agent in the treatment of androgen excess disorders. Cycle control is significantly enhanced when using oral contraceptives. Most women with PCOS are oligo-ovulatory at best, and continuous estrogenic exposure of the endometrium without exposure to progesterone enhances the potential for erratic breakthrough bleeding which can be heavy, as well as increasing the risk for development of endometrial hyperplasia and cancer of the endometrium. The progestin component in oral contraceptives will significantly reduce this risk. Cycle control with intermittent use of oral progestins such as medroxyprogesterone acetate will also result in regular withdrawal bleeding. Used on a regular basis this will also decrease endometrial hyperplasia and cancer risks. However, oral progestins alone will not significantly reduce androgenic symptoms and are often inadequate as a single agent for the control of all the symptoms of PCOS. The metabolic effects of oral contraceptives have raised some concerns about the use of these agents in insulin resistant women. Some but not all studies indicate worsening of insulin resistance in PCOS women on oral contraceptives. They have not, however, been shown to increase the rate of type 2 diabetes. Effects of oral contraceptives on vascular reactivity and inflammation in PCOS are yet not well studied, and it should be recognized that there may be potential adverse effects when considering these agents for PCOS treatment.

Anti-Androgens Spironolactone is an anti-mineralocorticoid agent that also acts as an anti-androgen. It is a potassium sparing diuretic that in high doses (100-200 mg/ day) demonstrates significant anti-androgenic properties. Spironolactone interferes with testosterone biosynthesis by reducing 17-hydroxylase activity and thus lowers plasma testosterone. It also inhibits dihydrotestosterone’s binding to the androgen receptor. It is not FDA-approved for treatment of androgenic symptoms but in many studies has been shown to be an effective agent in this regard. It is often combined with oral contraceptives to reduce testosterone action and production. Menstrual cycle irregularity can be seen with the use of spironolactone alone. Typically it is combined with oral contraceptives, thereby reducing this concern. Additionally it is a pregnancy category C drug so should be used with contraception to avoid pregnancy while taking it. Flutamine and finasteride can improve androgenic symptoms in PCOS. In general potential serious side-effects have limited their use in the United States. Flutamide

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is a nonsteroidal, nonhormonal antiandrogenic drug, which has been demonstrated to block the action of dihydrotestosterone (DHT) on androgen receptors. It has been associated with hepatocellular dysfunction. Finasteride is a 4-aza analog of testosterone and is a competitive inhibitor of both tissue and hepatic 5-alpha reductase. This results in inhibition of the conversion of testosterone to dihydrotestosterone. In small mostly uncontrolled studies it has been shown to be effective in the treatment of hirsutism. It does not seem to treat androgenic alopecia in women however, 5 unlike the effect seen in male pattern baldness in men. Eflornithine hydrochloride is an inhibitor of ornithine decarboxylase in skin. It is available as a topical cream that can slow the rate of hair growth and has been shown to have some effect in the treatment of facial hirsutism.

Insulin Sensitizing Agents Given the prevalence of insulin resistance seen in PCOS, a number of insulin-sensitizing agents have been studied in the treatment of symptoms. Currently metformin, a biguanide, and pioglitazone and rosiglitazone, thiazolidinediones, are available clinically, and all have been studied in PCOS. The single most common agent for use in PCOS is metformin. Metformin appears to work by reducing hepatic glucose output thereby reducing the demand for insulin. A meta-analysis of thirteen studies of metformin in PCOS concluded that metformin significantly enhanced the rate of ovulation. There was also evidence for improved insulin levels and reduced cholesterol. There is conflicting evidence that metformin’s effects are partially mediated through weight reduction. Metformin has been noted in several studies to be associated with weight reduction in the initial phase of treatment, but this is not consistently seen. The effects of metformin on pregnancy loss and gestational diabetes have been studied only in small uncontrolled trials. Current evidence is not sufficient to conclude a consistent positive effect. The thiazolidinedione therapies are associated with improved insulin action at the level of skeletal muscle and liver. The largest available study involved troglitazone, which is no longer on the market due to hepatotoxicity. However, significant improvements in ovulation were noted in a 48-week trial. Both pioglitazone and rosiglitazone have been shown to improve ovulatory rates in PCOS in small trials. Both are pregnancy category C agents and have not been studied in pregnancy. No association with weight reduction is noted with these agents. Several studies indicate slight increases in weight with use although metabolic improvements are noted.

Lifestyle Modification Weight reduction, of as little as 3-5%, has been associated with improvements in ovulation rates in PCOS women who are overweight or obese. Although studies are consistent in this regard, no large scale controlled trials are available to assess improvements in pregnancy rates. There are no specific dietary regimens that target PCOS and effective weight reduction has been demonstrated with a wide variety of approaches. Achieving and maintaining permanent weight reduction is a challenge that is often met with repeated failures and relapse. Severely restrictive diets have not been shown to improve outcomes over modest changes in diet that result in slow weight reduction. Metabolic parameters are also consistently improved with lifestyle modification that includes weight reduction. Exercise, although not a significant tool in initial weight reduction, is associated with better maintenance of weight reduction

Diagnosis and Management of Polycystic Ovary Syndrome

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over time and should be encouraged. Significant support is needed to encourage women with PCOS who are overweight or obese to consider lifestyle modification as the first line of therapy.

Key Points PCOS is a common reproductive disorder in women and is primarily manifest with symptoms of androgen excess and menstrual irregularity. Although identified as a disorder of reproduction, the pathophysiology of PCOS includes insulin resis- 5 tance, and therefore metabolic abnormalities are common. Treatment of PCOS should address both the endocrine and metabolic aspects of the disease. Attention should be particularly paid to glucose tolerance in overweight and obese women at diagnosis and followed closely. Newer treatments with insulin sensitizing agents have shown promise in the management of PCOS over the long-term, but additional trials are needed.

Suggested Reading 1. Rotterdam/ESHRE/ASRM sponsored PCOS Consensus Working Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81(1):19-25. 2. Azziz R, Woods KS, Reyna R et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004; 89(6):2745-9. 3. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352(12):1223-36. 4. Dunaif A. Finegood DT. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996; 81(3):942-7. 5. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2003; (3):CD003053. 6. Legro RS, Kunselman AR, Dodson WC et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999; 84(1):165-9. 7. Knowler WC, Barrett-Connor E, Fowler SE et al. Diabetes prevention program research group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346(6):393-403.

Chapter 6

Obesity: Recognition and Treatment in Women Erin E. Flaherty and Richard S. Legro

Introduction The increasing prevalence of obesity in the United States over the last decade makes the assessment and treatment of obesity a paramount issue and a challenge for medical professionals. According to clinical experts obesity is quickly reaching epidemic proportions, with 64% of the U.S. adult population being considered obese, or overweight, and 5% of this group is categorized as “extreme obesity”, with a BMI of >40. In clinical terms, a BMI >40 correlates to being overweight by 100 lbs in men and 80 lbs in women. Looking to the future, the number of teenagers (age 12-19) classified as overweight increased from 10.5% to 15.5% from 1999-2000, according to the CDC. This trend reinforces the need for obesity to be treated as a public health issue. The increased health risks of obesity include hypertension, elevated serum cholesterol and death related to cardiovascular diseases as well as diabetes, gallbladder disease, osteoarthritis, carpal tunnel, sleep apnea, respiratory problems and endometrial, breast and colon cancers. Specific to the obstetrician/gynecologist, obesity is associated with both increased gynecological and obstetrical morbidity. Major gynecological problems include abnormal uterine bleeding, ovulatory dysfunction and endometrial cancer. Adult weight gain is associated with increased risk for breast cancer in postmenopausal women. An overweight individual undergoing surgery has an increased risk of excess blood loss, increased operating time and longer exposure to anesthesia and infection. Obesity in pregnancy increases the risk of gestational hypertension, preeclampsia gestational diabetes, fetal macrosomia and cesarean delivery. Obesity is an independent risk factor for spontaneous abortion and pregnancy loss among women who undergo infertility treatment, as well as among natural conceptions. Thus, weight should be assessed at every annual gynecologic exam and during reproductive health counseling. It is estimated that 300,000 US adults die of obesity-related causes and the direct cost of obesity and physical inactivity have been estimated at 9.4% of the U.S. healthcare expenditures. Thus as a major cause of preventable death, obesity is a significant public health challenge. The U.S. Preventative Services Task Force issued recommendation of screening for obesity in 2003. The recommendations were to screen all adult patients for obesity and offer intensive counseling and behavioral intervention to promote sustained weight loss for obese adults. Obesity needs to be recognized as a chronic disease, and the patient, as well as practitioner, need to understand that successful treatment requires a lifelong effort.

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Assessment The diagnosis and classification of obesity has come to focus on the evaluation of the body mass index, (BMI). BMI is a practical approach for assessing body fat in a clinical setting. The BMI provides a more accurate measurement of total body fat compared with assessment by weight alone. However, the BMI can be an overestimation of adiposity in persons of short stature or who are very muscular, and an underestimation in persons who have lost muscle mass. BMI disregards gender, age, and ethnicity, but these factors do not markedly influence the validity of BMI for classifying individuals into broad categories of overweight and obesity. Overweight 6 is categorized by a BMI of 25-29.9 kg/m2 and obesity as BMI ≥ 30 kg/m2. The BMI can quickly be determined by using a BMI table or calculated by multiplying weight in lbs. by 703 and dividing by height in inches, squared, which gives a BMI as kg/ m2. There are two physical classifications of body fat distribution; gynecoid and android. Gynecoid is usually seen in women of reproductive age and has a more favorable prognosis. Gynecoid describes a “pear-shaped” distribution where the fat is concentrated on the hips and buttocks. Android type is more common in menopausal women as fat is redistributed to the trunk and abdomen, “apple-shaped”. The waist: hip ratio is >0.8. The android type is associated with increased complications from obesity. Assessment of associated risk for obesity-related diseases and mortality includes determination of degree of obesity and overall health status. Three factors are involved in assessment. 1. BMI 2. Waist circumference. Waist circumference has been found to be an independent risk factor for disease and is a good evaluation of those categorized as normal or overweight. A waist circumference >40 in for men and 35 in for women is associated with an increased risk of diabetes, dyslipidemia and cardiovascular disease secondary to excess abdominal fat. 3. Overall medical risk. High absolute risk of mortality occurs when there is coexisting heart disease or other atherosclerotic disease, type 2 diabetes mellitus, sleep apnea, hypertension, cigarette smoking, high LDL cholesterol, impaired fasting glucose (>110-125), family history of early cardiovascular disease or age ≥55 in women, or postmenopausal status. Obesity is also associated with a greater risk of several non-lethal conditions including: osteoarthritis, gallstones, stress incontinence and menstrual disturbances.

Metabolic Syndrome Metabolic syndrome is a clustering of risk factors for cardiovascular disease. The Expert Panel on the Detection, Evaluation, and Treatment on High Blood Cholesterol in Adults (Adult Treatment Panel III) defines the syndrome as three or more of the following criteria: 1. Abdominal obesity: waist circumference >102 cm in men and >88 cm in women; 2. Hypertriglyceridemia: ≥150 mg/dl; 3. Decreased high-density lipoprotein (HDL) cholesterol: <40 mg/dl in men and <50 mg/dl in women; 4. High blood pressure: ≥130/85 mm Hg; 5. High fasting glucose: ≥110 mg/dL.

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Obesity is a component of metabolic syndrome, but it is not absolutely required to make the diagnosis if other criteria are present. Diagnosis of metabolic syndrome is important to alert the clinician of increased risk of diabetes and cardiovascular disease. The prevalence of US adults having the metabolic syndrome is 22%, and it is even more common among high risk groups such as women with polycystic ovary syndrome with about a third of women affected.

Treatment 6

Diet and Excercise The first step towards treating obesity includes nutrition counseling, dietary modification and exercise. A reasonable initial weight loss goal is 10% reduction of one’s current weight, with a timeline of 6 months of therapy. To achieve a weight loss of 1-2 pounds per week, the patient should follow a diet that consists of 500-1000 fewer calories per day but still meets nutritional needs. This would translate into a 1000-1200 kcal/day diet for most women and 1200-1600 kcal/ day for men. If this level of intake leaves the patient hungry, the total kcal/day can be increased by 100-200 kcal. The patient needs to undergo nutrition education to include: 1. Energy value of different foods 2. Food composition—fats, carbohydrates, and proteins 3. Evaluation of nutrition labels to determine calorie content and food composition 4. Food preparation—avoidance of high calorie ingredients 5. Avoidance of high caloric foods 6. Adequate water intake 7. Reduced portion sizes 8. Limiting alcohol consumption To maintain the weight loss individuals need to follow a balanced, low calorie diet and sustained physical activity. Most weight loss occurs because of decreased caloric intake, but sustained physical activity can help prevent weight regain. An exercise regimen should be started with the goal of exercising at least 30 minutes 3-4 times/week and then gradually increased in frequency and duration. Increased physical activity is important in efforts to lose weight because it increases energy expenditure and plays an integral role in weight maintenance. Exercise can also help prevent the decrease in muscle mass often found during weight loss. The long-term goal is to develop the habit of exercising 30 minutes of moderate intensity activity on most days of the week. Behavior therapy can also play a significant role in providing tools for overcoming barriers to compliance with dietary therapy and/or increased physical activity. Specific strategies include self-monitoring of both eating habits and physical activity, stress management, stimulus control, problem solving, contingency management, cognitive restructuring and social support. In regards to children, intensive, family-based behavioral treatment programs have a favorable effect on children’s weight for as long as ten years.

Pharmacotherapy Pharmacotherapy can supplement dietary changes and exercise to promote weight loss. Pharmacotherapy can be utilized after 6 months of combined intervention of

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diet and increased physical activity in patients with a BMI >30 with no concomitant obesity-related risk factors for diseases, and in patients with a BMI >27 with concomitant obesity-related risk factors or diseases. The amount of extra weight loss attributed to these agents is less than 5 kilograms at 1 year evaluation. Thus, the major role of medications is to help the patient comply with their diet and physical activity plans while losing weight. The use of long term medication to aid in the treatment of obesity may be indicated for carefully selected patients to prevent the weight regain often seen after weight loss, but there are no guidelines for how long a weight loss drug should be continued. Initially, if a patient has not lost 2 kg after 4 6 weeks on a medication, it is not likely that the patient will benefit from the drug.

Categories of Weight Loss Drugs Appetite Suppressants These agents decrease food intake by reducing appetite or increasing satiety. The mechanisms of action are to increase secretion of dopamine, norepinephrine, or serotonin into the synaptic neural cleft, to inhibit the reuptake of these neurotransmitters into the neuron or a combination of the two effects. There are three classes of anorexiant drugs, and all affect neurotransmitters in the brain. 1. Affect catecholamines: dopamine and norepinephrine. These noradrenergic agents are useful for short term treatment and include the drugs phenteremine, diethylpropion, phendimetrazine and benzphetamine. Stimulants act via catecholamine neurotransmitters, such as amphetamines and phenylpropanolamine. Phenylpropanolamine, which was an over-the-counter medication, was removed secondary to an association with hemorrhagic stroke. Side effects of this class of medications include insomnia, dry mouth, constipation, euphoria, palpitations and hypertension. 2. Affect serotonergic: Fenfluramine and dexfenfluramine are included in this class. These medications have been associated with valvular heart disease and pulmonary hypertension. In 1997, the “Phen/fen” combination was withdrawn from the market after reports of valvopathy after as little as one month’s use of this medication. The mechanism apparently involves serotonin stimulation of fibroblast growth and fibrogenesis. 3. Affect more than one neurotransmitter. Sibutramine (Meridia) is an appetite suppressant that works via norepi and serotonergic mechanisms in the brain (Fig. 6.1). Side effects include tachycardia and hypertension. The newly discovered endocannabinoid (EC) system and cannabinoid CB1 receptor play an important role in appetite and energy regulation and offer a novel target for a new class of anti-obesity drugs. Rimonabant, the first specific CB1-receptor blocker to enter clinical development, has been shown to reduce food intake and body weight in treated animals, and there are also beneficial effects in the adipocyte. The results of phase 3 studies involving obese patients have shown that rimonabant induces significant weight loss and improves metabolic risk factors for diabetes and cardiovascular disease. It is anticipated that this drug will be available in the near future for the treatment of obesity in the U.S. Common side effects in preclinical studies included depression, anxiety, and nausea. Certainly, close monitoring for side effects with any weight loss medication is necessary. Several randomized controlled studies of weight loss medications have been performed, but questions remain concerning long-term effects on health, the

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6

Figure 6.1. Mechanisms of action of sibtramine. Adapted from: Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002; 346(8):591-602.

optimal duration of treatment, and the use of combination regimens including polypharmacy and combination with lifestyle interventions.

Decrease Nutrient Absorption Orlistat (Xenical) binds GI lipases in the lumen of gut, which prevents hydrolysis of dietary fat (triglycerides) into absorbable free fatty acids and monoacylglycerols (Fig. 6.2). Orlistat is an irreversible lipase inhibitor and thus decreases the amount of ingested dietary fat that is absorbed Side effects of this medication include decreased absorption of fat-soluble vitamins and nutrients, flatulence, fecal urgency and incontinence, steatorrhea, oily spotting and increased frequency of defecation.

Other Medications and Herbal Supplements Many agents have as an unintended side effect weight loss. These include metformin, a biguanide used to treat type 2 diabetes, acarbose, an alpha-glucosidase inhibitor also used to treat type 2 diabetes, and topiramate an anti-epileptic drug. It should be noted that these agents do not have an FDA indication for the treatment of obesity and trials, including those specifically in some cases designed as weight loss trials have shown a lack of efficacy or an unfavorable risk benefit ratio. Therefore their use can not be routinely recommended. Dietary supplements and herbal preparations are not prospectively reviewed by the FDA for safety or efficacy. These agents are only reviewed if they are shown to present a “significant or unreasonable risk”, as has been the case with ephedra supplements. Herbals and supplements include chitosan, chromium picolinate, conjugated linoleic acid, ephedra alkaloids (ma huang) and garcinia cambogia. There is insufficient data on these agents except for ephedra alkaloids and caffeine, which do have randomized, controlled trials that indicate efficacy in promoting weight loss. Chromium picolinate, an essential trace mineral and cofactor to insulin, which improves insulin action and is available as an over the counter supplement. A meta-analysis of 10 double-blind randomized clinical trials with this supplement found a relatively small weight reduction of 1.1-1.2 kg (0.08-0.2 kg/wk) compared with placebo during a treatment period of 6-14 wk in patients with an average BMI of 28-33, without any appreciable side effects. Thus the risk benefit ratio for weight loss appears as favorable, if not more so, than with other herbal or pharmacologic medications.

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6

Figure 6.2. Mechanisms of action of orlistat. Adapted from: Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002; 346(8):591-602.

Surgery Bariatric surgery is currently the most successful approach to rescuing patients with severe obesity and reversing or preventing the development of several diseases associated with obesity. There are an increasing number of surgeries being performed for the treatment of obesity. This rise in procedures can be attributed to the increased population of “extreme obesity” as well as the failure of diet, exercise and medical therapies. Another factor could be the ability to perform the surgery laproscopically. Surgery can be an additional treatment option for patients with a BMI >40 who failed lifestyle changes with or without medication supplementation and have obesity-related comorbid conditions. Surgery alone will not correct any underlying psychological eating disorders. Additionally, reduction of cardiovascular morbidity and mortality does not occur due to weight loss through surgery alone. The Swedish Obese Subjects (SOS) Study, which was an observational study, did show that the average long term weight loss for the surgical patient is 20 kg, versus, no change for those using medical treatment. The SOS study was also able to demonstrate improvements in or prevention of comorbid conditions associated with

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obesity when compared with similar patients undergoing medical therapy. In a 24-month follow-up evaluation, there was a decreased incidence in hypertension, diabetes and lipid abnormalities, but by 8 years, only a decrease in diabetes was noted. Another notable finding was a decreased caloric intake and greater physical activity in surgery vs. control patients throughout the follow-up period. Different surgical procedures are available to treat obesity (Fig. 6.3), and have evolved since the first bariatric surgery performed in the 1950s with the introduction of the jejunoileal bypass and subsequently the gastric bypass in 1967. 1. Roux-en-Y gastric bypass (RYGB) limits gastric capacity and causes mild 6 malabsorption. This procedure involves the construction of a proximal gastric pouch whose outlet is a Y-shaped limb of small bowel of varying lengths. The proximal stomach is separated from the remaining portion of the stomach with staples. 2. Biliopancreatic bypass combines a limited gastrectomy with a long Roux limb intestinal bypass, works primarily through malabsorption. 3. Laparoscopic adjustable gastric band is placed around the upper-most portion of the stomach and restricts capacity, usually less than 30 ml in volume. There is restricted passage to the subsequent part of the stomach, leading to weight loss by decreased dietary intake. The band can be adjusted by the infusion of saline through a subcutaneous port. 4. Vertical banded gastroplasty involves stapling the upper stomach to limit gastric capacity. There is a larger weight loss after gastric bypass compared with other types of surgery, and this may be related to altered gut-to-brain signaling. Surgery is not without risks however. Among surgeons, there is a learning curve in which those with fewer than 20 procedures had a 5% mortality rate, as compared with greater than 50 had a near zero mortality. The length of surgery also stabilized after 150 cases. Complications also decreased from 12.5% for fewer than 100 cases, to 3% after 150 cases. Such complications include anastomotic leak, subphrenic abscess, splenic injury, pulmonary embolism, wound infection and stoma stenosis. Perioperative mortality is influenced by age; in a young patient with a BMI <50, there was a 1% mortality rate in comparison to a patient with a BMI >60 and comorbidities such as diabetes, hypertension, or cardiovascular disease, the mortality jumped to 2-4%. Women of reproductive age who have undergone bariatric surgery require counseling and management of subsequent pregnancies. Patients with adjustable gastric banding should be advised that they are at risk of becoming pregnant unexpectedly after weight loss following surgery. All patients are advised to delay pregnancy for 12-18 months after surgery to avoid pregnancy during the rapid weight loss phase in order to avoid malnutrition and small-for-dates features in the neonate. After restrictive procedures (where iron containing foods such as red meat may be poorly tolerated) increased iron is needed. After gastric bypass procedures (in which the duodenum—where most iron is absorbed—is bypassed) increased iron must be taken during pregnancy to allow adequate absorption in the proximal jejunum. Furthermore, adequate calcium intake or supplementation should be verified. Women with a gastric band should be monitored by their general surgeons during pregnancy because adjustment of the band may be necessary. Women who have undergone bypass surgery do not appear to be at undue risk for adverse pregnancy outcomes, and initial results from larger case series have been promising.

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6

Figure 6.3. Types of bariatric surgical procedures.

Key Points Obesity is a serious and prevalent disorder whose effective management requires ongoing care and a lifetime commitment. The increased prevalence of obesity in children and adolescents indicates the urgent need to implement effective preventative interventions, beginning early in life, to improve dietary habits and increase physical activity. Medications can be an adjunct only for those at

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substantial medical risk and in whom nonpharmacologic treatment has not resulted in sufficient weight loss to improve health or prevent regain. Surgery is becoming a viable option for the long-term success of maintained weight loss but still requires a commitment to behavioral changes and nutrition education.

Acknowledgements This work was supported by PHS K24 HD01476, a GCRC grant MO1 RR 10732 to Pennsylvania State University and K24 HD01476.

6

Suggested Reading 1. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002; 346(8):591-602, [This is an excellent review article of the treatment of obesity]. 2. Mokdad AH, Ford ES, Bowman BA et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003; 289(1):76-9. 3. North American Association for the Study of Obesity and the National Heart, Lung, and Blood Institute. The practical guide: Identification, evaluation, and treatment of overweight and obesity in adults. Bethesda, MD: National Institutes of Health, 2000, (Report No.: 00-4084), [This is an evidence based and very practical guide for the diagnosis and management of obesity and was central to the preparation of this chapter]. 4. Hu FB. Overweight and obesity in women: Health risks and consequences. J Womens Health 2003; 12(2):163-72. 5. Colditz GA. Economic costs of obesity and inactivity. Med Sci Sports Exerc 1999; 31(11 Suppl):S663-7. 6. McTigue KM, Harris R, Hemphill B et al. Screening and interventions for obesity in adults: Summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003; 139(11):933-49. 7. Executive summary of the third report of the national cholesterol education program (ncep) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel iii). JAMA 2001; 285(19):2486-97. 8. Ehrmann DA, Liljenquist DR, Kasza K et al. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 2005. 9. Epstein LH, Valoski A, Wing RR et al. Ten-year outcomes of behavioral family-based treatment for childhood obesity. Health Psychology 1994; 13(5):373-83. 10. Snow V, Barry P, Fitterman N et al. Pharmacologic and surgical management of obesity in primary care: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2005; 142(7):525-31. 11. Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353(20):2121-34. 12. Li Z, Maglione M, Tu W et al. Meta-analysis: Pharmacologic treatment of obesity. Ann Intern Med 2005; 142(7):532-46. 13. Pittler MH, Stevinson C, Ernst E. Chromium picolinate for reducing body weight: Meta-analysis of randomized trials. Int J Obes Relat Metab Disord 2003; 27(4):522-9. 14. Sjostrom L, Lindroos AK, Peltonen M et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351(26):2683-93, [This is the best and longest longitudinal study of a cohort of obese patients, some receiving bariatric surgery and some medical therapy. The long term outcomes for medical therapy are poor compared to bariatric surgery]. 15. Buchwald H, Avidor Y, Braunwald E et al. Bariatric surgery: A systematic review and meta-analysis. Jama 2004; 292(14):1724-37.

Chapter 7

Hormonal Contraception Sarah Prager and Jody Steinauer

Background There are 6.3 million pregnancies annually in the United States, and almost half of them are unplanned. Approximately 50% of the women who become pregnant unintentionally are using some form of contraception at the time of conception. In the United States, unintended pregnancy, especially among women under age 25, is more of a problem than in other Western nations, with teen pregnancy rates in five northern European countries and Canada ranging from 5-53% of the U.S. rate. This is thought to be due, at least in part, to the fact that adolescent women in the U.S. are less likely than their European counterparts to use contraception of any kind; most specifically, hormonal contraceptives. Contraceptive failures occur for a variety of reasons. Most failures are partially due to imperfect use. Some women may not understand how best to use their method or how to handle common mistakes like missed pills or late placement of a contraceptive patch. Providers can help women determine which method will be safest and most effective, given the individual’s particular medical and social situation. By understanding each method’s mechanism, side effects, and contraindications, providers can help women to contracept safely and effectively. Each contraceptive method has characteristics that are more or less beneficial for an individual woman, such as efficacy, cost, frequency of intervention, protection against sexually transmitted infections (STIs), and other health benefits (Tables 7.1 and 7.2). In general, efficacy of a method increases with decreased frequency of intervention (i.e., placing an IUD once every 5-10 years as opposed to taking a contraceptive pill daily). This chapter will deal exclusively with hormonal methods of contraception though other methods (abstinence, lactational amenorrhea, natural family planning, male and female condoms, diaphragms, cervical caps, and copper intrauterine devices) exist and are used effectively by many women (Tables 7.1 and 7.2).

Assessing Evidence about Contraception As we describe each of the contraindications to individual methods, we will be using Medical Eligibility Criteria for Contraceptive Use, a guide produced by the World Health Organization that can be purchased and is available on their Web site. This easy-to-use resource summarizes the evidence for dozens of potential contraindications for contraceptive use and provides guidelines for safety in prescribing every contraceptive method. The guideline ascribes one of four categories to each potential contraindication and method: (1) indicates that the benefits clearly outweigh the risks and the method is safe to be used in any circumstance; (2) indicates that the benefits generally outweigh the risks, and Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

Every 5-7 years Every 10-12 years 0.8%

Copper IUD 0.6%

0.1%

0.05%

3%

3%

8%

8%

8%

8%

15-21%

85%

$250-300

$300-400

$450-750

$45-60

$35

$30-38

$38-45

$30-50

$20-50

$0.25-3

$0

Average Cost

No

No

No

No

No

No

No

No

No

Yes

No

Protection against STDs/AIDS

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

No

Other Health Benefits

Requires clinician visit

Requires clinician visit

Requires clinician visit

Requires clinician visit

Not currently available

Specific prescribing precautions: organ prolapse; chronic vaginitis, constipation.

Condoms and female condoms

Comments

Note that the column STDs/HIV protection means acquisition of the infection. All hormonal methods decrease risk of pelvic inflammatory disease. Modified with permission from: Steinauer J. A new era of contraception. Johns Hopkins Advanced Studies in Medicine 2005; 5(6):285-293.

0.1%

0.05%

0.3%

0.05%

0.3%

0.3%

Levonorgestrel intrauterine system

Monthly

Every 3 years

Weekly

Transdermal patch

Vaginal ring

0.3%

Implants

Daily

Progestin only pills

0.3%

Monthly

Daily

Combined hormonal pills

2-6%

Every 3 months

Each act of intercourse

Barrier methods

85%

1-Month injection

None

No method

Failure Rate Perfect Typical Use Use

3-Month injection

Frequency of Intervention

7

Contraceptive Method

Table 7.1. Comparison of contraceptive methods

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one may almost always use the method; (3) indicates that the risks generally outweigh the benefits and use of the method is usually not recommended unless other more appropriate methods are not available or acceptable; and (4) indicates that the risks always outweigh the benefits, and the method should not be used in any circumstance. For each method described we provide the evidence-based WHO contraindications, and in some cases, these may differ from the product label as approved by the U.S. Food and Drug Administration (FDA).

Combination Hormonal Contraception Combination Oral Contraception Oral contraceptive pills are the most common method of birth control used by women in the United States, with approximately 11.7 million current users (30.6% of the sexually active population). () Over 80% of women born in the United States since 1945 have used oral contraceptive pills at some time in their lives, and this method is currently used by more than 100 million women worldwide. Combination oral contraceptives (COCs) contain an estrogen and a progestin. Ethinyl estradiol (EE) is the most commonly used estrogen, and there are at least seven different progestins commonly used in the U.S. COCs are available in monophasic and multi-phasic (bi- and triphasic) formulations. Monophasic formulations contain the same amount of hormones in each active pill, whereas multiphasic preparations contain varying amounts of estrogen/progestin (usually progestin) in each hormonally active pill. Typically, COCs are packaged with 21 active pills and 7 placebo pills, although in the US there are two exceptions: Mircette with 21 active pills, 5 pills containing EE only and 2 placebo pills, and Seasonale with 84 active and 7 placebo pills. The primary mechanism of action for COCs is ovulation suppression (90-95%). Secondary mechanisms include thickened cervical mucus (which can limit sperm penetration), thinned endometrium (which can limit implantation) and decreased tubal motility. These secondary effects are mostly due to the progestin component of COCs. Combined oral contraceptives have the potential to be a highly effective method of contraception; however actual user failure rates (8%) are higher than perfect user rates (0.3%). Many women have difficulty taking a pill every day, but other obstacles contribute to the failure rate. Insurance limitations on number of packs of pills prescribed, or state limitations on contraception coverage for poor women are also obstacles to using birth control appropriately. As well, many practitioners mistakenly believe that a pelvic examination and pap smear are required before refilling or initiating a prescription for combined hormonal contraception. In actuality, only a blood pressure measurement is required prior to initiating a combined hormonal method. Thus patient and provider education, and policy changes, are necessary to promote maximally effective use of COCs. It is partially because of the high failure rate of COCs that longer term methods of contraception have been developed and are gaining popularity. In addition to its contraceptive effect, women using COCs may benefit from the side effect of decreased menstrual bleeding and more predictable menses. COCs decrease the incidence of anemia and menstrual cramping.

7

7

• • • • • •

• Lactation not affected • Reduced risk of endometrial and ovarian cancers • Fewer ovarian cysts • Less mittelschmerz • Fewer sickle cell crises • May reduce risk of PID, seizures • Can be used with anti-convulsants

Progestin-only injections

• • • • • • • • • •

• Lactation not affected • Decreased menstrual pain and blood loss

Progestin-only pills

Menstrual changes Weight gain Headaches Hair loss Adverse impact on lipids Mood changes

Menstrual changes Mood changes Weight gain or loss Headaches Hair loss

Spotting, bleeding Amenorrhea Mood changes Headaches Hot flashes

Side Effects • Nausea, vomiting • Headaches • Dizziness • Mastalgia • Chloasma • Vaginal spotting and bleeding • Mood changes

Progestin-only implants • Lactation not affected • Less blood loss • Fewer ectopic pregnancies

Noncontraceptive Benefits • Less dysmenorrhea and blood loss • Less PMS • Protects against PID • Decreased ovarian and endometrial cancers • Fewer benign breast masses, ovarian cysts • Fewer ectopic pregnancies • Reduces acne

Method Combined pills, injection, patch, and ring

• • • •

• • • •

continued on next page

Allergic reaction Excessive weight gain Glucose intolerance Depression

Infection at implant site Anesthesic reaction Complicated removal Depression

• None

Complications • VTEs • Myocardial infarction (MI) • Hypertension • Severe depression • Hepatic adenoma • Cervcial adenocarcinoma

Table 7.2. Major methods of contraception and some related safety concerns, side effects and noncontraceptive benefits

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• Prevents most STIs, cervical dysplasia • Enhanced self-image possible

• Reduces risk of STIs and cervical dysplasia • Loss of sensation or spontaneity • Rare anaphylactic reaction • Allergic reaction to latex to latex (use polyurethane • Skin irritation condoms) • May reduce STI and cervical dysplasia risk • Reduces risk of cervical STIs, PID and possibly cervical dysplasia

Abstinence

Male latex condom

Female condom

Diaphragm/cervical cap

• TSS • Anaphylactic reaction to latex

• Potentially,Toxic shock syndrome (TSS)—no cases reported

• None known

• Surgical complications: hemorrhage, infection, organ damage, anesthetic complications, pain • Ectopic pregnancy

Reproduced from: Hatcher R, Zieman M et al. A Pocket Guide to Managing Contraception. Tiger: Bridging the Gap Foundation, 2005.

• Vaginal and bladder infections • Vaginal erosions from poorly fitted device • allergy to spermicide/latex

• Difficult to use • Vaginal and bladder infections

• None excerpt possible peer pressure • Partner may seek sex elsewhere

• Pain at surgical site • Pelvic adhesions • Subsequent regret

• Women: reduced risk of endometrial or ovarian cancer, ectopic pregnancy, PID • Men: none known

• PID following insertion • Uterine perforation • Bleeding with expulsion

Sterilization

Complications

Noncontraceptive Benefits Side Effects • Lactation not affected • Copper-IUD increases menstrual • Copper T and LNG IUDs reduce risk blood loss, cramping for ectopic pregnancy • LNG IUD may cause irregular • LNG IUD reduces cramping and blood loss bleeding or amenorrhea

Method IUD

Table 7.2. Continued

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7

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Combined oral contraceptive use provides protection against many cancers. COC use for 5 years provides a 50% reduction in risk of ovarian cancer, and use for 10 years reduces risk by 80%. This protection extends for 30 years after discontinuation of COCs, and also applies to women carrying BRCA mutations. COCs containing at least 30 μg of estrogen provide protection against endometrial cancer. This is especially important among high-risk groups such as women with polycystic ovarian syndrome, obesity and perimenopausal women. Women who have taken COCs have a reduced risk of death from colorectal cancer. After more than 50 studies about the effect of COCs on risk of breast cancer, the consensus is that COCs have minimal to 7 no effect and may actually protect against metastatic disease. Though COCs appear to be protective for many cancers, their use is associated with a 60% increased risk of adenocarcinoma of the cervix, which is a rare cancer with an annual incidence of 0.5/100,000 women. COCs containing 50 μg or more of estrogen have been associated with an increased risk of hepatocellular adenoma but no increased risk of hepatic carcinoma. Hormonal contraception is not for everyone, and some women have bothersome side effects of COCs. These include physical symptoms such as nausea and vomiting (approximately 12%), especially in the first few cycles, breast tenderness or pain, and headaches. Some women are bothered by intermenstrual spotting, (commonly occurs in the first few cycles) and the uncommon development of amenorrhea. Rarely, women note decreased libido or anorgasmia. Mood changes, depression, anxiety, irritability and fatigue have been reported by women taking COCs, though placebo-controlled studies have demonstrated no increased risk of these side effects. Finally, some women simply don’t like the stress of having to remember to take a pill everyday. Contraindications for all combined hormonal methods, which fall into WHO categories 3 and 4, are listed in Table 7.3. COCs should be used with caution, if at all, in women with these conditions. In particular, pay close attention to the guidelines when considering prescribing COCs to a woman with hypertension, a personal or family history of blood clots or venous thromboembolic events (VTEs), or other types of vascular compromise.

Extended Use Combined Oral Contraception The primary reason for COC failure is forgetting to start the next cycle of contraception at the appropriate time. By the end of the placebo week, up to 25% of women have developed an ovarian follicle large enough to ovulate unless immediately suppressed by hormones. Since the beginning of each pack is a high-risk time to miss pills, a few modifications of the COC regimen might improve efficacy. One method is to shorten the number of placebo days per cycle. Two such pills in Europe continue estrogen and progestin into the fourth week, leaving fewer days for placebo, and in the U.S., Mircette® (desogestrel/ethinyl estradiol [EE]) continues estrogen for 5 days into the fourth week and leaves 2 placebo days. While physiologically it makes sense that shortening the placebo period might increase efficacy, no studies have tested this hypothesis. Another modification to the traditional COC regimen is to reduce the number of “starts” by cycling women for longer than the typical 28-day period. Seasonale® (levonorgestrel/EE), an extended cycle pill approved by the FDA, does this by administering 12 weeks (84 days) of active hormone followed by 7 days of placebo. A woman taking Seasonale® will have only four withdrawal bleeds per year. A large, randomized, multicenter trial found that Seasonale® had a failure rate of 0.60 per

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Table 7.3. When risks outweigh benefits in initiating combined hormonal contraception WHO Medical Condition Category Breastfeeding <6 weeks postpartum 4 Postpartum nonbreastfeeding, and breastfeeding >6 weeks to ≤6 months 3 Smoking <15 cigs/day and age ≥35 years 3 Smoking ≥15 cigs/day and age ≥35 years 4 Current or past DVT or PE 4 Major surgery with prolonged immobilization 4 Controlled hypertension or elevated BP in range of 140-159/90-99 3 Uncontrolled hypertension 4 Vascular disease 4 Multiple risk factors for arterial cardiovascular disease (CVD) 3 Current and h/o ischemic heart disease 4 Stroke 4 Known thrombogenic mutations 4 Valvular heart disease with thrombogenic complications 4 Diabetes with vascular involvement or of >20 years duration 3 Migraine with aura, at any age 4 Migraine without aura and age ≥35 years 3/4* Headache without aura and age <35 years 2/3 Current breast cancer 4 H/o breast cancer and no evidence of disease 3 Active hepatitis or severe cirrhosis 4 Benign or malignant liver tumors 4 *This indicates that initiation of COCs is a category 3, but initiation of COCs after development of migraines is a category 4. Modified from: WHO Medical Eligibility Criteria for Contraceptive Use. 3rd ed. Geneva: Reproductive Health and Research World Health Organization, 2004.

100 woman-years, based on Pearl Index calculations. This compares favorably to a traditional regimen pill of the same hormonal doses, Nordette® 28 (levonorgestrel/ EE), which has a failure rate of 1.78 per 100 woman-years in studies. Studies have shown continuous COC use for up to one year without a placebo period to be safe and acceptable, and products with more extended regimens are undergoing FDA consideration. It is also possible to prescribe extended cycle regimens using traditionally packaged COCs in an off-label manner, which gives women the option of cycling every 6, 8 or 12 weeks, or not at all. However, this may mean that women have to pay out of pocket for extra pills because of insurance limits on number of packs per year, and it may be difficult for some women to follow directions when not packaged for this purpose. Studies of extended cycle COC regimens have demonstrated comparable efficacy and side effect profiles to traditional regimens although continuous users may experience more frequent spotting in the first three cycles than cyclic users. No study has demonstrated superior contraceptive efficacy; however, studies were not large enough to have the statistical power to test this hypothesis.

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Women who might especially benefit from extended cycles are those who have symptoms exacerbated by their menses. This might include women with seizure disorders, endometriosis, menstrual headaches, premenstrual dysphoric disorder, menorrhagia or dysmenorrhea. By limiting the number of times a woman menstruates, one can also reduce the amount of suffering due to these conditions.

Transdermal Contraceptive System The Ortho Evra® (norelgestromin/EE) transdermal system, or “patch,” is a combination hormonal contraceptive method that was introduced in 2002. This is a 7 1.75 x 1.75 inch patch that administers estrogen and progestin through skin absorption. In the FDA-approved regimen it is applied weekly for three weeks, followed by a patch-free week, during which time a woman will have a withdrawal bleed. It can be worn on any part of the body except the breasts. It should be placed on the first day of menses, and if this is done, no backup initial contraception is needed. If the patch is initiated after the first day of menses, a backup method should be used for one week. The patch releases 150 μg of norelgestromin (the primary active metabolite of norgestimate) and 20 μg of EE per day. The hormones are absorbed through the skin, avoid first pass metabolism through the liver, and achieve a constant serum level of hormones. Patch users have a 60% higher average serum estrogen level than users of a 35 μg COC, though the peak level reached daily in COC users is 25% higher than that of patch users. This may have implications on the risk of rare adverse effects related to estrogen such as VTE, though currently there are not data to suggest whether the risk is increased compared with COC use, and no specific prescribing restrictions are currently recommended. The patch works by the same mechanism as COCs and has a comparable failure rate (0.88 pregnancies per 100 woman-years). However, in the initial efficacy trials, the failure rate was higher in women who weighed more than 198 pounds (90 kg). The lower efficacy of the patch in larger women may apply to other low-dose combined hormonal methods as well; most efficacy studies did not include women whose body weight exceeded 198 pounds, and secondary data analyses of this question are ongoing. Women who are overweight should therefore be counseled that the patch (and possibly other low-dose, combined hormonal methods) may offer them less protection against pregnancy than other methods. There is evidence that women find it easier to adhere to weekly patch use than to daily COC use. In one study, 88% of women using the patch were perfectly compliant (no missed or late patches) compared with 78% of perfectly compliant women using COCs. There are no data to indicate whether this improved adherence will lead to reduced failures. Certain adverse events are specific to the patch, such as local skin reactions in 20% of women, of which only 2.6% are treatment-limiting. Partial and complete patch detachment also occurs in 2.8% and 1.8% of women respectively. When this happens, a woman should place another patch immediately, and go to her provider or pharmacy for a replacement patch. If a woman is late in placing a patch during the first week, i.e., has been without a patch for more than 7 days, she should use emergency contraception (EC) if indicated, place a patch as soon as possible, and use a back-up method for one week. If she is 1-2 days late with the second or third patch in a cycle, she can simply replace her patch immediately without EC or a back-up method, but if she is more than 2 days late, she must take additional precautions (Table 7.4).

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Table 7.4. An algorithm for missed or late contraceptive patch When Patched Missed 1st week patch

2nd-3rd week patch

4th week patch

Management [Patient Instructions] • Use emergency contraception if unprotected intercourse has occurred. • Place the patch immediately. • Use a back-up method for 7 days. • Change patch each week on the same day of the week from now on. • 1-2 days late: Remove the old patch and place a new one immediately. No back-up method or emergency contraception is needed. • >2 days late: Remove the old patch and place a new one on immediately. Use EC if unprotected intercourse has occurred (especially if she is 4 days or more late applying her patch). • Use back-up method for 7 days. Change the patch each week on the same day of the week. • Remove the patch. • Place a new patch on the usual day. • No back-up method or EC is needed.

Reproduced from: Hatcher R, Zieman M et al. A Pocket Guide to Managing Contraception. Tiger: Bridging the Gap Foundation, 2005.

Research on extended cycle patch use shows results of delayed menses and fewer bleeding days when compared to cyclic patch use. However there is also concern that using the patch in a continuous manner may cause an accumulation of EE in the blood, leading to higher than acceptable levels. Until there are more data, I would caution against using the patch in a continuous manner. The side effect profile for the patch is very similar to that of COCs, with the exception of more common complaints of spotting, breast symptoms and dysmenorrhea as compared to COCs. Spotting and breast symptoms typically resolve after the first two cycles, and dysmenorrhea, though more common with the patch than with COCs, is not usually a cause of discontinuation. Contraindications for the patch are the same as for COC (Table 7.3).

