Textbook of Benign Prostatic Hyperplasia

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Textbook of Benign Prostatic Hyperplasia 2Nd Ed. Kirby, R. S. Informa Healthcare 190186555X 9781901865554 9780203640449 English Prostate--Hypertrophy, Prostate--Hypertrophy-Treatment, Prostatic Hyperplasia--diagnosis, Prostatic Hyperplasia--therapy, Adrenergic alpha-Antagonists-therapeutic use. 2005 RC899.T49 2005eb 616.6/5 Prostate--Hypertrophy, Prostate--Hypertrophy-Treatment, Prostatic Hyperplasia--diagnosis, Prostatic Hyperplasia--therapy, Adrenergic alpha-Antagonists-therapeutic use.

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Page i Second Edition TEXTBOOK OF BENIGN PROSTATIC HYPERPLASIA

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Textbook of Benign Prostatic Hyperplasia 2Nd Ed. Kirby, R. S. Informa Healthcare 190186555X 9781901865554 9780203640449 English Prostate--Hypertrophy, Prostate--Hypertrophy-Treatment, Prostatic Hyperplasia--diagnosis, Prostatic Hyperplasia--therapy, Adrenergic alpha-Antagonists-therapeutic use. 2005 RC899.T49 2005eb 616.6/5 Prostate--Hypertrophy, Prostate--Hypertrophy-Treatment, Prostatic Hyperplasia--diagnosis, Prostatic Hyperplasia--therapy, Adrenergic alpha-Antagonists-therapeutic use.

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Page iii Second Edition TEXTBOOK OF BENIGN PROSTATIC HYPERPLASIA Edited by Roger S Kirby MA MD FRCS (Urol) FEBU Visiting Professor of Urology St. George’s Hospital London, UK John D McConnell MD Professor of Urology University of Texas Southwestern Medical Center Dallas, Texas, USA John M Fitzpatrick MCh FRCSI FC Urol (SA) FRCSGlas FRCS Consultant Urologist and Professor of Surgery Mater Misericordiae Hospital and University College Dublin Dublin, Ireland Claus G Roehrborn MD Professor of Urology University of Texas Southwestern Medical Center Dallas, Texas, USA Peter Boyle PhD Director, Division of Epidemiology and Biostatistics European Institute of Oncology, Milan, Italy

LONDON AND NEW YORK A MARTIN DUNITZ BOOK

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Page iv © 2005 Taylor & Francis, an imprint of the Taylor & Francis Group First published in the United Kingdom in 2005 by Taylor & Francis, an imprint of the Taylor & Francis Group, 2 Park Square, Milton Park Abingdon, Oxon OX14 4RN, UK Tel.: +44 (0) 1235 828600 Fax.: +44 (0) 1235 829000 Website: www.tandf.co.uk This edition published in the Taylor & Francis e-Library, 2005. To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. British Library Cataloguing in Publication Data Data available on application Library of Congress Cataloging-in-Publication Data Data available on application ISBN 0-203-64044-6 Master e-book ISBN ISBN 0-203-69366-3 (OEB Format) ISBN 1-90186-555-X (Print Edition) Distributed in North and South America by Taylor & Francis 2000 NW Corporate Blvd Boca Raton, FL 33431, USA Within Continental USA Tel.: 800 272 7737; Fax.: 800 374 3401 Outside Continental USA Tel.: 561 994 0555; Fax.: 561 361 6018 E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0) 1264 332424 E-mail: [email protected] Composition by Parthenon Publishing

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Page v Contents     Preface   Foreword   List of Contributors  

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Section I:  Basic Science  

1.  Macro-anatomy of the prostate J S Dixon, J A Gosling 2.  Embryology and development of the prostate E Shapiro, M S Steiner 3.  Molecular control of prostatic growth A Turkes, K Griffiths 4.  Molecular aspects of benign prostatic hyperplasia M R Freeman, M E Gleave, L W K Chung 5.  Human prostatic adrenoceptors K-E Andersson, M G Wyllie 6.  The pathology of benign prostatic hyperplasia D G Bostwick 7.  Bladder responses to obstruction G E Lemack, J D McConnell 8.  Molecular genetics of benign prostatic hyperplasia S F Shariat, E I Canto, K M Slawin