Combined Contraceptive Vaginal Ring NuvaRing® (etonogestrel/EE), introduced in the U.S. in 2001, is another way to administer combined hormonal contraception. The ring has an outer diameter of almost 2 inches, and a cross-sectional diameter of approximately 1/8 inch. It is self-inserted into the vagina, left in place for three weeks, and then removed for one ring-free week. If the ring is initially placed on the first day of menses, no back-up contraception is needed, but if it is placed on day 2-5, a back-up method should be used for seven days. The ring is meant to be left in place during intercourse, though it can be removed for up to three hours without reduced efficacy. The ring releases approximately 120 μg of etonogestrel and 15 μg EE daily through the vagina, and serum levels are adequate for 35 days. This method of administration, similar to transdermal release, avoids first-pass metabolism through

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the liver. The mechanism of action for the ring is the same as for COCs and the patch, but it is unique in that the progestin used in the ring suppresses ovulation in all users. Women generally find it easy to use the ring and use it perfectly in 86% of cycles. The cumulative failure rate is similar to that of COCs (1.18 per 100 woman-years), though among women who use the ring perfectly the cumulative failure rate is lower (0.77 per 100 woman-years). Overall, the ring is well tolerated; 95% of women find it easy to insert and remove, and 83% deny feeling it during intercourse. In addition to the side effects known to be associated with COCs (nausea, head7 aches, breast tenderness, etc), ring users experience unique side effects. Fifteen percent of study participants discontinued the ring due to vaginal symptoms including vaginitis, leukorrhea, “feeling the ring” when it is in place, and, very rarely, expulsion. On the other hand, the ring resulted in a more desirable bleeding pattern when compared with COCs. Studies of extended cycle vaginal ring use have demonstrated high satisfaction rates with continuous use of ring for 49- and 91-days as well as year-long continuous use. Unscheduled bleeding was lowest with the traditional 28-day cycle; however, overall bleeding days were reduced with postponement of withdrawal bleeding. Because each ring, if left in place, releases adequate serum levels for 35 days, it could be used as a once-a-month extended cycle regimen (therefore not requiring additional rings purchased per year). Most of the contraindications and precautions for the ring are similar as those for COCs and the patch, and the World Health Organization (WHO) criteria can be applied (Table 7.3). If a woman removes her ring for more than 3 hours, she should replace it immediately, use EC if applicable, and use a back-up method for 7 days. If she is late in replacing her ring after the ring-free week, she should do the same. Contraindications that are specific to the ring include chronic vaginitis, pelvic organ prolapse and severe constipation.

Injectable Combined Hormonal Contraception Currently, there is not an injectable form of combined hormonal contraception available in the United States. Lunelle® (medroxyprogesterone acetate/estradiol cypionate), a 0.5 ml suspension that is injected intramuscularly into the deltoid or gluteus maximus every 28-30 days, was taken off the market in 2002. It is still used some in other countries and may be available in the U.S. in the future.

Progestin Only Contraceptive Methods Progestin Only Pills The progestin only pill (POP), also commonly called the mini-pill, contains only progestin and is taken daily without any pill-free days. The mechanism of action is identical to the progestin-related mechanisms for COCs. The primary mechanism is thickening of the cervical mucus (this action is short lived, and requires punctual dosing to be effective). Progestin use also causes decreased tubal and endometrial motility and thin, atrophic endometrium. Only about 50% of women will have ovarian suppression with the currently available POP. Because the major mechanism of action requires punctual dosing to maintain effectiveness,

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women must take the POP within one hour of the same time each day. If 27 or more hours have lapsed since the last dose, a woman should take her POP immediately, consider using EC (if indicated), and should also use a back-up method for 2 days. If taken correctly, the efficacy of POPs equals that of COCs, with a failure rate of 0.3%-8%. However, this efficacy may be slightly inflated because most women using POPs are at reduced risk for pregnancy because of their lactating or perimenopausal status. Women using POPs experience many of the same noncontraceptive benefits of women using COCs, such as improvements in menstrual side effects and decreased risk of endometrial cancer. POPs confer no protection against ovarian and 7 colon cancers. The progestin only pill can be safely used in many women for whom estrogen is contraindicated. These include women with a history of clots or VTE, hypertension , coronary artery disease or cerebrovascular disease; women over 35 years who smoke; and recently post-partum or breastfeeding women. The main disadvantage to POP use is the need for a strict dosing regimen. Adherence to daily dosing at the same time every day is often prohibitive, and most women prefer the increased flexibility in timing of administration allowed with COCs. The only absolute contraindication for progestin use is current breast cancer, but there are several conditions in which the risks of POP use generally outweigh the benefits (Table 7.5).

Table 7.5. When risks outweigh benefits in initiating progestin only pills and Levonorgestrel/Etonogestrel implant (Implanon)* WHO Medical Condition Category Breast Feeding (<6 weeks postpartum) 3 Current DVT/PE 3 Current and h/o ischemic heart disease 2/3** Stroke 2/3** Migraine with aura 2/3** Unexplained vaginal bleeding (implant only) 3 Current breast cancer 4 H/o breast cancer and NED 3 Viral hepatitis (active) 3 Cirrhosis (severe) 3 Liver tumors (benign or malignant) 3 Drugs that affect liver enzymes (rifampicin or certain anticonvulsants) 3 *This table also applies to Implanon, which will be discussed below. **This indicates that initiation of POPs is a category 2, but continuation of POPs after development of this condition is a category 3. Reproduced from: WHO Medical Eligibility Criteria for Contraceptive Use. 3rd ed. Geneva: Reproductive Health and Research World Health Organization, 2004.

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Progestin Only Intramuscular Injection Depo-Provera® (medroxyprogesterone acetate, 150 mg/ml), is given as an intramuscular injection into the deltoid or gluteus maximus every three months (11-13 weeks). It is highly effective, with a failure rate of only 0.3%, and is acceptable to most women. The need to return to a clinic every 3 months for an injection may be considered a disadvantage of this method. A new, low-dose formulation of Depo-Provera was approved in 2005 that can be administered subcutaneously, and has the potential to be self-administered. This formulation, Depo-subQ-Provera 104™, has equivalent efficacy with no pregnancies noted in 720 women over one 7 year. It is considered to be one of the main reasons for the drop in teen pregnancy in the 1990s. The mechanism of action for Depo-Provera differs from other progestin-only methods. Because the progestin dose is larger, Depo-Provera suppresses ovulation by inhibiting the LH and FSH surges. The FSH surge is blocked to a lesser degree, thus women don’t usually suffer from hypoestrogenemia. Depo-Provera also thickens cervical mucus, atrophies the endometrium, and slows tubal and endometrial motility, but its primary action is ovulation suppression. Depo-Provera is a good method for women with contraindications to estrogen, and the reliable ovulation suppression decreases recurrence of ovarian cysts in susceptible women. Most women with endometriosis also experience improvement in pain symptoms, and Depo-subQ Provera 104™ has been FDA approved specifically for the indication of treating pain due to endometriosis. Women experience a decrease in menstrual bleeding and dysmenorrhea, and a decreased incidence of anemia. Half of women using Depo Provera become amenorrheic after 1 year of use. Additionally, women with sickle cell disease experience a reduction in the frequency and severity of crises on Depo-Provera, and in women with epilepsy Depo-Provera decreases seizure frequency. There are several undesirable side effects of Depo-Provera. Most women experience spotting and irregular menses for the first several months of use. After the first six months, most women experience a significant reduction in, if not absence of, their menses. These bleeding side effects are the main reasons for dissatisfaction and discontinuation. Another significant side effect is weight gain. Studies have shown that women can gain an average of 5.4 pounds in the first year, and 16.5 pounds after 5 years. Women who are overweight or obese when they initiate Depo-Provera are at increased risk of significant weight gain. Interestingly, in the only randomized, placebo-controlled trial to assess weight gain, Depo-Provera was not associated with weight gain in women of normal weight at baseline. As opposed to most other forms of hormonal contraception where return to fertility is immediate, return to fertility in Depo-Provera users is delayed. It takes an average of 10 months from the last injection to ovulate, but can take as long as 18 months. If a woman plans to conceive within the next 2 years, Depo-Provera may not be the ideal contraceptive method for her. Recently there has been much discussion about the effect of Depo-Provera on bone mineral density (BMD) and a concern about fracture risk. In 2004, the FDA added a Black Box Warning to Depo-Provera stating that the method should not be used for longer than 2 years unless it is the only contraceptive option. There is evidence that BMD is decreased in women using Depo-Provera, but there is also evidence that this decrease is reversible once Depo-Provera is discontinued, While concern is appropriate, it is premature to limit use of this contraceptive method to 2

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Table 7.6. When risks outweigh benefits in initiating Depo-Provera Medical Condition Breastfeeding <6 weeks postpartum Multiple risk factors for cardiovascular disease Systolic BP ≥60 or DBP ≥100 Current deep vein thrombosis (DVT) or pulmonary embolism (PE) Vascular disease Current and h/o ischemic heart disease Stroke Migraine with aura Unexplained vaginal bleeding Current breast cancer H/o breast cancer Diabetes with nephropathy/retinopathy/neuropathy DM with vascular involvement or of >20 years duration Active hepatitis or severe cirrhosis Benign or malignant liver tumors

WHO Category 3 3 3 3 3 3 3 2/3 3 4 3 3 3 3 3

Modified from: WHO Medical Eligibility Criteria for Contraceptive Use. 3rd ed. Geneva: Reproductive Health and Research World Health Organization, 2004.

years, especially in teens who are at very high risk for unintended pregnancy. It is not likely that the bone mineral density loss associated with Depo-Provera is sufficient to raise the risk of osteoporosis later in life. Similar to progestin only pills, Depo-Provera has only one true contraindication, that of current breast cancer. There are several other conditions for which it may not be the most appropriate method (Table 7.6). In general, Depo-Provera is safe and well tolerated and should remain a powerful component of one’s contraceptive armamentarium. Deciding about the appropriate time to initiate Depo-Provera can be a challenge. It is best to first administer within 5 days of the onset of a woman’s last menstrual period. If outside of this time frame, or if outside of the repeat dosing window of 11-13 weeks, certain precautions should be taken (Fig. 7.1).

Implantable Progestin Contraception Implanon® (etonogestrel) is a single-rod, subdermal implant that slowly releases etonogestrel—the active metabolite of desogestrel—and provides reliable contraception for up to three years [package insert]. Using a special device, it is inserted under the skin of the upper arm by a medical professional. This method was approved in 2006 at the time of publication, but is not yet marketed. Implanon is a highly effective method with no pregnancies occurring in more than 70,000 woman-cycles in the original studies. Similar to other progestin-only methods, its main side effect is irregular bleeding, and this is currently the primary reason for discontinuation.

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Figure 7.1. Initial injection or late reinjection (more than 13 weeks since last injection) of DMPA or switching from DMPA to COCs or another hormonal method. Reproduced from: Hatcher R, Zieman M et al. A Pocket Guide to Managing Contraception. Tiger: Bridging the Gap Foundation, 2005.

Levonorgestrel Intrauterine System The levonorgestrel intrauterine system (LNG-IUS), Mirena®, is one of two forms of intrauterine contraception (IUC) currently available in the United States (the other is the ParaGard®, which is a copper intrauterine device [IUD]). IUC is inserted into the uterus by a health care professional. Insertion can occur at any time during the menstrual cycle and rarely requires local anesthesia. Perforation is very rare (less than 1 in 1000) and expulsion is also uncommon (2.9%). LNG-IUS is a highly effective method of contraception, with equivalent efficacy to sterilization (0.1% failure rate per year for LNG-IUS and 0.8-3.7% for various sterilization

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methods). The LNG-IUS releases 20 μg of levonorgestrel daily and results in effective contraception for up to 7 years (though it is currently only FDA approved for 5 years of use). Its primary mechanism of action is to thicken cervical mucus (the progestin effect). Its secondary mechanisms include alteration of uterotubal fluid such that sperm migration is impaired, a weak foreign body reaction that reduces the receptivity of the endometrium to implantation, and the prevention of ovulation (in 5-15% of cycles). Many women using the LNG-IUS note spotting during the first 1-6 months. However, the overall effect of this method is to reduce menstrual blood loss (70-90%) and at 12 months post-insertion, approximately 20% of women are amenorrheic. 7 IUC is under-utilized in the U.S. compared with other developed nations—only 1% of U.S. women at risk for unintended pregnancy use IUC. Providers and patients commonly believe that there is a relationship between IUC use and pelvic inflammatory disease (PID). There is a slight, transient increased risk for PID at the time of IUC insertion thought to be due to the presence of bacteria in the cervix at the time of insertion. This risk of transient PID is between 1 and 8 per 1000. For this reason, any woman at risk for sexually transmitted infections (STIs) should be screened at or before the time of IUC insertion. If a woman is found to have visible cervicitis, placement of IUC should be delayed until at least 3 months after treatment. If the IUC is placed on the same day as screening for gonorrhea and chlamydia, and the test returns as a positive, it is safe to treat the patient with appropriate antibiotic therapy for cervical infection and leave the IUC in place. After the first 20 days, there is no increased risk of PID, and IUC is not associated with an increase in future tubal infertility. Furthermore, the LNG-IUS may decrease risk of PID secondary to the barrier provided by the thickened cervical mucus. Though the manufacturer has not yet incorporated this information into its package insert, this much maligned contraceptive method may actually provide protection against PID and tubal infertility. Like all methods of contraception, there are certain contraindications or cautions for use of the LNG-IUS (Table 7.7). Overall, this method is well tolerated, and 81% of LNG-IUS users continue its use for 1 or more years. Its acceptability to both patients and providers is improving as more data regarding its many benefits and few adverse side effects become better understood.

Emergency Contraception The purpose of contraception is to prevent pregnancy, but, it can be difficult to adhere perfectly to any birth control regimen. When a woman forgets her pills, does not replace a patch right on time, or is a condom user and experiences a condom break, she can employ emergency contraception (EC) to decrease her risk of pregnancy. It is estimated that 51,000 pregnancies were averted by EC use in 2000, and it may account for 43% of the decrease in abortion since 1994. EC specifically refers to methods used to prevent pregnancy after intercourse has already happened. There are three approaches to providing EC: high doses of combined oral contraceptives, high doses of progestin only pills, or placement of a copper-T IUD. The copper-T IUD is most effective, and also least commonly used in the United States. Of the hormonal methods, the progestin-only method is preferred because of its lower incidence of nausea and vomiting. The mechanisms of action for EC are multiple: inhibition of ovulation (primary mechanism); thickening of cervical mucus which traps sperm; inhibition of tubal

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Table 7.7. When risks outweigh benefits in initiating intrauterine contraception

7

WHO Medical Condition Category Pregnancy 4 Postpartum, puerperal sepsis 4 Immediately after septic abortion or pregnancy 4 Distorted uterine cavity 4 Current DVT (Only for LNG IUS) 3 Unexplained vaginal bleeding, before evaluation 4 Gestational trophoblastic disease (benign/malignant) 3/4 Cervical, endometrial cancers 4/2 Ovarian cancer 3/2 Breast cancer current (only for LNG IUS) 4 H/O breast cancer and NED (only for LNG IUS) 3 PID current or within last 3 months 4/2 Current sexually transmitted infection 4/2 Increased risk of STI 2-3 Active hepatitis, severe cirrhosis, or liver tumors (Only for LNG IUS) 3 Modified from: WHO Medical Eligibility Criteria for Contraceptive Use. 3rd ed. Geneva: Reproductive Health and Research World Health Organization, 2004.

transport; disruption of fertilization; early cell division or transport of the embryo; and disruption of the endometrium to prevent implantation. It is important to note that none of these mechanisms disrupt a pregnancy once it has been established. A woman not desiring pregnancy should take EC as soon as she realizes she has had unprotected intercourse. She can use either of the hormonal methods within 5 days after unprotected intercourse, and the copper-T IUD within 8 days, but sooner is always better as the efficacy decreases with each hour. The combined hormonal EC provides a 75% reduction in the incidence of pregnancy, and the progestin only EC provides an 89% reduction. Because EC is more effective the sooner it is taken after unprotected intercourse, some states have made it more accessible to women through policy changes. Practitioners should consider advanced provision of EC either by giving women a prescription or the actual pills as a back-up to their regular contraceptive method. Several countries and seven states (AK, CA, HI, ME, NH, NM, WA) allow women to obtain EC directly from a pharmacist without a prescription. The FDA is considering making EC available over the counter, which would also help improve access and decrease unintended pregnancy. Advanced provision is associated with an increase in use of EC, more prompt use of EC, no change in baseline contraceptive use, and no decrease in condom use. The original method of prescribing EC (the Yuzpe method) involves 2 doses of COCs given 12 hours apart. The total dose needs to include at least 100 μg of EE, and either 100 μg norgestrel or 50 μg levonorgestrel. If taken within 12 hours after

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Table 7.8. Emergency contraception options using combination oral contraceptives Brand Name of COC Ovral®, Ogestrel® Alesse, Levlite® Nordette® 28, Levlen® Levora®, Lo/Ovral®, Low-Ogestrel® Triphasil®, Tri-Levlen® Trivora®

Number of Pills to Take with Each Dose* 2 white pills 5 pink pills 4 light-orange pills 4 white pills 4 yellow pills 4 pink pills

*This dose is then repeated after 12 hours. Reproduced from: Steinauer J. A new era of contraception. Johns Hopkins Advanced Studies in Medicine 2005; 5(6):285-293.

unprotected intercourse, a woman’s risk for pregnancy is 0.5%; If not taken at all, her risk is 8%. There are a number of brands of COCs that can be used as EC (Table 7.8). The preferred method of EC is the progestin only method which is more effective and better tolerated than the combined method. Plan B® is a commercially available progestin-only EC product that consists of two pills, each with 75 μg levonorgestrel. The package insert indicates that one pill should be taken as soon as possible after unprotected intercourse, followed 12 hours later by the second pill [package insert]. There is evidence that taking both pills at the same time provides equal protection against pregnancy. The side effects from EC are primarily nausea and vomiting. These are reported by 50% and 19%, respectively, of women using combined EC, and 23% and 6%, respectively, of women using progestin only EC. Practitioners should prescribe anti-emetics if using combined EC or if a patient has previously had nausea/vomiting with progestin only EC. If a patient vomits within 1 hour of taking EC, she should repeat the dose. The FDA-approved contraindications for EC are the same as for COCs and POPs, respectively [package insert]; however according to the WHO’s, evidence-based guidelines, there are no contraindications for either method of EC. It is important to remember that the ultimate goal of EC is prevention of pregnancy, and to that end, when approached for an EC prescription, practitioners should take the opportunity to do contraceptive counseling with the patient. A woman can safely start any of the above mentioned forms of contraception immediately (i.e., the next day) following EC use, with the exception of the LNG-IUS. If her period does not come when expected on the birth control method or within 21 days of taking EC, she should take a pregnancy test.

Conclusion The incidence of unintended pregnancy remains high in the US, largely due to underutilization of highly effective and reliable forms of contraception. Although oral contraceptive pills are the most common hormonal method in the United States, providers should encourage patient to use methods that require less

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frequent interventions and have higher efficacy. With the tools provided in this chapter, an appropriate method of hormonal contraception can be found for almost any woman.

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1. All methods of combined hormonal contraception (COCs, patch, ring) have low failure rates if used correctly. However, it may be easier for a woman to remember to place a patch once a week or a ring once a month than it is to take a pill every day. Don’t be afraid to prescribe these newer forms of combined hormonal contraception. 2. Progestin-only methods (POPs, Depo-Provera, Mirena) should not be reserved only for women with contraindications to estrogen. The progestin injection and intrauterine contraceptive have much higher efficacy than COCs and are highly acceptable to women. 3. Depo-Provera is a very safe method of contraception. Though concerns regarding decreases in bone mineral density are warranted, there isn’t evidence at this point to suggest that Depo-Provera affects long-term bone health or puts women at risk for development of osteoporosis or fracture. 4. The Mirena LNG-IUS (and the ParaGard IUD) is the most effective method of contraception currently available in the United States. It is even more effective at preventing pregnancy than tubal sterilization. Concerns that many providers and patients have regarding the association between IUC and PID are unfounded. In fact, there is now evidence to suggest that Mirena may decrease a woman’s risk of PID and tubal infertility. 5. Emergency contraception is safe and easy to use. Progestin-only EC, like Plan B, has very few side effects and is typically very well tolerated. While all women trying to avoid pregnancy should be encouraged to consistently use an effective method of contraception, advanced and frequent provision of EC to sexually active women of reproductive age can prevent many unplanned pregnancies. Ideally, Plan B will be available over the counter, so women can access it in a more timely and efficacious manner.

Suggested Reading 1. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect 1998; 30(1):24-29, 46. 2. Speroff L, Darney PD. A Clinical Guide for Contraception. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2005. 3. WHO. Medical Eligibility Criteria For Contraceptive Use. 3rd ed. Geneva: Reproductive Health and Research World Health Organization, 2004. 4. Hatcher RA et al. Contraceptive Technology. 18th ed. New York: Ardent Media INC., 2004. 5. Hatcher R, Zieman M et al. A Pocket Guide to Managing Contraception. Tiger: Bridging the Gap Foundation, 2005. 6. Steinauer J. A new era of contraception. Johns Hopkins Advanced Studies in Medicine 2005; 5(6):285-293. 7. Stewart FH, Harper CC, Ellertson CE et al. Clinical breast and pelvic examination requirements for hormonal contraception: Current practice vs evidence. JAMA 2001; 285(17):2232-2239. 8. American Cancer Society Web site. http://www.cancer.org/docroot/NWS/content/ NWS_1_1x_Slight_Risk_for_Rare_Cancer_Linked_to_Oral_Contraceptives.asp; Accessed 2005.

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9. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception 2003; 68(2):89-96. 10. Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: A randomized trial. Obstet Gynecol 2003; 101(4):653-661. 11. Patient Information Sheet Norlegstromin/ethinyl estradiol (marketed as Ortho Evra): U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research, 2005. 12. Stewart FH, Kaunitz AM, Laguardia KD et al. Extended use of transdermal norelgestromin/ethinyl estradiol: A randomized trial. Obstet Gynecol 2005; 105(6):1389-1396. 13. Miller L, Verhoeven CH, Hout J. Extended regimens of the contraceptive vaginal ring: A randomized trial. Obstet Gynecol 2005; 106(3):473-482. 14. Guillebaud J. Contraception: Your Questions Answered. 4th ed. Edinburgh, London, New York, Oxford, Philadelphia, St. Louis, Sydney, Toronto: Churchill Livingstone, 2004. 15. Scholes D, LaCroix AZ, Ichikawa LE et al. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med 2005; 159(2):139-144. 16. Hubacher D, Lara-Ricalde R, Taylor DJ et al. Use of copper intrauterine devices and the risk of tubal infertility among nulligravid women. N Engl J Med 2001; 345(8):561-567. 17. Westhoff C. Clinical practice. Emergency contraception. N Engl J Med 2003; 349(19):1830-1835. 18. Raine TR, Harper CC, Rocca CH et al. Direct access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs: A randomized controlled trial. JAMA 2005; 293(1):54-62.

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Chapter 8

Endometriosis Sireesha Reddy

Definition and Epidemiology Endometriosis is a condition that is characterized by the presence of functional endometrial glands and stroma outside of the uterine cavity. This condition is found to be highly prevalent in women of reproductive age. However, the exact prevalence of endometriosis is unknown. It is believed approximately 20-50% of cases undergoing laparotomy reveal endometriosis at the time of surgery. The median age of women who have endometriosis is 37. Because 15% of these women are under the age of 30, endometriosis can also occur in the younger adult women and also in adolescence especially when there is an association with uterine anomalies. Although endometriosis is considered an estrogen-dependent disease with treatments focusing on this mechanism, rare cases have been identified in both premenarchal and postmenopausal females.

Pathogenesis Two main theories attempt to explain how endometriosis disseminates outside of the endometrial cavity and at almost all body sites: (1) the retrograde menstruation theory, whereby, endometrial cells via menstrual flow efflux through the fallopian tubes to implant and develop in ectopic sites; and (2) the metaplastic theory, whereby peritoneal serosa or the Mullerian remnants spontaneously differentiate into endometrial tissue in ectopic locations. Endometriosis is a slow and progressing condition which justifies its classification into three types: (1) superficial endometriosis, which may start as papules that turn red and finally black (2) ovarian endometriomas (3) deeply infiltrating endometriosis. Several factors such as anatomical defects (uterine anomalies), environmental toxins (dioxin), defects in immune regulatory cells (diminished clearing by macrophages), elevated inflammatory mediator expression (elevated prostaglandin levels) and recently, growth mediators (elevated aromatase expression) may play a role in the initiation of endometriosis.

Diagnosis Diagnosis of endometriosis is often problematic. Although patients classically present with pelvic pain, dysmenorrhea, dyspareunia, pelvic mass and infertility, there are also many patients who are asymptomatic. It has been found that 25% of all women who experience pelvic pain and 40-50% of infertile women have endometriosis. Most symptoms that women experience are a result of local infiltration of endometriosis into the pelvis: pelvic pain, dyschezia (painful defecation), abdominal bloating, dyspareunia, back pain, dysuria and suprapubic pain. Menstruation can greatly accentuate these symptoms.

Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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Because of the poor correlation between these symptoms and the diagnosis of endometriosis, there should be a careful clinical evaluation in combination with judicious use and critical interpretation of laboratory tests, imaging techniques, and, in most instances, surgical staging combined with histological examination of excised lesions. A thorough medical history should be taken focusing on duration and location of pain in addition to a precise physical examination noting areas of pain and tenderness. Family history can reveal female relatives with similar symptoms or even a diagnosis of endometriosis suggesting a higher risk for developing endometriosis. Laboratory markers such as serum CA-125 are of limited value. It is usually elevated only in advanced stages of endometriosis and can also be elevated in other gynecological conditions; therefore not suitable for routine screening. Transvaginal ultrasound and magnetic resonance imaging are often helpful, particularly in detec- 8 tion of endometriotic cysts. Recently, transrectal ultrasound and magnetic resonance imaging were shown to be valuable in detection of deep infiltrating lesions, especially in the rectovaginal septum. For most clinicians, laparoscopy allows a direct assessment of the pelvis for endometriotic foci and the ability to make a definitive diagnosis through appropriate biopsies. Laparoscopy also allows for the possibility of treatment through resection of endometriotic lesions and endometriomas and lysis of adhesions. Medical treatment options are effective, as are surgical treatment options. Complications associated with surgery, however, push the balance in favor of empiric short term medical therapy whenever possible. Clinicians often choose to treat women with endometriosis-related complaints with a first-line medical therapy. If that fails, then a second-line medical therapy is warranted under most conditions. Laparoscopic surgery is often reserved for patients in whom second-line medical therapy has failed or is contraindicated by desire to conceive.

Treatment Goals of treatment should involve addressing patient’s primary complaints as well as reproductive wishes. The most comprehensive treatment plan will include relief of symptoms, removal of all endometriotic lesions, and restoration of pelvic anatomy and delaying progression of the disease. Despite important advances in treating endometriosis, the optimal therapy has not been yet identified. Medical and surgical therapies, individually or in combination, may be needed to achieve the appropriate treatment plan.

Medical Treatment The mainstay of medical therapy focuses on the principle that endometriosis is an estrogen-dependent condition. Many clinical observations show that estrogen is essential for the growth of endometriosis. Endometriosis has been shown to regress and become inactive in states of amenorrhea and menopause. Therefore, treatment of endometriosis often relies on drugs that suppress ovarian steroids and induce a hypoestrogenic state that causes atrophy of ectopic endometrium. The most widely used agents to achieve this goal are oral contraceptives and GnRH agonists. The evidence-based support for medical therapy is mostly observational.

Oral Contraceptives Oral contraceptives (OCs) containing 20-35 μg of ethinyl estradiol can be used in a conventional regimen with monthly withdrawal bleeds or as a long-cycle regimen with continuous administration of OCs for 3 or 6 months followed by a

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hormone-free interval of 7 days. This regimen may be used for women who suffer from dysmenorrhea or pelvic pain. Symptomatic relief can be achieved in 75-100% of women in observational studies. Continuous use of OCs prevents the cyclic fluctuations of serum levels of ethinyl estradiol and progestogen and, hence, the cyclic variations of metabolic serum parameters. Although the long-cycle regimen is initially associated with an elevated rate of irregular bleeding, the total number of bleeding days that require sanitary product protection is lower than during conventional OC treatment. Many physicians tend to prescribe extended OC cycles for postponement of menstruation or reduction of frequency of regular bleeding.

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Progestins Progestins can cause suppressed gonadotropin levels to induce a hypoestrogenic state. Because of its direct action on the endometrium resulting in atrophy and decidualization, it is believed the mechanism of action is similar on endometriosis. Medroxyprogesterone acetate (150 mg of the Depot product every 3 months) can be used as a treatment for endometriosis. The side effect of slow return to ovulation is often seen as an undesirable side effect in women desiring fertility. Medroxyprogesterone acetate orally at 30 mg continuously for 90 days was shown to have benefit in women with laparoscopically confirmed mild to moderate endometriosis. After therapy a repeat laparoscopy revealed marked regression of endometriotic lesions and ovulation returned within two to three weeks of discontinuing treatment. Megestrol acetate at 40 mg per day has been found to provide symptomatic relief in as much as 85% of treated patients. The side effects of oral progestins can be breakthrough bleeding and spotting, depression, weight gain and breast tenderness. Norethindrone acetate has been used successfully in both symptomatic relief as well as resulting in regression of lesions in post-treatment surgical observation. The dosage should start at 5 mg daily to be gradually titrated to effect until a maximum of 50 mg maximum daily.

Gonadotropin Releasing Hormone Analogs Gonadotropin releasing hormone analogs (GnRH) cause a temporaty medical menopause resulting in hypogonadism and hypoestrogenism by acting on the pituitary to reduce gonadotropin synthesis and secretion. Most of the side effects experienced occur because of the hypoestrogenic state including hot flashes, vaginal dryness, mood lability and decreased libido. The GnRH agonists have been shown to work well in reducing pain symptoms associated with endometriosis such as dysmenorrhea, dyspareunia, and noncyclic pelvic pain. GnRH agonists are often initiated with the onset of menses, but a more rapid response is observed with mid-luteal administration. A limit of 6 months per treatment course is required due to loss of bone mineral density during therapy, but this can be extended via the addition of ‘add-back’ therapy with estrogens. Retreatment with these drugs is supported by limited data. Several investigators have studied the use of GnRH agonists as surgical adjuncts. Their use preoperatively has not been shown to be of value. Similarly, 3 months of postoperative administration has failed to enhance treatment. However, 6 months of postoperative GnRH agonists appear to improve the duration of relief of pain symptoms. Symptoms often recur after discontinuation of therapy, and hypoestrogen-related side effects limit the long-term use of most medications. Furthermore, these therapies are of limited value in patients with a desire to become pregnant because they inhibit ovulation.

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New Therapies Mifepristone, an antiprogestogen, is currently being studied. This appealing therapy to treat endometriosis may work without suppressing ovarian function. Aromatase inhibitors may have similar characteristics as they can inhibit estrogen production selectively in endometriotic lesions without affecting ovarian function; an observational trial in a small group of women who had exhausted all other medical therapies including GnRH agonists showed reduction in pain symptoms. Levonorgestrel intrauterine device has proven effective in relieving dysmenorrhea associated with endometriosis, as well as pain associated with rectovaginal endometriosis. This approach is promising in the long-term management of endometriosis as it limits systemic absorption of hormones, minimizing side effects. The most current 8 research has targeted anti-inflammatory mechanisms and modulators of the immune system. TNF-binding protein-1 and IL-12 have been shown to be effective in reducing endometriotic lesions in animal models, while pentoxifylline and INF-alpha 2b have shown encouraging results in clinical studies.

Surgical Treatment Often surgical treatment is considered when medical therapy has failed. With advances in laparoscopy, this technique has become the method of choice in the surgical evaluation and treatment of endometriosis. Laparotomy may still be used in cases of severe endometriosis which may involve other major organs and if adhesive disease is suspected. However, in all other cases, laparoscopy offers both diagnostic and therapeutic capabilities by confirming the presence of endometriosis and then the option to resect if reasonable. Laparoscopy also has many advantages: (1) being an outpatient procedure (2) minimizing hospital stay (3) lowering morbidity (4) smaller incisions and (5) superior visualization of lesions. Although there is controversy concerning the optimal approach to the treatment of endometriosis, the general opinion is if surgery is being performed then resecting as much of the visualized endometriosis as possible should be the goal. Laparoscopic resection of endometriosis utilizes various energy sources: electrocautery (monopolar and bipolar) and lasers. Excision of the lesions allows for safer and improved diagnostic results especially when evaluating superficial versus deeply infiltrating lesions in comparison to simple superficial fulguration and coagulation of endometriotic implants. Since endometriosis is a progressive disease and the extent of disease varies at diagnosis, recurrence rates can be also variable. Less than a third of patients experience recurrence of symptoms within three years after laparoscopy and approximately 50% experience symptom recurrence five years after laparoscopy. In patients who have mild to moderate endometriosis, 90% will respond with improved symptoms in the first year. In the remaining 10%, one-third will show disease regression, another third show disease progression and the remainder show no change in disease. Most patients will obtain relief of symptoms after laparoscopy for at least a year. Other surgical options exist for patients with ongoing pelvic pain especially midline pain with associated dysmenorrhea. LUNA (laparoscopic uterosacral nerve ablation) and presacral neurectomy (via laparoscopy or laparotomy) have been used with varying results. Patients who have ongoing symptoms and have completed childbearing should have the option of proceeding to a total abdominal hysterectomy with or without a bilateral salpingoopherectomy. Even with this last approach,

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there is a small risk of recurrence (3%) so there should be long term followup of these patients.

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1. Endometriosis is the presence of endometrial glands implanted outside of the uterine cavity. 2. Endometriosis is a condition that mostly affects women of reproductive age. 3. More common symptoms of endometriosis are pelvic pain and infertility. Pain does not correlate to the extent of disease. 4. Most common medical therapies are oral contraceptives and GnRH analogs. 5. Laparoscopic resection of endometriosis can result in at least one year of symptom-free interval with a high probability of recurrence in 3-5 years.

Suggested Reading 1. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997; 24:235-258. 2. Valle RF. Endometriosis: Current concepts and therapy. Int J Gynecol Obstet 2002; 78:107-119. 3. Montogomery Rice V. Conventional medical therapies for endometriosis. Ann NY Acad Sci 2002; 955:343-352. 4. Valle RF, Sciarra JJ. Endometriosis: Treatment strategies. Ann NY Acad Sci 2003; 997:229-239.

Chapter 9

Hyperprolactinemia Ghassan Haddad and Michael A. Thomas

Introduction Prolactin (PRL) is a hormone that primarily affects lactation; however, the clinical effects of hyperprolactinemia extend far beyond the mammary glands and affect distant organs such as the gonads, bones, as well as the brain in cases of tumors. Hyperprolactinemia is the most common endocrine disorder of the hypothalamic-pituitary axis. It is diagnosed when the serum prolactin level is consistently elevated above 25 ng/ml. Prolactin, like other anterior pituitary hormones, is under constant hypothalamic control. However, its predominant control is tonic-inhibitory through the action of prolactin inhibitory factors (PIF). The major PIF is dopamine. Dopamine inhibits PRL secretion via D-2 receptors on the surface of the anterior pituitary lactotroph cells. Some of the weak PRL releasing factors (PRF) include thyroid releasing hormone, vasoactive intestinal peptide, angiotensin II, serotonin, and vasopressin. Under normal physiologic conditions, the role of these weak stimulatory agents is not clear, and therefore the predominant control of PRL secretion remains the inhibitory effect of dopamine.

Biochemistry PRL is a glycoprotein hormone secreted primarily by the anterior pituitary lactotrophs. During pregnancy, the decidua secretes PRL as well, but decidual prolactin does not enter the circulation. It is concentrated in the amniotic fluid with levels exceeding those in the serum (10-100 fold that in the maternal or fetal serum). During pregnancy, the elevation in serum prolactin is solely due to pituitary secretion. PRL is secreted in different forms: prolactin (monomer), “big” prolactin (dimer), and “big big” prolactin, a polymer. Prolactin hormone can also vary in the size of the glycoprotein moieties attached to the amino acid basic structure. The three different forms differ in their potency as well: The big big prolactin is less bioactive than the smaller counterparts.

Etiology Hyperprolactinemia has several causes which can be divided into three major categories: physiologic, pharmacologic, and pathologic (Table 9.1).

Physiologic Physiologic causes include pregnancy, lactation, nipple stimulation, exercise, sleep, and stress. Except for pregnancy and lactation, the increase in serum PRL levels from physiologic stimulation is typically modest. In contrast, during pregnancy, PRL levels rise to a range of 200-400 ng/ml at term. During lactation, basal levels are elevated (40-50 ng/ml) and increase 2-10 fold with suckling. Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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Table 9.1. Causes of hyperprolactinemia

9

Pathological Pituitary/ Hypothalamic

Physiological

Pharmacological

Pathological Nonpituitary

Pregnancy

Phenothiazines

Hypothyroidism

Prolactinomas

Breast feeding

Haloperidol

Acromegaly

Sleep

MAO inhibitors

Chest wall lesions (herpes zoster, surgery, trauma)

Nipple stimulation

TCAs

Chronic renal failure

Craniopharyngiomas Meningiomas

SSRIs Exercise

Liver cirrhosis Butyrophenones

Stress Risperidone

Ectopic prolactin secretion

Thioxanthenes

Seizures

Other pituitary adenomas Sarcoidosis affecting the stalk Aneurism

α-Methyldopa

Metoclopramide

Trauma with stalk transection

Domperidone Reserpine Protease inhibitors Verapamil Estrogens (high doses)

Pharmacologic Since dopamine exerts the main control on PRL secretion, any medication that affects dopamine action can lead to abnormal PRL secretion. Estrogens in high doses can inhibit dopamine release and therefore increase PRL. Neuroleptic drugs such as phenothiazines, butyrophenones, risperidone, thioxanthenes as well as anti-depressants like tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors can competitively block the D-2 receptor and increase PRL. Antiemetics like metoclopramide (Reglan) exert the same action. A third of patients who take antiemetics will exhibit galactorrhea. Other medications that deplete the sympathetic mediators (including dopamine) can elevate PRL, such as alpha methyldopa. Protease inhibitors, used in HIV-positive patients, may also increase PRL levels, though the exact mechanism for this increase is unknown. Pharmacologically-induced hyperprolactinemia resolves within 3-6 months after discontinuing the medication.

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Pathologic Diseases that lead to hyperprolactinemia can be broadly categorized into one of two categories: hypothalamic-pituitary disorders and “peripheral” disorders.

Peripheral Disorders Chest wall lesions (following chest surgery, herpes zoster, nipple piercing) as well as prolonged nipple stimulation can increase serum PRL levels as well as cause galactorrhea. This occurs via a reduction in hypothalamic dopamine. Notably, routine breast exams are not associated with increased PRL. Chronic renal failure, due to a decreased clearance of PRL, can result in hyperprolactinemia. Renal transplant reverses it. Forty percent of patients with hypothyroidism have mildly elevated PRL levels, due to the increase in thyroid releasing hormone, which is also a PRL releasing factor. Some rare causes of ectopic hyperprolactinemia include small cell carci- 9 noma of the lung as well as colorectal cancer. Liver cirrhosis can also cause an elevation of PRL, possibly secondary to decreased clearance.

Hypothalamic-Pituitary Disease Pituitary or extra-pituitary lesions can compress the pituitary stalk and consequently cut-off (partially or completely) the inhibitory dopaminergic input from the hypothalamus to the anterior pituitary. PRL levels are typically less than 100-150 ng/ml. Examples include traumatic stalk transection, craniopharyngiomas, hamartomas, vascular aneurisms, granulomatous diseases such as tuberculosis and sarcoidosis, and nonfunctional pituitary tumors. However, the most common cause of persistent hyperprolactinemia is a prolactin secreting adenoma or prolactinoma. Prolactinomas are the most common functional pituitary tumors. About 11% of autopsies performed on “normal” subjects showed the presence of incidental pituitary adenomas, 44% of which stained positive for prolactin. Other pituitary conditions that can present with hyperprolactinemia are acromegaly and Cushing’s disease. Acromegaly is caused by a growth hormone secreting adenoma. About 30-40% of such adenomas cosecrete prolactin. This is not a surprise given the common embryologic origin of the somatotrophic cells (GH secreting cells) and the mammotrophic cells (PRL secreting cells) of the anterior pituitary. The associated hyperprolactinemia partially explains the hypogonadism observed in acromegalic patients. Cushing’s disease, caused by an ACTH secreting pituitary adenoma, can also be associated with hyperprolactinemia. Although the association is infrequent, mixed adenomas secreting both ACTH as well as PRL have been reported.

Prolactinomas Prolactinomas are pituitary adenomas (a monoclonal tumor) that secrete PRL. Like other pituitary adenomas, they can be classified into microadenomas or macroadenomas based on their size (less than 10 mm and greater than 10 mm, respectively). It is important to differentiate between the two because microadenomas are unlikely to compress the optic chiasm, while macroadenomas can compress it resulting in visual field damage which can be irreversible. In addition, macroadenomas, through a mass effect, can compromise other pituitary cells (such as gonadotrophs, thyrotrophs, and ACTH releasing cells). The overwhelming majority of prolactinomas are benign tumors, meaning that they do not metastasize to distant organs. Very few cases of malignant prolactinomas are

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reported in the literature; however, prolactinomas can be locally destructive, especially the macroadenomas. In addition to affecting pituitary function by a local mass effect, they can invade the optic chiasm as well as the adjacent cavernous sinus causing cranial nerve neuropathies (CN III, IV, V1, V2, VI). In women, the slightest elevation in prolactin can cause menstrual disturbances. Men, on the other hand, tend to present with symptoms of local mass effect. Physiologic effects of hyperprolactinemia in men (low libido, impotence, and infertility) are less sensitive to the hyperprolactinemia than symptoms in females (oligomenorrhea or amenorrhea). When to check a PRL level? • Any patient (male or female) with galactorrhea • Any male patient with erectile dysfunction • Any female patient with amenorrhea or oligomenorrhea 9 • Any female patient with symptoms of premenopausal hypogonadism • Patients with neurological symptoms suggestive of pituitary adenomas (severe headaches, visual field changes) • Patients with incidental pituitary adenomas discovered while imaging the brain for unrelated reasons

Evaluation Although prolactin is secreted in a pulsatile fashion, a random blood test usually suffices. If the prolactin is mildly elevated on initial evaluation (<40 ng/ml), it is prudent to repeat it prior to making a diagnosis of hyperprolactinemia. If the mild prolactin elevation is persistent on subsequent testing or if the initial level is greater than 40 ng/ml, then a specific cause should be sought. A TSH level should always be checked to rule out primary hypothyroidism, as this can result in an elevated PRL level (due to the PRL stimulating effect of TRH). A renal panel should be checked, as compromised kidney function leads to decreased clearance of PRL. Brain imaging, using gadolinium enhanced MRI (preferred) or CT scanning is mandatory to rule out hypothalamic-pituitary lesions. Although microadenomas typically produce serum PRL levels less than 100 ng/ml, while macroadenomas typically show levels greater than 100 ng/ml, a serum level cannot distinguish between the two. For example, a macroadenoma can produce very high serum PRL levels (greater than 1000 ng/ml), but due to an intrinsic artifact in the immunoassay (termed “the hook” effect), the result is read as a value less than 100 ng/ml. Only when the serum is diluted (1:100 dilution) will the true value of PRL be measured. In addition, other pituitary tumors (nonfunctioning pituitary macroadenomas and hypothalamic tumors) can cause elevations of PRL with values less than 100 ng/ml (by compressing the dopaminergic inhibitory fibers from the hypothalamus). Such tumors need to be accurately diagnosed and differentiated from microprolactinomas because their treatment is completely different. Therefore, while the initial blood test is helpful in diagnosing hyperprolactinemia, brain imaging is warranted to accurately identify the cause.

Galactorrhea Galactorrhea is defined as the presence of a milky nipple discharge at any time in men and in women with no recent history of pregnancy or breast-feeding. Evaluation of galactorrhea in the office includes examining the breast discharge on a slide under a microscope. The finding of fat globules is diagnostic.

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Treatment Observation Patients with microprolactinomas who are otherwise asymptomatic (no loss of libido or sexual dysfunction in men, or no menstrual irregularity or infertility in women) could be expectantly managed with serial PRL determinations. Patients who have evidence of hypogonadism due to the hyperprolactinemia need to be treated to avoid the complications of prolonged hypogonadism (the most important is osteoporosis).

Medical Treatment Whenever possible, medical treatment should always be sought first because of the high response rate and the relatively few complications. This applies to 9 both micro- and macroprolactinomas. Even without therapy, 93% of microprolactinomas do not enlarge when followed over a period of 4-6 years; moreover, any increase in size is paralleled by an increase in prolactin serum levels. Therefore, if the initial brain imaging shows the presence of a microprolactinoma, follow up as well as response to treatment can be done by periodically checking serum prolactin levels. PRL levels should be checked periodically while on medical therapy. Once the PRL levels have normalized, the dosages could be slowly tapered down to a lower dose; however, therapy is typically life-long as the tumor tends to grow back once the drugs are discontinued. Occasionally, the drugs can be discontinued after several years and the patient reevaluated. About 20% of patients are able to completely discontinue the medication and remain normoprolactinemic. The mainstay of medical treatment is dopamine receptor agonists (D2 agonists).

Bromocriptine (Parlodel) The first widely used dopaminergic agent used to treat prolactinomas was bromocriptine. Response rate is over 80-90%. PRL serum levels show a drop as early as 24 hours after starting therapy. In patients with macroadenomas, improvement in visual symptoms starts a few days to two weeks after therapy is initiated. Over 80% of patients will have a reduction in tumor size. The most common side effects are GI related (nausea and vomiting). Other side effects are orthostatic hypotension, nasal congestion, and occasionally, psychotic symptoms. Side effects can be minimized by starting with a lower dose at bedtime and gradually increasing it to BID dosing. If side effects persist, switch from oral to vaginal administration. Prolactin levels should be checked 4 weeks after starting therapy as well as 4 weeks after adjusting the dose. In amenorrheic patients who desire pregnancy, bromocriptine is the drug of choice due to its established fetal safety profile.

Cabergoline (Dostinex) Cabergoine is another dopamine agonist. Unlike other agonists, cabergoline has a long half-life and therefore is administered twice weekly. It also appears to have fewer side effects compared to bromocriptine. Similar to bromocriptine, it can be given vaginally in the event of intolerable side effects. Due to its lower side effect profile and long half-life, cabergoline is often used as first line treatment except in patients who desire pregnancy (more data exist on the safety of bromocriptine exposure during early pregnancy). It is more expensive than bromocriptine.

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Other Dopamine Agonists Pergolide is a dopamine agonist used to treat Parkinson’s disease. It is less commonly used than bromocriptine but appears to be as effective. Another dopamine agonist, not available in the United States, but with efficacy comparable to that of bromocriptine, is quinagolide.

Surgery Surgery should not be offered as first line therapy due to lower success rates compared to medical therapy and a higher complication rate. The surgical cure rate for microadenomas is in the range of 50-60%, while for macroadenomas it is about 25%. Complications include visual loss, other cranial nerve injuries (CN III, IV, V), cerebrospinal fluid rhinorrhea, meningitis, and damage to other pitu9 itary cells. Surgical mortality for macroadenomas is about 0.9%, while morbidity is 6-20%.

Radiotherapy Radiotherapy is generally considered as third line treatment due to the high success rates of medical therapy and surgery when indicated.

Pregnancy Considerations (Table 9.2) For women who desire pregnancy, bromocriptine is the drug of choice to assist in achieving ovulation. It has a well-established safety profile when used during the first few weeks of gestation. Fewer data are available on cabergoline. For patients with microadenomas, bromocriptine can be stopped after conception. Such patients have a very low incidence of tumor enlargement during pregnancy (<5%) and therefore periodic imaging and visual field testing is not routinely recommended. Nor is it necessary to measure prolactin levels in pregnancy, as there is no correlation between tumor enlargement and serum prolactin levels. For patients with macroadenomas, the risk of clinically significant tumor enlargement during pregnancy is about 26%. There is no clear answer as to the best therapeutic approach, but three management strategies exist: 1. Stop the bromocriptine (or other dopamine agonist) after conception and closely follow up the patients (with visual field testing and imaging) for signs of tumor enlargement 2. Perform a prepregnancy tumor debulking (however, such patients usually still require bromocriptine to achieve ovulation) 3. Continue bromocriptine for the duration of the pregnancy. The few studies on bromocriptine exposure during late gestation suggest that this is safe for the fetus.

Table 9.2. Clinical course of prolactinoma in pregnancy Prolactinoma Type Microadenoma Macroadenoma Macroadenoma

Previous Therapy None None Yes

Symptomatic Enlargement 1.4% 26.2% 3.0%

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All pregnant patients with macroadenomas should have monthly visual field testing.

Key Points 1. Regardless of the prolactin level, newly diagnosed hyperprolactinemia patients of suspected pituitary origin should have brain imaging performed to rule out a macroadenoma or other stalk compressing lesions. 2. Females tend to present earlier than males due to menstrual disturbances. 3. The primary therapy for prolactinomas is medical. Second line treatment is surgical, and third line is radiotherapy. 4. Patients desiring to conceive should preferably be placed on bromocriptine.

Suggested Reading 1. Biller BM, Baum HB, Rosenthal DI et al. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992; 75(3):692-7. 2. Mah PM, Webster J. Hyperprolactinemia: Etiology, diagnosis, and management. Semin Reprod Med 2002; 20(4):365-74, [This is a good review article on hyperprolactinemia. It would serve as an excellent supplement to reading this chapter). 3. Luciano AA. Clinical presentation of hyperprolactinemia. J Reprod Med 1999; 44(12 Suppl):1085-90, [This is worth reading in full. It is a good clinical review of how patients (both men and women) with elevated prolactin levels typically present to thei physician]. 4. Kletzky OA, Marrs RP, Howard WF et al. Prolactin synthesis and release during pregnancy and puerperium. Am J Obstet Gynecol 1980; 136(4):545-50. 5. Pollock A, McLaren EH. Serum prolactin concentration in patients taking neuroleptic drugs. Clin Endocrinol (Oxf ) 1998; 49(4):513-6. 6. Honbo KS, Van Herle AJ, Kellett KA. Serum prolactin levels in untreated primary hypothyroidism. Am J Med 1978; 64(5):782-7. 7. Molitch M. Medical management of prolactin secreting pituitary adenomas. Pituitary 2002; 5(2):55-65. 8. Webster J, Piscitelli G, Polli A et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. N Engl J Med 1994; 331(14):904-9. 9. 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(2):225-36, (discussion 236-7). 10. Rossi AM, Vilska S, Heinonen PK. Outcome of pregnancies in women with treated or untreated hyperprolactinemia. Eur J Obstet Gynecol Reprod Biol 1995; 63(2):143-6.

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Chapter 10

Premenstrual Syndrome Stephanie A.M. Giannandrea, Linda H. Chaudron and Tana A. Grady-Weliky

Introduction Clinical descriptions of premenstrual symptoms have been reported in the medical literature since the time of Hippocrates. Emotional and physical symptoms occurring along a continuum of severity are common during the luteal phase of the menstrual cycle. Premenstrual syndrome (PMS) is a complex of mild to moderate emotional and/or physical symptoms, which typically do not interfere with patients’ usual level of functioning. Up to 75% of reproductive-aged women have reported premenstrual symptoms at some time during their lives. Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome, which affects 3-8% of reproductive-aged women. The hallmark of premenstrual syndrome at all levels of severity is the exclusive occurrence of symptoms during the luteal phase of the menstrual cycle with remission typically within 3 days of menses onset. A diagnosis of premenstrual syndrome (PMS) requires at least one physical or emotional symptom from the International Classification of Diseases—10th edition (ICD-10). Premenstrual dysphoric disorder, PMDD, is a more severe condition in which there is a marked mood change (depression, mood swings, irritability or anxiety) as well as the presence of other physical and somatic symptoms. Prospective symptom rating for at least two menstrual cycles and disruption in social and/or occupational functioning are required to fulfill the “research” criteria for this diagnosis found in the Appendix of the Diagnostic and Statistical Manual— 4th edition-Text Revision (DSM-IV-TR) and listed in Table 10.1. The presence of the diagnosis of PMDD in the DSM classification has been met with significant controversy. The controversy centered on the fact that only women could be affected by this diagnosis and that it could potentially lead to gender discrimination. After a period of discussion and debate, it was determined that the diagnostic criteria for PMDD would remain as “research” criteria to improve understanding of the etiology and to identify the best treatment options.

Risk Factors Family history of mood disorder, history of severe mood swings or negative reactions to oral contraceptives, obesity, poor diet, and lack of exercise are among the factors that increase a woman’s susceptibility to the development of PMS/ PMDD. A history of sexual or physical abuse also appears to put women at greater risk for PMS.

Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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Table 10.1. Premenstrual dysphoric disorder criteria* A. In most menstrual cycles during the past year, five (or more) of the following symptoms were present for most of the time during the last week of the luteal phase, began to remit within a few days after the onset of the follicular phase, and were absent in the week postmenses, with at least one of the symptoms being either (1), (2), (3), or (4): 1. Markedly depressed mood, feelings of hopelessness, or self-deprecating thoughts 2. Marked anxiety, tension, feelings of being “keyed up,” or “on edge” 3. Marked affective lability (e.g., feeling suddenly sad or tearful or increased sensitivity to rejection) 4. Persistent and marked anger or irritability or increased interpersonal conflicts 5. Decreased interest in usual activities (e.g., work, school, friends, hobbies) 6. Subjective sense of difficulty in concentrating 7. Lethargy, easy fatigability, or marked lack of energy 8. Marked change in appetite, overeating, or specific food cravings 9. Hypersomnia or insomnia 10. A subjective sense of being overwhelmed or out of control 11. Other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sensation of “bloating,” weight gain Note: In nonmenstruating females (e.g., those who have had a hysterectomy), the timing of luteal and follicular phases may require measurement of circulating reproductive hormones. B. The disturbance markedly interferes with work or school or with usual social activities and relationships with others (e.g., avoidance of social activities, decreased productivity and efficiency at work or school). C. The disturbance is not merely an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although it may be superimposed on any of these disorders). D. Criteria A, B, and C must be confirmed by prospective daily ratings during at least two consecutive symptomatic cycles. (The diagnosis may be made provisionally prior to this confirmation.) *DSM-IV-TR research criteria

Clinical Symptoms and History Premenstrual syndrome is characterized by mood swings, depressed mood, irritability and/or anxiety, which may be accompanied by physical symptoms. These symptoms occur exclusively during the luteal phase of the menstrual cycle. Common physical symptoms observed in PMS are breast tenderness, abdominal bloating, headache, and joint and muscle aches. The diagnosis of PMDD requires marked mood disturbance (depression, irritability, mood swings) as well as the presence of other emotional and/or physical symptoms. Additionally, a significant

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reduction in social and/or occupational functioning is required for the diagnosis of PMDD. The functional impairment tends to be in social as opposed to occupational domains. Prospective daily recording of the presence and severity of symptoms for at least two menstrual cycles is used to confirm the diagnosis of PMDD. Specific diagnostic criteria for premenstrual dysphoric disorder are shown in Table 10.1.

Differential Diagnosis A comprehensive history and physical examination are indicated to rule out other possible causes of the emotional and physical symptoms of PMS. The differential diagnosis includes premenstrual molimina, hypothyroidism, perimenopause and major mood or anxiety disorders. Most ovulatory women experience some physical changes (e.g., breast tenderness, bloating, and food cravings) during the 10 luteal phase. If these physical symptoms do not interfere with normal life functions, the term molimina can be applied. Hypothyroidism can share many of the same symptoms as PMS; however there should be no cyclic variation. A thyroid stimulating hormone level is a sufficient screen, if warranted by clinical suspicion. There is also considerable overlap between the symptoms of perimenopause and those of PMS. Many women experience symptoms of emotional irritability, cyclic mastalgia, bloating and hot flashes as part of the perimenopause. It is likely that similar pathophysiologic factors mediate symptoms in both disorders. In a practical sense, to document PMS, women should maintain a calendar of symptoms that can be correlated with the reproductive cycle. For PMDD, women must meet the DSM-IV-TR diagnostic criteria (Table 10.1). Distinguishing the emotional symptoms observed in PMS from those present in other major mood or anxiety disorders (e.g., major depressive disorder, dysthymia, panic disorder) is important because of the different treatment strategies. Women with PMS respond to unique therapeutic interventions, such as calcium carbonate, gonadotropin releasing hormone agonists and intermittent dosing with serotonin reuptake inhibitors (SRIs). If patients present with continuous mood or anxiety symptoms across the menstrual cycle, the diagnosis of PMS cannot be made. If patients exhibit mood and/or anxiety symptoms across the menstrual cycle with an increase in severity during the luteal phase, the appropriate diagnosis is premenstrual exacerbation (PME) of the underlying condition, not PMS. Therefore, diagnostic verification of premenstrual syndrome is best accomplished through prospective daily symptom recording (or “charting”). This prospective rating is required to make a diagnosis of PMDD. A number of valid and reliable diagnostic instruments, e.g., Calendar of Premenstrual Experiences (COPE), Premenstrual Symptoms Screening Tool (PSST), Visual Analogue Scale (VAS), Daily Record of Severity of Problems (DRSP), are available to document emotional and physical symptoms across the menstrual cycle. These forms include emotional, physical and functional symptoms that patients rate or “chart” daily using a Likert-type scale to assess the presence, timing, and severity of symptoms. The diagnosis of PMS/PMDD is verified if there is: (1) demonstrated evidence of a relative absence of symptoms during the follicular phase of the menstrual cycle; (2) significant increase in emotional and/or physical symptoms during the luteal phase of the menstrual cycle; and (3) functional impairment during the luteal phase of the menstrual cycle (for PMDD).

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Etiology The etiology of PMS is not completely known, but appears to be multi-factorial. Fluctuating hormones across the menstrual cycle play a role, since PMS is not observed in prepubertal girls or in menopausal women. Recent studies have also suggested a role for serotonin and other neurotransmitters in the etiology of PMS. Because of the temporal relationship of PMS symptoms to corpus luteum function, the most obvious explanation for PMS would be the systemic and psychological effects of sex steroids produced by the corpus luteum. However, multiple studies have shown no difference between women with PMS and controls with respect to circulating levels of progesterone and estrogen. Investigators have examined daily steroid levels, peak steroid levels and ratios of progesterone to estradiol, generally with the same conclusion—no significant difference between women with PMS and controls. Nonetheless, there is adequate evidence to suggest intrinsic differences in sensitivity to physiologic levels of estrogen and progesterone. Administration of a gonadotro- 10 pin releasing hormone (GnRH) agonist to women with PMS, which suppresses output of estrogen and progesterone, can relieve their psychological symptoms, whereas women without PMS do not show any consistent difference in mood. Allopregnanalone, a metabolite of progesterone produced in the ovary and the brain, is believed to play an important role because of its influence on GABA receptors. Recent efforts have focused mainly on neurotransmitter sensitivity to steroid hormones. The serotonergic pathway has received much attention, in part because of its therapeutic implications. Use of the serotonin agonist μ-chlorophenylpiperazine in women with PMS acutely improves depression and anxiety. The introduction of metergoline, a serotonin antagonist, has been shown to reproduce premenstrual symptoms in women who had demonstrated improvement on serotonergic reuptake inhibitors. Further, numerous placebo controlled trials of serotonin reuptake inhibitors (SRIs) have shown superior efficacy in reduction of premenstrual symptoms. The physical symptoms of PMS are largely unexplained. Many women with PMS are bothered by mastalgia, fluid retention, and bloating. No consistent differences have been shown in women with PMS with respect to prolactin, cortisol, or thyroid hormone levels. Progesterone is a substrate for deoxycorticosterone (DOC)— a potent mineralocorticoid. Renal 21-hydroxylase converts progesterone to DOC in the kidney. This extraglandular DOC is thought by some to mediate the bloating and fluid retention seen in PMS. However, a recent study of desoxycorticosterone levels showed similar menstrual cycle variation in controls and women with PMS. In summary, the etiologies of PMS and PMDD are not understood. Current knowledge suggests that many of the psychological symptoms occur because of an increased central sensitivity to physiologic levels of estrogen and progesterone. This enhanced sensitivity appears to occur through serotonergic-mediated pathways. Physical manifestations of PMS are not understood but may ultimately prove to be another manifestation of increased sensitivity to normal cyclic hormonal variation.

Treatment Therapeutic strategies for management of premenstrual symptoms can be divided into two phases. First, the patient records or “charts” her symptoms for two menstrual cycles, during which lifestyle interventions may be started. If she remains symptomatic after the charting period and initial interventions, pharmacologic therapy should be strongly considered.

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Lifestyle Interventions Patients with mild to moderate premenstrual symptoms have reported that reducing caffeine, refined sugars, or sodium intake can be helpful. Although increased exercise has been found to reduce symptoms of major depressive disorder, there is no definitive evidence that it results in improvement of PMDD symptoms. There are no recent controlled studies to support the anecdotal reports of the benefits of a healthy diet and exercise for premenstrual syndrome. Nonetheless, these interventions are recommended because of their other benefits and safety.

Nutritional, Vitamin and Alternative/Complementary Treatment Strategies Vitamin and mineral supplementation may also be beneficial. Dietary supplements with increased tryptophan have been utilized in an effort to reduce premen10 strual symptoms, particularly carbohydrate craving. A variety of herbal medications have also been used for treating PMS. This has been particularly welcomed by many patients who prefer so-called natural remedies. Other alternative strategies that have been investigated include acupuncture, massage therapy, and homeopathic remedies. Randomized controlled trials of Vitamin B6, calcium, and carbohydrate-rich dietary supplements have demonstrated efficacy in premenstrual syndrome. A recent meta-analysis revealed that vitamin B6 in daily doses of 50-100 mg reduced premenstrual mood and physical symptoms. Calcium supplementation has also been shown to be efficacious in the management of moderate to severe premenstrual symptoms. A randomized controlled trial comparing calcium carbonate to placebo revealed that 1200 mg of calcium carbonate resulted in a significant reduction of physical (water retention, food craving and pain) and emotional (negative affect) premenstrual symptoms. Magnesium supplementation has also been studied in the treatment of PMS with inconsistent findings. An early study revealed improvement in negative affect and reduced overall score in women treated with 360 mg of magnesium daily compared to the placebo group, but this was not supported by a more recent, placebo-controlled study. Treatment with a carbohydrate-rich beverage, PMS EscapeTM, compared to placebo revealed improvement in premenstrual mood symptoms. Dosing strategies and outcomes for vitamins and other supplements are listed in Table 10.2. Most studies of herbal remedies have been open label, which limits the ability to interpret positive findings. However, most open trials and several controlled trials have shown subjective improvement in physical and some emotional symptoms in women who have taken these agents for at least 3 menstrual cycles. Evening of primrose oil, St. John’s Wort (hypericum perforatum), and Chaste Tree (Vitex agnus castus) are among the herbal remedies that have been studied in the treatment of PMS. Of the herbal remedies, chasteberry/chaste tree (vitex agnus castus) is the most promising based on recent randomized controlled trials. Dosing strategies for herbal remedies are noted in Table 10.2. In summary, vitamin B6, calcium, carbohydrate-rich supplements and possibly magnesium may prove to be beneficial for patients with PMS. However, there is not convincing evidence to date regarding the sole use of herbal remedies or alternative treatments for the management of PMS. Clinicians need to be aware of these options as many patients express interest in their use. Moreover, adjunctive use of these treatment methods may be beneficial in the engagement of patients in treatment.

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Table 10.2. Vitamin, nutritional, and herbal dosing strategies for PMDD Agent Vitamin B6 Calcium carbonate3 PMS EscapeTM 4 Agnus vitus extract5 (chasteberry)

Therapeutic Dose 50-1002 mg 1200 mg 2 drinks daily 5 days prior to menses onset 20 mg6

Side Effects1 Peripheral neuropathy None reported None reported Acne, urticaria, intermenstrual bleeding

1) Studies did not consistently report common side effects. However, suggested guidelines for dosing should be followed as risk of side effects and/or complications may increase with dosage increases. 2) Do not exceed 100 mg daily secondary to the risk of peripheral neuropathy and other adverse effects. 3) Patients may elect to use over-the-counter agents, e.g., TUMS. It may be administered by chewing 4 tablets daily (two tablets twice daily). 4) A carbohydrate rich drink that was available for research purposes. There may be limited general availability. 5) Patients need to be aware of the lack of safety data among all herbal medications. Different formulations may contain different amounts of the active ingredient. 6) Most studies utilized the following formulation—Vitex agnus castus L extract Ze 440. Specific formulations including the exact extract included in the tablet need to be examined prior to initiation of any herbal remedy. Other ingredients (fillers) should be examined to determine presence of additional active agents, which may cause side effects.

Psychoeducation Clinical experience has shown that by charting symptoms daily women learn more about when their symptoms occur and what may exacerbate or minimize them. This close monitoring may facilitate lifestyle changes that lead to a modest but meaningful degree of symptom reduction. However, the degree of symptomatic improvement is rarely complete. If dietary, nutritional, herbal or psychotherapeutic interventions have not been effective, medication is generally indicated in order to reduce symptoms and enhance the woman’s quality of life.

Cognitive Behavioral Therapy (CBT) Several investigators have utilized cognitive behavioral therapy to manage moderate to severe PMS, but the results have been inconsistent. Recent work has compared the efficacy of cognitive behavioral therapy alone and in combination with SRIs. Both formal CBT and medications were found to reduce symptoms, but women treated with medications had a faster onset of relief. The group who received CBT alone experienced more sustained improvement in their symptoms compared to those who received medication alone. Interestingly, the combination of psychotherapy and medication therapy did not seem to offer any particular advantage over either treatment alone.

Pharmacologic Interventions Antidepressants Selective serotonin reuptake inhibitors (SSRIs) are first line agents for PMDD treatment. Recommended treatment guidelines for SSRI use in PMDD are included

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in Table 10.3. Numerous double-blind, randomized controlled clinical trials have shown that almost all SSRIs are superior to placebo for treatment of the emotional and physical symptoms of PMDD. The majority of these trials have shown symptom improvement within three cycles of active treatment. Fluoxetine and sertraline are the most studied selective serotonin reuptake inhibitors in PMDD. Fluoxetine has consistently proven more effective than placebo in randomized studies. In a study including 277 patients who would meet current criteria for PMDD, fluoxetine at doses of 20 mg or 60 mg daily was superior to placebo in reducing premenstrual emotional and physical symptoms. This study found a statistically significant difference in response rate during the first treatment cycle with 52 percent of patients on fluoxetine demonstrating moderate improvement (defined as at least 50 percent reduction in baseline symptoms) compared to 22 percent of patients on placebo. The 60 mg daily dose, however, produced more side effects and 10 higher dropout rates without superior efficacy compared to the 20 mg daily dose. Other randomized controlled trials of daily and/or intermittent (luteal) dosing of fluoxetine have found it to be more effective than placebo in the treatment of severe premenstrual syndrome. Cohen and colleagues found that fluoxetine was more effective in the reduction of overall PMS symptoms, particularly emotional symptoms and social functioning at doses of 10 mg and 20 mg administered during the premenstrual time. Twenty milligrams of fluoxetine was shown to be more effective than both the 10 mg dose and placebo in the treatment of physical symptoms. Fluoxetine has been found to improve physical symptoms, work functioning and quality of life associated with PMDD as well.

Table 10.3. Continuous (daily) SSRI/SNRI dosing and treatment strategies for PMDD SSRI Fluoxetine Sertraline Paroxetine

Starting Dose (mg) 10-20 25-50 10-20

Therapeutic Dose (mg) 20 50-1502 20-30

Citalopram

10-20

20-30

Venlafaxine

50

50-2003

Common Side Effects1 Insomnia, nausea, fatigue Nausea,diarrhea, insomnia Dry mouth, constipation, nausea, sedation Headache, sweating, dry mouth, sedation Nausea, dizziness, insomnia, decreased libido

1) Sexual dysfunction (anorgasmia and decreased libido), sleep alterations (insomnia, sedation, hypersomnia) and gastrointestinal distress (nausea and diarrhea) are common side effects across all SSRIs. Specific side effects that may be more likely to occur with the identified SSRI are listed. 2) Patients with PMDD will typically demonstrate a response to sertraline doses of 50-100 mg daily. However, a subset of patients may require slightly higher doses (up to 150 mg). If a patient is taking another SSRI and tolerating it well, but has a partial response at the dosages listed, it would be appropriate to raise the dose of the specific SSRI prior to switching to another agent. 3) Patients with PMDD typically respond to lower venlafaxine doses of 50-100 mg daily. However, a subset of patients may require venlafaxine doses of 225 or 300 mg daily.

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Sertraline has also been found to be more effective than placebo for PMDD in multiple randomized controlled trials. In a study of 243 women with PMDD, sertraline at 50 to 150 mg daily was more effective than placebo for premenstrual emotional and physical symptoms. Overall response rate (defined by clinician observer ratings of “much” or “very much” improved) in this study was significantly different with a 62% response in the sertraline group and a 34% response in the placebo group. Additional double-blind studies of sertraline have also shown that doses of 50 to 150 mg administered daily or just during the luteal phase are effective in improving overall function and reducing a range of premenstrual symptoms. Paroxetine and citalopram have also been found to be effective for the treatment of PMDD. Recent studies of controlled release paroxetine at doses of 12.5 mg and 25 mg daily revealed significant improvement in emotional symptoms of PMS compared to placebo. Physical symptoms were noted to improve with continuous and luteal phase administration of the 25 mg paroxetine CR dose compared to 12.5 mg 10 daily and placebo. In an early study of daily paroxetine treatment compared with maprotoline, a noradrenergic antidepressant, and placebo, immediate release paroxetine was found to be significantly better than maprotoline or placebo for improvement of premenstrual mood and physical symptoms. Although the majority of clinical trials of SSRIs have examined continuous administration of medication throughout the menstrual cycle, SSRIs may also be administered only when the patient is symptomatic. This method, called luteal phase or “intermittent” dosing, involves initiating medication at the time of ovulation and discontinuing it at the time of onset of menses. Several double blind, controlled trials have documented the effective use of luteal phase dosing strategies with SSRIs including fluoxetine, sertraline, controlled-release paroxetine, and citalopram. Some data support intermittent dosing as the preferred strategy. One study compared several dosing strategies for citalopram in patients with severe premenstrual syndrome: continuous, “semi-intermittent” (low dose in the follicular phase and full dose in the luteal phase) and intermittent (full dose in the luteal phase only). As compared with placebo (given continuously), all active treatment groups significantly reduced premenstrual symptoms, but intermittent and “semi-intermittent” dosing strategies were more effective than continuous dosing. The efficacy of intermittent dosing is an important finding because many patients would prefer to take medication only during their symptomatic period. Both continuous and intermittent dosing studies with SSRIs have demonstrated symptomatic reduction during the initial treatment cycle with further improvement over the course of active treatment. To help women with PMS and regular menstrual cycles initiate intermittent or luteal phase dosing, clinicians may instruct patients to begin the antidepressant 2 weeks prior to the time their period is expected. Patients should remain on the medication over the two weeks and discontinue medications on the day of menses onset. Interestingly, patients do not experience discontinuation symptoms after stopping the SSRIs, nor do they develop adverse effects with start up of medication at the time of each new cycle. Other antidepressant agents have been studied for the treatment of PMDD. Venlafaxine, a serotonergic and noradrenergic reuptake inhibitor, has been found to be efficacious in treatment of PMDD. In one trial, 60% of women treated with venlafaxine (continuous dosing) had at least a 50% reduction in total symptoms compared to 35% of women on placebo. Many women experienced rapid relief of

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symptoms within the first treatment cycle on a dose of 50 mg of venlafaxine. An open-trial of luteal phase administration of venlafaxine at doses of 75-112.5 mg demonstrated efficacy in the treatment of premenstrual mood and physical symptoms. Symptomatic improvement at these doses may be secondary to the fact that venlafaxine has greater serotonergic activity than noradrenergic activity at lower doses compared to the higher doses. Fluvoxamine, another SSRI, approved for the treatment of obsessive compulsive disorder has also been studied in the treatment of PMS, but results are inconsistent suggesting the need for further study. Clomipramine, a tricyclic antidepressant, has been found to be more effective than placebo for PMDD in both continuous and luteal phase dosing studies. Open label studies have suggested that nortriptyline and nefazodone are effective for premenstrual symptoms, but these agents have not been tested in randomized controlled trials. Antidepressants that are not SSRIs are cur10 rently considered second-line therapies due to the limited data as well as reduced tolerability and side effect profile. Importantly, several comparative studies have found antidepressant agents with increased serotonergic activity to be more effective than those with primary noradrenergic activity, such as desipramine and maprotoline or dopaminergic action, such as bupropion. These medications with minimal, if any, serotonergic activity, have limited, or no, efficacy in the management of PMDD compared to placebo.

Anxiolytics Alprazolam, a triazolobenzodiazepine anxiolytic agent, has also been studied in the treatment of premenstrual syndrome. Of five randomized controlled trials, four found alprazolam to be more effective than placebo. In positive studies, alprazolam was particularly effective for management of premenstrual anxiety. Clinicians should remain cautious when prescribing alprazolam given its risk of tolerance and dependence. Buspirone, a nonbenzodiazepine anxiolytic agent, has not been found to be better than placebo for the treatment of PMS.

Hormonal Treatments If treatment is unsuccessful with a SRI or a second-line psychotropic agent, hormonal therapies should be considered. Spironolactone, a diuretic and steroid antagonist, has been shown to reduce premenstrual bloating, weight gain and negative emotions. Oral contraceptives are frequently used for treatment of mild to moderate premenstrual symptoms. There are several open trials supporting the efficacy of an oral contraceptive containing drospirenone, a progestogen that is also an analogue of spironolactone, for moderate to severe premenstrual symptoms. Progesterone has also been used for the treatment of premenstrual syndrome, but a recent meta-analysis found that progesterone and other progestogens were no more effective than placebo. In contrast, gonadotropin releasing hormone (GnRH) agonists, including leuprolide and buserelin, were superior to placebo in the reduction of premenstrual emotional (irritability, depression) and physical (bloating, breast tenderness) symptoms in four double-blind controlled studies. Although GnRH agonists may be effective for PMDD, the parenteral route of administration (for leuprolide), cost, and potential side effects, including hot flushes and vaginal dryness, make them a third line treatment strategy.

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Key Points Premenstrual symptoms are common among reproductive-aged women. Mild to moderate symptoms are reported in up to 75% of women with severe symptoms and functional impairment (PMDD) affecting 3-8%. A comprehensive assessment of symptoms, including prospective daily symptom ratings for at least two consecutive menstrual cycles is needed to make the diagnosis of premenstrual dysphoric disorder. While patients are recording or “charting” their symptoms across the menstrual cycle, clinicians may encourage patients to engage in healthy lifestyle interventions (diet and exercise) as well as undergo trials of calcium supplementation (1200 mg daily) and/or use of vitamin B6 50-100 mg daily. While patients may express interest in herbal medications, it is important to keep in mind that the majority of positive studies have been open trials. Moreover, most alternative and complementary treatments, such as St. John’s Wort, relaxation, massage therapy and 10 magnesium, do not have demonstrated efficacy for treatment of PMDD. If the patient does not respond to the initial interventions and a diagnosis of severe PMS or PMDD is confirmed with the prospective ratings, a trial of an SSRI should be initiated. The most appropriate dosing method (intermittent or luteal phase vs. continuous administration) remains uncertain. However, recent data and clinical experience suggest that the initial antidepressant trial should be one utilizing a luteal phase or intermittent dosing strategy (Table 10.4). Because ovulation testing may be too burdensome and costly, it is reasonable for patients to begin taking the prescribed SSRI two weeks prior to the expected onset of menses, which should approximate onset of the luteal phase. Patients should complete a course of at least three cycles on this medication prior to considering an alternate treatment strategy. Typically, patients will begin to notice a reduction in symptoms within three to five

Table 10.4. Intermittent (Luteal) SSRI/SNRI dosing strategies for PMDD SSRI/SNRI Fluoxetine Sertraline3

Starting Dose (mg) 10 50

Therapeutic Dose (mg) 202 50-100

Paroxetine CR

12.5

12.5-25

Venlafaxine

75

75-112.5

Discontinuation Effects1 Same as placebo Headache, nausea, dry mouth, sexual dysfunction Nausea, asthenia, dizziness reduced libido, diarrhea, sweating, tremor4 Headaches, vivid dreams, sweating, muscle cramps, insomnia

1) Luteal phase administration of SRI/SNRIs have not demonstrated significant side effects with initiation or discontinuation with each cycle. Agents with shorter T1/2 may be more likely to produce mild to moderate discontinuation effects. The controlled trials of these agents did not demonstrate increased drop-out rates for active medication compared to placebo. 2) Fluoxetine 20 mg was more effective than 10 mg for the management of premenstrual physical symptoms. 3) Intermittent sertraline did not demonstrate significant improvement compared to placebo for physical symptoms. 4) Side effects were seen more often in patients on paroxetine CR 25 mg compared to 12.5 mg.

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days of medication therapy with luteal phase dosing. However, some patients may require several cycles before noticing any significant change. There are no current data to support switching to a different SSRI if the initial one fails or moving from luteal phase to continuous dosing strategies. Nevertheless, clinical experience suggests that these two strategies may be utilized in the event of an initial treatment failure. Therefore, if the patient does not demonstrate any improvement in her symptoms after several luteal phase treatment cycles, it is reasonable to begin a trial of an alternate SSRI for three cycles with luteal phase dosing if the patient has been compliant with this regimen. Alternatively, the patient may be tried on the same or a different SSRI with continuous dosing. The most appropriate duration of pharmacological treatment for PMDD has not been determined. Studies have demonstrated a return of symptoms after discontinuation of treatment with a faster return of symptoms in patients with brief treat10 ment duration. Therefore, following the demonstration of a positive response to treatment, it is currently recommended for the patient to remain on the effective dose for at least 12 months. With better identification of patients with PMDD and appropriate diagnostic verification, clinicians will improve the quality of life for women with severe premenstrual symptoms. Enhanced physician, patient and public education about PMDD may foster more research in the area, which should lead to improved understanding of PMDD and to the development of more specific therapies.

Suggested Reading 1. Wittchen HU, Becker E, Lieb R et al. Prevalence, incidence and stability of premenstrual dysphoric disorder in the community. Psychol Med 2002; 32:119-132. 2. Perkonigg A, Yonkers KA, Pfister H et al. Risk factors for premenstrual dysphoric disorder in a community sample of young women: The role of traumatic events and posttraumatic stress disorder. J Clin Psych 2004; 65:1314-1322. 3. Hylan TR, Sundell K, Judge R. The impact of premenstrual symptomatology on functioning and treatment seeking behavior: Experience from the United States, United Kingdom, and France. J Womens Health Gend Based Med 1999; 8:1043-1052. 4. Steiner M, Streiner DL. Validation of a revised visual analog scale for premenstrual mood symptoms: Results from prospective and retrospective trials. Can J Psychiatry 2005; 50(6) :327-332. 5. Roca CA, Schmidt PJ, Smith MJ et al. Effects of metergoline on symptoms in women with premenstrual dysphoric disorder. Am J Psychiatry 2002; 159:1876-1881. 6. Stevinson C, Ernst E. Complementary/alternative therapies for premenstrual syndrome: A systematic review of randomized controlled trials. Am J Obstet Gynecol 2001; 185:227-235. 7. Hunter MS, Ussher JM, Cariss M et al. Medical (fluoxetine) and psychological (cognitive-behavioural therapy) treatment for premenstrual dysphoric disorder. A study of treatment processes. J Psychosom Res 2002; 53:811-817. 8. Grady-Weliky TA. Premenstrual dysphoric disorder. N Engl J Med 2003; 348:433-438. 9. Halbreich U, Bergeron R, Yonkers KA et al. Efficacy of intermittent, luteal phase sertraline treatment of premenstrual dysphoric disorder. Obstet Gynecol 2002; 100:1219-29. 10. Borenstein J, Yu HT, Wade S et al. Effect of an oral contraceptive containing ethinyl estradiol and drospirenone on premenstrual symptomatology and health-related quality of life. J Reprod Med 2003; 48:79-85. 11. Wyatt K, Dimmock P, Jones P et al. Efficacy of progesterone and progestogens in management of premenstrual syndrome: A systematic review. BMJ 2001; 323:1-8. 12. Wyatt KM, Dimmock PW, Ismail KMK et al. The effectiveness of GnRHa with and without ‘add-back’ therapy in treating premenstrual syndrome: A meta analysis. BJOG 2004; 111:585-593.

Chapter 11

Treatment of the Menopausal Woman Ghassan Haddad and Daniel B. Williams

The Menopause The menopause is defined by the World Health Organization as the point in time of permanent cessation of menstruation due to loss of ovarian function. Clinically, the menopause is characterized by persistent amenorrhea for a period of twelve months. Laboratory findings in the menopause generally reveal low serum estradiol levels with elevated follicle stimulating hormone (FSH) levels. The specific levels may vary depending on the assay used. The perimenopause, or climacteric, is defined as the period of diminishing ovarian function preceding the menopause to one year following the final menses, generally lasting between 2 and 8 years. Currently, the average age of menopause in the United States is approximately 51 years and the average life expectancy is approximately 80 years. Consistent with this, almost one half of the average woman’s life is spent in the post-menopausal period.

The Transition The reproductive life span can be divided into three phases: the reproductive years, the perimenopause, and the postmenopause. The perimenopause can be further subdivided into early and late stages. The greatest stability and efficiency of ovarian function is between the ages of 25 and 34. Ovulatory variability is greatest before the age of 20 and after the age of 40 years, resulting in an increased frequency of anovulatory cycles, erratic cycle length, and abnormal uterine bleeding. The early perimenopause is characterized by slowly declining ovarian function, increasing frequency of anovulatory cycles, irregular cycle lengths, fluctuating gonadotropin levels, and an overall increase in FSH and luteinizing hormone (LH) levels. FSH levels, in particular, may fluctuate widely, changing with each cycle, largely due to a decrease in the number of ovarian follicles. With loss of ovarian follicles as well as granulosa cells, inhibin levels, which normally provide negative feedback on the pituitary FSH secretion, decrease. This results in the loss of the negative feedback loop between inhibin and FSH, leading to an elevation of FSH levels. FSH levels trend upward starting in the late reproductive years, even before changes in the menstrual cycle, once inhibin levels fall low enough to allow a rise in FSH levels. Thus, the routine measurement of serum FSH to determine if a woman is perimenopausal can be misleading. Therefore, clinical evaluation becomes important in making the diagnosis of perimenopause. Symptoms of early perimenopause are variable but include: hot flashes, premenstrual dysphoria, breast tenderness, insomnia and the menstrual cycle changes described above. As the transition proceeds to the late perimenopause phase, continued alterations in the production and subsequent levels of sex steroid hormones occur. Ovulation eventually ceases and the supply of ovarian follicles is eventually exhausted, Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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resulting in permanent loss of fertility. However, the ovarian stroma continues to produce androstenedione and testosterone in significant amounts. As estrogen levels decline into the postmenopausal range, estradiol is no longer made by the follicle, but by peripheral conversion of estrone, testosterone, and, most importantly, androstenedione. The major estrogen sources throughout this period are the adrenal glands via the conversion of androstenedione to estrone in adipose tissue. In addition, the adrenals continue to secrete testosterone and small amounts of estrogen, as well as dihydroepiandrostenedione (DHEA) and dihydroepiandrostenedione-sulfate (DHEAS). However, with increasing age, the adrenals produce smaller amounts of androgen, which also results in diminished peripheral estrogen production over time. With the menopause, significant reductions in estrogen levels are noted with a less significant decrease in androgen levels. FSH and LH levels increase markedly without change in other pituitary hormones. Finally, at the completion of the late perimenopause, now 12 months after the last menses and beginning the meno11 pausal phase, gonadotropin levels have reached their final menopausal levels (usually >40 mIU/ml).

Symptoms of Menopause Common early symptoms of menopause include hot flashes, insomnia, irritability, and mood disorders, which can occur secondary to vasomotor instability. Physical changes include vaginal atrophy, urinary stress incontinence and skin atrophy. Long term health risks that have been attributed to the hormonal changes from menopause, include: osteoporosis, cardiovascular disease, and in some studies Alzheimer’s disease, macular degeneration, and stroke.

Vasomotor Symptoms Vasomotor instability or the “hot flash” is a common complaint of the perimenopausal and menopausal woman, affecting 60 to 85% of all women. Hot flashes usually occur suddenly, though some women may experience an aura or premonition of the impending hot flash, and generally begin with an intense feeling of heat in the face and thorax. Visible flushing or reddening of the face and neck often follows, with a rise in heart rate and skin blood flow. Skin resistance drops rapidly, resulting in increased skin conductance of heat and a sensation of skin warmth. An increase in peripheral blood flow, heart rate, and finger temperature can result in palpitations and profuse sweating. Although hot flashes occur for 0.5 to 5.0 years on average after last menses, they may persist beyond five years, and up to 10% of women experience hot flashes for greater than 15 years. Their frequency ranges from 5 to 50 per day, with an average duration of 4 minutes. Women who have undergone surgical menopause are more likely to experience hot flashes than naturally menopausal women, often reaching an incidence of 100% in the first year postoperatively and most commonly described as severe. Although hot flashes often occur spontaneously, they may also be provoked by stress, emotional situations, external heat or warm weather, confining spaces, alcohol use, or caffeine use. Therefore, avoidance/modification of these factors can improve symptoms in some patients. The cause of hot flashes remains unclear, but they are thought to occur secondary to sudden changes in hypothalamic control of temperature regulation. Estrogen is believed to reduce hot flashes by modulating the firing rate of thermosensitive neurons in the preoptic area of the hypothalamus. Hot flashes are worse at night for

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Table 11.1. Currently available and combined oral HRT preparations in the US Medication Single Agent Conjugated equine estrogens Estradiol Estropipate (piperazine estrone sulfate)

Combined Agents Conjugated equine estrogens/medroxyprogesterone acetate Conjugated equine estrogens/methyltestosterone Estradiol/norgestimate Estradiol/norethindrone Ethinyl estradiol/ norethindrone

Brand Name

Available Doses

Cenestin Menest Premarin Estrace Ogen Ortho-Est

0.3, 0.625, 0.9, 1.25 (mg) 0.3, 0.625, 1.25, 2.5 (mg) 0.3, 0.45, 0.625, 0.9, 1.25 (mg) 0.5, 1, 2 (mg) 0.75, 1.5, 3, 6 (mg) 0.75, 1.5 (mg)

Prempro

0.3/1.5; 0.45/1.5; 0.625/2.5; 0.625/5 (mg/mg) 0.625/0 x 21days, then 0.625/5 x 7 days (mg/mg) 1.25/2.5 (mg/mg)

Premphase Estratest

Prefest Activella FemHRT

1/0 x 21 days, then 1/0.09 x 7 days (mg/mg) 1/0.5 (mg/mg) 5/1 (μg/mg)

Reprinted with permission from: Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems: A comparative review. Am J Drug Deliv 2005; 3:7-16.

many women, resulting in night sweats, multiple episodes of awakening, and overall nonrestful sleep. The resulting decreased sleep efficiency caused by hot flashes may explain the associated chronic fatigue and irritability from which many menopausal women suffer. The most effective treatment for hot flushes is estrogen, which can be given through a variety of regimens, that are described below and listed in Tables 11.1-11.3.

Regimens for Hormone Replacement Estrogen can be administered by oral, parenteral, topical or transdermal routes with similar effects and there are several different formulation choices available. Continuous estrogen therapy is recommended, though doses and route of administration can be changed relative to patient preference. Oral estrogen is the most popular in the United States. Transdermal estrogen patches avoid the first pass effect on the liver and offer the convenience of less frequent administration (usually weekly). Topical estradiol gel also avoids the first pass effect; it is rubbed on the arm once daily. Finally, a slow release vaginal ring can provide sustained symptomatic relief for 3 months at a time. There are lower doses available for the patches and pills that prevent bone loss as well as hot flashes. It is important to remember that a woman

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Table 11.2. Currently available transdermal/topical ERT preparation in the US Medication Single Agent Estradiol

Brand Name

Available Doses

Alora Climara

0.05, 0.075, 0.1 (mg) 2 x per wk 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 (mg) 1 x per wk 0.05, 0.01 (mg) 2 x per wk 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 (mg) 1 x per wk 1.25g 1 x per day

Estraderm Vivelle EstroGel

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Combined Agents Estradiol/norethindrone

Combipatch

Estradiol/levonorgestrel

ClimaraPro

0.05/0.14; 0.05/0.25 (mg/mg) 2 x per wk 0.045/0.015 (mg/mg) 1 x per wk

Reprinted with permission from: Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems: A comparative review. Am J Drug Deliv 2005; 3:7-16.

with an intact uterus should receive a progestin in addition to her estrogen for endometrial protection. There are a number of different progestins that can be used for HRT including the medroxyprogesterone (MPA) and micronized progesterone, as well as 19-nor testosterone derivatives such as norethindrone. Progestins are usually given cyclically or continuously. Tables 11.1 and 11.2 list some of the combination products. Estrogens, if given orally, are usually administered daily with differences in regimens dependent on how the progestin is given. A variety of topical and transdermal agents with weekly administration are also available (Table 11.2). Cyclic therapy usually involves the administration of the progestin agent for 10-14 days each month. Since the estrogen is given daily, it is easiest to administer the progestin agent from the 1st to the 12th of each month. This usually results in a predictable, monthly, withdrawal bleed. Quarterly therapy consists of daily administration of estrogen, with a progestin administered for 14 days every 3 months. This typically will result in a withdrawal bleed every 3 months, which is preferable to some patients. Continuous combined therapy involves the daily administration of both an estrogen and a progestin. The goal of continuous therapy is to produce amenorrhea by inhibition of endometrial growth. Tables 11.2-11.4 list the various types and doses of estrogen and progestins that are currently available.

Alternative Treatments for Hot Flashes There are a number of alternative therapies for women who are symptomatic from menopausal hot flashes but cannot take estrogen therapy. Venlafaxine hydrochloride and paroxetine are serotonin reuptake inhibitors that effectively reduce hot flash frequency and severity. Other drugs in this class, including fluoxetine, may also be effective, but there are few published data. Recent studies suggest that women

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Table 11.3. Currently available single intravaginal ERT preparations in the US Medication Conjugated equine Estrogen cream Estradiol cream

Brand Name Premarin cream

Dienestrol cream

Orthodienestrol

Estradiol tablets

Vagifem tablets

Estradiol ring

Estring

Estrace cream

Femring

Available Doses 0.625 mg/g; 1-2 g daily x 2 wk, then 1 g daily 1-3 x wk 0.1 mg/g; 2-4 g daily x 2 wk, then 1 g daily 1-3 x wk 0.01 mg/g; 1-2 app qd x 2 wk, then taper to 1-2 x wk 0.025 mg daily x 2 weeks, attempt to discontinue over 3 to 6 mos 0.075 mg/d ring; insert ring vaginally every 90 days 0.05 mg, 0.1 mg/d ring; insert vaginally every 90 days

Reprinted with permission from: Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems: A comparative review. Am J Drug Deliv 2005; 3:7-16.

given neurontin have fewer hot flashes than those given placebo. Low dose progestins are effective in the treatment of menopausal symptoms to a moderate degree, but still a form of hormonal therapy and may be a source of concern in patients with a history of breast cancer. Two antihypertensives, clonidine and methyldopa, have been used to treat vasomotor symptoms, suggesting a role for adrenoreceptors in the physiology of these symptoms. Low dose clonidine, is partially effective in the relief of hot flashes, but for many women, adequate therapy requires substantial doses and severe side effects. Methyldopa, at doses of 500 to 1000 mg/d, has been shown to be twice as effective as placebo for the treatment of hot flashes. Veralipride is a dopamine antagonist that has been shown to be active in the hypothalamus, effectively inhibiting flushing at a dose of 100 mg/day. However, it is associated with major side effects such as galactorrhea and mastodynia. Bellergal is a combination of belladonna alkaloids, ergotamine tartrate, and phenobarbital that has been proven to be slightly better than placebo in the treatment of hot flashes, but with significant sedating effects.

Alternative Medicine This approach includes dietary supplements, which are not considered to be drugs by the Food and Drug Administration (FDA) and therefore are not subject to the strict regulation and safety guidelines imposed on conventional medications. As a result, significant variation can occur in the content and potency of each batch of supplement. Phytoestrogens are plant-derived compounds with estrogen effects soybeans are a particularly rich source of phytoestrogens with approximately 1 to 3 mg of phytoestrogen per gram of soy protein. Since it would be very difficult to consume sufficient soy to alleviate menopausal symptoms in a typical Western diet, some patients opt to take soy supplements. Some (but not all) studies have suggested that isoflavones in soy products reduce the frequency and severity of hot

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Table 11.4. WHI absolute risks/benefits* Heart disease Invasive breast CA CVA VTE Osteoporotic fracture Colon CA

HRT +7 +8 +8 +18 -47 -6

ERT -5 -7 +12 +7 -56 +1

*Number of events per 10,000 women/yr compared to placebo.

flashes, favorably effect lipid profiles and increase bone mineral density (BMD).

11 Black cohosh or remifemin is another popular herbal medication that has been used

to treat menopausal symptoms. Clinical trials show that it is superior to placebo for relief of hot flashes and short term safety data are reassuring. However, many of the efficacy studies are open label and there are no long term safety studies, particularly with respect to effects on breast and endometrium. Finally, vitamin E at a dose of 800 IU daily has been shown to be only slightly more effective than placebo in the treatment of menopausal symptoms. Further study is needed in this area to determine whether there is a definitive benefit from these forms of therapy.

Genitourinary With declining estrogen levels, vaginal pH rises from acidic to basic levels, resulting in the decline of the previously predominant lactobacilli and a newly hospitable environment to previously atypical bacteria colonizing the vagina, most significantly enterobacteria. This is thought to result in an increased risk of urinary tract infections. There are also marked atrophic changes of the urethra, resulting in dysuria and frequency. Atrophy of the vulva and vagina can also be seen in the menopause. Genital symptoms include: decreased lubrication, burning, itching, discharge, dyspareunia, and sexual dysfunction. Urinary symptoms include frequency, dysuria, hematuria, and incontinence. Numerous studies have demonstrated the effectiveness of local, oral, or transdermal estrogen for treating symptoms of vulvar and vaginal atrophy. A review of the literature shows conflicting results regarding the role of estrogen therapy in treating urinary incontinence, including a meta-analysis that concluded that estrogen has only a small effect, if any, on urinary incontinence.

Local Therapy (Vaginal or Topical Administration) Estrogen creams, estrogen tablets and the estrogen ring are options for localized hormonal therapy, which can allow administration of a lower dose of estrogen, avoiding systemic effects. The low dose estradiol vaginal ring (Estring) is placed in the vagina delivering estrogen associated with no detectable changes in blood estradiol or estrone levels. These alternative methods of localized estrogen therapy offer important alternatives for those women who cannot or choose not to receive oral or transdermal therapy. Localized estrogen therapy primarily addresses symptoms related to vaginal atrophy.

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Osteoporosis Osteoporosis is defined pathologically as an absolute decrease in the amount of bone, resulting in an increased risk of fracture with minimal trauma. It is a major long-term health risk associated with the loss of estrogen from the menopause. Hip fracture incidence appears to be race dependent, with a lifetime risk of hip fracture of 17.5% in white women, but only of 5.6% in African American women. However, although hip fractures are much less common in nonwhites, they remain a significant problem for all elderly women and men, regardless of race. By extreme old age, one of every three women and one of every six men will have a hip fracture. Of all hip fractures 12 to 20% will be fatal and 50% of survivors will require long-term nursing care, resulting in total annual costs of 6.1 billion dollars in the United States.

Pathophysiology The pathophysiology of osteoporosis is based on a disruption of the bone re- 11 modeling unit coupling process, which involves osteoclasts, the bone resorbing cells, and osteoblasts, the bone forming cells. In adults 25% of trabecular bone (i.e., vertebrae, forearm) and 3% of cortical bone (i.e., hip) is absorbed and replaced each year. Osteoporosis occurs when bone resorption by osteoclasts is greater than bone formation by osteoblasts. Loss of estrogen in the early menopause can be associated with a significant reduction in bone during the first 5-8 years of the menopause (trabecular, 5%/yr; cortical, 1-2%/yr), Bone loss in the early postmenopausal period is associated with increased osteoclast activity with normal osteoblast activity, which primarily affects trabecular bone. In contrast, the later menopausal period is associated with normal osteoclast activity in the face of decreased osteoblast activity, primarily affecting cortical bone. Consistent with these differences, bone loss associated with early menopause occurs primarily in trabecular bone (i.e., vertebral and distal forearm), while the slow progressive bone loss consistent with aging occurs primarily in cortical bone (i.e., hip).

Risk Factors and Diagnosis Some of the risk factors for osteoporosis include low estrogen, low bone density, trauma, inadequate peak bone mass, family history, low body weight, inactivity, excessive glucocorticoid use or Cushing’s syndrome, osteomalacia, long term heparin therapy, multiple myeloma, long-term anticonvulsant use, hyperthyroidism, hepatobiliary disease, excessive caffeine intake, smoking, heavy alcohol use and type I diabetes mellitus. Osteoporosis is generally diagnosed on the basis of low bone mineral density or clinical evidence of bone fragility in a patient who has no other reason for low bone mass (e.g., osteomalacia, myeloma, etc.). Bone mineral density (BMD) is usually measured by dual-energy X-ray absorptiometry (DEXA) which utilizes transmission of two energy beams passed through bone and then compared to a standardized control. Using DEXA, osteoporosis is defined as a BMD greater than 2.5 SD below the mean value of peak bone mass in young normal women (T score of <-2.5). Osteopenia, or low bone mass, is defined as T score between -1 and -2.5. A normal bone mass is defined as T score -1 or higher. DEXA should be performed in all postmenopausal women ≥60-65 y/o, those 50-60 y/o with one or more risk factors for osteoporosis, and all postmenopausal women with fractures.

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Biochemical markers of bone metabolism that reflect bone formation or breakdown may occasionally be useful in the clinical treatment of patients with osteoporosis. The three principle markers of bone formation are alkaline phosphatase, osteocalcin and procollagen I carboxy peptide, while the markers of bone resorption include: hydroxyproline, hydroxylysine glycosides, collagen crosslink molecules and N-telopeptide.

Prevention/Treatment of Osteoporosis Estrogen Estrogen is useful prevention (i.e., maintaining BMD) or treatment of osteoporosis (reducing the fracture risk). Estrogens typically exert their positive effects on BMD by inhibiting osteoclast activity. Numerous observational and prospective studies have demonstrated the effectiveness of estrogen treatment in increasing BMD. The Women’s Health Initiative (WHI) study also demonstrated efficacy for fracture reduction. Recent data indicates that CEE doses of 0.45 mg/day are equally effective in 11 maintenance of BMD, and that 0.3 mg of CEE has positive effects upon hip and spine BMD compared to placebo. This is also true of lower doses (45-50 μg) of transdermal estradiol. The lower doses are also effective for treatment of hot flushes or vaginal maturation indices. However, it is important to note that fracture prevention data do not exist for these lower doses. Selective Estrogen Receptor Modulators Selective estrogen receptor modulators (SERMs) are an attractive alternative to estrogen for the treatment of postmenopausal osteoporosis. Like estrogens, SERMs act by inhibiting osteoclast activity. Unlike estrogen, SERMs exert mixed effects in different tissues. SERMs have potent estrogen agonist effects in some tissues while exerting estrogen antagonist effects in others. Raloxifene and tamoxifen are two of the best known and most studied SERMs. Tamoxifen (an adjuvant for breast cancer treatment) has been shown to have estrogen agonistic effects on bone, lipid profiles, and endometrial tissue. Therefore, while tamoxifen use is associated with improved bone mass and cholesterol profiles, stimulation of the endometrium results in an increased risk of endometrial hyperplasia and cancer in postmenopausal women. In contrast, raloxifene has a mixed agonist-antagonist profile that makes it particularly useful for the treatment of osteoporosis. Raloxifene has been shown to have solely estrogen antagonist effects in the breast and endometrium, but with estrogen agonist effects in bone and on lipid profiles, thus mitigating the risk for endometrial hyperplasia and breast cancer. In a prospective randomized, placebo controlled trial, raloxifene treatment significantly reduced the risk of vertebral fracture in patients with existing osteoporosis (RR = 0.5 and 0.7 with 60 mg/day and 120 mg/day, respectively). Interestingly, women treated with Raloxifene had a lower incidence of breast cancer during this study, but an increased risk of venous thromboembolism (VTE) was noted, which is similar to that seen with estrogen use. In women treated with 60 mg/day of Raloxifene, a marked decrease in total cholesterol levels and LDL was noted with a minimal reduction in HDL levels. Multiple studies have illustrated the antiestrogenic effects of raloxifene on endometrial tissue and its safety for use in postmenopausal women. Thus, SERMs appear useful for the treatment of osteoporosis without the increased risk of breast cancer or endometrial hyperplasia and cancer associated with estrogen replacement use.

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Bisphosphonates Bisphosphonates are potent inhibitors of bone resorption that act by exerting a direct inhibitory effect on mature osteoclasts. Bisphosphonates such as alendronate, risedronate, and ibandronate, have a low bioavailability ranging from 1.5% to 3.5%. It is important to take these medications on an empty stomach with no other liquids than water and separate from calcium supplements, and remain upright for 30-60 minutes following administration. Multiple clinical trials have demonstrated the utility of bisphosphonates in the prevention and treatment of osteoporosis utilizing a variety of treatment regimens. These data include fracture reduction risk at the hip and spine. Such regimens include daily, weekly, or more recently, monthly administration. Further studies have explored dosing frequency by examining the benefits of once weekly bisphosphonate dosing, to examine potential improved tolerance without compromising efficacy. Overall, both the daily and weekly treatment regimens demonstrated significant increases in BMD, but with fewer serious upper GI ad- 11 verse experiences among those patients receiving the weekly dosing regimen. Thus, bisphosphonates are an effective alternative treatment for osteoporosis for patients who do not require estrogen therapy. Other Treatments Calcitonin is another agent that can be used to prevent osteoporosis and also acts by inhibition of the resorptive activity of osteoclasts. Calcitonin can be given as an intranasal spray at a dose of 200 IU/day. However, there are no data regarding hip fracture prevention with this agent. Sodium Fluoride has also been shown to increase bone density; however, increased fracture rate associated with increased skeletal fragility suggest that high dose fluoride would be a poor choice for the treatment of osteoporosis. In contrast, lower doses combined with calcium may be beneficial, as suggested in some studies. Calcium is generally recommended in postmenopausal women with a dietary calcium intake of 1200-1500 mg/d in addition to more specific therapy. It is clear that calcium alone will not adequately prevent bone loss.

Cardiovascular Disease Cardiovascular disease is the leading cause of death in women over the age of 50 in the United States. Before the age of menopause, cardiovascular disease occurs predominantly in males. However, after menopause, the rate of cardiovascular disease in women increases until it eventually equals that of men by age 70. Numerous observational studies have demonstrated an association between estrogen replacement therapy and low risk of cardiovascular disease. Estrogen replacement therapy has been shown to decrease total cholesterol, low-density lipoprotein, lipoprotein A, and increase high-density lipoprotein levels; which was assumed to be the explanation for this association. Recently, prospective randomized blinded studies like the Heart and Estrogen/progestin Replacement Study (HERS) and Women’s Health Initiative (WHI) failed to show any efficacy for either secondary prevention (HERS) or primary prevention (WHI) of coronary artery disease. Because of the prospective, blinded, randomized design of those two studies, they merit a separate discussion.

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HERS Study and Secondary Prevention of Cardiovascular Disease In contrast to the findings of multiple other cohort studies regarding secondary prevention, the findings of the HERS study challenged the concept of estrogen’s efficacy for the secondary prevention of cardiovascular disease. In this prospective, randomized clinical trial, estrogen therapy did not change the rate of cardiovascular events among women with established coronary artery disease, despite favorable changes in the lipid profile. The daily use of combination hormone replacement therapy did not reduce the overall risk of nonfatal myocardial infarction or cardiovascular disease related-death. An increased incidence of deep venous thrombosis, pulmonary emboli, and gallbladder disease was noted among women treated with estrogen, consistent with prior observational studies. These results led the investigators to caution against starting women on estrogen therapy for secondary prevention of cardiovascular disease but to suggest its continuation only among women already receiving estrogen therapy.

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WHI Study and Primary Prevention of Cardiovascular Disease The Women’s Health Initiative (WHI) trial was a large, placebo controlled randomized multicenter trial looking at the effects of hormone replacement therapy (HRT) or estrogen replacement therapy (ERT) versus placebo in menopausal women. In this study, HRT consisted of conjugated equine estrogens (CEE) 0.625 mg/d combined with medroxyprogesterone acetate (MPA) at a dose of 2.5 mg/d. One arm of the study looked at hysterectomized women on ERT vs. placebo (n = 10,739). Another part of the study compared nonhysterectomized women on HRT vs. placebo (n = 16,608). Study endpoints included MI (fatal and nonfatal, breast cancer, stroke, venous thromboembolic events (VTE), colorectal cancer and hip fracture. Patients in the HRT arm were followed for an average of 5.2 years while patients in the ERT arm were followed for an average of 6.8 years. Although the goal of the WHI was to address the issue of primary prevention of coronary artery disease, it came to similar conclusions as the HERS study, which addressed secondary prevention. During the first year of use, the relative risk (RR) of cardiac events in users of combined estrogen/progesterone replacement was 1.52 (1.01-2.29). In the estrogen only arm (for women who have had a hysterectomy), there was no increased risk of cardiac events. The main criticism of WHI is that the population studied was an older population with a mean age of 63 years. Such an older population is very likely to have a high prevalence of preexisting subclinical cardiac disease. Table 11.4 lists absolute risk/benefits of both study arms (number of events per 10,000 women/yr compared to placebo). Based upon HERS and the WHI, hormone replacement therapy is no longer an accepted treatment for prevention of cardiovascular disease.

Alzheimer’s Disease Alzheimer’s disease (AD) is a significant health problem for aging men and women in the United States. After age 65 the prevalence of Alzheimer’s disease exponentially increases with age, with the number of affected persons doubling every five years and commonly affects women far more often than men. Multiple epidemiological studies have suggested a beneficial effect of estrogen on AD, while others have shown no benefit. In the WHI memory study (WHIMS), investigators found an increase in all-cause dementia in the HRT arm although this was not seen in the

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ERT arm. AD was not addressed separately in this study, and the results are further limited by small numbers of cases. The women in this study were 65 years or older. Based on the current literature, estrogen probably does not slow or improve AD progression, and when HRT is given to older women it may increase the risk of dementia.

Risks of Homone Replacement Estrogen Replacement Therapy and Breast Cancer Breast cancer is a leading cause of death in American women 40 to 55 years old and currently, one in nine women will be diagnosed with breast cancer. Of all American women, 12.6% will be diagnosed with breast cancer in their lifetime and 3.5% of all women will die of this disease. Unfortunately, the peak incidence of breast cancer occurs among post-menopausal women, the same women for whom the choice of whether to take HRT becomes an issue, along with its apparent risks and ben11 efits. Until the results of the Women’s Health Initiative trial were published in July of 2002, there was no clear consensus on the relationship of HRT to breast cancer incidence, although some studies showed a small increase with long-term use. The WHI trial showed that there was a statistically significant increase in breast cancer HRT arm (intact uterus) during the fifth year of use only (RR = 1.99, 1.18-3.35), bringing the relative risk among users of the combined estrogen/progesterone to 1.26 (1.00-1.63) over at least 6 years. Interestingly, patients in the estrogen-only arm did not show an increase in invasive breast cancer (RR 0.77{0.59-1.01}) but rather showed a trend toward a decrease in the incidence of invasive breast cancer although this did not achieve statistical significance.

Estrogen Replacement Therapy and Endometrial Cancer Endometrial cancer is the most common gynecologic malignancy and the fourth most common cancer in women. Risk factors for the development of endometrial cancer have traditionally included obesity, nulliparity, and late menopause. Multiple studies have demonstrated a strong correlation between the use of unopposed estrogen and an increased incidence of endometrial cancer. The addition of a progestin induces endometrial regression and stabilization thereby preventing the development of endometrial hyperplasia and cancer. Therefore, the importance of prescribing a combination estrogen and progestin therapy in women with an intact uterus receiving hormone replacement therapy is clear.

Venous Thromboembolic Events Venous thromboembolic events (VTEs) represent a broad category (including pulmonary embolus and deep venous thrombosis) of potentially life-threatening risks that are associated with ERT/HRT use. Based on prior observational studies, and the results of prospective trials such as HERS I, HERS II, and WHI, it appears that there is a 2-fold increase in the risk of VTE in users of ERT/HRT. Estrogens, particularly those given orally, stimulate hepatic production of clotting factors. Accordingly, some studies suggest that women taking transdermal estrogens are not at greater risk of VTEs. Nonetheless, the use of ERT/HRT would be contraindicated in patients with a prior history of VTEs.

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Other Risks of HRT Observational studies of the risk of stroke among users of HRT have yielded inconsistent results. The WHI study demonstrated an increased risk among combination HRT users as well as users of estrogen alone compared to placebo. A metaanalysis of randomized clinical trial found that oral estrogen use was primarily associated with increased risk of ischemic stroke rather than hemorrhagic stroke or transient ischemic attacks. HRT appears to increase the risk of gallbladder disease in observational studies as well as randomized clinical trials. Estimates from the WHI suggests that the magnitude of the absolute risk translates into about 3 additional cases per 1000 women. Previous cholecystectomy is not a contraindication to HRT.

Benefits 11

Colon Cancer Colon cancer is the third leading cancer and cause of cancer death in women. Multiple studies (retrospective as well as observational cohort studies like the Nurses Health Study) have suggested an association between HRT and a decreased incidence of colon cancer and were confirmed by recent findings from the WHI. In the WHI trial, patients receiving HRT had a significantly lower incidence of colon cancer compared to placebo. However, there was no such reduction in the ERT arm. Macular Degeneration Macular degeneration (MD) is the leading cause of legal blindness in the United States, accounting for 25 to 60% of all new cases. The pathogenesis of MD is unknown and currently there is no effective medical therapy, with surgical photocoagulation being useful in only a limited number of patients. Multiple retrospective studies as well as data from the WHI has suggested that HRT may decrease the incidence of MD. Skin As postmenopausal women age, there is a linear decrease in skin collagen content of 2.1% and skin thickness of 1.13% per year from premenopausal levels during the initial 15 to 18 postmenopausal years. HRT prevents some of this collagen loss but is not currently an indication for long term estrogen use.

Benefits of Hormone Replacement There is an increased prevalence of sexual dysfunction following the menopause. Causes include psychogenic, endocrinologic, vascular, neurogenic, muscular, medication-related and infection. Endocrinologic changes associated with loss of estrogen at the menopause include vulvo-vaginal atrophy and possibly decreased desire or arousal. The use of ERT or HRT can improve symptoms of sexual dysfunction by improving genital sensation, as well as decreasing pain and burning during intercourse. Some studies suggest that a combination of estrogen and testosterone may improve libido.

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Key Points on HRT Use In the past, HRT was prescribed for women for a multitude of potential health benefits. It was previously thought that HRT, in addition to its beneficial role in osteoporosis, could protect against cardiac disease, stroke, and Alzheimer’s disease. The recent prospective, randomized, and blinded studies have challenged the validity of this. Based on current literature, HRT is indicated today only for the treatment of vasomotor symptoms and vaginal atrophy, and prevention/treatment of osteoporosis. HRT should be prescribed in the lowest effective dose for the shortest period of time. Therefore, bone-specific agents would likely be more appropriate in patients requiring long-term osteoporosis prevention/treatment. Ultimately, the decision regarding whether or not to take hormone replacement therapy is a personal one, to be decided by the patient herself with guidance from her physician.

Suggested Reading 1. Writing group for the women’s health initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321-333. 2. Shumaker SA, Legault C, Kuller L et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004; 291:2947-2958. 3. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280:605-613. 4. Anderson GL, Limacher M, Assaf AR et al.Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:1701-1712. 5. Draper MW. The role of selective estrogen receptor modulators (SERMs) in postmenopausal health. Ann N Y Acad Sci 2003; 997:373-377. 6. Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems: A comparative review. Am J Drug Deliv 2005; 3:7-16. 7. LeBlanc ES, Janowsky J, Chan BK et al. Hormone replacement therapy and cognition: Systematic review and met-analysis. JAMA 2001; 285:1489-1499. 8. Shumaker SA, Legault C, Kuller L et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004; 291:2947-2958. 9. Shumaker SA, Legault C, Rapp SR et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study: A randomized controlled trial. JAMA 2003; 289:2651-22662. 10. Lindsay R, Gallagher JC, Kleerekoper M. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002; 287:2668-2676. 11. Utian WH, Shoupe D, Bachmann G et al. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001; 75:1065-1075.

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Chapter 12

Reproductive Endocrinology Diagnostic Imaging Peter Klatsky and Victor Y. Fujimoto

Introduction The last few decades have witnessed rapid advances in diagnostic and therapeutic options in modern medicine. While the field of reproductive endocrinology has stayed away from many diagnostic modalities using ionizing radiation, the field has benefited from advances in imaging modalities such as ultrasound and magnetic resonance. In this chapter, we will review the general principles of these techniques and offer examples from reproductive endocrinology where imaging has proved helpful.

Principles of Ultrasound and Magnetic Resonance Imaging (MRI) Sonographic imaging relies on the different transmitting and reflecting properties of ultrasound waves through various types of tissues. Ultrasound waves are transmitted and reflected waveforms received through the transducer, ultimately leading to the creation of images. An important setting on an ultrasound transducer is the frequency of the ultrasound waves transmitted. Lower frequency sound waves are better able to transmit through deeper tissue but have less clarity. These frequencies are often employed in transabdominal imaging and are particularly helpful in larger patients with deep adipose tissue. Abdominal ultrasound usually utilizes 3-5 MHz in transmitting images. Scans that require less penetration but greater detail, such as transvaginal ultrasound, are best obtained by using higher frequency sound waves, usually 7 MHz. Abdominal ultrasound is best performed in patients with a full bladder, where the bladder functions as a window through which ultrasound waves can travel unimpeded to penetrate underlying pelvic structures. Transvaginal ultrasound functions best in patients with empty bladders so that the uterus lies in its naturally-flexed position and is not artificially displaced away from the vagina. An anteverted uterus is more likely to place the ovaries closer to the transvaginal transducer. Magnetic resonance takes advantage of the physical principle that the nuclear spin of hydrogen ions varies depending on its chemical environment. MRI utilizes radiofrequency to measure this spin and its variances throughout the body to create excellent images of soft tissue structures and planes between tissues.

Ambiguous Genitalia Diagnostic imaging assists providers in making a rapid diagnosis and planning appropriate gender assignment and treatment strategies. The finding of ambiguous genitalia is considered by the American Academy of Pediatrics to be a pediatric emergency. Electrolyte abnormalities from severe congenital adrenal hyperplasia can be life-threatening. Similarly urgent is the social crisis that results in long-term stig-

Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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mata that develop when parents are unable to tell friends and family whether they have just had a baby boy or girl. The initial workup to determine the infant’s gender includes blood tests to assess hormone levels, electrolyte concentrations, as well as karyotyping. Unfortunately, the results of some these tests, (e.g., karyotyping) can take 48 hours or more to obtain results. An abdominal ultrasound can provide immediate data to assist a family in understanding their newborn’s phenotype, likely gender assignment and reproductive potential. An abdominal ultrasound should be immediately performed to assess the presence of a cervix, uterus, fallopian tubes, and ovaries or gonads. Evidence of a uterus on ultrasound is the most important finding and will most likely reassure parents that their newborn will develop into a phenotypic female. The most common cause of virilization of a female infant at birth is congenital adrenal hyperplasia, which can be managed medically by replacing cortisol. Other causes of ambiguous genitalia include gestational hyperandrogenism often related to maternal hyperandrogenism during pregnancy. A genotypic male infant with 5-alpha reductase deficiency can also present initially as a minimally-virilized 12 female infant. While ultrasound is the first step, nondiagnostic exams are not uncommon, and MRI can also provide useful information. A diverse array of mullerian anomalies can be identified by MRI with its improved ability to identify the cervix, uterus, and gonads. Many of these structures cannot be seen consistently on ultrasound. One study demonstrated that MR could identify the uterus in 93% of patients, the vagina in 95%, the penis in 100%, the testis in 88%, and the ovary in 74% of patients. The advantage of MRI is that it can better elucidate soft tissue structures through use of T1- and T2-weighted sequences and its ability to look with equal clarity through multiple depths of tissue. MR also offers larger visual fields than ultrasound, with multiple planes of images that can be viewed simultaneously to identify and correlate related structures. In addition to assisting with rapid determination of accurate gender assignment, MR is also useful in planning surgical reconstruction, such as with a transverse vaginal septum or aplastic vagina in Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome.

Amenorrhea Many cases of mullerian anomalies present for the first time during adolescence with primary amenorrhea (Figs. 12.1-12.5). Fifteen percent of these women will have abnormal pelvic exams. Breast development, normal growth and pubarche in the presence of a blind-ending or absent vagina suggests either mullerian agenesis, transverse vaginal septum, or imperforate hymen. Lagging thelarche or pubarche in a young woman with tall stature and a blind-ending vagina may suggest androgen insensitivity syndrome. After a physical exam, ultrasound and karyotyping are the first steps to assess for a uterus, vagina, or gonads. Any patient with a female phenotype and 46 XY genotype must have her gonads removed after completion of puberty or sooner depending on the condition as they are at risk for malignancy. Distinguishing a transverse vaginal septum from an imperforate hymen is important in determining an appropriate and safe therapeutic approach. While ultrasound is helpful, MRI is the gold standard for identifying corresponding structures and planning surgical treatment (Fig. 12.3).

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Figure 12.1. MRI showing sagittal view of a patient with Mullerian agenesis or Mayer-Rokitansky-Kuster-Hauser syndrome. Note the absence of a uterus posterior to bladder.

Mullerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome) results from the abnormal or absent development of the mullerian duct structures (Fig. 12.1). Patients with this condition display a variety of anomalies, most commonly complete or partial agenesis of the uterus, vagina, or cervix. About 10% of patients have a uterus but an incomplete outflow track and therefore present with cyclic pain but absent vaginal bleeding (Figs. 12.2-12.4). Ovarian function is preserved in all of these patients and can be evidenced by normal pubertal growth and development, as well as by measuring basal body temperatures and serum progesterone levels to assess ovulation. Any patient with mullerian anomalies needs an abdominal ultrasound, MRI, or intravenous pyelogram to examine the kidneys and ureteral development (Fig. 12.5). Unilateral renal agenesis has been documented in 30% of cases, most commonly in association with a unicornuate uterus with a mullerian ductal remnant. The affected or absent kidney is generally ipsilateral to the aplastic mullerian horn. When physical exam and ultrasound are inadequate or incompletely diagnostic, MR imaging is usually successful in characterizing mullerian anomalies and planning potential surgical treatments. In a review of 29 patients at University of

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Figure 12.2. Abdominal ultrasound demonstrating hematometria associated with vaginal agenesis.

Figure 12.3. MRI showing sagittal view of hematocolpometria in patient with transverse vaginal septum.

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Figure 12.4. Coronal MRI of pelvis in a patient with an obstructed Mullerian duct remnant associated with uterine didelphis.

California - San Francisco, MRI correctly identified anatomic anomalies in all of the patients as confirmed by surgical or further invasive findings. The MRI results influenced or changed clinical treatment decisions in a quarter of patients who had previously undergone ultrasound imaging. Of particular value was the improved ability to identify gonads and establish that suspected adnexal lesions were actually components of obstructed mullerian duct anomalies. MRI can also identify vaginal tissue and determine partial or complete agenesis, as well as duplication of vaginal and cervical development. Thin sections using transverse images are most helpful in delineation of these structures, and pretreatment with mild estrogen stimulation will assist in creating contrast along the vaginal wall. Many mullerian anomalies present later in life, not with primary amenorrhea, but in the workup of primary infertility or recurrent pregnancy loss. MRI may also be useful in the evaluation of these women, for its ability to identify and distinguish the fibrous tissue of a septate uterus from the myometrium of bicornuate uterus. The former patients can benefit from hysteroscopic resection of their septum; the latter patients cannot. It is important to distinguish an arcuate or didelphic uterus from a septate uterus before recommending treatment. A uterine septum can be safely resected, decreasing the risk of recurrent miscarriage. An arcuate uterus is a normal variant, without negative impact on reproductive outcome and does not require additional abdominal imaging. Conversely, patients with a didelphic uterus

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Figure 12.5. Intravenous pyelogram showing an absent right renal collecting system as might be seen associated with mullerian anomalies.

require imaging to rule out renal anomalies. Distinguishing a fibrous septa from a patient with a didelphic uterus is important as attempting hysteroscopic resection in a patient with a didelphic or bicornuate uterus can lead to unintentional surgical perforation.

Secondary Amenorrhea The most common cause of secondary amenorrhea in a young woman is pregnancy. If a patient has a positive pregnancy test, ultrasound can be performed to date the pregnancy and to rule out an ectopic pregnancy (the latter would be of particular concern in any patient with pain, vaginal spotting, or risk factors such as prior tubal surgery, sexually transmitted infections or pelvic inflammatory disease). A gestational sac should be visible by transvaginal ultrasound (TVUS) in most pregnancies when the serum level of human chorionic gonadotropin (βhCG) is above 1500 IU/L. An empty endometrial cavity in a patient with a βhCG level above 1500 IU/L might indicate an ectopic pregnancy, although a multiple gestation could not be ruled out.

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In patients with secondary amenorrhea or oligomenorrhea, anovulatory conditions must be considered. These will be discussed along with appropriate diagnostic procedures in the following pages.

Infertility The workup of female infertility usually begins with an assessment of sexual and menstrual history, followed by a diagnostic workup to identify and treat a particular cause of infertility. Imaging techniques play a crucial role in the diagnosis of anatomic infertility, especially as these techniques determine the need for surgery. In recent years, imaging techniques have emerged as important in diagnosing ovulatory defects, as well.

Anatomic and Tubal Factor Infertility Two causative tubal factors that lead to infertility are bilateral tubal occlusion and the presence of a hydrosalpinx. Clinical risk factors for tubal factor infertility include a history of sexually-transmitted infection, pelvic inflammatory disease, 12 tubal surgery, or severe abdominal-pelvic adhesions. The resulting adhesions block sperm or embryo transport to prevent fertilization and implantation. Hysterosalpingogram or sonohysterogram have become the first line tools for evaluation and diagnosis of tubal and anatomic causes of infertility.

Hysterosalpingogram One of the oldest and most widely used diagnostic imaging modalities in infertility is the hysterosalpingogram (HSG); see Figures 12.6-12.8. A hysterosalpingogram consists of a series of plain films utilizing a liquid contrast that is injected into the cervical canal. Images are taken revealing the contour of the endometrial cavity and fallopian tubes with spillage of contrast into the abdominal cavity (Table 12.1).

Figure 12.6. Normal appearing HSG.

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Figure 12.7. HSG with unilateral tubal occlusion.

Figure 12.8. HSG with bilateral hydrosalpinges.

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Table 12.1. Performing an HSG 1. 2. 3. 4. 5. 6.

Study should be performed on day 5-9 of menstrual cycle. Premedicate with 600 mg ibuprofen (antibiotics for high risk patients). Cleanse the cervix with antiseptic solution. Insert HUMI or acorn tip catheter; remove open angle speculum. Under fluoroscopic observation, SLOWLY instill 10 ml warm oil based contrast. Take images as contrast fills uterine cavity and as soon as bilateral spill is identified. 7. May consider oblique planes for selected images. 8. Instilling contrast and taking images should take less than one minute. 9. After uterine and tubal assessment is completed, have patient roll 360˚ and take final image to look for fluid collections representing peritubal adhesions.

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A normal HSG will demonstrate a smoothly-contoured endometrial cavity without filling defects. It will also demonstrate thin, nearly imperceptible tubes with contrast fluid spilling bilaterally. Tubal disease is suggested by absent spillage or evidence of a hydrosalpinx. With time, distal tubal occlusions can lead to the development of a hydrosalpinx which is characterized by severely damaged tubal epithelium. Both tubal occlusion and dilation can cause infertility. Even when one tube is patent, the presence of a contralateral hydrosalpinx will decrease pregnancy rates. Presumably, the hydrosalpinx fluid has an embryotoxic effect. Infertile patients with a hydrosalpinx should be treated with salpingostomy, salpingectomy or proximal tubal occlusion. The latter two methods have been shown to improve pregnancy rates and the preferred approach has yet to be determined by a prospective, randomized trial. Hysterosalpingography has a sensitivity of 65% and a specificity of 83% for detecting tubal disease. A significant false positive rate with the technique is partly attributed to tubal spasm during injection of contrast. Measurement of Chlamydia trachomatis antibodies has been useful in identifying additional patients at risk for tubal disease despite normal HSGs. Some providers now recommend laparoscopy with chromopertubation despite a normal HSG, for any patient with high antibody titers to Chlamydia trachomatis because of the relatively low sensitivity of HSG. Peritubal adhesions secondary to prior infection or endometriosis are often missed on HSG but can be appreciated during laparoscopy. Other authors have suggested eliminating the HSG and using only Chlamydia antibody titers to screen for tubal disease, but the low specificity and positive predictive value of titers alone continues to make HSG a clinically important study. Although water soluble contrast agents offer somewhat clearer images, the difference in diagnostic quality is not significant. Oil-based contrasts, such as ethiodized poppy-seed oil or ethiodiol, have been associated with less pain and bleeding, and have shown a trend toward decreased infection rates. An additional advantage to performing an HSG with oil based contrasts is the potential therapeutic benefit. Increased pregnancy rates have been documented within the first several months following the procedure. These results have not been appreciated using water soluble contrasts and for that additional reason we prefer oil-soluble media, particularly in patient populations that will not be able to afford future cycles

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of in vitro fertilization. The mechanism for improved pregnancy rates after HSG with oil-based contrast is unknown, but one proposed mechanism is impairment of phagocytosis by macrophages that are present in the peritoneum and fallopian tubes and presumably interfere with fertilization. In vitro studies have repeatedly demonstrated that exposure to oil-based media impairs macrophage ability to phagocytose sperm, which may increase the chance of fertilization. Anecdotally, we have found that patients tolerate the procedure much better when warmed contrast is used and it is injected slowly. Patients should receive 600 mg of ibuprofen one hour prior to the procedure to reduce cramping and discomfort. We also avoid placing a Foley or other balloon type catheter through the internal cervical os as this can obscure intracavitary distortions in the lower uterine segment and increase the risk of ascending infection. An acorn tip or HUMI cannula does not share these properties. Antibiotic prophylaxis is unnecessary, although patients at high risk for infection could be given 24 hours of doxycycline after the procedure. Abnormalities of the uterine cavity, specifically the presence of polyps, submucosal myomas, and fibrous uterine septa, have also been found to decrease live birth rates. Therapeutic options for intracavitary lesions include D&C, polypectomy, and 12 hysteroscopic resection. Prior to the development of new sonographic techniques, these lesions were diagnosed by either HSG or hysteroscopy. Abnormalities on HSG appear as space occupying lesions distorting the endometrial cavity.

Sonohysterogram In many practices, sonohysterograms (SoHGs) have replaced hysterosalpingograms for screening to assess for lesions in the endometrial canal and rule out hydrosalpinges for infertile patients considering intrauterine inseminations (IUI, Table 12.2) or in vitro fertilization (IVF, Table 12.3). SoHGs are office procedures that involve canulating the cervix with a small catheter and instilling approximately 10 ml of saline (Table 12.4). This procedure allows real time imaging and is quicker and less painful than an HSG. Figures 12.9-12.17 demonstrate the types of clinical information that can be obtained by SoHG compared to other imaging techniques.

Table 12.2. Pretreatment imaging for IUI 1. HSG and Chlamydia trachomatis titers. 2. Laparoscopy with chromotubation if elevated Chlamydia titers or endometriosis (especially with “kissing ovaries” sign). 3. If endometrial abdominally, consider SoHG. 4. If large, obscuring fibroids, consider MRI.

Table 12.3. Pretreatment imaging for IVF 1. No need for HSG. 2. SoHG: rule out intracavitary myomas, polyps, and hydrosalpinx. 3. Antral follicle count. 4. Assessment of endometrial thickness and morphology for embryo transfer.

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Table 12.4. Performing a SoHG

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Perform study within 10 days of LMP. Patient should void prior to study. Consider antibiotic prophylaxis in high risk patients. Clean cervix with antiseptic solution. Identify 5 Fr catheter with a 2 ml balloon. Balloon catheter is prepared, tested, and primed with saline. Eliminate bubbles in tubing which can create artifact on ultrasound. Insert catheter; slowly inflate balloon with water. Remove speculum, insert vaginal ultrasound probe. Slowly instill 5-10 ml of warm saline from 20-30 ml syringe. Multiple images of endometrial cavity are taken in sagittal and coronal planes. Rule out hydrosalpinx. Look for spill/free fluid in bilateral adnexae.

*Note: Taking care to instill fluid slowly into both the catheter balloon and the endometrial cavity will minimize patient discomfort.

A SoHG is ideally performed during the proliferative phase of the menstrual cycle when the endometrial lining is thinner in order to decrease false positive findings. Use of prophylactic antibiotics is not routinely recommended but could be considered in patients at high risk for cervicitis or subsequent PID.

Figure 12.9. Septate uterus on SoHG transverse view.

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Figure 12.10. Axial MRI image of a septate uterus.

Figure 12.11. SoHG image of endometrial polyps.

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Figure 12.12. TVUS of endometrial polyps.

Figure 12.13. SoHG of a submucosal fibroid.

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Figure 12.14. Axial MRI of bicornuate uterus. This may appear similar to both a septum or arcuate uterus on HSG.

Figure 12.15. HSG of a patient with an arcuate uterus.

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Figure 12.16. Normal SoHG, sagittal view. Note bright echogenicity of SoHG catheter.

Figure 12.17. Normal SoHG, transverse view.

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While ultrasound is not effective at identifying tubal patency, it can accurately and comfortably assess intracavitary pathology as well as identify the presence of a hydrosalpinx. Some authors have attempted to use sonohysterograms to identify patients at risk for nondilated tubal occlusion as well. By instilling more than 10 ml of saline and watching for accumulation of free fluid surrounding the ovary, this approach attempts to demonstrate tubal patency. Sensitivity for this test was improved by using lactose particles to increase visualization and echogenicity in spilled fluid. Unfortunately, results are unreliable and have a positive predictive value of only 40%.

MR-Hysterosalpingography Although some have attempted to use 3-D dynamic MR-hysterosalpingography to visualize both the endometrial cavity and tubes with decreased exposure to ionizing radiation from HSG imaging, we do not feel that the high costs and technical difficulties are not outweighed by any potential benefits of this modality. This is an expensive study that does not improve on sensitivity, specificity or patient comfort.

Recurrent Pregnancy Loss Some women have no difficulties conceiving pregnancy but are plagued by recurrent early miscarriages. Common causes include chromosomal anomalies, infectious and connective tissue diseases, but the most readily treatable explanation is a problem with the uterine cavity. Anomalies of the mullerian system have been found in approximately 15% of women with three or more early pregnancy losses. The most common uterine anomaly in this group is a septate uterus. Endometrial polyps, adhesions, and submucosal myomata are also implicated in infertility. See Figures 12.9-12.14, and Figure 12.18. It is especially important to rule out and correct any anatomic anomalies that could cause a spontaneous abortion, before undergoing in vitro fertilization. While HSG and hysteroscopy used to be the gold standard for endometrial evaluation, sonohysterography has proved more than adequate in evaluation of the uterine cavity. SoHG has a greater than 90% sensitivity and a positive predictive value of 65-100% for detecting intracavitary lesions when compared to hysteroscopy. SoHG can also be useful in detecting adhesions, or uterine synechia, that may have formed after an intrauterine procedure such as dilation and curettage (Fig. 12.18). Unlike hysteroscopy, SoHG can reliably distinguish between an arcuate, a bicornuate, and a septate uterus. Sonohysterograms can also identify hydrosalpinges and evidence of adnexal masses, all of which should be excised prior to proceeding with any form of assisted reproductive technology or intrauterine insemination. Transvaginal ultrasound without saline contrast can also be used to assess uterine morphology, but with decreased sensitivity and specificity. Endometrial polyps appear as focal areas of increased echogenicity within a wider endometrial stripe (Fig. 12.12). Unfortunately, sensitivity for detecting polyps decreases from 93.1% to 64.5% and the specificity decreases from 93.9% to 75.5% on transvaginal ultrasound without saline contrast. A divergent endometrial stripe can be evidence of a uterine septum or arcuate uterus. Benefits of SoHG over transvaginal ultrasound include the ability to reliably assess the endometrial cavity in a patient with a myomatous uterus, in which heavy “shadowing” artifact can obscure visualization of a contiguous endometrial stripe. SoHG also better distinguishes between a hyperplastic endometrium and

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Figure 12.18. Uterine cavity synechiae (adhesions) and polyps on SoHG.

an endometrial polyp, as well as identify the difference between an arcuate and a septate uterus. Similarly, HSG is unreliable at distinguishing between any of these conditions and has proven particularly unreliable at distinguishing between mullerian anomalies, such as a septum and an arcuate uterus. SoHG is twice as accurate as transvaginal ultrasound or HSG in identifying uterine cavity defects.

Ovulatory Disorders The lack of regular ovulatory cycles, called anovulation, is another cause of infertility. The workup for anovulation is largely hormonal, but several imaging modalities can be useful as well. Hyperprolactinemia is a treatable cause of infertility that is usually caused by a prolactin secreting pituitary adenoma or microadenoma. Since prolactin levels correlate poorly with size of an adenoma, MRI of the pituitary is indicated in any patient with an elevated prolactin. Other authors have suggested that MRI is unnecessary as the natural history of a microadenoma is unpredictable and the majority resolve or remain stable without surgery. If resources for a pituitary MRI are scarce, it is reasonable to treat empirically with bromocriptine unless the patient has signs of a macroadenoma, such as decreased visual fields (bitemporal hemianopsia) or severe headache. In that case an MRI should be sought, but a lateral film of the skull is usually sufficient to diagnose empty sella syndrome. Polycystic ovary syndrome (PCOS) is another anovulatory condition that contributes to infertility. An international consensus conference in 2003 created a working definition for PCOS, the “Rotterdam criteria.” These criteria defined PCOS as the presence of any two of three findings: 1. A history of oligo- or anovulation 2. Clinical or biochemical evidence of hyperandrogenism

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Figure 12.19. Polycystic ovary with classic “ring of pearls” appearance on transvaginal ultrasound.

3. Polycystic ovaries on ultrasound: Defined as 12 or more follicles measuring 2-9 mm in each ovary or ovarian volumes of greater than 10 ml. Ovaries from a woman with polycystic ovarian syndrome classically demonstrate an abundance of peripherally situated follicles that create the “ring of pearls” appearance that typifies this syndrome (Fig. 12.19). However, authors have debated the importance of finding multiple follicular cysts on ultrasound as many fertile women with regular menstrual cycles have a similar ovarian appearance on ultrasound.

Diminished Ovarian Reserve Diminished ovarian reserve is a term used to identify women who are nearing the end of their naturally reproductive years. In older women, this may be the result of approaching climacteric and a natural decline in follicular development. Younger women may experience a similar phenomenon called premature ovarian failure (POF) when it occurs before age 41. POF is often the result of an autoimmune attack on ovarian tissue and is associated with other autoimmune diseases such as autoimmune hypothyroidism. Other causes include exposure to ionizing radiation or alkylating chemotherapeutic agents during treatment for cancer earlier in a woman’s reproductive lives. These exposures damage developing ovarian follicles and supportive stroma, leading to POF and infertility. Women with no prior history of environmental exposures should be screened for subclinical hypothyroidism as this is the most common associated autoimmune disease. Diagnosis of diminished ovarian reserve has traditionally been made using biochemical testing including a day 3 FSH and estradiol level, or a day 10 FSH after a clomiphene citrate challenge of 100 mg from days 5-9 of the cycle. Both of these

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Figure 12.20. Transvaginal ultrasound of a normal follicular ovary with 9 follicles.

markers were used to predict success rates for women undergoing various infertility treatments. A problem with all attempts to assess ovarian reserve is that they are nonspecific and can change with each cycle. Age alone is a good predictor and has been associated with sonographically observed decreases in mean ovarian volume and number of follicles. Most markers for ovarian reserve are used to plan expectations and outline treatment options for women with clinical infertility. Ultrasound measurement of the ovarian antral follicle count (AFC) is a reproducible test with low inter-observer variability at clinically important levels (low AFC) and can predict response to gonadotropin stimulation. When compared with age and other biochemical markers, the AFC appears to be the single best predictor of response to IVF treatment. Patients with a basal AFC of 4 or fewer follicles have significantly higher rates of cycle cancellation (41% vs 6.4%) and lower pregnancy rates (24% vs 58%) in IVF cycles. These low pregnancy rates are primarily the result of increased cancellation rates and decreased numbers of eggs retrieved,. Furthermore, an AFC of less than or equal to two follicles and ovarian volume of less than 4 cm3 are predictive of menopausal status. AFC is reliable in women over 35 (Fig. 12.20). Younger women have greater intercycle variation in AFC and less reliable correlation between the AFC and response to IVF. In women over 35, accurate measurement of antral follicle count can help predict responsiveness before proceeding with expensive assisted reproductive technologies. Patients with discouraging results should be counseled sympathetically about alternative methods of family development such as ovum donor cycles and adoption.

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Figure 12.21. Transvaginal ultrasound of endometrioma with homogenous low level echoes.

Endometriosis Endometriosis is characterized by ectopic endometrial tissue outside the uterine cavity which can cause pain, adhesions and infertility. Endometriosis often presents clinically with a long history of cyclic pelvic pain that may be exacerbated by vaginal penetration. The evidence that endometriosis is implicated in infertility derived from observations that endometriosis is present at laparoscopy in 21% of women being evaluated for infertility and only 6% of fertile women undergoing laparoscopic tubal ligation. It is estimated that 30% to 50% of women with endometriosis are infertile. Laparoscopy remains the gold standard for diagnosis and treatment for this disorder; however as less invasive diagnostic modalities have also gained favor, noninvasive diagnostic imaging techniques have proved worthwhile as well. The most commonly used imaging technique in endometriosis is ultrasound. Transvaginal ultrasound is useful in identifying endometrial cysts or endometriomas. These lesions are often found during a pelvic pain or infertility evaluation, but they can be found incidentally during imaging of the abdomen and pelvis for other indications. Endometriomas typically appear as homogenous, hypoechoic ovarian cysts with low level echoes (Fig. 12.21). They often have septations and can occur in multiples or as a single cystic mass. While mural nodularity suggests neoplasm, these nodules must be distinguished from hyperechoic wall foci, a finding which correlates strongly

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Figure 12.22. “Kissing ovaries” sign. Note how dense adhesions bring the ovaries together in the posterior cul de sac.

with endometriomas. These densities are usually smaller and more echogenic than those associated with neoplasia. In the presence of septations, low level internal echoes, and hyperechoic wall foci, a multiloculated mass is 64 times more likely to be an endometrioma than any other adnexal mass. With in vitro fertilization, simple endometriomas need not be removed prior to proceeding with a cycle. Care should be taken to avoid entering the endometrioma during egg retrieval as its contents are potentially toxic to the ovaries. The “kissing ovaries” sign is an interesting sonographic feature seen in patients with severe endometriosis and pelvic adhesions (Fig. 12.22). Identifying adjacent and “kissing” ovaries at ultrasound is a strong marker for the presence of severe endometriosis. This is one of the few times that ultrasound can be reliably used to diagnose pelvic adhesions. One study demonstrated a positive predictive value of greater than 90% for endometrial implants involving the bowel and fallopian tubes in these patients. Other signs of adhesions include posteriorly-displaced uterus and ovaries which may be appreciated by ultrasound as a fixed, retroverted uterus. Thus, these findings can eliminate the need for further invasive diagnostic procedures, and laparoscopy can be avoided in a patient wishing to attempt hormonal control of her disease. A concerning characteristic of endometriomas is the presence of hyperechoic deposits in the cyst wall. Nevertheless it can be difficult to distinguish between true endometriomas and neoplasms. In order to better characterize an adnexal mass that may be a neoplasm or an endometrioma, both CT and MRI can be used. When available, MR imaging avoids exposure to ionizing radiation and can improve the

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diagnostic accuracy and specificity of ultrasound. MR images are not as badly affected by adhesive disease and allow for a larger field of view than ultrasound. Magnetic resonance imaging may reduce the need for invasive surgical diagnostic procedures. Endometriosis appears as a region of a low signal intensity on T1 within an area of high signal intensity on T2. High intensity nodules on the bowel or bladder suggest involvement of these tissues. An additional advantage of MR over laparoscopy is its ability to show extraperitoneal sites of involvement and lesions that would be obscured by dense adhesions on laparoscopy. Unfortunately, MR performs poorly at diagnosing peritoneal adhesions that do not involve the ovaries. MRI and laparoscopy can therefore be complementary in severe cases.

Fibroids Leiomyomata are benign smooth muscle neoplasms. The predominant symptoms in patients with large fibroids are menorrhagia and pelvic pressure. They are usually diagnosed by ultrasound or physical exam, but ultrasound can be limited in a very enlarged uterus with multiple myomas. In an enlarged uterus, MR can help 12 identify clinically important submucosal myomas and plan surgical treatment. SoHGs are helpful in identifying location of fibroids and whether they can be removed hysteroscopically. Hysteroscopic removal is attempted in all patients with submucosal fibroids with at least half of their volume in the endometrial canal. The clinical significance of intramural and subserosal fibroids is controversial. Some authors suggest myomectomy for patients with repetitive failed IVF cycles and no explanatory factors except intramural fibroids. Large fibroids that distort the endometrial canal are particularly worrisome. Ultrasound and SoHG have been recommended to evaluate the endometrial cavity and location of women with small to moderate-sized fibroids. Women with large fibroids can benefit from MRI studies in order to assist in preoperative visualization and surgical planning. MR is also useful in identifying the endometrial stripe and ovaries in patients whose large myomas cause too much shadowing and artifact to accurately assess the endometrium or adnexae (Fig. 12.23). Although extremely rare, malignant leiomyomata have a characteristic appearance on MR. Malignant leiomyomata appear as ill-defined lesions which can be hyperintense on T1 images secondary to hemorrhagic changes. Well-defined lesions are nearly always benign. MRI can also appreciate different signal intensities to differentiate adenomyosis from an enlarged, myomatous uterus. Different signal intensities within myomas can also be helpful in predicting response to treatment in patients considering treatment with GnRH or uterine artery embolization. Embolization occludes vessels leading to myomas and causes them to regress by cutting off their blood supply. Although submucosal fibroids respond well to embolization, this procedure is still not recommended in women desiring future fertility as there are only limited data available on pregnancy outcomes.

Key Points After reading this chapter you should be able to understand and identify: 1. The strengths and weaknesses of different diagnostic imaging modalities used in reproductive endocrinology 2. Appropriate clinical situations to utilize different imaging modalities 3. How to perform and interpret hysterosalpingograms and sonohysterograms 4. The appropriate imaging modalities used in the clinical workup for infertility

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Figure 12.23. Axial MRI of myomatous uterus.

Special thanks to Dr. Fergus Coakley and the Department of Radiology at UCSF for assistance in providing radiographic images.

Suggested Reading 1. Practice committee of the American Society of Reproductive Medicine. Current Evaluation of amenorrhea. Fertil Steril 2004; 82:S33-39, [Excellent text: Highly recommended for a basic understanding of the causes and appropriate diagnostic evaluation of patients with amenorrhea and primary or secondary infertility]. 2. Hricak H, Chang YC, Thurnher S. Vagina: Evaluation with MR imaging. Part I. Normal anatomy and congenital anomalies. Radiology 1988; 169(1):169-74. 3. Lindheim SR, Adsuar N, Kushner DM et al. Sonohysterography: A valuable tool in evaluating the female pelvis. Obstet Gyn Survey 2003; 58:770-84. 4. Ayida G, Chamberlain P, Barlow D et al. Uterine Cavity assessment prior to in vitro fertilization: Comparison of transvaginal scanning, saline contrast hysterosonography and hysteroscopy. Ultrasound Obstet Gynecol 1997; 10:59-62, [Excellent article highlighting the importance of using sonohysterograms to evaluate the endometrial cavity]. 5. Soares SR, Barbosa dos Reis MM, Carnagos AF. Diagnostic accuracy of sonohysterography, transvaginal sonography, and hysterosalpingography in patients with uterine cavity diseases. Fertil Steril 2000; 73:406-11. 6. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81(1):19-25, [Important paper addressing a major condition in reproductive endocrinology]. 7. Bansci LF, Broekmans FJ, Eijkemans MJ et al. Predictors of poor ovarian response in in vitro fertilization: A prospective study comparing basal markers of ovarian reserve. Fertil Steril 2002; 77(2):328-36. 8. Bis KG, Vrachliotis TG, Agrawal R et al. Pelvic endometriosis: MR imaging spectrum with laparoscopic correlation and diagnostic pitfalls. Radiographics 1997; 17(3):639-55.

Part II Infertility

Chapter 13

An Overview of Female Infertility Sandra L. Torrente and Valerie Montgomery Rice

Overview According to the 1995 National Survey of Family Growth, the percentage of women reporting some form of fecundity impairment rose from 8% in 1988 to 10% in 1995 which some believe is related in part to a trend toward delayed childbearing. Numerous observational studies have demonstrated that 80-90% of couples that have unprotected intercourse for 12 months will conceive. Thus, the accepted definition of an infertile couple is the failure to conceive after 12 months of intercourse without any form of birth control. Evaluation for infertility is indicated for couples who fit this definition as well as those who have significant risk factors for infertility who may have less than 12 months of exposure to the possibility of pregnancy (e.g., history of oligomenorrhea or sexually transmissible infections). The general causes of infertility and the frequencies are listed in Table 13.1. In this chapter we will focus on the female factors affecting infertility (Table 13.2). An increasing number of women are waiting to start their families until completion of education and/or training, one factor that has led to women seeking pregnancy later in life. In the 1970s women over 35 years of age accounted for 5% of pregnancies and today they account for up to 14% of the pregnancies. Women in general will experience a decreased fecundity rate at 37.5 years of age. This is attributed in great part to a decline in the number of healthy oocytes, directly influencing the rate of conception. When evaluating a patient for infertility, ideally the medical history and physical exam are obtained from the couple. One must obtain a complete obstetrical and gynecological history from the female. The menstrual history is an excellent indictor of ovulatory status. A complicated obstetrical history may suggest the need for maternal fetal medicine consultation prior to initiating therapy, especially if the planned infertility treatment predisposes to multiple births. The gynecologic history can give clues about risk factors for tubal scarring (Chlamydia infection, surgery for endometriosis) or cervical factor infertility (ablation for abnormal Pap smear). The sexual history is obviously relevant. The sexual history should include frequency of coitus especially in the periovulatory period. Complaints of sexual dissatisfaction are common among infertile couples who often feel that spontaneity is lost in striving to achieve pregnancy. Dyspareunia may suggest that endometriosis is the problem. Use of a lubricant may affect sperm motility. Finally, the history of contraception use is important to establish if the patient has experienced any complications with hormonal therapy, particularly a deep venous thrombosis. It is not uncommon for couples to seek help from different medical providers; therefore, try to obtain any previous infertility work up the couple has been through.

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Table 13.1. General causes of infertility Female factor Male factor Unexplained factors

40% 40% 20%

Table 13.2. Causes of female infertility Tubal factor Ovulatory dysfunction Endometriosis Unexplained Cervical factor Uterine factor

13

35% 35% 20% 10% 3% Rare

A general medical history is imperative in determining other major medical problems affecting a patient’s fertility. A patient should be in optimal health prior to initiating fertility therapy. Many common chronic medical conditions such as diabetes mellitus, hypertension and obesity will increase a patient’s risk for miscarriage and pregnancy complications. Lastly, taking a social history will identify any habits which may influence a patient’s fertility. Tobacco, marijuana, and cocaine use will affect fecundity rates in women as well as men. There is a known dose-response relationship between the number of cigarettes smoked and length of time it takes to achieve pregnancy. Marijuana affects the fertility directly by inhibiting secretion of GnRH in both men and women. Cocaine is also known to decrease spermatogenesis. An example of a history form for an infertile woman is provided in Table 13.3. Steps in the evaluation of infertility are summarized in Table 13.4 and Figure 13.1.

Ovulatory Disorder Patients with an ovulatory disorder that is not due to ovarian failure have several medical options available. There are three types of ovulatory dysfunction that are classified by the World Health Organization (WHO):

Hypothalamic-Pituitary Failure (Hypogonadotropic Hypogonadal Anovulation) Patients with this form of anovulation suffer from hypothalamic amenorrhea. Patients will have low estrogen levels, low gonadotropin levels (FSH and LH), normal prolactin levels and will not bleed after a progesterone challenge. The classic patients seen with this disorder are those that suffer from anorexia nervosa, or athletes with a low BMI (<17), and women under high stress. Treatment • Lifestyle modification including reducing exercise, improving nutritional intake, and addressing any underlying psychological issue will help return ovulatory function. If lifestyle modification does not improve anovulation use of gonadotropins can be considered. Because of low estrogen levels, these patients do not usually respond to clomiphene.

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Table 13.3. Infertility History (female) Marital History Married___ # of years_____# Prior marriages_____ Single___ Separated___ Divorced___ Widowed___ Menstrual History Last menstrual period________ Regular ___yes ___no Menarche_____ Intermenstrual bleeding ___yes ___no Interval_____ Dysmenorrhea ___yes ___no Duration_____ Amenorrhea___ primary___ secondary___ Virilization: ___hirsutism ___balding ___acne ___voice changes Obstetric History Gravida: __term __premature __stillborn __spontaneous abortion __induced abortion Ectopic pregnancies: ___right ___left Complications: ___pregnancy ___postpartum Gynecologic History Last Pap smear________ Previous abdominal or pelvic surgery ___yes ___no Endometriosis ___yes ___no Abnormal pap ___yes ___no

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Previous Infertility or Endocrinology PCT ___yes ___no HSG ___yes ___no BBT ___yes ___no Endometrial BX ___yes ___no Laparoscopy ___yes ___no Sexual History Frequency _____ time per _____ Satisfied Dyspareunia

___yes ___no ___yes ___no

Lubricant use

___yes ___no

Habits Cigarettes Alcohol Marijuana Other drugs

___yes ___yes ___yes ___yes

___no ___no ___no ___no

___# ___# ___# ___#

DES exposure PID STD

___yes ___no ___yes ___no ___yes ___no

Studies Hormonal studies Semen analysis Medication

___yes ___no ___yes ___no ___yes ___no

Other studies

___yes ___no

Contraception: None___ Oral contraceptive IUD Diaphragm Female sterilization Male sterilization

___yes ___yes ___yes ___yes ___yes

per day drinks per _____ times used per _____ times used per _____

Past Medical History Patient Operations: Hospitalizations: Current medications: Birth defects: Inherited disease (i.e., cystic fibrosis, sickle cell):

Family

___no ___no ___no ___no ___no

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Table 13.4. Evaluation of infertility Test Serum FSH Hysterosalpingogram Serum progesterone Serum TSH Serum prolactin Semen analysis on partner

Purpose Evaluate ovarian reserve Tubal patency and uterine configuration Establish ovulation Confirm euthyroid state Rule out adenoma Evaluate male

Time of Cycle Day 2 or 3 Day 7-11 About 7 days after LH surge N/A Luteal phase N/A

13

Figure 13.1. Infertility algorithm.

Hypothalamic-Pituitary Dysfunction (Normogonadotropic Normoestrogenic Anovulation) Patients with this form are usually oligomenorrheic women. Many women in this category have polycystic ovarian syndrome (PCOS) and will have an elevated LH/FSH ratio, elevated androgens, and enlarged ovaries with multiple follicles. Of the three types of ovulatory dysfunction, this is the most common.

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Treatment • Lifestyle style modification for women with anovulatory infertility often consists of weight loss. Women with a BMI>27 and oligomenorrhea should be counseled on weight loss as first line therapy for infertility. A loss of 5-10% of body weight may be enough to restore ovulation. • Ovulation induction is the initial step taken if weight is not an issue or if the patient remains anovulatory after weight loss. The first line of therapy is clomiphene citrate, a SERM with estrogen antagonist and agonist effects that increases gonadotropin release. Clomiphene is given on cycle days 5 through 9 at a dose of 50 mg/day (if ovulation does not occur in the first cycle the dose is increased in subsequent cycles). The LH surge will occur 3-12 days after the last dose of clomiphene. The LH surge can be determined using urinary ovulation predictor kits. Ovulation can be expected to occur 24-48 hours after detection of a positive result. • Insulin sensitizing agents (Metformin) used concurrently can improve the response to clomiphene in PCOS patients. Metformin works to decrease gluconeogenesis, and intestinal uptake of glucose. • Once ovulation is established, if the patient does not become pregnant in six 13 cycles, intrauterine insemination (IUI) should be considered. • If ovulation induction with IUI does not achieve pregnancy after three to six cycles of positive ovulation IVF should be considered.

Ovarian Failure (Hypergonadotropic Hypoestrogenic Anovulation) Patients with this form of anovulation present with premature ovarian failure Gonadotropin levels are elevated and estrogen levels are low. Treatment • Oocyte donation and IVF is highly successful for this group of patients. • Hormone replacement therapy is generally recommended for symptomatic relief and to prevent osteoporosis.

Hyperprolactinemic Anovulation Patients will present with oligomenorrhea or amenorrhea and sometimes galactorrhea. Fasting prolactin levels are elevated and estradiol levels are often decreased. First one must rule out a pituitary adenoma with an MRI. Treatment • A dopamine agonist is generally the first line treatment.

Tubal Disorders Infertility occurs when the fallopian tubes or fimbria are scarred or blocked and cannot transport the ovum or sperm, or serve as the site of fertilization. Previous history of salpingitis (tubal infection), pelvic inflammatory disease, endometriosis, or abdominal surgery can all lead to tubal scarring. Seventy-five percent of tubal disease can be attributed to a previous Chlamydia infection, often asymptomatic. The United States Preventative Task Force (USPSTF) recommends that clinicians routinely screen women under the age of 25 and sexually active and other asymptomatic women at increased risk for Chlamydia infection. Hysterosalpingography (HSG) is used to evaluate tubal patency.

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Treatment • Surgical options for tubal repair depend on the site of obstruction and severity of tubal damage. • Proximal tubal obstruction can be treated with hysteroscopic or fluoroscopically-guided catheterization of the fallopian tube. • IVF is the treatment of choice for tubal disease that cannot be surgically corrected. If there is a hydrosalpinx present, salpingectomy prior to IVF improves the outcome with IVF.

Endometriosis Patients with known endometriosis may suffer from infertility, sometimes due to adhesions causing tubal blockage or decreased tubal motility. However, the mechanism of infertility is not understood for patients with mild disease and no apparent anatomic distortion. Some studies suggest that patients with minimal to mild endometriosis that do not apparently have tubal blockage still should undergo ablative treatment to reduce endometriosis, as a means of improving fertility.

13 Treatment

• Laparoscopic resection or ablation of endometriosis and adhesiolysis is preferable to medical treatment for infertile patients. • Ovulation induction (clomiphene or gonadotropins) and IUI can be offered if there is at least one normal, patent fallopian tube. • IVF should be offered if surgery and ovulation induction/IUI fail or if the endometriosis is extensive.

Uterine Disorders Patients with uterine abnormalities will present more likely with recurrent pregnancy loss and not primary infertility. The uterine abnormalities most commonly seen are submucosal leiomyomas, endometrial polyp, septate uterus, and uterine synechiae which all can interfere with implantation.

Treatment • Leiomyomas—The need for surgery in an otherwise asymptomatic infertile woman depends upon the size and location of the fibroids. Abdominal myomectomy is the treatment of choice for large intramural or subserosal leiomyomas, especially if they distort the endometrial cavity. Small fibroids in these locations do not require treatment. Hysteroscopic myomectomy is preferred for submucosal leiomyomas which are associated with increased miscarriage rate unless resected. • Endometrial polyps—should be removed by operative hysteroscopy. • Septa and synechiae—should be treated with hysteroscopic resection.

Cervical Disorders Unfavorable cervical mucus at midcycle may act as a physical barrier for sperm penetration. Similarly, the cervix may cause infertility in women with stenotic cervical os, cervical surgery or ablation for dysplasia or chronic cervicitis.

Treatment • Bypass the cervix with IUI and IVF if necessary. • Treat cervicitis, if present.

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Unexplained Infertility Ten to fifteen percent of couples present with a completely normal workup. Patients in this group may have problems that cannot be detected by available testing: ovum pick up, sperm transport, fertilization or implantation. However, older female age with decreased ovarian reserve or borderline semen parameters are common in couples with this diagnosis. Randomized, controlled clinical trials support the use of superovulation and IUI as first line treatment, resulting in 2-3 fold increase in cycle fecundity depending upon patient selection and the regimen used. Superovulation increases the number of eggs available to the sperm and corrects any subtle ovulation problems. The insemination delivers greater numbers of motile sperm closer to the egg for fertilization.

Treatment • Clomiphene alone or with IUI is the usually the first line of therapy. • Gonadotropin therapy with IUI has a higher multiple birth rate and is usually reserved for patients who fail to conceive with clomiphene. • If three cycles of gonadotropins and IUI fail, ART can be offered.

Definitions 1. Assisted reproductive technologies (ART)—all methods that involve direct retrieval of oocytes from the ovary (see chapter on ART). 2. Basal body temperature (BBT)—a test used to confirm ovulation. Patient is asked to record their oral temperature every morning before arising, starting with the onset of menstrual flow. The rise should be greater than 0.4 degrees Fahrenheit for the ten days or more preceding menses to indicate ovulation. 3. Clomiphene citrate—A selective estrogen receptor modulator (SERM) that acts as an estrogen antagonist and agonist. The agonist effect increases gonadotropin release. The starting dosage is generally 50 mg/day for 5 days starting on cycle day 5 (see Chapter 15). 4. Fecundability—The probability of achieving a pregnancy within one menstrual cycle. 5. Fecundity—The ability to achieve a live birth within one menstrual cycle. 6. Follicle-stimulating hormone (FSH)—A hormone produced by the pituitary gland. Pharmacologic preparations can be given as to cause follicle recruitment and growth within the ovary. 7. Hysterosalpingogram (HSG)—a radiological test that is performed to identify any uterine cavity or tubal defects. 8. Infertility—One year of unprotected coitus without conception. 9. In vitro fertilization (IVF)—A type of ART that includes ovarian stimulation, egg retrieval and sperm collection, the eggs are fertilized and incubated in the laboratory. Resulting embryos are later transferred to the uterus. 10. Intrauterine insemination (IUI)—Introduction of “washed” sperm into the uterus. 11. Intracytoplasmic sperm injection (ICSI)—Direct injection of a single sperm into an oocyte. 12. Luteinizing hormone (LH)—A hormone produced by the pituitary gland, which causes follicle development, egg maturity, and ovulation. LH can also be given as a medication.

13

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13. Ovarian hyperstimulation syndrome—A complication of ovulation induction therapy. There three grades: mild which consists of mild abdominal pain and the ovaries are <5 cm in diameter on ultrasound exam; moderate which the ovaries measure 5-10 cm in diameter; and severe in which the patient presents with intraperitoneal fluid and may also have oliguria, hypotension, and pleural effusions (see Chapter 15). 14. Post coital test (PCT)—A test to establish if the sperm and cervical mucus are compatible. The test is performed 2-8 hours after intercourse around the time of ovulation and requires a microscopic evaluation of the cervical mucous for the presence of motile sperm. Because of poor reproducibility and lack of predictive power, this test is not routinely recommended in the evaluation of the infertile couple.

Key Points

13

1. Establish if the cause of infertility is reversible or irreversible. If it is reversible (i.e., PCOS) correct the issue with appropriate medical or surgical therapy. If it is irreversible (i.e., ovarian failure) counsel in regards to ART with possible oocyte donation. 2. The most common cause of female infertility is ovulatory dysfunction. Fortunately with minimally invasive infertility therapy patients can reach a fecundity rate similar to that of couples without fertility problems. 3. Ensure appropriate counseling of the risk involved when using ovulation induction medication and IVF. 4. Women with known endometriosis should have optimal ablation or resection of endometriosis prior to infertility therapy. One must also ensure tubal patency.

Suggested Reading 1. Speroff ’s, Clinical Gynecologic Endocrinology and Infertility. 7th ed. Lippincott Williams and Wilkins, 2005, [For a thorough review of female infertility, Speroff ’s 7th ed, is the book all residents should have. It is what one should read during their RE/I rotation. Specifically Chapters 27 and 31 were referenced for this review]. 2. ACOG Practice Bulletin #34, February 2002. Management of Infertility Caused by Ovulatory Dysfunction, ACOG Compendium. 2005, [For a much more abbreviated review, but helpful for both interns and residents the ACOG Compendium is what one should read for a quick reference]. 3a. Smith S, Pfeifer S, Collins J. Diagnosis and management of female infertility. JAMA 2003; 290:1767-1770. 3b. Lobo R, Potential options for preservation of fertility in women. New England Journal of Medicine 2005; 353:64-73.

Chapter 14

Surgical Treatment of Female Infertility Mohammed Al-Sunaidi and Togas Tulandi

Introduction Due to widespread availability of assisted reproductive technologies, the need for reproductive surgery in infertile women has declined in recent decades. However, surgery still has a place in the management of infertile women. For example, young women with pelvic adhesions or blocked fallopian tubes that impair their fertility may benefit from early surgical intervention. On the other hand, women over the age of 35 with a long history of infertility or those who require a laparotomy for correction of their disorders are better treated with in vitro fertilization. Compared to laparotomy, reconstructive surgery by laparoscopy is preferable. In fact, most procedures that previously required a laparotomy can be performed by laparoscopy with equal or better results. In addition, laparotomy causes more adhesion formation. The incidence of adhesion formation after a single laparotomy is 47% after appendectomy and up to 91% after pelvic surgery. Almost all patients will develop adhesions after myomectomy by laparotomy, whereas the adhesion rate is about 70% after laparoscopic myomectomy. Laparoscopic surgery lessens adhesion formation due to minimal handling of the internal organs and elimination of operative site contamination with glove powders or lint. In addition there is a lower incidence of infection, and the relatively closed environment of laparoscopy helps to maintain tissue moistness. Moreover, patients prefer the faster recovery time with laparoscopy. Over the years, many laparoscopic modalities have been advocated including laser and ultrasound-scalpel; however the results are comparable to the use of conventional instruments such as scissors. One of the newest techniques is the use of robotic surgery during laparoscopy. Compared to human wrist movement, the robotic arm allows rotation of 360 degrees. The major disadvantage of robot-assisted endoscopy is the lack of tactile feedback or haptics. The large size of some of the robotic systems may also be a limitation. More importantly, to date there are no published data demonstrating that robotic surgery results in a better pregnancy rate than conventional laparoscopic surgery.

Diagnostic Laparoscopy Laparoscopy should only be performed after complete investigation of infertility such as semen analysis, hysterosalpingogram and assessment of ovulation. In the era of assisted reproductive technology, laparoscopy is not a routine test. However, it is indicated in young women with an abnormal hysterosalpingogram or a history of salpingitis, sexually transmitted disease, previous pelvic surgery, or endometriosis. The incidence of abnormal laparoscopic findings in infertile females with a normal hysterosalpingogram ranges from 21-68%. Abnormal findings can usually be corrected at the same laparoscopic setting. Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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14 Figure 14.1. Adhesions on the posterior wall of the uterus..

During the course of a diagnostic laparoscopy for infertility, the pelvis is carefully surveyed for the presence of endometriosis, adhesions and uterine abnormities. Tubal patency is checked by injecting dilute solution of methylene blue into the uterine cavity through the cervix. Tubal patency is indicated by the passage of the blue dye from the fimbriated end of the tube.

Laparoscopy Promoting Fertility Adhesiolysis Pelvic adhesions can result from pelvic inflammatory disease, previous pelvic surgery, endometriosis or previous appendicitis. Periadnexal adhesions impair tubal mobility and ovum pick-up mechanism (Figs. 14.1 and 14.2). Although pregnancy is possible in women with periadnexal adhesions, liberation of the adhesions can increase the pregnancy rate. When adhesions are extensive or involve vital organs (e.g., ureter or bowel), the patient may be better served by attempting pregnancy through in vitro fertilization.

Treatment of Endometriosis In infertile women with no other cause of infertility, endometriosis can be found in 40-50% of cases (Figs. 14.2-14.4). Endometriosis can be classified into minimal, mild, moderate and severe or stage I to IV. Its presence regardless of the stage decreases fertility. Compared to women whose endometriosis was not treated, treatment of stage I or II endometriosis is associated with a higher pregnancy rate.

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14 Figure 14.2. Close-up appearance of endometriosis in the cul-de-sac (“gun-powder” spots and white lesions).

Figure 14.3. Endometriosis vesicles on the ovary.

Treatment can be achieved with excision, ablation with electrocautery, laser, or harmonic scalpel. Pregnancy rates are similar with all of these modalities. Medical treatment by ovarian suppression with gonadotropin releasing hormone agonist (GnRHa) will improve the symptoms of endometriosis, but it delays

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14 Figure 14.4. Obliteration of the posterior cul-de-sac due to endometriosis.

conception for several months, and there is no evidence that pregnancy rates improve. Ovarian cysts due to endometriosis are called endometriomas (Fig. 14.5). An endometrioma that is ≥ 3 cm in diameter automatically qualifies for a classification of stage III or IV in severity. GnRHa treatment is ineffective in reducing the size of endometriomas of >1 cm. Treatment is surgical. It can be achieved either by fenestration and ablation (removal part of the cyst wall followed with coagulation of the inner side of the wall) or excision of the endometrioma cyst wall (Fig. 14.5). Excision of the endometrioma is associated with a higher pregnancy rate than fenestration and ablation. Furthermore, recurrence after fenestration and ablation is more likely than after excision. In advanced stage IV endometriosis, severe pelvic adhesions enveloping the whole pelvis can be encountered (frozen pelvis). Instead of subjecting the patients to a laparotomy with a low pregnancy rate, the patients are better treated with in vitro fertilization.

Treatment of Distal Tubal Occlusion The fallopian tube can be occluded proximally at the uterotubal junction, at the mid-portion, or distally. The most commonly encountered tubal obstruction is distal tubal occlusion, usually due to PID. Mid-tubal blockage is usually iatrogenic due to tubal sterilization. Hysterosalpingographic findings of proximal tubal occlusion should be interpreted with caution. It could be true tubal occlusion or tubal spasm.

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14 Figure 14.5. Excision of ovarian endometrioma.

Figure 14.6. Tubal anastomosis has been completed.

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Fimbrioplasty Fimbrioplasty is performed for the treatment of fimbrial phimosis, which is a partial obstruction of the distal end of the fallopian tube. The tube is patent, but there are adhesive bands surrounding its terminal end. The procedure involves dividing the peritoneal adhesive bands that surround the fimbria releasing fimbrial agglutination. In one series, treatment of severe fimbrial phimosis with laparoscopic fimbrioplasty resulted in 51% intrauterine pregnancy rate, 37% live birth rate and 23% ectopic pregnancy rate at two years of follow-up.

Terminal Salpingostomy Hydrosalpinx is complete distal tubal occlusion. Tubal reconstruction of hydrosalpinx is called terminal salpingostomy. The results depend on the degree of tubal damage. In general, the results are poor. The average pregnancy rate following salpingostomy is 30%, with an ectopic pregnancy rate of 5%. However, the rate of pregnancy can be as low as zero if the tube is rigid and thick without mucosal folds, and as high as 80% when tubal damage is minimal. In general, salpingostomy is recommended only for young women with mild distal tubal disease. Tubal surgery has the advantages of allowing for several preg14 nancies from a single procedure with no increase in multiple birth rate. In vitro fertilization is a better alternative for older patients, patients with severely damaged tubes and those with infertility due to multiple etiologies.

Surgical Management of Hydrosalpinx Prior to IVF The presence of hydrosalpinx reduces the probability of achieving a pregnancy in IVF. A meta-analysis showed that hydrosalpinx reduces the pregnancy rate in IVF cycles by 50%. This has been attributed to the leakage of hydrosalpinx fluid into the uterine cavity that could be toxic to the embryo. The fluid might also flush the embryo out of the uterine cavity or impair implantation. Removal of the hydrosalpinx (salpingectomy) significantly improved the pregnancy and live birth rates (36.6% versus 23.9% without salpingectomy and 28.6% versus 16.3%, respectively). Patients who benefit most from salpingectomy are those with hydrosalpinges visible on ultrasound (live birth rate 40% versus 17% without salpingectomy). Moreover, salpingectomy of bilaterally visible hydrosalpinges increased the delivery rate 3.5-fold (live birth 55% versus 15.8%), in one study. An alternative to salpingectomy is occlusion of the isthmic portion of the tube in the same manner as tubal sterilization. Ultrasound-guided aspiration of the hydrosalpinges fluid has also been advocated, but rapid built up of the fluid can occur. A simpler and yet effective approach is administration of antibiotics to women with hydrosalpinx undergoing IVF. Finally, young women with hydrosalpinx can be offered salpingostomy if the tubal damage is not extensive.

Treatment of Proximal Tubal Occlusion Proximal tubal occlusion, suggested by failure of contrast medium to enter the intramural or isthmic portion of either tube, is diagnosed in 10%-20% of hysterosalpingography. This could be due to tubal spasm, mucus plugs, debris, or true cornual blockage. In order to distinguish between true cornual obstruction and other pathologies, several methods including laparoscopy have been advocated. During laparoscopy, tubal patency can be assessed and some surgeons can also perform tubal reconstruction.

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Selective Tubal Catheterization A less invasive technique than tubal surgery is selective tubal catheterization (STC) or transcervical tubal cannulation. It consists of passing a catheter through the cervix into the proximal tubal ostium, and injecting contrast medium. Increased pressure generated by direct injection may overcome obstructions associated with plugging. It could be performed using balloon angiographic catheters or guide wires under fluoroscopic, hysteroscopic or ultrasound guidance. Due to the high incidence of false positive on hysterosalpingography, STC is the first line of treatment for bilateral proximal “tubal blockage”. Approximately, a quarter of patients diagnosed with bilateral proximal occlusion on hysterosalpingography do not have tubal obstruction. Among those with true occlusion, STC leads to an overall pregnancy rate of 34%. True cornual occlusion is usually due to salpingitis isthmica nodosa, where the cornual part of the tube is occluded and replaced by a firm nodule. The cumulative probability of conception after STC was 28%, 59%, and 73% at 12, 18, and 24 months of follow-up, respectively. In approximately 20% of patients, the tubes cannot be catheterized and the patients are best treated by IVF. Surgical treatment of such a blockage is not highly successful due to the severity of tubal damage or the presence of concomitant distal tube abnormalities. There are two operative procedures to correct proximal tubal 14 blockage, cornual reimplantation and microsurgical tubocornual anastomosis. Traditionally tubal reimplantation is performed by laparotomy and the success rate is poor. Tubocornual anastomosis can also be performed by laparoscopy; however the number of reported cases is small.

Treatment of Mid-Tubal Occlusion Treatment of mid-tubal occlusion is tubal anastomosis where the occluded portion of the tube is removed followed by anastomosis of the healthy segments (Figs. 14.6 and 14.7). Mid-tubal occlusion is usually due to previous tubal sterilization or previous ectopic pregnancy. Sterilization reversal is the most successful surgical reconstructive procedure for improving fertility. Factors influencing the success are patient’s age, sterilization technique, and tubal length. High pregnancy rates of up to 70% could be achieved in patients with tubal length of >4 cm compared to only 19% in those with shorter tubes. We consider laparoscopic sterilization-reversal in women younger than 39 years who have ≥4 cm of residual tube. For others, IVF is a better option.

Laparoscopic Treatment of Polycystic Ovary Syndrome (PCOS) The first line of treatment for anovulatory women with polycystic ovary syndrome is ovulation induction with ovulation-inducing drugs . This has replaced the outdated surgical treatment with ovarian wedge-resection. A modification of ovarian wedge resection is laparoscopic ovarian drilling (Fig. 14.9). This is performed by creating multiple holes on the surface of the ovary using either electrocautery or laser. As a result, the circulating level of androgen is reduced followed by restoration of pituitary-ovarian axis restoring ovulation. Ovarian drilling is associated with an ovulation rate of 80% and cumulative pregnancy rates at 12, 18, and 24 months of 54-68, 62-73, and 68-82 % respectively. There are two potential complications associated with ovarian drilling, periadnexal adhesion formation and premature ovarian failure. The incidence of postoperative

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14 Figure 14.7. Tubal insufflation following tubal anastomosis showing methylene blue dye solution.

Figure 14.8. Polycystic ovary.

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14 Figure 14.9. Laparoscopic ovarian drilling.

adhesion formation is estimated to be 19-43% and may be as high as 82%. This complication is more frequent with laser treatment than with electrocoagulation. Outcomes with medical treatments have rarely been directly compared with surgical outcomes. In a randomized trial, Palomba et al compared ovarian drilling with metformin treatment. The pregnancy rate at 6 months follow-up in the metformin group was 18.6% and in the ovarian drilling group was 13.4%. The live birth rate was higher in the metformin group (82.1%) than in the surgical group (29%). The management strategy favored by most reproductive endocrinologists is to advocate weight loss and or medication, including metformin. Laparoscopic ovarian drilling, though often successful, is used sparingly.

Hysteroscopy in Infertility Hysteroscopy is an operation to examine the uterine cavity using a thin caliber telescope (hysteroscope) introduced through the cervix. It gives information whether the uterine cavity is normal or contains a septum, fibroid, polyp, or adhesions. Hysteroscopy should be done in early follicular phase of the cycle or approximately 4 weeks after an injection of gonadotropin releasing hormone analog (GnRHa). GnRHa suppresses FSH and estrogen production and subsequently makes the endometrium thin. This allows optimal visualization of the uterine cavity.

Diagnostic Hysteroscopy Diagnostic hysteroscopy is usually performed under local anesthesia or paracervical block. It is done in the clinic or doctor’s office as an extension of a

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gynecological examination. In some cases the cervical opening needs to be dilated to allow passage of the hysteroscope. Office hysteroscopy involves the use of a small caliber rigid hysteroscope usually 3.5 mm or a fiberoptic 2.4 mm flexible hysteroscope. The most commonly used distending media are normal saline, Ringer’s lactate, or carbon dioxide gas. Compared to the use of CO2 gas, liquid distending medium is less irritating and associated with less pain. Furthermore, blood and gas produce bubbles that impair visualization. Endometrial polyps can sometimes be removed in the same setting using a polyp snare or hysteroscopic scissors. Hysteroscopy is a good diagnostic tool to verify findings that cannot be accurately diagnosed by other imaging techniques including hysterosalpingogram, ultrasound, or magnetic resonance imaging (MRI). Its use is invaluable in infertility. It has been shown that up to 50% of women in whom IVF-ET repeatedly failed were found to have intrauterine abnormalities. Correction of uterine abnormalities improved the pregnancy rate. In a review of 1000 office-based hysteroscopies prior to IVF, it was found that routine hysteroscopy examination detected uterine abnormalities in 30% of women starting IVF treatment.

14 Operative Hysteroscopy For treatment purposes, the operation is done under general or spinal anesthesia in the operating room. A solution of glycine 1.5% or sorbitol 3% is used to distend the uterine cavity. The possible complications of hysteroscopy include uterine perforation, bleeding, infection, and fluid overload in the lung or brain. These complications are rarely encountered; however severe electrolytes imbalance can be fatal.

Lysis of Intrauterine Adhesions Intrauterine adhesions (Asherman’s syndrome) usually occur after repeated curettages particularly those performed in the pregnant state (postpartum or abortion). Asherman’s syndrome can present with amenorrhea, hypomenorrhea, infertility or repeated miscarriage. Hysteroscopy is the best tool to diagnose and treat this condition. Adhesions are removed using hysteroscopic scissors or unipolar loop electrode. In order to allow rapid regeneration of the endometrium, a course of estrogen treatment is usually administered after the procedure. In general, 90 percent of patients will resume normal menses and 80 percent will achieve a term pregnancy, depending on the extent and severity of the adhesions.

Excision of Submucous Fibroid or Polyp Submucous myomas or endometrial polyps can cause excessive uterine bleeding. Furthermore, submucous myomas are associated with infertility or repeated miscarriages (Fig. 14.10). Treatment is by hysteroscopic excision. Varasteh et al. found that hysteroscopic removal of myoma of >2 cm led to a significantly higher pregnancy rate (62.5%) than that of <2 cm (33%). Cumulative live birth rates after removal of myoma of <2 cm were 25.0%, >2 cm were 41.7%, and >3 cm were 75.0%. Perez-Medina conducted a randomized study comparing the pregnancy rate after intrauterine insemination among women whose endometrial polyp was removed

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14 Figure 14.10. Hysteroscopic view of a submucous myoma.

or left in situ (control group). They found that after 4 cycles of insemination, the pregnancy rate in the polypectomy group was significantly higher (51.4%) than the control group (25.4%). Furthermore, 65% of women in the polypectomy group conceived prior to the first insemination. The authors postulated that endometrial polyp produces excessive amount of glycodelin impairing implantation. Glycodelin is a protein that facilitates implantation by decreasing natural killer cell activity.

Treatment of Uterine Septum The presence of uterine septum is associated with recurrent pregnancy loss rather than infertility. Uterine septum is relatively avascular. Hysteroscopic removal of uterine septum in women with recurrent miscarriages is associated with a live birth rate of 70%.

Key Points In this modern era of assisted reproductive technologies, reproductive surgery still has a place in the management of infertile women. Early surgical intervention can be offered to young women with a history of pelvic inflammatory disease, pelvic adhesions, blocked Fallopian tubes, and endometriosis. Most if not all reconstructive-operations can be performed by laparoscopy. On the other hand, women over the age of 35 with a long history of infertility or those who require a laparotomy are better treated with in vitro fertilization. Intrauterine abnormalities such as uterine septum, submucous myoma or endometrial polyp can impair live-birth rate. This can be improved by hysteroscopic treatment of these abnormalities.

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Suggested Reading

14

1. Al-Fadhli R, Tulandi T. Tubal disease in relation to infertility. In: Falcone T, Hurd WW, eds. Clinical Reproductive Medicine and Surgery. PA: Elsevier, (In Press). 2. Al-Jaroudi D, Herba MJ, Tulandi T. Reproductive performance after selective tubal catheterization. J Min Inv Gynecol 2005; 12:150-2 3. Beretta P, Franchi M, Ghezzi F et al. Randomized clinical trial of two laparoscopic treatments of endometriomas: Cystectomy versus drainage and coagulation. Fertil Steril 1998; 70:1176-80. 4. Hurst BS, Tucker KE, Schlaff WD. Hydrosalpinx treated with extended doxycycline does not compromise the success of in vitro fertilization. Fertil Steril 2001; 75:1017-9. 5. Johnson NP, Mak W, Sowter MC. Surgical treatment for tubal disease. Surgical treatment for tubal disease in women due to undergoing in vitro fertilisation. The Cochrane Database of Systematic Reviews. 2004, (Issue 3. Art. No.: CD002125.pub2). 6. Marcoux S, Maheux R, Berube S et al. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med 1997; 337:217-22. 7. Palomba S, Orio Jr F, Falbo A et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90:4068-74. 8. Perez-Medina T, Bajo-Arenas J, Salazar F et al. Endometrial polyps and their implication in the pregnancy rates of patients undergoing intrauterine insemination: A prospective, randomized study. Human Reprod 2005; 20:1632-5. 9. Pirwany I, Tulandi T. Laparoscopic treatment of polycystic ovaries: Is it time to relinquish the procedure? Fertil Steril 2003; 80:241-51. 10. Sacks G, Trew G. Reconstruction, destruction and IVF: Dilemmas in the art of tubal surgery. BJOG 2004; 111:1174-81. 11. Varasteh NN, Neuwirth RS, Levin B et al. Pregnancy rates after hysteroscopic polypectomy and myomectomy in infertile women. Obstet Gynecol 1999; 94:168-71. 12. Zeyneloglu HB, Arici A, Olive DL. Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization-embryo transfer. Fertil Steril 1998; 70:492-9.

Chapter 15

Ovulation Induction Jon C. Havelock and Karen D. Bradshaw

Introduction Approximately 25% of infertility can be attributed to ovulatory disorders. The goal of ovulation induction is to restore fecundity by restoring regular, ovulatory cycles. Ovulation induction may also be used for controlled ovarian hyperstimulation (COH) for treatment of other causes of infertility such as mild/moderate endometriosis, unexplained infertility, and for assisted reproductive techniques such as in vitro fertilization (IVF). When used in ovulatory patients, the goal of ovulation induction is not to restore ovulatory cycles but to increase fecundity through ovarian stimulation (Table 15.1). The World Health Organization (WHO) has provided a simplified classification system for disorders of ovulation. This grouping system describes the etiology of anovulation, and the most appropriate treatment for patients with ovulatory dysfunction is determined by their classification. WHO Group I patients have low follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels and low estradiol levels. These patients have hypothalamic-pituitary hypofunction, either congenital or acquired and have a negative progestin challenge test due to low endogenous estradiol levels. WHO group II patients have normal FSH and LH levels, and normal estradiol levels. Most anovulatory patients fall within this category, and >90% of these patients have polycystic ovarian syndrome (PCOS). These patients will have a positive progestin challenge test due to normal endogenous estradiol levels. WHO group III patients have elevated FSH and LH levels. Gonadotropins are elevated (often in the menopausal range) secondary to ovarian follicle depletion. These patients respond poorly to ovulation induction and are candidates for IVF-oocyte donation. Finally, hyperprolactinemic patients (WHO group V/VI), with or without a pituitary adenoma, may have ovulatory dysfunction. Elevated prolactin levels interfere with gonadotropin releasing hormone (GnRH) pulsatility and, as a result, impair ovulation.

Testing Prior to Ovulation Induction Since ovulation induction is pursued in the course of fertility treatment, a comprehensive fertility investigation should be performed prior to instituting therapy. A thorough history and complete physical examination of the female and male partner should be undertaken. Basic investigations for anovulation should include a day 3 FSH level (or random FSH if amenorrhea), thyroid stimulating hormone (TSH) level, and prolactin level. A progestin challenge test may be performed to determine the estrogen status and serves to help distinguish WHO group I from group II. A semen analysis should be performed as 25-40% of infertility has a male-factor component. A hysterosalpingogram may be ordered initially to evaluate uterine and Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

Pulsatile gonadotropin releasing hormone Intrauterine insemination

Adjuvant treatment

Gonadotropins

Primary treatment Secondary treatment

Etiology

Laparoscopic ovarian diathermy Glucocorticoids Intrauterine insemination

Weight Loss Clomiphene citrate Metformin Aromatase inhibitors Gonadotropins

WHO Group II Eugonadotropic hypogonadism

Intrauterine insemination

Oocyte donation

WHO Group III Hypergonadotropic hypogonadism

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WHO Group I Hypogonadotropic hypogonadism

Table 15.1. Ovulation induction treatment and indications

Intrauterine insemination

Gonadotropins

Dopamine agonists

WHO Group V/VI Hyperprolactinemia

Intrauterine insemination

Clomiphene citrate or gonadotropins

Unexplained infertility Endometriosis Male-Factor infertility IVF Clomiphene citrate or gonadotropins

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tubal anatomy, but this may be delayed in an anovulatory patient if there is no evidence of uterine/tubal disease on history and or physical examination. In hyperandrogenic PCOS patients, serum testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone levels may be obtained to determine the origin of the elevated androgens. A pelvic ultrasound may be performed as part of the 2003 criteria for PCOS diagnosis. These basic investigations ensure that the cause of anovulation is obtained and determine whether other causes of infertility are present. If other infertility factors are present, these may require additional treatments that are not addressed with ovulation induction, alone.

Ovulation Induction Monitoring The goal of ovulation induction is to maximize the chance of pregnancy while minimizing the complications, namely multiple pregnancy and ovarian hyperstimulation syndrome (OHSS). This is facilitated through ovulation induction monitoring. Ovulation induction monitoring may take the form of a menstrual diary, urine or serum LH measurements, or serial ultrasound with or without serial estradiol measurements. Since ovulation induction is used in conjunction with timed intercourse or intrauterine insemination (IUI), efforts are made to time ovulation with the presence of fresh sperm in the female reproductive tract. Since the oocyte has a lifespan of approximately 24 hours in the female genital tract, and sperm can survive up to 72 hours, the best chance for conception occurs if the sperm are present at the 15 time of, or just prior to ovulation. Ovulation occurs 34-36 hours after the start of the LH surge, 17-26 hours after urine LH detection, and at a follicular diameter of 20-27 mm. Furthermore, when ultrasound is used to monitor follicle development and human chorionic gonadotropin (hCG) is administered for final oocyte maturation (a pharmacological mimic of the LH surge), it appears that 15 mm is the smallest follicular size sufficient for ovulation. These surrogate markers for ovulation serve as a guideline for timing of intercourse or IUI. Estradiol levels are often used in conjunction with ultrasound for monitoring ovulation induction cycles. In unstimulated, monofollicular cycles, estradiol and follicle size show a highly correlated linear increase in the five days preceding ovulation, with a daily increase in follicular diameter of 1.2-2 mm/day (Randall and Templeton, 1991) and a corresponding increase in estradiol to an average preovulatory estradiol of 250 pg/ml. In COH cycles, greater preovulatory follicle numbers and estradiol levels are seen. Compared to natural cycles, there is a weaker correlation between follicle numbers and estradiol levels in multifollicular development. Nonetheless, estradiol levels typically reach 250 pg/ml per preovulatory follicle. Ultrasound monitoring of ovulation induction serves an additional purpose in monitoring endometrial development. A periovulatory endometrial thickness of ≥ 10 mm is a good prognostic factor for conception in COH cycles, and endometrial thickness of <7 mm is associated with a very poor likelihood of pregnancy. The finding of a thin endometrium by ultrasound gives prognostic information that may allow for changes in treatment to promote endometrial development.

Complications of Ovulation Induction Multiple Pregnancy One of the greatest concerns in ovulation induction is multiple pregnancy, especially higher order multiple pregnancy (triplets or greater). Multiple pregnancy is associated with significantly higher perinatal morbidity and mortality,

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primarily related to premature birth. Risk factors for higher order multiple pregnancy in ovulation induction include: age <32 years, PCOS diagnosis, estradiol >2000 pg/ml, ovulation induction with gonadotropins, and when more than three follicles are ≥14 mm. With careful monitoring of cycles, the risk of multiple pregnancy can be decreased.

Ovarian Hyperstimulation Syndrome (OHSS) Ovarian hyperstimulation syndrome is a clinical syndrome encompassing a constellation of signs and symptoms, including abdominal pain and distension, ovarian enlargement, nausea and vomiting, and ascites. Severe cases may include hydrothorax, oliguria, increased hematocrit, decreased renal function, and thromboembolic complications. Numerous severity classification systems have been described, and hospitalization is required in severe instances. The risk factors for OHSS are similar to the risk factors for multiple pregnancy: estradiol level >3000 pg/ml, large numbers of follicles and in younger age. For OHSS the best cure is prevention. Ovarian hyperstimulation syndrome does not occur in the absence of ovulation. In ovulation induction cycles deemed to be at risk for OHSS, cycle cancellation and withholding the injection for final follicular maturation (discussed later) will usually prevent OHSS. Another commonly used method of prevention of OHSS involves “coasting.” This involves terminating the ovulation induction medication (gonadotro15 pins) once the largest follicle is ≥14 mm, for 1-4 days, and the estradiol level is <3000 pg/ml. Other methods of prevention and treatment of OHSS are beyond the scope of this chapter.

Methods of Ovulation Induction The majority of patients seeking ovulation induction are women with PCOS. An ovulation induction treatment algorithm for women with PCOS can be seen in Figure 15.1.

Weight Loss Weight loss can restore ovulatory cycles for many women with PCOS. Approximately 80% of women with PCOS are obese, which is associated with hyperinsulinemia. The increased insulin has a direct effect on the ovary, resulting in increased androgen production. Weight loss of >5% has been shown to restore ovulation in some PCOS women. In addition, PCOS women who did not conceive with previous treatment and had a mean weight loss of 10.2 kg went on to have a 77% pregnancy rate with treatment. While this is an often overlooked mode of treatment, it should be considered first line treatment for overweight women with PCOS.

Clomiphene Citrate Clomiphene citrate (CC) is an estrogen analog that was first shown to induce ovulation in 1961 and was approved for clinical use in the United States in 1967. Clomiphene belongs to a family of compounds known as selective estrogen receptor modulators (SERMs). Other well-known SERMs include tamoxifen (breast cancer treatment) and raloxifene (osteoporosis treatment). Clomiphene is used for ovulation induction or controlled ovarian hyperstimulation in patients with normal endogenous estrogen levels. Clomiphene exerts both estrogen agonist and antagonist effects. Clomiphene blocks the negative feedback of endogenous estrogen at the hypothalamic and

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15 Figure 15.1. Ovulation induction treatment algorithm for polycystic ovarian syndrome (PCOS). DHEAS, dehydroepiandrosterone sulfate; IVF, in vitro fertilization.

pituitary levels. This results in a >50% increase in endogenous FSH which subsequently stimulates follicular growth. Ovulation rates approach 80%, with cumulative pregnancy rates of 30-40% over the course of a few cycles. This discrepancy between ovulation and pregnancy rates is thought to be due to the estrogen antagonist effects on the endometrium and cervical mucus. This may be detected by an endometrial thickness of <7 mm on ultrasound, which would suggest other forms of ovulation induction would be more effective. Clomiphene citrate (CC) is administered in a dose of 50-150 mg/day for 5 days, starting on day 2, 3, 4, or 5 of the menstrual cycle. The lowest starting dose is used initially and is only increased in subsequent cycles if the patient remains anovulatory at a given dose. While some physicians have used longer treatment regimens and higher doses, there is little evidence for effectiveness at doses greater than 150 mg. Once a patient is ovulatory with CC treatment, it is usually continued for up to 3-6 ovulatory cycles. Approximately 75% of conceptions occur in the first three treatment cycles. Ovulation can be confirmed with a single mid-luteal (7 days after ovulation) serum progesterone level of >5 ng/ml. Monitoring of clomiphene citrate cycles may be managed using ovulation prediction kits, basal body temperature monitoring, or ultrasound monitoring. If the woman is attempting conception in conjunction with timed intercourse, the fertile period is a 6-day period which is generally the day of ovulation and the 5 days preceding ovulation (Dunson et al, 1999), and intercourse every second day is recommended. If ovulation induction is used in conjunction with IUI, then the IUI should be performed the day of, or the day following a positive ovulation predictor

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test. Ultrasound monitoring of CC stimulated cycles has demonstrated that on the day of spontaneous LH surge, the preovulatory follicles are usually slightly larger than in natural, unstimulated cycles. If ultrasound monitoring is used in conjunction with IUI, hCG (5,000-10,000 IU) is typically administered when the lead follicle is ≥18 mm, and IUI is performed 36 hours later. While high-technology monitoring has not been shown to increase pregnancy rates over low-technology monitoring, ultrasound monitoring adds additional information on the endometrial effects of CC. Complications of CC include OHSS and multiple pregnancies. Original reports demonstrated twin pregnancy rates of 10% and higher order multiple rate (triplets or greater) of 1%. Clinically significant OHSS is uncommon in CC stimulated cycles. Side effects of CC include breast tenderness, bloating, hot flashes, abdominal discomfort, and mood changes. A rare side effect is changes in vision or sensitivity to light, which requires immediate discontinuation of the medication, as continuation may cause permanent visual changes.

Metformin There has been a plethora of evidence that PCOS is associated with hyperinsulinemia, which leads to the widespread use of insulin sensitizing agents for treatment. The most studied agent is the oral biguanide, metformin. The exact 15 mechanism of action of metformin in PCOS is unclear, but may be related to weight loss or direct suppression of androgen production by the ovary. Metformin is typically used at doses between 1500-2000 mg/day, and the main side effect is GI upset. Metformin may be used alone or in conjunction with CC. When metformin is used alone as an ovulation induction agent, ovulation rates are typically between 30-40%, but evidence for a significant increase in pregnancy rates is lacking. When metformin and CC are used together, ovulation rates approach 90%. In patients who did not previously ovulate with CC therapy, ovulation rates are approximately 75% when treated with CC plus metformin. A recent meta-analysis suggests that CC plus metformin has an approximately 3-fold greater pregnancy rate in PCOS women than CC alone. In clinical practice, metformin is usually used in conjunction with CC in obese PCOS patients or in patients who do not respond to CC. Currently, a large, randomized, double-blind, clinical trial comparing pregnancy rates in patients treated with CC, metformin, or CC plus metformin, is ongoing. This trial should determine the best treatment regimen for achieving pregnancy.

Aromatase Inhibitors Aromatase inhibitors are orally active agents that inhibit estrogen biosynthesis by inhibiting the aromatase enzyme, resulting in decreased circulating levels of estradiol. Under low estrogen conditions, there is decreased negative feedback and greater pituitary FSH release. While this medication is not approved for ovulation induction, it is increasingly being used for this purpose. The most commonly used aromatase inhibitor given for ovulation induction is letrozole. It is typically administered at a dose of 2.5-7.5 mg/day for a 5-day regimen, starting on day 3 of the menstrual cycle or occasionally as a single 20 mg dose given on day 3. While aromatase inhibitors have not been shown to be superior to CC, there are some studies that suggest they may be useful in patients who do not respond to CC.

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Laparoscopic Ovarian Diathermy Laparoscopic ovarian diathermy (LOD) is an endoscopic surgical procedure that has been found to be an effective mode of ovulation induction. This procedure involves creating 3-10 holes per ovary with an electric current or laser (see Chapter 14). Its use has primarily been in the CC resistant population, and a randomized, controlled study in this population has shown similar pregnancy rates in patients undergoing LOD compared to gonadotropin therapy. Furthermore, LOD has been shown to have equivalent pregnancy rates after 6-12 months when compared to 3-6 cycles of gonadotropin therapy with significantly lower multiple pregnancy rates in the LOD group. A recent study comparing metformin treatment versus LOD in a CC resistant population demonstrated similar ovulation rates, but higher pregnancy rates in the metformin group. With an expanding number of ovulation induction agents, the role of LOD in contemporary ovulation induction appears to be limited.

Glucocorticoids While not an ovulation induction agent on its own, glucocorticoids (namely dexamethasone) have occasionally been used in conjunction with CC in women who are unresponsive to CC. A subset of patients with PCOS have increased adrenal androgen production, reflected by elevated DHEAS levels. Administration of dexamethasone suppresses adrenal androgen production and can increase the ovulation rate among women with DHEAS levels >200 μg/dl. The most widely used 15 protocol includes dexamethasone administered at nighttime in a dose of 0.5 mg orally in conjunction with CC treatment.

Pulsatile Gonadotropin Releasing Hormone Gonadotropin releasing hormone (GnRH) was first identified in 1971 and is the hypothalamic releasing hormone responsible for FSH and LH synthesis and release from the pituitary. While it is rarely used in clinical practice, it is the most physiological method of ovulation induction for WHO group I ovulatory disorders, namely women who have hypogonadotropic hypogonadism. These women typically do not have the pulsatile GnRH secretion required for the synthesis and release of gonadotropins from the pituitary that are responsible for ovarian folliculogenesis and regular, cyclic menses. GnRH is typically administered in doses from 2.5-20 μg every 60-120 minutes. GnRH pulsatile therapy may be administered intravenously (IV) or subcutaneously (SC) but appears to be more effective by IV route. The LH surge and subsequent ovulation occur spontaneously, therefore not requiring an injection of hCG to induce follicular maturation, and pulsatile GnRH can be continued in the luteal phase to provide support for the corpus luteum. Ovulation rates are typically 75%/cycle, with pregnancy rates of 23%/ovulatory cycle and multiple pregnancy rate of 3.8%/cycle. The low multiple pregnancy rate is due to monofollicular development using this method of ovulation induction. In spite of high pregnancy rates and low multiple pregnancy rates, due to the need for a pump and indwelling catheter, this method of ovulation induction is not frequently used.

Dopamine Agonists Dopamine agonists are the first-line therapy for patients with anovulation related to hyperprolactinemia. Hyperprolactinemia is often due to prolactin-secreting pituitary adenomas. Hyperprolactinemia interferes with GnRH pulsatile secretion, thereby causing anovulation. Dopamine inhibits prolactin secretion, and administration of

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dopamine agonists results in both a decrease in tumor volume and restoration of ovulatory cycles. The most commonly used dopamine agonist for ovulation induction is bromocriptine, which is administered in a dose of 2.5-10 mg, daily in divided doses. Cabergoline is another dopamine agonist with a better side-effect profile and patient tolerability and is administered in a dose of 0.25-1 mg, given twice weekly. Cumulative pregnancy rates of 80% can be expected with bromocriptine treatment for anovulation due to hyperprolactinemia. Dopamine agonists are typically stopped once conception has occurred.

Gonadotropins for Ovulation Induction Background The anterior pituitary gonadotropins, LH and FSH, and the placental gonadotropin, hCG, are the three identified gonadotropins and all are used in ovulation induction. LH serves two distinct and essential functions. First, it is responsible for stimulating the synthesis of ovarian androgens in ovarian theca cells. These androgens serve as precursors for ovarian estrogen synthesis. Second, the LH surge, which occurs in response to a positive feedback effect of estradiol produced from a preovulatory follicle, causes oocyte maturation with resumption of meiosis, oocyte release, and a shift in production of ovarian steroids from a predominantly 15 estrogen-producing follicle to a progesterone-producing corpus luteum. The placental gonadotropin, hCG, is produced by the early pregnancy and functions through the same receptor as LH. As a result, it has the same activity as LH, and its primary biological purpose is to continue to support progesterone production by the corpus luteum throughout the first trimester and until the placenta develops. Finally, FSH stimulates ovarian follicle growth and stimulates aromatase activity in granulosa cells. The aromatase activity is responsible for conversion of the LH stimulated androgens from the theca cells into estrogens. While the physiological function of these hormones is to ensure regular, monofollicular ovulation and hormonal support in early pregnancy, these hormones can be used pharmacologically to induce ovulation in women with ovulatory defects or to induce superovulation (e.g., multifollicular development) in ovulatory patients to increase the chance of pregnancy. The first live birth from gonadotropin therapy occurred in 1962. The gonadotropins were obtained from the purified urine of postmenopausal women. These preparations were termed human menopausal gonadotropins (hMG) and initially contained 5% gonadotropins and numerous urinary protein contaminants. Due to the impurity and batch-to-batch variability of these preparations, mass was not an appropriate indicator of gonadotropin content. As a result, gonadotropin preparations have traditionally been expressed in international units (IU) of activity, as measured by a standard bioassay. Initial hMG preparations contained equivalent amounts of FSH and LH per unit. These preparations were typically administered by intramuscular injection (IM). Years later, a urinary FSH (uFSH) product was developed that had most of the LH activity removed although it still contained significant impurities. The rationale for this was that endogenous LH levels were adequate and that excessive LH activity could be harmful to folliculogenesis. Subsequently, a highly purified urinary FSH (uFSH-HP) was developed. This was >95% pure and offered the advantage of subcutaneous administration with little local irritation. Finally, the end of the last millennium brought the development

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of recombinant DNA technology and with it the development of recombinant FSH (rFSH). These products contain exclusively recombinant FSH, >99% pure, without significant batch-to-batch variation. Similarly rLH and rhCG have been developed and are available for clinical use. While there has been much progress in the development and use of gonadotropins, there is a paucity of evidence that any one preparation is clinically superior to another. Two different meta-analyses of several randomized, controlled trials gave different results with respect to pregnancy rates when comparing ovulation induction using FSH to hMG. The initial meta-analysis demonstrated a higher pregnancy rate in when FSH was used for ovarian stimulation for in vitro fertilization. In contrast, a reanalysis of this data with a larger number of studies showed little difference between these two preparations. Most recently, a meta-analysis comparing rFSH to hMG demonstrated no difference in clinical pregnancy rates. While the recombinant preparations are more expensive and at this point, they do not appear to offer any clinical advantage over hMG or uFSH, they have less batch variability, virtually no infectious risk that theoretically exists with urinary preparations, an essentially limitless supply that is not constrained by access to urine from postmenopausal women, and the ability to develop novel ovulation induction regimens with varying doses of rFSH, rLH, and rhCG. For most clinical purposes, any of the FSH or hMG preparations may be used interchangeably. 15 Multiple pregnancy and OHSS occur with higher frequency in patients treated with gonadotropins. A recent study of over 4000 gonadotropin plus IUI cycles revealed a 14.4% pregnancy rate/cycle, with an overall 25% multiple pregnancy rate, with a higher order multiple pregnancy rate of 6%. OHSS rates can be up to 11% in PCOS patients undergoing gonadotropin ovulation induction.

Follicular Maturation with hCG—The Terminal Act in Ovulation Induction The purpose of the LH surge is to initiate ovulation, maturation of the oocyte, and development of the corpus luteum. This can occur spontaneously with most types of ovulation induction but is usually brought on pharmacologically in large part for practical reasons. By administering an agent that mimics the LH surge, we are virtually ensure that the events that occur as a result of the LH surge take place, and we can also control the timing of these events. Since the LH surge precedes ovulation by approximately 36 hours, timing of IUI or intercourse may be coordinated with the pharmacologically induced surge. The most common agent used for follicular maturation is hCG. The structure of hCG is similar to LH, and it acts through the LH receptor to mimic the LH surge. There are both uhCG and rhCG products available. It is typically administered in doses of 5000-10000 IU for uhCG administered IM or SC, or 250 μg of rhCG administered SC. Both agents are equally effective in ovulation induction. The lower dose of uhCG may lower the risk of OHSS in patients at greatest risk. While hCG is the most common agent for inducing final follicular maturation, both LH and GnRH agonists may be used. The clinical use of LH for follicular maturation has been limited due to the large dose required for this purpose and its shorter half-life than hCG. GnRH agonists have been also been used, and they hold the advantage of stimulating an endogenous LH surge from the pituitary that is more physiological, potentially lowering the risk of OHSS.

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Gonadotropin Ovulation Induction in PCOS There are numerous protocols for ovulation induction with gonadotropins in PCOS women. The two most common protocols are the low dose step-up protocol and the step-down protocol, both of which are adequate. It has been suggested that the low dose step-up protocol has a lower rate of OHSS and multiple pregnancies, and possibly a higher pregnancy rate. Whatever protocol is used, close ultrasound and estradiol monitoring is essential for avoiding complications. The step-up protocol is typically started on cycle day 2 or 3 of the menstrual cycle, often after a progestin-induced withdrawal bleed (Fig. 15.2). The initial FSH starting dose is typically 75 IU/day, but has been effective at lower doses. The initial dose is given for 7 days, and ultrasound and estradiol levels are obtained. If follicles >10 mm are seen, the same dose is continued and patients return for ultrasound and estradiol testing every 1-2 days until the lead follicle is ≥17 mm in diameter. Follicular maturation is then initiated with hCG, but this may be withheld if there are greater than four follicles with ≥14 mm diameter or estradiol >2000 pg/ml, due to the risk of OHSS and multiple pregnancy. If after 7 days of initial stimulation the follicles are ≤10 mm, the same dose is continued for another 7 days and ultrasound examination is performed again. If the follicles are >10 mm, then the protocol is continued at the same dose (threshold dose) until a follicle ≥17 mm is seen. If the 15 follicles remain ≤10 mm, FSH dose is increased 37.5 IU daily for 7 days, and is increased 37.5 IU every 7 days until a threshold dose is reached.

Figure 15.2. Low dose step-up protocol for gonadotropin ovulation induction. FSH, follicle stimulating hormone; hCG, human chorionic gonadotropin; IUI, intrauterine insemination; IU, international units.

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The step-down protocol is started on cycle day 2 or 3 of the menstrual cycle at an FSH starting dose of 150-225 IU/day for 5 days (Fig. 15.3). Ultrasound and estradiol levels are then performed. If follicles ≥10 mm are seen, the dose is decreased by 37.5 IU every 3 days and the cycle monitored with ultrasound and estradiol every 1-2 days until the lead follicle ≥17 mm. Follicular maturation is then initiated with hCG unless the risk of OHSS or multiple pregnancy is too great. If after 5 days of initial stimulation, all follicles are <10 mm, the dose is increased by 37.5 IU every 2-3 days and monitored every 2-3 days, for up to 10 days, until follicles ≥10 mm are seen. At this point, the dose is decreased by 37.5 IU every 3 days until a mature follicle is seen. If there is still no growth after 10 days at the higher dose, the cycle is cancelled and a low dose step-up protocol may be considered.

Ovulation in Hypogonadotropic Hypogonadism Anovulation of this type, also termed WHO group I anovulation or hypothalamic anovulation, is due to low FSH and LH. As a result, these patients generally require a gonadotropin preparation that contains LH activity. This could be in the form of hMG, rFSH plus rLH, or rFSH plus low-dose rhCG. In hypogonadotropic hypogonadism, estradiol levels remain low in women stimulated with FSH only, due to the absence of LH activity driving ovarian androgen precursor production. In the absence of LH activity, ovulation is significantly diminished. As a result, stimulation protocols must contain LH activity. Ovulation induction for these 15

Figure 15.3. Step-down protocol for gonadotropin ovulation induction. FSH, Follicle stimulating hormone; hCG, Human chorionic gonadotropin; IUI, Intrauterine insemination; IU, International units.

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patients may be performed using either hMG or rFSH plus 75 IU rLH daily. Risk of OHSS and multifollicular development is lower than in WHO group II anovulation. As a result, increased doses of gonadotropins may be used. Ovulation induction is usually started with a dose of 75-225 IU/day of hMG or 75-225 IU/day rFSH plus 75 IU/day of rLH, for 5 days. Ultrasound and estradiol monitoring are performed after 5 days, and dose adjustments of hMG or rFSH may be increased or decreased by 75 IU/day, depending on the adequacy of response. This is continued until the lead follicle reaches at least 17 mm. Follicular maturation is then initiated with hCG unless the risk of OHSS or multiple pregnancy is excessive.

Gonadotropins in Controlled Ovarian Hyperstimulation (COH) Gonadotropins may be used in regularly ovulating women in order to increase their fecundability. Gonadotropin therapy is often used in conjunction with IUI in patients with unexplained infertility, mild male-factor infertility, and mild/ moderate endometriosis, with improved pregnancy rates. In women with endometriosis, gonadotropin treatment with IUI resulted in a 5-fold increase in pregnancy rates when compared to no treatment. In unexplained or male-factor infertility, gonadotropin treatment with IUI resulted in a 1.7-fold increase in pregnancy rates when compared to IUI alone. Controlled ovarian hyperstimulation is 15 often performed with a fixed-dose protocol, starting stimulation on cycle day 3 at an FSH or hMG dose of 150-225 IU/day for 5 days. Ultrasound and estradiol monitoring is then performed every 1-2 days once a follicle >10 mm is identified. Criteria for follicular maturation with hCG are identical to other ovulation induction protocols, and the same caution for OHSS and multiple pregnancy risks must be observed.

COH with Gonadotropins in in Vitro Fertilization (IVF) Gonadotropin stimulation is the mainstay of COH in IVF. The purpose of COH in IVF stimulation is to produce multiple follicles for transvaginal oocyte retrieval, in vitro fertilization of oocytes, and subsequent transfer of 1-3 embryos into the uterus after 3-5 days of in vitro embryo culture. The details of these protocols extend beyond the scope of this chapter.

Key Points 1. Ovulation induction remains a mainstay of infertility treatment of women with ovulatory disorders. 2. Weight loss and clomiphene citrate ± metformin are the first-line ovulation induction methods in PCOS women. 3. Gonadotropins are first-line for anovulation due to hypogonadotropic hypogonadism and are second-line therapy for PCOS. 4. The major risks of ovulation induction are OHSS and multiple pregnancy. These risks can be reduced with appropriate monitoring. 5. Future directions in ovulation induction will be directed at greater individualization of protocols to increase pregnancy rates and decrease multiple births through monofollicular ovulation.

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Suggested Reading 1. Dickey RP, Taylor SN, Lu PY et al. Risk factors for high-order multiple pregnancy and multiple birth after controlled ovarian hyperstimulation: results of 4,062 intrauterine insemination cycles. Fertil Steril 2005;83:671-83, [A large review of the risk factors for higher order multiple pregnancy in gonadotropin ovulation induction]. 2. Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004;19:2474-83, [A review of the role of pregnancy and ovulatory rates in ovulation induction protocols using metformin]. 3. Guzick DS, Carson SA, Coutifaris C et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999;340:177-83, [A randomized controlled trial examining the pregnancy rates in COH ± IUI in patients with unexplained and mild male-factor infertility]. 4. Dunson DB, Baird DD, Wilcox AJ et al. Day-specific probabilities of clinical pregnancy based on two studies with imperfect measures of ovulation. Hum Reprod 1999; 14:1835-1839. 5. Farquhar C, Vandekerckhove P, Lilford R. Laparoscopic “drilling” by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev 2001; CD001122. 6. Filicori M, Flamigni C, Dellai P et al. Treatment of anovulation with pulsatile gonadotropin-releasing hormone: Prognostic factors and clinical results in 600 cycles. J Clin Endocrinol Metab 1994; 79:1215-1220. 7. Haas DA, Carr BR, Attia GR. Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome. Fertil Steril 2003; 79:469-481. 8. Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: Rationale, results, reflections and refinements. Hum Reprod Update1999; 5:493-499. 9. Mitwally MF, Casper RF. Aromatase inhibitors in ovulation induction. Semin Reprod Med 2004; 22:61-78. 10. Randall JM, Templeton A. Transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and clomiphene citrate cycles. Fertil Steril 1991; 56:208-212. 11. van Santbrink EJ, Hop WC, van Dessel TJ et al. Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle. Fertil Steril 1995; 64:37-43. 12. van Wely M, Westergaard LG, Bossuyt PM et al. Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles. Cochrane Database Syst Rev 2003; CD003973.

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Chapter 16

Assisted Reproductive Technology Tiffany Von Wald and Kim Thornton

Introduction Assisted reproductive technology (ART) is by definition any treatment or procedure that includes the handling of oocytes and sperm or embryos outside the body for the purpose of establishing a pregnancy. In vitro fertilization (IVF) is the most common ART procedure. The first IVF baby was conceived in 1978 (Louise Brown) in Lancashire, England. IVF has been used in the United States since 1981.

Definitions In vitro fertilization (IVF): A process including controlled ovarian hyperstimulation, surgical removal (retrieval) of oocytes, fertilization in the laboratory, and transcervical transfer of embryos into the uterus. Gamete intrafallopian transfer (GIFT): A procedure that involves removing oocytes from a woman’s ovary, combining them with sperm, and using laparoscopy to assist in placing the unfertilized oocytes and sperm into the fallopian tubes. Zygote intrafallopian transfer (ZIFT): A procedure that involves removing oocytes from a woman’s ovary, fertilizing them in the laboratory with sperm, then placing the single-cell embryo (zygote) directly into the fallopian tube utilizing laparoscopy. Tubal embryo transfer (TET): A procedure that involves removing oocytes from a woman’s ovary and fertilizing them in the laboratory with sperm. The resultant embryo(s) are placed directly into the fallopian tube utilizing laparoscopy 2-3 days later. Donor oocytes: Eggs that are removed from one woman’s ovaries to be used by another for IVF. Indications often include premature ovarian failure, gonadal dysgenesis, recurrent IVF failure, natural menopause, and inheritable disorders. Gestational surrogacy: Treatment by which the gametes of the intended parents (genetic parents) are used to produce embryos, which are subsequently transferred to a woman who agrees to act as a host or surrogate carrier of the pregnancy. Microsurgical epididymal sperm aspiration (MESA): A technique whereby a small needle is used to extract fluid and relatively mature sperm directly from an epididymal tubule. Testicular sperm extraction (TESE): A procedure for extracting sperm by removing a small sample of testicular tissue through an incision in the testes under local anesthesia. Intracytoplasmic sperm injection (ICSI): A micromanipulation technique that involves injecting a sperm directly into an egg in order to facilitate fertilization. Assisted hatching (AH): A technique in which the zona pellucida (outer shell of the egg) is chemically or mechanically thinned prior to embryo transfer in order to improve the likelihood of subsequent hatching and implantation of the embryo. Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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Preimplantation genetic diagnosis (PGD): A technique used during IVF to test embryos for genetic disorders (aneuploidy or structural chromosomal abnormalities), inheritable single gene disorders, or gender, prior to embryo transfer. The procedure can involve evaluating the chromosomal composition of the oocyte via the extruded polar body, removing one or two blastomeres from the cleavage stage embryo, or by biopsy of the trophoectoderm of the blastocyst stage.

Infertility History and Evaluation An initial infertility evaluation is traditionally begun after one year of unprotected intercourse; however, an earlier evaluation may be indicated for increased maternal age, irregular menstrual cycles, previous pelvic inflammatory disease (PID) or pelvic surgery. One of the most important aspects of evaluating infertility is obtaining a thorough history from both partners. When evaluating the female partner, it is important to include the items listed in Table 16.1. When evaluating the male partner, it is important to include the items listed in Table 16.2. Every infertility evaluation should begin with a complete physical exam. When examining the female partner, it is important to document height and weight, as well as body mass index (BMI = weight in kilograms/height in meters squared). There is a clear association between weight and infertility as well as a correlation between the woman’s weight and the amount of gonadotropins needed to stimulate the ovaries. It is important to check for thyroid enlargement, nodules, or ten- 16 derness, as well as identifying excessive acne or facial hair, which may be associated with increased androgen levels. Evidence of acanthosis nigricans often indicates

Table 16.1. Evaluation of female partner Female: General Category Length of infertility Gravity and parity

Menstrual history

Family history Surgical history Gynecologic history Medication and allergy history Social history Review of systems

Specific Points Coital frequency, previous treatment History of spontaneous pregnancy, specific pregnancy outcomes, complications, history of recurrent pregnancy loss Length of cycles (normal 21-35 days), duration and type of flow (may indicate fibroids or oligovulation), menstrual cramps and breast tenderness (molimina-signs of ovulation), dyspareunia Recurrent pregnancy loss, endometriosis, birth defects, premature ovarian failure Tubal ligation, ovarian cysts, endometriosis, pelvic infections, appendectomy, D&C STDs, PID, abnormal pap smears and subsequent treatment

Tobacco use, alcohol use, illicit drug use Symptoms of thyroid disease, pelvic or abdominal pain, weight changes, hirsutism, galactorrhea

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Table 16.2. Evaluation of male partner Male: General Category

Specific Points

Length of infertility

Coital frequency, previous fertility, previous infertility treatment

Childhood illnesses and injuries

Mumps, testicular injuries, undescended testes

Family history

Infertility history, inheritable disorders

Urologic surgery

Vasectomy, herniorrhaphy

Past medical history

Diabetes, multiple sclerosis, STDs, recent febrile illnesses

Environmental toxins

Heat, pesticides, industrial toxins

Medication and allergy history

Sulfasalazine, cimetidine (gonadotoxic but reversible); antihypertensives, antipsychotics, antidepressants (ejaculatory dysfunction); anabolic steroids (decreased spermatogenesis)

Social history

Tobacco use (decreased motility), alcohol use, illicit drug use (marijuana- decreased sperm count)

Review of systems

Impotence, ejaculatory dysfunction

16 insulin resistance, a common finding with polycystic ovarian syndrome (PCOS). Other important features to note are: a “buffalo hump” (Cushing’s syndrome); short stature, webbed neck, and shield chest (Turner’s syndrome). Finally, a complete pelvic examination is crucial during the initial visit and should include evaluation for Mullerian defects, pelvic or abdominal masses, or tenderness, cervical abnormalities, and nodularity in the cul-de-sac. One should consider performing a cervical culture as well due to the association of chlamydia cervicitis and PID. During the examination of the male partner, one should first evaluate height, evidence of disproportionate limb length, secondary sexual characteristics, and gynecomastia (Klinefelter’s syndrome). The genitourinary examination should include location of the urethral meatus (hypospadias), palpating the testes for location and size, palpating bilateral vas deferens, and noting any varicocele. The evaluation of the infertile couple often includes a panel of screening tests. This includes a cervical Pap smear, maternal blood type and Rh, antibody screening, rubella status, RPR (syphilis), varicella status, hepatitis B, and cystic fibrosis. Screening for sexually transmitted diseases is also recommended for patients at high risk, and would include hepatitis C, HIV 1 and 2, HTLV, CMV, chlamydia, and gonorrhea. Once the initial screening tests are obtained, it is important to first document evidence of ovulation. This may be performed using basal body temperature charting (biphasic→ovulatory), urinary LH surge detection kits, or serum progesterone levels (>5 ng/ml→ovulatory). An endometrial biopsy (showing secretory phase) may also be performed, but this has limited use due to the cost and invasive nature of the test. “Luteal phase defect” is a condition in which inadequate progesterone is produced by the corpus luteum as evidenced by endometrial histological dating. This is a controversial topic when used in the evaluation of the infertile couple, and recent

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evidence suggests that an endometrial biopsy for histological dating does not differentiate fertile from infertile women, and thus, should not be used in the routine evaluation of infertility. Routine laboratory tests for infertility include a prolactin level (normal <20 ng/ mL) and TSH (normal <5 mIU/mL but varies with individual laboratories). Occasionally, one will want to obtain labs for excess androgen states (PCOS), such as free or total testosterone, DHEA-S, and 17-OH progesterone. A fasting glucose/insulin ratio is obtained in women with PCOS to identify insulin resistance, and a 24-hour urinary cortisol may be needed to rule out Cushing’s syndrome. An important feature of the infertility evaluation includes ovarian reserve testing. This is often performed by obtaining a cycle day 3 (CD3) serum FSH level. In general, a CD3 FSH <10 mIU/mL is considered normal, where 10-15 mIU/ mL is considered the “gray zone” and a CD3 FSH >15 mIU/mL is considered abnormal with diminished ovarian reserve. A CD3 estradiol is also often obtained, and if elevated, may indicate a shortened follicular phase with decreased ovarian reserve. A clomiphene challenge test is another route to evaluate ovarian reserve. It is often used in older women (>35 years) or those with shortened menstrual cycles. To perform the test, a CD3 FSH is obtained. Then, clomiphene 100 mg is given orally on days 5-9. On CD10, a repeat FSH level is drawn. If either the CD3 or CD10 FSH level is elevated (>10 mIU/mL), the test is abnormal. There is some evidence that the sensitivity of the clomiphene challenge test is higher than a basal CD3 FSH level (26% vs. 8%), although both tests are routinely used. 16 Lastly, an antral follicle count (AFC) may be obtained using transvaginal ultrasonography to assess the number of primordial follicles during the early follicular phase. In general, an AFC count of <4 follicles is associated with a poor ovarian response. Tubal patency and uterine cavity contour should be evaluated prior to beginning any infertility treatment. The most widely used test is the hysterosalpingogram (HSG). This is a radiological test performed as an outpatient procedure where dye is injected into the uterus through a small catheter and is imaged as it passes through the uterine cavity and fallopian tubes. It can display evidence of uterine fibroids, polyps, and synechiae (adhesions), as well as tubal patency. A sonohysterogram is an office procedure where saline is injected into the uterus under ultrasound guidance. Although it can detect uterine cavity abnormalities, it cannot show tubal patency. A hysteroscopy/laparoscopy may also be utilized to evaluate the uterine cavity and well as tubal patency through chromotubation, but this procedure is obviously much more invasive and requires general anesthesia. Finally, a semen analysis is required to rule out a male infertility factor. If the first semen analysis is abnormal, it should be repeated. Although normal reference values can vary between laboratories, the World Health Organization recommends the following normal reference values (Table 16.3).

Indications for ART As mentioned previously, IVF is the most common ART procedure performed. Although IVF was originally designed to treat tubal disease, it is now utilized as a treatment for many causes of infertility. In addition to tubal factor infertility, other indications include endometriosis, male factor infertility, ovulatory disorders, unexplained infertility, ovarian failure, and a history of inheritable disease.

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Table 16.3. Semen analysis: WHO normal reference values Volume pH Viscosity Sperm concentration Total sperm number Percent motility Forward progression Normal morphology Round cells Sperm agglutination

1.5-5.0 mL >7.2 <3 (scale 0-4) >20 million/mL >40 million/ejaculate >50% >2 (scale 0-4) >14% normal <5 million/mL <2 (scale 0-3)

Tubal Disease Tubal disease accounts for approximately 13.6% of indications for ART procedures in the US. Some patients with mild distal tubal obstruction may benefit from reconstructive surgery prior to proceeding with IVF. However, the pregnancy rates in general are lower than with IVF, and the risk of ectopic pregnancy is greater. IVF is the 16 recommended treatment for women who remain infertile after one year following reconstructive surgery. For women with severe distal tubal disease, IVF is the primary treatment. There is substantial evidence that pregnancy rates are improved in women who have surgical removal of hydrosalpinges prior to undergoing IVF. In one meta-analysis of three randomized controlled trials, the odds of pregnancy (OR = 1.75, CI 1.07-2.86) and of ongoing pregnancy and live birth (OR = 2.13, CI 1.24-3.65) were increased with laparoscopic salpingectomy for hydrosalpinges prior to IVF. The mechanism of this effect is not well understood, but fluid from the hydrosalpinges is inflammatory and may have a toxic effect on the embryo or the endometrium. Proximal or mid-tubal obstruction is also an indication for IVF. The most common reason for proximal obstruction is previous tubal sterilization. Microsurgical tubal reanastomosis can be effective in select candidates, although IVF may be a better choice for women who are poor surgical candidates and those who only desire one additional pregnancy.

Endometriosis Endometriosis accounts for approximately 6.7% of indications for ART in the US. Mild, moderate, and severe endometriosis has been shown to decrease fertility rates in women undergoing both IUI and IVF Pregnancy rates in patients with endometriosis have been demonstrated to have an approximate 45% reduction in pregnancy rates with IVF. Women with moderate and severe disease have a worse prognosis than those with mild and minimal disease. The proposed mechanisms include distorted anatomy (adhesive disease), abnormalities with oocyte development, and diminished endometrial receptivity. Although surgical management is an option for infertility treatment in women, IVF is often the treatment of choice in women who are older, those with other infertility diagnoses, or previous treatment failures.

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Male Factor Infertility Male factor infertility as a single reason accounts for approximately 18.8% of indications for ART in the US. Male factors can contribute to infertility in up to 35% of couples. The vast majority of sperm problems can be detected by a simple semen analysis. In men with mild semen abnormalities, intrauterine insemination with washed and concentrated sperm may be effective. In patients who fail to conceive after intrauterine inseminations with ovulation induction, the next step in treatment is IVF. IVF allows an assessment of whether fertilization occurs. In cases of no fertilization, intracytoplasmic sperm injection (ICSI) is then indicated. In men with severe abnormalities (references vary), poor fertilization is often expected. In this instance IVF is indicated as a first line therapy with the addition of ICSI. The indications for ICSI remain controversial but often include the following parameters: • Total motile sperm count <1 million • <4 % normal morphology • Previous IVF cycle with no or poor fertilization • Epididymal or testicular spermatozoa Because the manipulation with ICSI overrides potential natural protection to prevent fertilization by sperm with damaged DNA, there is the potential that children born after ICSI might be at increased risk for congenital birth defects and/or chromosomal abnormalities. However, most studies to date have failed to identify any increased incidence of major malformations above baseline in children born 16 after ICSI.

Ovulatory Disorders Chronic anovulation is a common cause of infertility and accounts for 6% of indications for ART procedures in the US. In most women with chronic anovulation, polycystic ovarian syndrome is the cause. Polycystic ovarian syndrome is a disorder characterized by hyperandrogenism and anovulation. Many women with polycystic ovarian syndrome are also very obese and may have insulin resistance. The majority of these patients will respond to conventional ovulation induction (clomiphene or gonadotropins). In women who are obese or insulin resistant, their response to ovulation induction may be enhanced with the use of insulin sensitizing agents such as metformin. When these treatment regimens fail, IVF is a reasonable and useful option. Although women with PCOS often obtain a larger number of oocytes during retrieval, there appears to be a lower fertilization rate, presumably due to the endogenous hormonal imbalance. Despite a reduced fertilization rate, IVF pregnancy rates in women with PCOS are comparable to ovulatory women. Women with PCOS who have high estradiol levels and a large number of preovulatory follicles are particularly at risk for the development of a syndrome called ovarian hyperstimulation syndrome (OHSS) because of their exaggerated response to gonadotropins. Women with a PCOS like response to gonadotropins are also at risk. Typical symptoms of OHSS include abdominal distension as a result of fluid shifts from the vascular space to body cavities, dehydration, nausea, and shortness of breath, weight gain, and pelvic pain. Depending on the severity, OHSS may be treated conservatively with fluid restriction or with paracentesis (removal of fluid from the abdominal cavity).

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Unexplained Infertility Although the exact prevalence of unexplained infertility is unknown due to differing diagnostic criteria, it ranges from 10-30%. In 2002, unexplained infertility accounted for 11.1% of indications for ART procedures in the US. The highest success rates for treatment are with IVF (28.5%). As one might expect, the success rates decrease in all forms of treatment as maternal age increases.

Diminished Ovarian Reserve Diminished ovarian reserve is a common diagnosis in ART centers and accounts for approximately 6.7% of indications for ART in the US. Diminished ovarian reserve implies that the ability to produce eggs is reduced. Causes of diminished ovarian reserve may include surgery, congenital abnormalities and advancing maternal age. Many women with diminished ovarian reserve will be diagnosed by ovarian reserve testing or after a previous stimulation cycle demonstrates production of low numbers of oocytes.

Other Indications for ART Women who have a family history of an inheritable disease may be candidates for IVF with preimplantation genetic diagnosis (PGD). PGD is most often utilized in this scenario when there is a single-gene disorder, sex-linked disorder, autosomal recessive disorder, or balanced translocation. PGD is also utilized in some women 16 with recurrent pregnancy loss, but the data are not clear regarding improved outcomes. To perform PGD one or two cells are removed from the embryo. These cells may then be analyzed for the presence or absence of a single gene order or for the presence of the correct number of chromosomes. This will enable couples to preconceptually evaluate embryos so that they can preferentially transfer those embryos that are not affected with a genetic disease or that have a normal chromosomal number. PGD is occasionally used for sex selection and family balancing, but this is highly controversial. Donor oocytes are indicated when a woman has premature ovarian failure, has undergone natural menopause or if a woman has demonstrated poor oocyte recovery and embryo quality with her own eggs. The latter indication is most often seen in women of advanced maternal age. Women who have Mullerian anomalies (congenital absence of the uterus and vagina) are often candidates for gestational carriers (surrogates). Likewise, women with severe uterine abnormalities (fibroids, adhesions) or a previous hysterectomy may also be candidates for gestational surrogacy. Because the success rates for IVF are so high, other techniques such as GIFT and ZIFT are rarely used. Occasionally, GIFT is performed for religious preferences. MESA and TESE are clearly performed for severe male factor infertility and oligo- or azoospermia. Assisted hatching is controversial and is used to potentially improve implantation rates. It is most frequently utilized in couples with recurrent failed cycles or prolonged in vitro culture, when a thickened zona pellucida is suspected.

Success Rates Success rates for IVF centers are difficult to quantify because they are site-specific and depend on numerous factors. These include but are not limited to: patient characteristics, degree of ovarian stimulation, embryo culture quality, number of

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Table 16.4. IVF pregnancy success rates based on maternal age, 2003 Maternal Age (in years) <35 35-37 38-40 41-42 >42

Live Births/Cycle 37% 30% 20% 11% 4%

embryos transferred, and transfer technique. In general, success rates are reported using the following terminology: • Pregnancy rate: definition varies from a positive serum or urine βhCG to live birth • Clinical pregnancy rate: the percent of patients with at least one gestational sac in the uterine cavity with fetal cardiac activity • Live birth rate: percentage of patients with a live birth from an ART cycle • Implantation rate: the number of clinical pregnancies divided by the number of embryos transferred The Centers of Disease Control and Prevention (CDC) reports the most recent 16 ART success rates from reporting centers in the US. In 2003, the total number of ART cycles reported was 112,872 while the number of live babies born as a result of ART cycles was 35,785. Of all the ART procedures performed, 74% were fresh, nondonor egg cycles. Of all the cycles cancelled, 82.9% were due to inadequate egg production. The rate of spontaneous abortion increases dramatically as the maternal age increases. The overall live birth rate per retrieval for different ART procedures using fresh, nondonor eggs was as follows: • IVF without ICSI (intracytoplasmic sperm injection), 33.4% • IVF with ICSI, 31.9% • GIFT 20.8% • ZIFT 25.9% • Combination of IVF with or without ICSI and either GIFT or ZIFT, 28.3% It is important to remember the success rates vary depending on the factors listed above, in addition to patient diagnosis. For example, in 2003 the highest live birth rate for fresh, nondonor cycles was in the ovulatory dysfunction infertility group (33.9%), while the lowest success rate was in the group with diminished ovarian reserve [14.3%]. The success rates also vary dramatically based on maternal age (Table 16.4).

Complications Multiple Gestation By far the greatest risk of IVF today is multiple gestations. Multiple gestations ultimately depend on the number of embryos transferred; thus the risk is primarily iatrogenic. In women under the age of 35 years, twin pregnancy rates can be as high as 40% when two high quality embryos are transferred. In general, ART increases the risk of multiple pregnancies by 10-fold above baseline (35% vs. 3% in the general

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population). It is true that the success rates in IVF improve with a greater number of embryos transferred, but only to a certain point. Beyond this point, only the risk of multiple pregnancy increases. Another risk factor for multiple pregnancy is maternal age. Younger women tend to be at higher risk of multiple pregnancy when more than one embryo is replaced. The problem with multiple gestations lies in the risks during pregnancy to both the fetuses and the mother. A greater risk of preterm delivery is the most significant consequence of multiple gestation. Multiples also have a higher risk of congenital malformations, and monochorionic twins are at increased risk of twin-twin transfusion syndrome. This can cause significant morbidity or even mortality for one or both fetuses. There also appears to be an increased risk of cerebral palsy in multiple pregnancies compared to singletons. Lastly, there appears to be a slightly higher risk of monozygotic twinning following ART compared to the general population. The mechanism of this is not well understood but is believed to be due to trauma to the zona pellucida with herniation of the blastocyst. Parents with multiple gestations, especially high-order multiples (three or more), frequently must face the decision of multifetal pregnancy reduction. This can be emotionally traumatic for couples that have struggled with the inability to become pregnant for long periods and the psychological morbidity is well documented. There are obstetrical risks for the mother associated with a multiple pregnancy as well. Women carrying multiple gestations, especially higher order gestations, are at increased risk of hypertension, preeclampsia, and preterm labor. They are more fre16 quently treated with prolonged bed rest and operative delivery compared to women carrying singleton pregnancies.

Ovarian Hyperstimulation Syndrome (OHSS) OHSS can occur when a woman over-responds to high-dose gonadotropin stimulation. Risk increases with larger numbers of developing follicles and greater number of eggs retrieved. Younger women also tend to be at higher risk of OHSS compared to older women. Pregnancy will also increase the risk of OHSS as well as the severity and duration of it. Although the pathogenesis is not well defined, OHSS appears to be dependent on hCG as well as angiogenic factors. Most women who present with OHSS show signs of increasing abdominal distention, ascites, nausea, vomiting, decreased urine output, hypercoagulability, and electrolyte imbalance. If symptoms are severe, there is also an increased risk of deep venous thrombosis. OHSS can be classified as mild, moderate, or severe; however it is uncommon to see severe OHSS requiring hospitalization. Most of the time, women with OHSS can be treated symptomatically with expectant management. Occasionally, women will need to undergo a paracentesis to remove excess abdominal fluid (often done transvaginally under ultrasound guidance). This procedure frequently results in immediate improvement in patient discomfort and symptoms.

Ectopic Pregnancy Pregnancies implanted outside the uterus are much more common in ART-conceived cycles than the general population (5% vs. 1-2%). The risk is higher in women with tubal disease or a prior history of ectopic pregnancy. The mechanism is not well understood but is likely due to natural migration of the embryo into the tube after transfer or inadvertent direct tubal embryo transfer. The risk of heterotopic pregnancy in the general population is very rare (1 in

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10,000), but the risk is increased substantially in women who conceive after IVF or ovulation induction.

Other Risks There is a small risk of internal bleeding, vascular injury, and infection from oocyte retrievals. Bleeding from the vaginal wall is fairly common after oocyte retrieval and usually stops spontaneously after the procedure or with the application of pressure. Severe pelvic infection is rare (<1%), and prophylactic antibiotics are usually not needed unless the patient is at high risk for pelvic inflammatory disease.

Fetal Risks There are currently a number of studies suggesting an increased risk of birth defects in babies conceived after IVF. In cases where IVF and ICSI has been performed for a severe male factor, a several-fold increase was found in spontaneous anomalies of the sex and autosomal chromosomes and an increased risk of inherited chromosomal defects. Another study has suggested an increased incidence, albeit small, of Beckwith-Wiedemann and Angelman syndromes, which are complex disorders of growth and development associated with aberrant imprinting at chromosome 11q15.5 and the UBEA3 gene locus on chromosome 15q11-13, respectively. These disorders are the result of genetic alterations affecting the regulatory mechanism of genes, rather than DNA sequence (imprinting). Finally, there is some evidence to indicate that the risk of birth defects (heart, muscle or skeletal) is slightly 16 higher in babies conceived through IVF as compared to babies conceived naturally. What remains to be determined is whether it is the IVF procedure itself or whether the increased risk is due to the infertility population undergoing treatment. Certainly ongoing research is required to better investigate the true fetal risks associated with ART outcome. Appropriate counseling of couples regarding the potential for risk associated with ART is recommenced.

Key Points 1 The infertility work-up involves a thorough evaluation of both male and female partner. 2. Indications for ART include male factor infertility, unexplained infertility, ovulatory disorders and ovarian failure. 3. Advanced ART procedures include PGD, oocyte donation and gestational surrogacy. 4. Interpretation of success rates must consider the IVF center, patient characteristics, stimulation protocols, number and quality of embryos transferred and transfer techniques. 5. Complications with ART are rare but include bleeding, infection, ovarian hyperstimulation and multiple pregnancy.

Suggested Reading 1. Steptoe PC, Edwards RG. Birth after the preimplantation of a human embryo. Lancet 1978; ii:366. 2. Wickland M, Enk L, Hamberger L. Transvesical and transvaginal approaches for the aspiration of follicles by use of ultrasound. Ann N Y Acad Sci 1985; 442:184. 3. Palermo G, Jorid H, Devroey P et al. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992; 340:17.

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4. Van Steirteghem AC, Liu J, Joris H et al. Higher success rate by intracytoplasmic sperm injection than by subzonal insemination Report of a second series of 300 consecutive treatment cycles. Hum Reprod 1993; 8:1005. 5. Handyside AH, Kontogianni EH, Hardy K et al. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990; 3:768. 6. Green BB, Weiss NS, Daling JR. Risk of ovulatory infertility in relation to body weight. Fertil Steril 1988; 50(5):721-6. 7. Chong AP, Rafael RW, Forte CC. Influence of weight in the induction of ovulation with human menopausal gonadotropin and human chorionic gonadotropin. Fertil Steril 1986; 46(4):599-603. 8. Westrom L, Wolner-Hanssen P. Pathogenesis of pelvic inflammatory disease. Genitourin Med 1993; 69(1):9-17. 9. Gardner D et al. Textbook of assisted reproductive techniques. 2nd ed. London: Taylor and Francis, 2004. 10. Speroff L, Fritz M. Clinical gynecologic endocrinology and infertility. 7th ed. Philadelphia: Lippincott Williams and Wilkins, 2005. 11. Coutifaris C et al. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004; 82(5):1264-72. 12. Barnhart K, Osheroff J. Follicle stimulating hormone as a predictor of fertility. Curr Opin Obstet Gynecol 1988; 10(3):227-32. 13. Hendricks DJ et al. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: A meta-analysis and comparison with basal follicle-stimulating hormone level. Fertil Steril 2005; 83(2):291-301. 14. World Health Organization. Laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. Cambridge University Press, 1999. 15. Johnson NP, Mak W, Sowter MC. Laparoscopic salpingectomy for women with hydrosalpinges enhances the success of VF: A Cochrane review. Hum Repro 2002; 17(3):543-8. 16. Adapted from the Centers for Disease Control and Prevention (CDC). 2003 ART Success Rates (www.cdc.gov/reproductivehealth/art.htm). 17. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002; 77(6):1148-55. 18. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 2003; 72:156-160, [CrossRef ] [ISI] [Medline]. 19. Maher ER, Brueton LA, Bowdin SC et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet 2003; 40:62-64. 20. Olson CK, Keppler-Noreuil KM, Romitti PA et al. In vitro fertilization is associated with an increase in major birth defects. Fertil Steril 2005; 84(5):1308-45.

Chapter 17

Alternative Medicine and Female Infertility Hey-Joo Kang, Pak Chung and Raymond Chang

Acupuncture Acupuncture is a vital therapeutic modality in traditional Chinese Medicine and its use can be traced back for centuries. The theory behind acupuncture is based upon the premise that there are patterns of energy flow, or Qi, through the body, which are essential for health. When a disease state exists, the flow of Qi is interrupted and its correction will assist in the healing process. Acupuncture can correct imbalances of flow at identifiable points close to the skin. The flow of Qi is based upon a meridian system of vital channels. The meridians consist of 20 channels interconnected by about 400 acupoints. These acupoints correspond to specific areas on the surface of the body, which demonstrate higher electrical conductance, thought to be due to the increased density of gap junctions along cell borders. These gap junctions serve as “sinks,” or converging points for electromagnetic fields. In addition, a higher metabolic rate, temperature, and calcium ion concentration are also observed at these points. The role of acupuncture in reproductive endocrinology is based upon a more modern and scientific approach that has begun to emerge in the past two decades. A review on acupuncture and female infertility suggested possible etiologies why acupuncture may improve female fertility. Acupuncture has been shown to induce a rise in β-endorphin levels that persists for up to 24 hours after treatment. Beta-endorphin is derived from its precursor protein, pro-opiomelanocortin (POMC), which is present in abundant amounts in neuronal cells of the arcuate nucleus of the hypothalamus, pituitary, medulla, and in peripheral tissues including intestines and ovaries. POMC cleaves to form adrenocorticotropic hormone and β-lipoprotein. Cleavage of β-lipoprotein results in the formation of neuropeptides including β-endorphin. Endogenous opioid/neuropeptides are believed to influence the menstrual cycle by their actions on gonadotropin releasing hormone (GnRH) secretion. The close proximity of the hypothalamic GnRH pulse generator and β-endorphin center within the arcuate nucleus allows neuropeptides to influence GnRH secretion and, in turn, play a role in ovulatory function. β-endorphin acts to curtail the release of GnRH and blunt the effects of other neuropeptides that are excitatory to the hypothalamus. The role of these opioid peptides has also been implicated in the initiation of the midcycle luteinizing hormone (LH) surge in normal ovulatory women. In fact, the levels of β-endorphin in ovarian follicular fluid of ovulatory women are higher than levels in circulating plasma. Levels of β-endorphin are highest in the preovulatory follicle, compared to other times in the menstrual cycle. Since acupuncture treatment impacts β-endorphin levels, which in turn affects GnRH secretion and the menstrual cycle, it is logical to hypothesize that acupuncture Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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may influence ovulation and fertility. Animal studies have revealed that acupuncture treatment normalized GnRH secretion and affected peripheral gonadotropin levels. In human data, various authors have shown that in normally ovulatory or even anovulatory women, acupuncture also influenced plasma levels of follicle stimulating hormone (FSH), LH and estradiol. The use of electroacupuncture for ovulation induction in anovulatory women with polycystic ovarian syndrome has been reported. The percentage of ovulatory cycles in all subjects was shown to improve from 15% to 66% up to three months after treatment. Responsive patients had significantly lower body mass index, waist-to-hip circumference ratio, serum testosterone concentration, serum testosterone/sex hormone binding globulin ratio, and serum basal insulin level. Therefore, in these selected patients with polycystic ovarian syndrome, acupuncture could be utilized as an alternative or adjunct to conventional pharmacological ovulation induction. Besides the central modulation of the hypothalamic-pituitary-ovarian axis, the effect of acupuncture on the autonomic nervous system has been described. Acupuncture induces long lasting cardiovascular effects via actions that are sympatho-inhibitory. Sympathetic nerve activity, as measured by norepinephrine levels, skin temperature, blood pressure and pain tolerance threshold, is noted to decrease after acupuncture. Endometrial thickness, morphology, and uterine artery blood flow have been implicated as crucial parameters for implantation success of human embryos. Despite conflicting results in the utilization of these parameters to predict outcome of 17 in vitro fertilization cycles, it is generally assumed that adequate endometrial thickness with a normal pattern is required to optimize pregnancy rates. Since endometrial thickness correlates with the adequacy of uterine artery blood flow via its central sympatho-inhibitory effect, acupuncture may reduce uterine artery impedance and therefore increase blood flow to the uterus. Pulsatility indices have been found to be reduced, hence, blood flow increased, following eight consecutive treatments of electroacupuncture. This effect was believed to be caused by a central inhibition of sympathetic activity. To date, there have been few well-designed studies on the potential impact of acupuncture on infertility treatment outcome. One of the most frequently quoted studies is a prospective study by Paulus et al, who evaluated the effect of acupuncture on pregnancy rate in 160 women undergoing in vitro fertilization. Acupuncture was performed in half of the patients 25 minutes before and after embryo transfer while the control group did not receive any acupuncture treatment. Clinical pregnancies were found to be higher in the acupuncture group than the control group (42.5% vs. 26.3%, respectively). The exact mechanism accounting for this result is not known. Other than its potential central role in affecting hypothalamic pituitary ovarian function and peripheral role in improving uterine blood flow and implantation function, acupuncture has been definitively shown to reduce stress and anxiety through its sympatho-inhibitory property. Undoubtedly, infertility is stress inducing and anxiety provoking. The use of acupuncture to reduce stress is a very viable option when couples undergo the stringent process of evaluation and treatment of infertility. Compared to the conventional administration of antidepressants and anxiolytic drugs, side effects of which are largely unknown on the outcome of infertility treatment, acupuncture presents a relatively benign and simple alternative.

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Herbal Treatments Tonic herbs are generally nontoxic—the safest of all herbs—and usually can be taken on a long-term basis. They can be administered either individually or in compound remedies in which several herbs work together synergistically to strengthen and tone your body. Tonics can be taken as capsules, tinctures, decoctions, infusion or tea. Tonic herbs are commonly thought to enhance female fertility. They are often used in traditional Chinese medicine and by holistic and alternative medical practitioners to boost or balance hormone production in women. It should be cautioned that the mechanism of action and efficacy of many of these herbs have not been substantiated by conventional Western standards. Chaste berry (vitex agnus-castus)—This European herb is one of the more well-established Western herbs relating to female hormone regulation. It is thought that the sites of action of chaste berry are the hypothalamus and pituitary gland, and that chaste berry increases LH secretion and regulates the release of FSH. Serum progesterone level has been observed to increase with its consumption. The use of chaste berry has been implicated in women with short luteal phase or documented luteal phase defect. Whether this reversal of luteal phase defect is due to improved folliculogenesis or ovulatory event is largely unknown. Chaste berry also inhibits prolactin release and may have a role in the setting of hyperprolactinemia-related menstrual irregularities and infertility. It is also thought to soothe premenstrual tension. To be able to derive the potential benefits of chaste berry, it may have to be taken for three to four months. Other commonly used herbs which have been anecdotally shown to be benefited 17 for female fertility include Black Cohosh, or Cimicifuga racemosa, Red Clover, or Trifolium pretense, and Dong Quai, or Angelica sinensis. The use of herbs during infertility treatment, however, has to be carefully considered. Most of the commonly used herbs for fertility enhancement contain a fair amount of plant estrogens or phytoestrogens. Therefore, the decision on medication dosage adjustment during treatment, such as in vitro fertilization, which normally hinges upon estrogen levels, may be impacted by the ingestion of these herbs.

Vitamins and Dietary Supplements Many vitamins have been implicated in promoting human reproduction. Ascorbic acid (vitamin C) has long been associated with fertility through three of its principal functions, namely promotion of collagen synthesis, hormone production, and protection of cells via production of free radicals. There is evidence that both ovary and testis accumulate ascorbic acid, and both gonads show cycles of tissue remodeling and of steroid secretion that is ascorbate-dependent. One study on in vitro fertilization suggests that the supply of ascorbic acid to the ovary might be a rate-determining factor in the ability of the preovulatory follicle to respond to gonadotropin stimulation. Ascorbic acid may also prevent gametes from damage by free radicals during fertilization. Further research is required to study the exact mechanism of action of ascorbic acid in gonadal physiology and fertility. Vitamin B12 (cobalamine) deficiency has been reported as an etiology in infertility. Pernicious anemia, though rarely encountered in women of childbearing age in developing countries, has been associated with oligo- to anovulation. Once treated, conception was noted to quickly occur through resumption of ovulation.

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Vitamin B6 (pyridoxine) and vitamin E have been shown to be vital to human reproduction. Women deficient in these vitamins demonstrate return of normal menstrual function and fertility upon replacement. Vitamin B6 has been used in the treatment of premenstrual symptoms, but whether symptoms are actually due to primary insufficiency is unclear. There are many dietary supplements which have been associated with improving female fertility: folic acid, magnesium, selenium, iron and zinc. In a study investigating the effects of caffeine on conception, women drinking green tea (as opposed to other caffeinated beverages) were found to approximately double their odds of conception, though the design of the study did not control for several potential variables. One supplement, L-arginine, an amino acid, was used as an adjunct in poor responders during in vitro fertilization treatment. Believed to be able to improve circulation to the reproductive organs, including the endometrium, L-arginine may play a role in enhancing oocyte development and implantation of the embryo. Battaglia et al studied uterine and follicular Doppler flow in response to L-arginine treatment during in vitro fertilization treatment in poor responders. The L-arginine treatment group showed multiple benefits, including improved Doppler flow rates, a lower cancellation rate and an increased number of oocytes collected and embryos transferred. Out of 17 women supplemented with L-arginine, 3 conceived as compared to 0 of 17 in the nonsupplemented group. Many studies have attempted to show particular vitamins or dietary supplements 17 may be involved in regulation or improvement of female fertility are small and not necessarily randomized or placebo-controlled. Given the benign nature of these supplements (in appropriate dosages) and lack of adverse effects in general, it seems reasonable to recommend that women interested in fertility evaluate their own nutritional needs and personalize inclusion of these elements in their diet or as daily supplements. More studies are needed to establish their exact role in reproduction.

Mind/Body Techniques Infertile women most often turn to modern western medicine to increase their chances of conception. However medical treatments may only represent part of the solution. Some believe that adding mind/body techniques may help women cope with the mental and physical stress associated with the evaluation and treatment process. Although it is difficult to quantify the impact of stress on the outcome of infertility treatment, mind/body programs have been positively shown to improve handling of stress, reduce anxiety, change one’s attitude and outlook, and banish negative thoughts. These attributes will benefit infertile women in regaining control of their lives and improve a couple’s relationship during their struggle to conceive. In one well-known study done in Boston on 284 infertile women, stress level was significantly reduced, and 42% became pregnant within 6 months of completing the mind/body program.

Key Points Alternative medicine encompasses various approaches to female fertility. Acupuncture has been used for thousands of years in traditional Chinese medicine. Its benefits have long been recognized to improve health, decrease stress, and more recently, potentially improve reproductive capabilities. Herbal treatment has also been an integral part of alternative medicine to treat menstrual and ovulatory

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dysfunction, and indirectly infertility. Certain vitamins and dietary supplements are vital in the metabolism and health of reproductive cells and organs. Last but not least, mind/body programs and psychological counseling will serve to relieve stress and anxiety associated with infertility. Western medicine is usually quite targeted at the ‘diseased’ organ whereas the approach in alternative medicine is toward the entire body. When the overall well being of the individual is cared for, improvement in reproductive function should follow. We have only begun to correlate the beneficial effects of alternative approaches in infertility treatment with western biologic plausibility.

Suggested Reading 1. Chang R, Chung P, Rosenwaks Z. Role of acupuncture in the treatment of female infertility. Fertil Steril 2002; 78:1149-1153. 2. Paulus W, Zhang M, Strehler E et al. Influence of acupuncture on the pregnancy rate in patients who undergo assisted reproduction therapy. Fertil Steril 2002; 77:721-724. 3. Stener-Victorin E, Waldenstrom U, Andersson SA et al. Reduction of blood flow impedance on the uterine arteries of infertile women with electro-acupuncture. Hum Reprod 1996; 11:1314-7. 4. Hardy M. Herbs of special interest to women. J Am Pharm Assoc 2000; 40(2):234-42. 5. Luck MR, Jeyaseelan I, Scholes RA. Ascorbic acid and fertility. Biol Reprod 1995; 52:262-266. 6. Battaglia C, Salvatori M, Maxia N et al. Adjuvant L-arginine treatment for in vitro fertilization in poor responder patients. Hum Reprod 1999; 14:1690-1697. 7. Westphal LM, Lake Polan M, Sontag Trant A et al. A nutritional supplement for improving fertility in women. J Reprod Med 2004; 49:289-293. 8. Domar AS, Seibel MM, Benson H. The mind/body program for infertility: A new behavioral treatment approach for women with infertility. Fertil Steril 1990; 53:246-9.

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Chapter 18

Male Infertility Stephanya Shear and Jeanne O’Brien

Epidemiology Male infertility is the sole cause of 20% of couple infertility and contributes an additional 30% as a cause for combined couple infertility. Most men seeking infertility counseling and evaluation are referred through gynecologists or primary care physicians caring for the female partner. Thus, specialized knowledge or training about infertility is very important as is the ability to work closely with reproductive endocrinologists and gynecologic physicians. With the advancement of assisted reproductive technologies (ART) and microsurgical techniques, many men previously labeled as sterile are now capable of fathering children.

Physiology Physiologically, male fertility requires good erectile function; spermatogenesis; normal endocrine function (specifically testosterone and FSH); and ejaculation. In addition, sexual intercourse timed appropriately to ovulation is an important key to conception. Because of the anxiety and stress that is often associated with couple infertility, male patients often describe difficulty with erections. Obviously, if sexual intercourse is not occurring then conception is impossible! This information must be addressed specifically with the patient as he may not volunteer it. Erectile dysfunction secondary to various disease states including diabetes and atherosclerosis must also be elucidated. Any previous history of genitourinary cancers or pelvic surgeries that may have impaired erectile function should also be addressed. Spermatogenesis has traditionally been described as requiring a 74 day cycle (recent studies have indicated it may actually be shorter than this time period). Any insult or intervention will usually require at least one spermatogenic cycle prior to seeing its effect. Follicle stimulating hormone (FSH) and testosterone are imperative for normal spermiogenesis. When FSH is elevated it can be an indication that the testes are not producing sperm in normal amounts related to various causes including: testicular failure; genetic abnormalities, toxic exposures (including radiation, chemotherapy, and heat). The teaching used to be if FSH was elevated by at least twice the upper limit of normal, the probability of finding sperm even on testicular biopsy was almost zero. This has changed with the development of new microsurgical techniques, including microscopic testicular sperm extraction (micro TESE). Nonetheless, FSH levels are useful in counseling patients on potential outcomes of the infertility evaluation. If FSH is elevated (greater than twice normal) in a patient with severe oligospermia or azoospermia, the patient must be instructed that advanced reproductive techniques (ART) would most likely be required in order to have a biological child. If Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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the patient is unwilling, financially or psychologically, to undergo ART, other options such as donor sperm insemination or adoption should be discussed. Testosterone, another crucial hormone, contributes to libido, erectile function, and sperm production. Obviously, intercourse must be timed to the periovulatory period. Sperm are able to live in the cervical mucus for an average of approximately 48 hours. Patients should be instructed to have sexual intercourse near the time of anticipated ovulation.

Differential Diagnosis Differential diagnosis of the causes of male infertility may be broken down into three categories: Pretesticular (endocrine) causes include: • Pituitary disease: e.g., hypogonadotropic hypogonadism: low LH, FSH and testosterone levels; Kallman syndrome (associated anosmia); isolated FSH deficiency • Congenital syndromes: Prader-Willi syndrome • Elevated exogenous or endogenous androgen levels: anabolic steroid use, metabolic disorders or androgen secreting tumor • Elevated estrogen levels: hepatic dysfunction (e.g., cirrhosis), estrogen secreting tumors, morbid obesity • Elevated prolactin: pituitary prolactin secreting tumor, idiopathic hyperprolactinemia • Elevated glucocorticoids • Hyperthyroidism Testicular causes include: 18 • Genetic/karyotypic abnormalities • Anatomic abnormalities: cryptorchidism (bilateral/unilateral); vanishing testes syndrome (bilateral anorchia—XY males with impalpable testes) • Gonadotoxins: chemotherapy, radiation; cigarettes, marijuana, alcohol abuse, heavy metal exposure (lead, mercury), sulfa drugs • Varicocele: Primary laboratory characteristic is combined finding of low motility and low sperm count. Increased abnormal morphology secondary to a stress pattern may be seen as well. Varicoceles can be diagnosed in approximately 35% of infertile men on physical exam only. Varicoceles diagnosed with scrotal ultrasound are defined as subclinical and there is no proven benefit to surgical repair. • Structural defects (structural sperm defects which prevent normal motility): immotile cilia syndrome; immotile viable sperm • Orchitis: Post pubertal mumps, epididymo-orchitis, syphilis, gonorrhea, and leprosy • Antisperm antibodies (testicular injury, previous vasectomy) • Testicular cancer • Idiopathic: occurs in as many as 25% of patients with abnormal semen analysis Post-Testicular causes include: • Ductal obstruction (CBAVD, vasectomy, scarring from sexually transmitted diseases) • Retrograde ejaculation (multiple sclerosis, diabetes, retroperitoneal lymph node dissection) • Anejaculation (spinal cord injury, retroperitoneal lymph node dissection, diabetes)

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Evaluation History and Physical The comprehensive history should include all past and current medical problems related to reproductive function. Men who have previously fathered children or a pregnancy with the same or different partner are said to have secondary infertility. Men who have never fathered a child are considered to have primary infertility. The length of time the couple has been attempting a pregnancy and the frequency of intercourse should be ascertained. The ideal frequency of intercourse is every day to every other day. Use of artificial lubricants, even water soluble or natural sources, should be discouraged as they may impair sperm motility. Men should be asked about exposures to pesticides, chemicals, organic solvents, or heat (tanning booths, short order cooks, and foundry workers). Men who smoke tobacco or marijuana are at risk for infertility as these drugs decrease sperm concentration (oligospermia) and effect motility. Illicit drug and copious alcohol use can disrupt the hypothalamic-pituitary axis and adversely affect testicular function. Anabolic steroids can result in testicular atrophy and abnormal or absent spermiogenesis. Many medications can affect sperm concentrations and function including: prescription and over-the-counter medications, vitamin and protein supplements and herbal remedies. A list of pharmacological and environmental causes of infertility is given in Table 18.1. The surgical history should include questions regarding a history of cryptorchidism (undescended testis) and patient’s age at the time of repair. Cryptorchidism can 18 cause oligospermia or even azoospermia, if bilateral. Correction of hypospadias, chordee or hernia should also be ascertained as well as any surgery on the bladder neck, urethra, rectum or pelvis. A history of urethral strictures and/or STDs may result in urethral and ductal obstruction causing reduced sperm counts. Men who have been treated for testicular cancer or Hodgkin’s lymphoma may have reduced sperm counts related to their disease as well as treatments such as chemotherapy and radiation. Surgery for testicular cancer may include retroperitoneal lymph node dissections and this can injure the sympathetic nerves involved in ejaculation. The review of systems should include questions regarding diabetes (partial or retrograde ejaculation), cystic fibrosis (CF)—pertinent positives include: history of pneumonia, recurrent sinusitis or bronchitis—(congenital absence of the vas deferens), multiple sclerosis (impaired ejaculation), and spinal cord injuries (erectile dysfunction). There are several rare conditions which impact fertility that can be

Table 18.1. Pharmacological and environmental causes of infertility Diethylstilbesterol (DES) Testosterone Ketoconazole Nitrofurantoin Calcium channel blockers Cigarettes Cocaine Sulfa drugs

Radiation Chemotherapy Heat Pesticides Lead Alcohol Marijuana Solvents

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uncovered during the review of systems. Recurrent respiratory infections can be associated with nonmotile sperm and may suggest primary ciliary dyskinesia (Kartagener’s syndrome). Congenital anosmia (inability to smell) may be associated with Kallmann’s syndrome—hypogonadotropic hypogonadism. Emphasis is placed on a thorough genitourinary examination. The male patient should be examined in a warm room. Normal virilization should be noted. The presence of gynecomastia should prompt questions regarding marijuana use or an evaluation for a prolactin producing pituitary tumor. Normal testicular size is 20 cm3 and the testicle should be firm but not hard,not unlike the feel of a hard boiled egg. An orchidometer can be used to assess size or it can be approximated by measuring. A normal testicle is at least 2.5 × 3 × 4 cm. The epididymis and vas deferens should be palpated and any thickening should suggest the possibility of obstructive causes of infertility. The spermatic cords should be examined in the upright position to evaluate the man for a varicocele-dilation of the spermatic pampiniform plexus. It is thought that varicoceles may impact sperm quality by increasing testicular temperature or perhaps by causing reflux of adrenal metabolites via incompetent veins. However, 15% of the general male population has a varicocele, and up to 45% of men with infertility present with a varicocele. Grading of varicoceles is based on physical exam alone though occasionally ultrasound may be used as a confirmatory study or if body habitus makes examination difficult. Absence of the vas deferens is found in 1-2% of all infertile men and 10% of men with low sperm counts. It can be unilateral or bilateral. It is often associated with other genitourinary abnormalities such as absence of the ipsilateral kidney or incomplete epididymis formation. Importantly, 18 80% of men with bilateral congenital absence of the vas (CBAVD) have at least one cystic fibrosis mutation. Men with CBAVD and their partners should undergo genetic testing and counseling regarding possible CF gene carrier status.

Laboratory Studies All men undergoing infertility evaluation and counseling should have a semen analysis. Two samples should be given one week apart with two or three days of abstinence prior to the sample for optimal analysis. Masturbation without use of lubricants is preferred. Normal semen parameters, based on World Health Organization criteria, are given in Table 18.2. More than one abnormal parameter is common. If ejaculate volume is low, the man should give a urine sample within minutes of ejaculation to look for sperm in the urine after ejaculate collection errors are ruled out (spilled specimen, incomplete collection). If sperm are found in the urine and his history is not indicative of obstruction, the man is considered to have retrograde

Table 18.2. Classification of semen abnormalities* Oligospermia Azoospermia Teratospermia Asthenospermia Leukocyto(Pyo)spermia *Based on WHO criteria.

<20 million sperm/ml Absence of sperm in the ejaculate <30 % normal morphology <50% sperm motile >1 million/ml WBCs

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ejaculation. Low sperm volume with no sperm in the post ejaculatory urine sample may be secondary to ejaculatory duct obstruction or ejaculatory duct absence. Both can be further evaluated by transrectal ultrasound. A reduced sperm count, or oligospermia, is defined as an ejaculate with <20 million sperm per milliliter. Azoospermia is defined as the absence of sperm in the ejaculate. Men with either should undergo hormonal analysis to determine if the source of low sperm count is pretesticular—the hypothalamic-pituitary axis, testicular—primary testicular failure, or post testicular—obstruction or absence of the vasa. Treatment ultimately depends on the source: medical intervention for hypothalamic abnormalities, sperm cryopreservation for severe oligospermia with primary testicular failure versus surgical correction for post testicular obstruction. Sperm should have tail movement regardless of motility. Asthenospermia or poor motility is most often seen in the setting of other semen abnormalities. Movement of the tails without progression may be secondary to presence of sperm antibodies or agglutination (clumping) of the sperm. If antibodies are present, couples have successfully had pregnancies after in vitro fertilization and intracytoplasmic sperm injection (ICSI). Teratozospermia is the presence of a disproportionate concentration of morphologically abnormal sperm. According to the World Health Organization (WHO), 30% of the sperm should be classified as structurally normal. Others who advocate for more stringent histologic grading use strict criteria to examine the sperm head. Using the so-called strict criteria, only four percent of sperm are typically defined as 18 normal. Morphologically abnormal sperm are less likely to fertilize an egg. Pyospermia-—white blood cells in the ejaculate is often treated with antibiotics though often without a documented source of infection. Patients are instructed to ejaculate frequently and a repeat semen analysis is completed after antibiotic treatment. There are various tests to analyze sperm function (such as electron microscopy for 0% motility) if the semen analysis appears normal. As a practical matter, these tests are not frequently performed as couples usually proceed to in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) if a functional problem is suspected. Depending on the history, physical exam and semen analysis, a patient may require hormone analysis. Useful serum tests include FSH, LH, testosterone, and prolactin. Endocrine evaluation will often assist in distinguishing between pretesticular and testicular causes of infertility though endocrine causes of male infertility are fairly rare. In clinical practice, the initial consult is sometimes performed without the required two semen analyses. Laboratory tests and sperm testing can be performed at a future date with follow up scheduled to review all results and formulate a possible treatment plan.

Radiologic Studies If an abnormality is noted on the testicular exam, an ultrasound should be performed immediately to look for testicular masses consistent with cancer. Men with testicular cancer can have reduced sperm counts and will often present seeking consultation for infertility. Men with a low ejaculate volume and a negative post-ejaculatory urinalysis, normal testosterone and palpable vasa should undergo

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transrectal ultrasound. Findings of dilated seminal vesicles (>1.5 cm in AP diameter) are suggestive of partial or complete obstruction. Patients with CBAVD may also have dilation of the seminal vesicles, but diagnosis of vasal agenesis is made by clinical examination alone and does not require ultrasound. Scrotal ultrasound is not indicated for nonpalpable varicocele as these are of little clinical significance.

Management The results of the diagnostic evaluation will guide treatment. Pretesticular etiologies are differentiated by endocrine analysis, and the specific findings will determine the treatment. High testosterone, low FSH and LH are indicative of anabolic steroid use. Low FSH, LH, T and high prolactin are suggestive of a prolactin pituitary tumor and warrant MRI evaluation. These etiologies are generally treated with medications or patient counseling. The most common cause of infertility is a varicocele. Clinically significant varicoceles are diagnosed by physical examination alone. Semen analysis and endocrine profile supplement the physical examination and aid the physician and the patient in determining whether surgical repair would be beneficial. Surgical management of varicocele includes microsurgical subinguinal varicocelectomy, laparoscopic ligation of the varicocele and radiologic embolization. Recent studies have indicated that varicoceles when repaired surgically may result in sperm in the ejaculate in 55% of azoospermic men though many of these men will require ART for successful pregnancy. Postoperative varicocele pregnancy rates can be as high as 40% for all grades of varicocele. Intervention for obstruction of the vas deferens or the epididymis is reconstruction: either vasovasostomy or vasoepididymostomy. As noted above, transrectal ul- 18 trasound can support a diagnosis of seminal vesicle or ejaculatory duct obstruction if dilated seminal vesicles (>1.5 mL), ejaculatory duct cysts or prostatic utricular cysts are present. Obstruction from a prostatic utricular cyst or ejaculatory duct obstruction is treated with transurethral resection of the cyst or transurethral resection of the ejaculatory ducts, respectively. Treatment of male infertility depends on the classification. Final treatment relies on diagnosis; however testicular causes, with the exception of a varicocele, are challenging to treat as they are often irreversible. Testicular biopsy is indicated when diagnosis cannot be made by physical exam, semen analysis, and endocrine profile. For example, azoospermic men with ductal obstruction will have normal hormone parameters and a normal testicular exam. Testicular causes of infertility are varied and may include cryptorchidism, viral orchitis, trauma, infections, obstruction, toxins and idiopathic etiologies. Men can attempt ART with sperm taken from the ejaculate, testicular extraction /biopsy or sperm aspiration from the epididymis even if the etiology of the infertility is idiopathic or is not amenable to surgical or medical correction.

Post Evaluation—Follow Up Care All patients should have a follow up semen analysis three months after any treatment, whether it is a medical or surgical. If there is no change in seminal parameters within a designated period of time (usually one year for surgery, and 1-2 spermiogenesis cycles for medical therapy) the couple should be counseled regarding ART, donor sperm, and adoption.

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Other Surgical and Medical Treatments for Infertility Retrograde ejaculation—sympathomimetic medications (ephedrine, pseudoephedrine). Urine can be alkalinized with oral sodium bicarbonate and the sperm separated and used for ART anejaculation in the spinal cord patient—electrostimulation to the glans penis or prostate/seminal vesicle. With the latter two, the patient must be pretreated with nifedipine and closely monitored for autonomic hypertensive dysreflexia. Urethral strictures—stricture ablation or reconstructive repair.

Key Points/Summary • Male factor infertility can be caused by pretesticular, testicular and post testicular abnormalities. History, physical exam, endocrine analysis and radiologic studies will guide diagnosis and treatment. • A full examination for male infertility should include a complete medical and reproductive history, a physical exam by a urologist or male reproductive specialist and at least two semen analyses. • An endocrine evaluation should be performed if there is an abnormal semen analysis, combined with impaired sexual function, and/ or physical exam findings suggestive of hormonal dysfunction. • Men with an abnormal testicular exam should have an immediate scrotal ultrasound to look for testicular masses consistent with cancer.

Suggested Reading 18

1. Goldstein M. Surgical management of male infertility and other scrotal disorders. In: Walsh PC et al, eds. Campbell’s Urology. Philadelphia: WB Saunders, 2002. 2. Sigman M, Jarow J. Male Infertility. In: Walsh PC et al, eds. Campbell’s Urology. Philadelphia: WB Saunders, 2002. 3. Lipshultz LI et al. Infertility in the Male. Baltimore: Mosby, 1997.

Chapter 19

Your Environment; Your Fertility— Is There a Link? Shanna H. Swan

Introduction Fertility, the ability of people to produce offspring, was a concept formerly applied only to the female. Demographers traditionally defined the fertility rate as the average number of live-born children per woman of reproductive age. However, fertility is one of the few measures that reflect the joint health of two individuals, and we have only recently begun to appreciate the extent to which fertility depends on the health and environment of both the male and female partner, as well as the interaction between partners. Males appear to be solely responsible for infertility in about 20% of infertile couples and contribute to infertility in another 30-40%. Using the demographic definition above, fertility declined 50% worldwide between 1950 and 2000. Between 1976 and 1998, the percent of women in the United States aged 35-39 who were childless increased from 10.5% to 19.8%. Moreover, the number of annual office visits for infertility increased from 600,000 to 2 million between 1968 and 1990. While these data indicate that fertility, at least by the demographers’ definition, has declined, they do not answer the critical question; Are a woman and her partner who desire pregnancy less able to conceive today than a comparable couple of the same age 50 years ago? They also do not address causes of the decline and, in particular, the role of environmental factors, which is the focus of this discussion. These trends undoubtedly reflect, at least in part, changes in nonenvironmental factors that affect a couple’s ability and/or desire to conceive. Women and their partners may choose to delay childbearing, resulting in decreased fertility when their first pregnancy attempt occurs at an older age. Several nonenvironmental factors may also influence trends in fertility: increasing access to and acceptability of contraception and assisted reproduction, changes in attitudes towards voluntary pregnancy termination, rates of sexually transmitted diseases, and the education of women and their role in the workforce. These factors vary geographically, temporally, and within ethnic/racial groups. Moreover, they are interrelated in complex ways. Several more useful measures of “fertility potential” are available. Fecundity (or fecundability) has been defined as, “the monthly probability of conception in the absence of contraception outside the gestation period and the temporary sterile period following the termination of a pregnancy”. The National Center for Health Statistics uses a measure of decreased fecundity, “impaired fecundity”, which they define as a woman’s inability to conceive or bear a child to term. The number of cycles of unprotected intercourse with-

Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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out conception, or “time-to-pregnancy” (TTP) is another useful measure and infertility is often diagnosed when TTP exceed 12 months (or cycles). Changes in fecundity and impaired fecundity in the US have been examined by comparing responses to the National Survey for Family Growth (NSFG) in 1982, 1988 and 1995. This analysis found increases in impaired fecundity over that time period, and the authors suggested that this change was due to more couples voluntarily delaying child-bearing. We questioned that interpretation, however, since the greatest increase in impaired fecundity was seen in women under 25, precisely the age group in which subfecundity, because of delayed childbearing, would be least likely. These data suggest that, at least in the US, fecundity declined between 1982 and 1995. Limited data have recently become available from the sixth cycle of the NSFG. However, data on live birth rates between 1990 and 2000 suggest a reversal of the decline seen in previous reports. This reversal is seen across race/ethnic groups and for most age groups. Data on impaired fecundity, perhaps the most relevant statistics for assessing trends in involuntary subfertility, are not yet available but are expected later in 2006. On balance, the limited data available do not allow us to draw any conclusions about trends in fecundity. Reproductive health is affected by the interaction of multiple factors, among them age, genetics, nutrition, lifestyle behaviors, reproductive tract infections, stress, and pharmaceutical use. In recent years, scientists have increasingly reported evidence that certain pollutants in the environment may also play an important role, contributing at least in some cases to underlying causes of fertility problems. A surprisingly wide range of compounds has been implicated, particularly in studies of laboratory animals and wildlife, although for the most part the data on the effects of these chemicals on human fertility is still inconclusive. 19 What is now clear is that environmental chemicals may impact fertility at multiple developmental stages, with differing effects. Many chemical exposures have been shown to impact human and/or animal fertility when exposure occurs during adulthood. These are summarized in Table 19.1. Adult exposures tend to cause changes that are transient; for example, men exposed to DBCP who were azoospermic recovered the ability to produce sperm once exposure had ceased. On the other hand, exposures during development, summarized in Table 19.2, cause changes that are permanent (such as DES-caused cervical and uterine abnormalities) and often cause effects at much lower levels than those needed to cause changes in adults. These tables are not intended to be exhaustive but rather to give examples of such exposures.

The Environment and Reproductive Factors in the Male One action of environmental exposures on fertility is through their effect of semen quality. This question was first examined in the workplace, where exposures are usually far higher than those encountered environmentally. There is a large body of literature demonstrating strong relationships between work place exposures and decreases in semen quality and other factors that can affect a couples’ fertility. For example, widespread concern was generated in the late 1970s following reports of sterility and decreased sperm counts in workers exposed to the agricultural nematocide DBCP. The chlorinated hydrocarbon pesticide chlordecone (kepone) was withdrawn because of its severe effects on semen quality. Ethylene dibromide (EDB) was an active component of approximately 100 pesticides. Its use was severely restricted in 1984 due to reduced sperm counts and semen quality. For a more complete treatment, see Schettler et al, Generations at Risk (1999).

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More recently, adult exposure to several pollutants at low environmental levels has been linked to reduced semen quality. If these exposures have increased over time, these could, in principle, contribute to the reported declines in sperm concentration. For example, after we saw significantly poorer semen quality in men living in agricultural mid-Missouri compared to men living in urban centers, we examined pesticide metabolite levels in the men’s urine. We found several (alachlor, atrazine and diazinon, particularly) to be linked to poor semen quality. A range of other low-level environmental exposures have been linked to impaired semen quality including phthalates, PCBs and DDT, maternal smoking, water chlorination by-products and air pollution. Does it follow that men (or couples) exposed to these environmental chemicals have impaired fecundity? Among Danish couples attempting to conceive for the first time, men whose initial sperm concentration was less than 40 x 106/ml had significantly reduced fecundability and took longer to conceive. In mid-Missouri, sperm concentration of 35% of fertile men fell below 40 x 106/ml, a point below which fecundity decreases significantly. Among men living in central Minneapolis, only 19% fell below this cut-off. Since poor semen quality in these men was linked to pesticide exposure, it is plausible—though far from proven—that these chemicals can impair human fecundity. We cannot, however, conclude that a decrease in sperm count directly implies a decrease in fecundity on a population level. Even if semen quality is declining, there may be no net decrease in couple fecundity. For example, if couples trying to conceive are better educated (such as through the use of home kits to detect ovulation), this will tend to increase conception success. Increased female fertility, for example, as a result of the declining incidence of sexually transmitted disease, which has occurred in the United States since 1980 (CDC 2000), will also in- 19 crease couple fecundity.

The Environment and Reproductive Factors in the Female Measures of female fertility are more difficult to quantify. For example, a measure analogous to sperm count, ovarian follicular number, is more difficult to ascertain, as it requires a vaginal ultrasound. Thus, this endpoint has been rarely studied. However, failure to conceive may be the reflection of a hidden increase in early pregnancy loss. Since a marker for early loss must be ascertained in urine samples collected soon after conception, this too is logistically difficult and few studies have related this endpoint to environmental exposures. Endometriosis is a fertility-related endpoint that has been examined with respect to some environmental exposures, notably dioxin; human data on this association are conflicting. Alterations in menstrual function, such as short follicular phase, may contribute to impaired fecundity. These studies are also quite difficult since they require prospective collection of daily urine samples and extensive hormonal analysis. For these reasons, there are far fewer studies of environmental causes of impaired female factors than male. However, many environmental agents that have been shown to adversely effect male fertility have also been related to impaired female reproductive function when that has been examined. Examples include; cigarette smoke, radiation, lead, ethylene glycol ethers and water chlorination by-products (total trihalomethane).

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Pesticides Includes insecticides, fungicides, herbicides, rodenticides, and fumigants

Disinfection by-products Result of drinking water treatment Ethylene oxide Chemical sterilizer used in dental and medical practices Heavy metals Lead, mercury, manganese, cadmium

Exposure Sources and Uses Bisphenol A (BPA) Monomer used to make polycarbonate plastic, resins Chlorinated hydrocarbons Dioxins/furans, PCBs, some pesticides (organochlorines) and wood preservative (pentachlorophenol)

Fetal loss^ (H, A) Reduced fertility‡ (H) Hormonal changes (A) Menstrual irregularitiesΔ (H) Menstrual irregularitiesΔ (H) Reduced fertility‡ (H, A) Fetal loss^ (H, A)

Decreased semen quality* (H) Hormonal changes (H, A)

Menstrual irregularitiesΔ (H, A) Hormonal changes (H, A) Reduced fertility‡ (A) Endometriosis (H, A) Fetal loss^ (H, A) Fetal loss^ (H) Menstrual irregularitiesΔ (H) Fetal loss^ (H, A)

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Decreased semen quality* (H, A) Reduced fertility‡ (H, A) Fetal loss in female partner (H) Sperm chromosome abnormalities (H) Hormonal changes (H)

Decreased semen quality* (H) Reduced fertility‡ (H, A) Hormonal changes (H)

Decreased semen quality* (H) Fetal loss in female partner (H)

Decreased semen quality* (H,A)

Reported Effects in Males (in animals (A) and/or humans (H)) Decreased semen quality* (A)

Reported Effects in Females (in animals (A) and/or humans (H)) Chromosomal abnormalities, (A) Recurrent miscarriage (H)

Table 19.1. Chemical exposures during adulthood that may alter fertility-related endpoints

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Reported Effects in Males (in animals (A) and/or humans (H)) Decreased semen quality* (H)

Decreased semen quality* (H)

Decreased semen quality* (H) Reduced fertility‡ (H) Fetal loss in female partner (H) Hormonal changes (H) Reduced fertility‡ (H) Decreased semen quality (H) Hormonal changes (H)

Reported Effects in Females (in animals (A) and/or humans (H)) Fetal loss^ (A) Menstrual irregularitiesΔ (A) Reduced fertility‡ (A) Fetal loss^ (H) Reduced fertility‡ (H) Reduced fertility‡ (H) Fetal loss^ (H, A) Hormonal changes (H, A) Menstrual irregularitiesΔ (H)] Reduced fertility‡ (H) Fetal loss (H) Early menopause (H) Hormonal changes (H)

(H) Data from human studies. (A) Data from human studies. *, Decreased semen quality may include decreased sperm concentration, sample volume, motility or percent normal morphology. ‡, Reduced fertility may include infertility, increased time to pregnancy (reduced fecundity), greater proportion with failure to conceive in 12 months. Δ, Menstrual irregularities may include altered cycle length, irregular cycles, abnormal bleeding, anovulation in humans, estrous cycle irregularities in animals. ^, Fetal loss may include spontaneous abortion (clinical or sub-clinical and stillbirth). Table modified with permission from: Challenged Conceptions: Environmental Chemicals and Fertility. Carlson A, Eddy E, Giudice L et al, eds. A Report of the Fertility/Pregnancy Compromise Working Group of the Collaborative on Health and the Environment. 2005.

Exposure Sources and Uses Phthalates Plasticizers added to soften plastics like PVC; also in cosmetics, toys, pharmaceuticals, and medical devices Glycol ethers Paints, varnishes, thinners, printing inks, semiconductor industry Other solvents Benzene, toluene, xylene, styrene, 1-bromopropane, 2-bromopropane, perchloroethylene, trichloroethylene, and others Cigarette smoke Active and/or passive smoking

Table 19.1. Continued

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19

Cigarette smoke Maternal smoking Diethylstilbestrol (DES) Pharmaceutical thought (erroneously) to prevent recurrent or threatened spontaneous abortion

Organochlorine pesticides DDT/DDE, linuron, others Pesticides Includes insecticides, fungicides, herbicides, rodenticides, and fumigants

Exposure Sources and Uses Bisphenol A (BPA) Monomer used to make polycarbonate plastic, resins Chlorinated hydrocarbons Dioxins/furans, PCBs

Malformations of reproductive tract≠ (H,A) Altered hormone response (A)

Malformations of reproductive tract≠ (H,A) Altered hormone response (A) Menstrual irregularitiesΔ (H,A) Reduced fertility≠ (H,A) Uterine fibroids (A) ] Fetal loss (H)

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Altered sex ratio (H,A) Altered puberty onset (A) Malformations of reproductive tract≠ (H,A) Reduced fertility (A) Decreased semen quality* (H)

Malformations of reproductive tractΔ (A)

Reported Effects in Males (in animals (A) and/or humans (H)) Altered prostate development (A) Decreased semen quality* (A) Hormonal changes (A) Malformations of the reproductive tract≠ (H,A) Decreased semen quality* (H,A) Altered sex ratio (H,A) Altered puberty onset (H)

Altered sex ratio (H,A) Altered puberty onset (A)

Malformations of the reproductive tract≠ (A) Altered estrous cycle (A) Reduced fertility‡ (A) Hormonal changes (H, A) Altered sex ratio (H,A) Altered puberty onset (H) Delayed time to pregnancy (H)

Reported Effects in Females (in animals (A) and/or humans (H)) Altered puberty onset (A) Obesity (A)

Table 19.2. In utero exposures that may alter fertility-related endpoints

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Hormonal changes (A) Altered puberty onset (A)

Hormonal changes (A)

Reported Effects in Females (in animals (A) and/or humans (H)) Hormonal changes (A) Altered puberty onset (H)

Hormonal changes (A) Decreased semen quality*(A) Decreased testes size (A)

Decreased semen quality* (A)

Shortened anogenital distance (H) Malformations of reproductive tract≠ (A) Hormonal changes (A) Decreased semen quality* (A) Hormonal changes (A)

Reported Effects in Males (in animals (A) and/or humans (H))

*, Decreased semen quality may include decreased sperm concentration, sample volume, motility or percent normal morphology. ‡, Reduced fertility may include infertility, increased time to pregnancy (reduced fecundity), greater proportion with failure to conceive in 12 months. Δ, Menstrual irregularities may include altered cycle length, irregular cycles, abnormal bleeding, anovulation in humans, estrous cycle irregularities in animals. ^, Fetal loss may include spontaneous abortion (clinical or sub-clinical and stillbirth). ≠, malformations of the reproductive tract: In males, may include shortened anogenital distance, undescended testicles (cryptorchidism), and abnormalities of the testicles or epididymis. In females, may include hypoplastic ovaries, reduced number of follicles, and structural abnormalities of the oviducts, uterus, cervix, and/or vagina. Table modified with permission from: Challenged Conceptions: Environmental Chemicals and Fertility. Carlson A, Eddy E, Giudice L et al, eds. A Report of the Fertility/Pregnancy Compromise Working Group of the Collaborative on Health and the Environment. 2005.

Exposure Sources and Uses Heavy metals Lead, mercury, manganese, cadmium Phthalates Plasticizers added to soften plastics; also found in cosmetics, toys, pharmaceuticals, and medical devices Perfluorinated compounds (PFOS, PFOA) Used to make fabrics stain-resistant/ water-repellant; in coating of cooking pans, floor polish, insecticides Polybrominated diphenyl ethers (PBDEs) Flame retardants found infurniture foam, mattresses, textiles, and electronics Octylphenol/nonylphenol Surfactants

Table 19.2. Continued

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Factors That May Alter a Couples’ Fertility While we have focused here on environmental exposures, a wide range of environmental, infectious, endocrine, lifestyle and genetic factors may play a role in infertility. These factors may result in a range of clinical endpoints including fetal loss (both subclinical and clinical), menstrual dysfunction, endometriosis, uterine fibroids, and hormonal irregularities. Clearly, a full discussion of all factors and their influence on each of these endpoints is beyond the scope of this brief discussion. However, several general comments may be helpful. Exposure to factors that can alter fertility may occur at any time from gestation to adulthood. Adults today carry an enormous body burden of chemicals of which we are likely unaware since these exposures are “invisible” except by examining levels in human samples (such as blood and urine). In a study led by Mount Sinai School of Medicine in New York, in collaboration with the Environmental Working Group and Commonweal, researchers at two major laboratories found an average of 91 industrial compounds, pollutants, and other chemicals in the blood and urine of nine volunteers, with a total of 167 chemicals found in the group (http:// www.ewg.org/reports/bodyburden/). Like most of us, the people tested do not work with chemicals on the job and do not live near an industrial facility. While it is not possible to provide full toxicological profiles of the chemicals that are prevalent today, an overview of the contaminants found most frequently in the Mt. Sinai survey may be useful. PCBs, which were used as industrial insulators and lubricants prior to being banned in the US in 1976, persist for decades in the environment and accumulate up the food chain, to man. A recent study found PCBs to be associated with reduced semen quality. There are 210 different 19 dioxins and furans, which are by-products of PVC production, industrial bleaching, and incineration. These chemicals can also persist for decades in the environment and are found in air, water, soil and food. Dioxins are developmental toxicants affecting the developing endocrine (hormone) system. For example, a significant deficit of male babies was reported among couples exposed to high levels of dioxin. Organochlorine pesticides (such as DDT and chlordane) also accumulate up the food chain to man and have been shown to cause cancer and numerous reproductive effects. There are a range of organophosphate insecticide metabolites, such as breakdown products of chlorpyrifos and malathion which are potent nervous system toxicants found most commonly as residues in food. Metals, including lead, mercury, arsenic and cadmium, have long been shown to cause lowered IQ, developmental delays, behavioral disorders and cancer at doses found in the environment. Most exposures to lead are from lead paint. Most exposures to mercury are from fish, particularly canned tuna. The main sources of arsenic exposures are from arsenic (CCA) treated lumber and contaminated drinking water. Sources of cadmium exposure include pigments and bakeware. Phthalates, plasticizers found in a wide range of cosmetic and personal care products, have recently been associated with reduced semen quality and in animal models cause birth defects of male reproductive organs. Unfortunately, we cannot reduce our body burden of past exposures, most of which persist in the body for decades. Work place exposures, which may be avoidable, can be far higher, and it is in those settings that we have learned much of what we know about human reproductive risks. Workers, particularly those attempting

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to conceive, should be provided with full information on the reproductive risks of the agents with which they are working. If economics permit, it would be prudent for those of reproductive age to avoid occupational exposure to reproductive toxins. Setting aside fetal and childhood exposures and occupational setting exposures, we are left with exposure to currently used chemicals in the home and the surrounding environments. The routes of these exposures (i.e., water, air, food, skin) are limited. There are steps that one can take to limit exposure via each of these routes. There are several nongovernmental organizations that have produced excellent web-based facts sheets for consumers that provide practical information based on good science. These are provided below.

Key Points Though data suggest causal links between environmental exposures and fertility-related endpoints, many uncertainties remain, particularly with respect to human fertility. Fertility and the related endpoint, impaired fecundity, can be caused by female, male, couple-dependent factors, or some combination of these. Identifying the role of environmental factors, on the clinical level, will seldom be possible, except for extreme examples, such as pharmaceuticals (e.g., DES), or some occupational exposures (such as DBCP). Nonetheless, environmental factors may well be having adverse effects on population fertility. An awareness of the emerging evidence can help clinicians educate their patients about potential exposures to avoid (pesticides, heavy metals, phthalates). Unraveling the extent of these effects, and the principal agents of concern, are the challenges now faced by researchers in this field.

Web-Based Resources General Information on Fertility and the Environment An excellent overview, used extensively in this review, Challenged Conceptions: Environmental Chemicals and Fertility, Carlson A, Eddy E, Giudice L et al, eds. A report of the Fertility/Pregnancy Compromise Working Group of the Collaborative on Health and the Environment, October 2005. Proceeding of February 2005 Vallombrosa Workshop Understanding Environmental Contaminants and Human Fertility Compromise: Science and Strategy (http://www.healthandenvironment.org/ working_groups/fertility). The Collaborative for Health and the Environment (CHE) maintains a web page that provides accurate and timely information on the environment and fertility (http:/ /www.healthandenvironment.org/infertility) and more general information on environment and health http://www.healthandenvironment.org. Infertility and Related Reproductive Disorders by Ted Schettler includes an excellent discussion of the role of the environment (http://www.healthandenvironment.org/ infertility/peer_reviewed).

Food Food News, an affiliate of the Environmental Working Group (EWG) has compiled a Shoppers Guide for Pesticide in Produce. The report suggests substituting organic for conventional produce that is consistently contaminated with pesticides and, when organic products are not a choice, to consume fruits and vegetables with consistently low pesticide loads (http://www.foodnews.org/walletguide.php).

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Water The EWG has conducted an extensive survey of drinking water sources by state and compiled the Clean Water Report Card (that will help consumers evaluate the quality of their own drinking water (http://www.ewg.org/reports/reportcard/ home.html)

Personal Care Products The EWG has conducted an extensive, chemical-by-chemical evaluation of personal care products called Skin Deep (http://www.ewg.org/reports/skindeep/).

Fish Consumption A report with a pocket size shopping guide on contaminants in fish, Healthy Fish, Healthy Families has been compiled Physicians for Social Responsibility (http:/ /www.mercuryaction.org/fish/).

Suggested Reading

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1. Bonde JP, Ernst E, Jensen TK et al. Relation between semen quality and fertility: A population-based study of 430 first-pregnancy planners. Lancet 1998; 352:1172-1177. 2. Challenged Conceptions: Environmental Chemicals and Fertility. In: Carlson A, Eddy E, Giudice L et al, eds. A Report of the Fertility/Pregnancy Compromise Working Group of the Collaborative on Health and the Environment. 2005 (http:// www.healthandenvironment.org/working_groups/fertility) 3. Carlsen E, Giwercman A, Keiding N et al. Evidence for decreasing quality of semen during past 50 years. BMJ (Clinical Research Ed) 1992; 305:609-613. 4. Centers for Disease Control and Prevention. Tracking the Hidden Epidemics: Trends in STDs in the United States 2000. Atlanta: Centers for Disease Control and Prevention, 2001. 5. Chandra A, Stephen EH. Impaired fecundity in the United States: 1982-1995. Fam Plann Perspect 1998; 30:34-42. 6. Duty SM, Silva MJ, Barr DB et al. Phthalate exposure and human semen parameters. Epidemiology 2003; 14:269-277. 7. Evenson DP, Jost LK, Perreault SD et al. Application of the sperm chromatin structure assay to the Teplice Program semen studies: A new method for evaluating sperm nuclear chromatin damage. In: Sram RJ, ed. Teplice Program: Impact of Air Pollution on Human Health. Prague: Academia, 2001:167-180. 8. Faroon O, Kueberuwa S, Smith L et al. ATSDR evaluation of health effects of chemicals. II. Mirex and chlordecone: Health effects, toxicokinetics, human exposure, and environmental fate. Toxicol Ind Health 1995; 11:1-203. 9. Fenster L, Waller K, Windham G et al. Trihalomethane levels in home tap water and semen quality. Epidemiology 2003; 14:650-658. 10. Glebatis DM, Janerich DT. A statewide approach to diethylstilbestrol—the New York program. N Engl J Med 1981; 304:47-50. 11. Goldsmith JR. Dibromochloropropane: Epidemiological findings and current questions. Ann N Y Acad Sci 1997; 837:300-306. 12. Hauser R, Chen Z, Pothier L et al. The relationship between human semen parameters and environmental exposure to polychlorinated biphenyls and p,p’-DDE. Environ Health Perspect 2003; 111:1505-1511. 13. Jensen TK, Jorgensen N, Punab M et al. Association of in utero exposure to maternal smoking with reduced semen quality and testis size in adulthood: A cross-sectional study of 1,770 young men from the general population in five European countries. Am J Epidemiol 2004; 159:49-58. 14. Mocarelli P, Brambilla P, Gerthoux PM et al. Change in sex ratio with exposure to dioxin. Lancet 1996; 348:409. 15. Schettler T, Solomon G, Valenti M et al. Generations at risk: Reproductive Health and the Environment. Cambridge: MIT Press, 1999.

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16. Schrader SM, Turner TW, Ratcliffe JM. The effects of ethylene dibromide on semen quality: A comparison of short-term and chronic exposure. Reproductive Toxicology 1988; 2:191-198. 17. Seibel MM. Infertility: A comprehensive text. In: Seibel MM, ed. Diagnostic Evaluation of an Infertile Couple. Stamford: Appleton and Lange, 1997:3-28. 18. Slutsky M, Levin JL, Levy BS. Azoospermia and oligospermia among a large cohort of DBCP applicators in 12 countries. Int J Occup Environ Health 1999; 5:116-122. 19. Swan SH, Elkin EP, Fenster L. Have sperm densities declined? A reanalysis of global trend data. Environ Health Perspect 1997; 105:1228-1232. 20. Swan SH, Hertz-Picciotto I. Reasons for infecundity. Fam Plann Perspect 1999; 31:156-157. 21. Swan SH, Kruse RL, Liu F et al. Semen quality in relation to biomarkers of pesticide exposure. Environ Health Perspect 2003a; 111:1478-1484. 22. Swan SH, Brazil C, Drobnis EZ et al. Geographic differences in semen quality of fertile U.S. males. Environ Health Perspect 2003b; 111:414-420. 23. United Nations Population Information Network (POPIN) dictionary of demographic and reproductive health terminology (1990). Retrieved 2002, (from http://www.un.org/ popin/). 24. Ventura SJ, Abma JC, Mosher WD et al. Estimated pregnancy rates for the United States, 1990-2000: An update. National Vital Statistics Report 2004; 52:1-9. 25. Whorton D. The effect of occupation on male reproductive function. In: Spira A, Jouannet P, eds. Human Fertility Factors. Paris: Editions INSERM, 1981:339-348.

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Index

213

A

C

Acupuncture 100, 189, 190, 192 Adenoma 15, 32, 68, 70, 90-92, 136, 148, 149, 165, 171 Adhesiolysis 150, 154 Adrenarche 10, 12 Age 3, 10-15, 17, 20, 21, 23, 33, 48, 56, 57, 62, 65, 71, 82, 84, 88, 107, 108, 113, 115, 116, 118, 137, 138, 145, 149, 151, 153, 159, 163, 168, 179, 184-186, 191, 196, 201, 202, 209 Alternative/complementary treatment 100, 105, 110, 115 Amenorrhea 4, 17, 18, 20, 21, 23-25, 28, 29, 31-35, 39, 45, 47, 49, 50, 65, 68-70, 85, 92, 107, 110, 121, 124-126, 146, 147, 149, 162, 165 Androgen excess 47, 48, 50, 51, 53, 55 Androgen insensitivity syndrome (AIS) 16, 20, 31, 35, 121 Antifibrinolytic agent 44 Antral follicle count (AFC) 34, 129, 138, 181 Appetite suppressant 59 Aromatase inhibitor 15, 87, 166, 170 Ascorbic acid 191 Asherman’s syndrome 29, 31, 35, 162 Asthenospermia 197, 198 Azoospermia 19, 184, 194, 196-198

Calcium supplement 100, 105, 115 Cardiovascular disease 51, 56-59, 62, 71, 77, 108, 115, 116 Cervical factor 145, 146 Chaste berry 191 Chemicals 120, 196, 202-205, 207-210 Classification of endometriosis 84, 156 Clomiphene citrate (CC) 137, 149, 151, 166, 168-171, 176 Combined oral contraceptive (COC) 67, 70-75, 78-82 Contraception 7, 35, 44, 53, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 80, 81, 82, 145, 147, 201 Contraceptive vaginal ring 66, 68, 73, 74, 82, 109, 111, 112 Controlled ovarian hyperstimulation (COH) 165, 167, 168, 176, 178 Craniopharyngioma 19, 32, 91

B Bariatric surgery 61, 62 Bisphosphonate 115 Body mass index (BMI) 10, 19, 51, 56, 57, 59-62, 146, 149, 179, 190 Breast cancer 19, 56, 70, 71, 75, 77, 80, 111, 114, 116, 117, 168

D Delayed puberty 15-17, 21 Depo-Provera 76, 77, 82 Depressive disorder 97, 98, 100 Diet 54, 58-63, 96, 100, 101, 105, 111, 115, 191-193 Distal tubal occlusion 128, 156, 158 Dopamine 3, 19, 35, 59, 89, 90, 91, 92, 93, 94, 104, 111, 149, 166, 171, 172 Dysfunctional uterine bleeding (DUB) 36-41, 43-45

Index

INDEX

Index

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E

Gonadotropin 3-6, 8-11, 14-17, 19, 21, 28, 32-34, 38, 45, 86, 98, 99, 104, 107, 108, 125, 138, 146, 149-151, 155, 161, 165-168, 171-176, 179, 183, 186, 189-191 Gonadotropin therapy 151, 171, 172, 176 Gonadotropin releasing hormone (GnRH) 3-14, 19, 21, 29, 32, 33, 45, 48, 85-88, 98, 99, 104, 141, 146, 155, 161, 165, 171, 173, 189, 190 analog 86, 88, 161 pulse generator 4, 8, 10, 12, 48, 189

Ectopic pregnancy 37, 38, 40, 68, 69, 125, 147, 158, 159, 182, 186 Emergency contraception (EC) 59, 72-75, 79-82 Endometrial ablation 44, 45 Endometrial cavity 7, 31, 84, 125, 126, 128-130, 135, 141, 150 Endometriosis 37, 45, 72, 76, 84-88, 128, 129, 139-141, 145-147, 149, 150, 152-156, 163, 165, 166, 176, 179, 181, 182, 203, 204, 208 Environment 6, 84, 112, 120, 137, 153, 180, 196, 201-203, 205, 207-209 Estrogen 3-6, 8-10, 13-16, 18-21, 23, 25, 27, 29, 32, 35, 38, 43, 53, 67, 70, 72, 75, 76, 82, 84-87, 90, 99, 108-118, 124, 146, 148, 149, 151, 161, 162, 165, 168-170, 172, 191, 195 Estrogen replacement therapy (ERT) 110, 111, 112, 115-118 Etiology 12, 13, 21, 25, 28, 89, 96, 99, 165, 166, 189, 191, 199 Eugonadal 25, 28, 29, 31 Extended use contraception 70

F Fecundity 20, 145, 146, 151, 152, 165, 201-203, 205, 207, 209 Fertility 19, 20, 35, 43, 45, 76, 86, 108, 141, 146, 150, 152-154, 159, 165, 180, 182, 189, 190-192, 194, 196, 201-209 Fimbrioplasty 158 Follicular phase 4-8, 49, 97, 98, 103, 161, 181, 203

G Galactorrhea 32, 90-92, 111, 149, 179

H Heavy menstrual bleeding 36 Herbal medicine 60, 100, 101, 105, 112, 191, 192, 196 Hormone replacement therapy (HRT) 39, 109, 110, 112, 116-119, 149 Hot flashes 68, 86, 98, 107-112, 170 Human chorionic gonadotropin (hCG) 8, 9, 14, 20, 38, 125, 167, 170-176, 185, 186 Hydrosalpinx 126, 128-130, 135, 150, 158 Hyperandrogenism 44, 48, 49, 121, 136, 183 Hypergonadotropic hypogonadism 17-19, 32-34 Hypogonadism 15-20, 23, 25, 27, 29, 30, 32-35, 86, 91-93, 146, 166, 171, 175, 176, 195, 197 Hypogonadotropic hypogonadism 17, 19, 20, 32, 33, 171, 175, 176, 195, 197 Hysterectomy 45, 87, 97, 116, 184 Hysterosalpingogram 41, 42, 126, 129, 141, 148, 151, 153, 162, 165, 181 Hysteroscopy 41-45, 129, 135, 150, 161, 162, 181

I Impaired glucose tolerance 51 Implanon 75, 77 Implantable contraception 77 Implantation 3, 8, 9, 67, 79, 80, 126, 150, 151, 158, 159, 163, 178, 179, 184, 185, 190, 192 In vitro fertilization (IVF) 18, 19, 129, 135, 138, 140, 141, 149-154, 156, 158, 159, 162, 163, 165, 166, 169, 173, 176, 178, 179, 181-187, 190-192, 198 Infertility 8, 25, 28, 31, 39, 42, 56, 79, 82, 84, 88, 92, 93, 124, 126, 128, 135-139, 141, 145-154, 158, 161-163, 165-167, 176, 179-185, 187, 189-202, 205, 207-209 Infertility treatment 56, 138, 145, 176, 181, 182, 190-193 Inhibin 4, 5, 8, 11, 12, 107 Injectable hormonal contraception 74 Insemination 19, 129, 135, 149, 151, 162, 163, 166, 167, 174, 175, 183, 195 Insulin resistance 31, 35, 48, 51, 53-55, 180, 181, 183 Intracytoplasmic sperm injection (ICSI) 19, 151, 178, 183, 185, 187, 198 Intrauterine contraception (IUC) 78-80, 82 Intrauterine device (IUD) 37, 44, 65, 66, 69, 78, 87, 147

K Kallman syndrome 20, 32, 195, 197 Klinefelter syndrome 19, 180

L L-arginine 192 Laparoscopic ovarian diathermy (LOD) 171, see also Ovarian drilling Laparoscopic uterosacral nerve ablation (LUNA) 87

215

Laparoscopy 85-87, 128, 129, 139-141, 147, 153, 154, 158, 159, 163, 178, 181 Levonorgestrel-releasing intrauterine system (LNG-IUS) 44, 45, 78, 79, 81, 82 LH surge 6-8, 148, 149, 167, 170-173, 180 Luteal phase 4, 7-9, 96-98, 103-106, 148, 171, 180, 191 Luteal phase dosing of serotonin reuptake inhibitors 103, 104, 106

M Male infertility 181, 194, 195, 198-200 McCune-Albright syndrome (MAS) 12, 13, 15 Menarche 3, 10, 11, 15, 21, 23, 33, 36, 39, 47, 49, 147 Menopause 3, 12, 36, 41, 45, 57, 85, 86, 99, 107-113, 115-118, 138, 165, 172, 178, 184, 205 Menorrhagia 36, 38-41, 72, 141 Menstrual irregularity 48, 50-53, 55, 93, 191, 204-207 Menstruation 4, 9, 11, 20, 31, 32, 38, 84, 86, 107 Metabolic syndrome 31, 35, 51, 57, 58 Metaplastic theory 84 Metformin 52, 54, 60, 149, 161, 166, 170, 171, 176, 183 Metrorrhagia 36 Mifepristone 87 Mind/body technique 192 Mirena 44, 78, 82 Mullerian anomalies 20, 21, 35, 121, 122, 124, 125, 135, 136, 180, 184 Multiple gestation/pregnancy 125, 185-187

N Nonsteroidal anti-inflammatory drug (NSAID) 44 NuvaRing 73

Index

Index

Index

216

Reproductive Endocrinology and Infertility

O

Pituitary 3, 5, 9-12, 14, 17, 19-21, 25, 32, 48, 53, 86, 89-92, 94, 95, 107, 108, 136, 146, 148, 149, 151, 159, 165, 169-173, 189-191, 195-199 Polycystic ovary syndrome (PCOS) 12, 15, 21, 29, 31, 35, 40, 41, 47-55, 58, 136, 148, 149, 152, 159, 165, 167-171, 173, 174, 176, 180, 181, 183 Precocious puberty 12-15, 21 Pregnancy 5, 7-9, 16, 18, 19, 21, 25, 33-35, 37-41, 43-45, 52-54, 56, 62, 65, 68, 69, 72, 75-77, 79-82, 89, 90, 92-94, 121, 124, 125, 128, 129, 135, 138, 141, 145-147, 149-151, 153-156, 158, 159, 161-163, 167-176, 178, 179, 182-187, 190, 196, 198, 199, 201-203, 205-207, 209 Preimplantation genetic diagnosis (PGD) 179, 184, 187 Premenstrual dysphoric disorder (PMDD) 72, 96-106 Premenstrual syndrome (PMS) 68, 96-105 Presacral neurectomy 87 Primary amenorrhea 23, 29, 31, 32, 121, 124 Progesterone 3, 4, 7-9, 12, 13, 16, 18, 21, 25, 35, 38, 40, 41, 43, 49, 53, 74, 76, 86, 99, 104, 109, 110, 116, 117, 122, 146, 148, 167, 169, 172, 180, 181, 191 Progestin 16, 18, 19, 21, 25, 35, 43, 44, 52, 53, 66-68, 70, 72, 74-77, 79-82, 86, 110, 111, 115, 117, 165, 174 Progestin challenge test 16, 25, 165 Progestin only pill (POP) 66, 74, 75, 77, 79, 81, 82 Prolactin (PRL) 14, 15, 19, 21, 25, 32, 33, 49, 50, 89-95, 99, 136, 146, 148, 149, 165, 171, 181, 191, 195, 197-199 Prolactinoma 19, 29, 32, 34, 90-95 Proliferative phase 6, 8, 38, 130 Prospective daily rating 97 Psychotherapy 101

Obesity 39, 43, 50, 51, 56-63, 70, 96, 117, 146, 195, 206 Oligospermia 194, 196-198 Oocyte donation 18, 149, 152, 165, 166, 187 Operative hysteroscopy 150, 162 Oral contraceptive 18, 21, 43, 53, 67, 70, 79, 81, 85, 88, 96, 104, 147 Ortho Evra 72 Osteoporosis 19, 35, 77, 82, 93, 108, 113-115, 119, 149, 168 Ovarian drilling 159, 161, see also Laparoscopic ovarian diathermy Ovarian failure 17, 18, 21, 29, 33-35, 50, 137, 146, 149, 152, 159, 178, 179, 181, 184, 187 Ovarian hyperstimulation syndrome (OHSS) 152, 167, 168, 170, 173-176, 183, 186 Ovarian reserve 137, 138, 148, 151, 181, 184, 185 Overweight 54-57, 72, 76, 168 Ovulation 4-8, 18, 20, 21, 29, 35, 38, 40, 41, 43-45, 47, 54, 67, 70, 74, 76, 79, 86, 94, 107, 122, 146, 148-153, 159, 165-176, 179, 180, 183, 187, 190, 191, 194, 195, 203, 205, 207 Ovulation induction 18, 20, 21, 35, 44, 149, 150, 152, 159, 165-176, 183, 187, 190 Ovulatory dysfunction 39, 41, 47, 56, 146, 148, 152, 165, 185, 192

P Pelvic inflammatory disease (PID) 66, 68, 69, 79, 80, 82, 125, 126, 130, 147, 149, 154, 156, 163, 179, 180, 187 Pelvic magnetic resonance imaging (MRI) 41, 42 Pelvic ultrasound 49, 167 Perimenopause 98, 107, 108 Phytoestrogen 111, 191

R Retrograde menstruation 84

S Saline sonohysterogram (SSH) 41, 42, 44, 45 Scrotal ultrasound 195, 199, 200 Secondary amenorrhea 23, 29, 34, 125, 126 Secretory phase 8, 9, 38, 43, 180 Selective estrogen receptor modulator (SERM) 114, 149, 151, 168 Selective serotonin reuptake inhibitor (SSRI) 90, 101-106 Semen analysis 20, 147, 148, 153, 165, 181-183, 195, 197-200 Serotonin reuptake inhibitor (SRI) 90, 98, 99, 101, 104, 105, 110 Sonohysterogram 41, 42, 126, 129, 135, 141, 181 Spermatogenesis 20, 146, 180, 194 Spironolactone 52, 53, 104 Sterilization 69, 78, 82, 147, 156, 158, 159, 182 Surrogacy 178, 184, 187

T Tanner stage 10, 11 Teratozospermia 198 Testosterone 11-15, 19, 20, 28, 31-34, 48-50, 52-54, 108-110, 118, 167, 181, 190, 194-196, 198, 199 Thelarche 10-12, 15, 21, 121 Transvaginal ultrasonography 42, 45, 181 Treatment 12, 14, 18-21, 34, 35, 38, 41, 43-45, 51-61, 64, 72, 79, 84-87, 92-96, 98-107, 109-112, 114-116, 119-122, 124, 129, 137-139, 141, 145, 146, 149-151, 153-156, 158, 159, 161-163, 165-172, 176, 178-184, 187, 189-193, 196, 198-200, 202, 204

217

Tubal catheterization 159 Tubal disease 42, 128, 149, 150, 158, 167, 181, 182, 186 Tubal infertility 79, 82 Turner’s syndrome 33, 34, 180 Type 2 diabetes 51, 53, 57, 60

U Ultrasound 12-14, 17, 28, 42, 43, 47, 49, 50, 85, 120-125, 130, 135-141, 152, 153, 158, 159, 162, 167, 169, 170, 174-176, 181, 186, 195, 197-200, 203 Unintended pregnancy 65, 77, 79, 80, 81

V Vaginal maturation index 16, 21 Varicocele 180, 195, 197, 199 Vasectomy 180, 195 Vasomotor symptom 25, 45, 108, 111, 119 Vitamin 41, 60, 100, 101, 105, 112, 191-193, 196 von Willebrand disease (VWD) 37, 39-43

W Waist circumference 48, 51, 57 WHO criteria 70, 71, 74, 75, 77, 80, 146, 165, 166, 171, 175, 176, 182, 197, 198 Women’s Health Initiative (WHI) 112, 114-118

Index

Index

LANDES

BIOSCIENCE

V ad e me c u m

Table of contents 1. The Menstrual Cycle

12. Reproductive Endocrinology Diagnostic Imaging

2. Puberty and Its Disorders

4. Dysfunctional Uterine Bleeding 5. Diagnosis and Management of Polycystic Ovary Syndrome 6. Obesity: Recognition and Treatment in Women 7. Hormonal Contraception

14. Surgical Treatment of Female Infertility 15. Ovulation Induction 16. Assisted Reproductive Technology 17. Alternative Medicine and Female Infertility 18. Male Infertility 19. Your Environment; Your Fertility—Is There a Link?

8. Endometriosis 9. Hyperprolactinemia 10. Premenstrual Syndrome 11. Treatment of the Menopausal Woman

Reproductive Endocrinology and Infertility

13. An Overview of Female Infertility

3. Amenorrhea

V ad eme c um

LANDES

BIOSCIENCE

LANDES

BIOSCIENCE

V ad e me c u m Reproductive Endocrinology and Infertility

The Vademecum series includes subjects generally not covered in other handbook series, especially many technology-driven topics that reflect the increasing influence of technology in clinical medicine. The name chosen for this comprehensive medical handbook series is Vademecum, a Latin word that roughly means “to carry along”. In the Middle Ages, traveling clerics carried pocket-sized books, excerpts of the carefully transcribed canons, known as Vademecum. In the 19th century a medical publisher in Germany, Samuel Karger, called a series of portable medical books Vademecum.

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