 

Section II:  Epidemiology  

9.  Measuring and assessing BPH in population groups M J Barry 10.  Descriptive epidemiology of benign prostatic hyperplasia H A Guess, C J Girman 11.  Etiology of benign prostatic hyperplasia G S Sonke, C A Mochtar, L A L M Kiemeney 12.  Epidemiology of acute urinary retention K Thomas, P Boyle 13.  Natural history of benign prostatic hyperplasia J Shah

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Page vi  

Section III:  Evaluation  

14. Evaluating symptoms and functional status  201 G S Adey, M P O’Leary, M J Barry 15. Screening for prostate cancer in patients with benign prostatic hyperplasia  211 D E Drachenberg, M K Brawer 16. Flow rate and postvoid residual issues  227 E P Arnold 17. Urodynamics and benign prostatic hyperplasia  241 A E Te, E F Ikeguchi, J Choi, S A Kaplan 18. Imaging and benign prostatic hyperplasia  255 D Rickards 19. Prostatic needle biopsy in men with BPH: histopathologic interpretation and clinical significance  267 M R Feneley, S R J Bott 20. Neurologic and neurophysiologic assessment  279 C J Fowler, K J O’Malley, R S Kirby  

Section IV:  Medical Treatment  

21. Medical management—watchful waiting P Hegarty, J M Fitzpatrick, R C Bruskewitz 22. The placebo effect in the treatment of benign prostatic hyperplasia C G Roehrborn 23. Dutasteride in the treatment of the BPH patient J D McConnell, C G Roehrborn 24. Finasteride in the treatment of benign prostatic hyperplasia J D McConnell 25. Combination therapy in the treatment of BPH C G Roehrborn 26. The differential effects of adrenoceptor antagonists on prostate tissue growth N Kyprianou 27. Terazosin in the treatment of obstruction of the lower urinary tract M Brawer, J M Fitzpatrick 28. Doxazosin in the treatment of benign prostatic hyperplasia R S Kirby 29. Alfuzosin A Jardin 30. Tamsulosin C R Chapple

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 287  295  319  327  339  351  357  365  377  391

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Page vii 31. Phytotherapeutic agents in the treatment of LUTS and BPH K Dreikorn, J M Fitzpatrick 32. Uroselectivity revisited K-E Andersson, M G Wyllie

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Section V:  Surgical/Interventional Options  

33. Surgical interventions for BPH J Shah, C G Roehrborn 34. Transurethral laser prostatectomy B S Stein 35. Transurethral needle ablation (TUNA) for treatment of benign prostatic hyperplasia C C Schulman, A R Zlotta 36. Interstitial laser therapy for benign prostatic hyperplasia T McNicholas 37. Transurethral microwave thermotherapy S St Clair Carter, A Tubaro 38. Temporary stents J Nordling

  441   483   495   507   519   529

 

Section VI:  Shared Care  

39. The impact of BPH on sexual function C C Carson    Index

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  543   557

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Page viii Preface Unlikely as it seems from our perspective, it is 8 years since the first edition of the Textbook of Benign Prostatic Hyperplasia was first published. Rather a lot has happened in this increasingly important disease area since then. The realization has dawned that more than half of all men beyond middle age—and more and more of us now fall into this category—suffer some quality of life impairment due to this highly prevalent disease. Moreover, an important link between lower urinary tract symptoms (LUTS) due to BPH and sexual dysfunction has recently been established. Basic science has advanced considerably and we now are beginning to have a clearer understanding of the molecular mechanisms that underlie the abnormal growth patterns that characterize this common medical problem. Methods of diagnosis have been refined and invasive testing, such as urodynamics and cystoscopy, are now much less frequently employed. Medical therapy is increasingly employed and the recently reported MTOPS study suggests that the combination of a 5α-reductase inhibitor and an αblocker provides the optimum means of relieving symptoms and preventing disease progression. Surgery has also evolved dramatically. Laser prostatectomy using the holmium laser, and a host of other minimally invasive technologies, are now seriously challenging standard transurethral resection (TURP) as the gold standard intervention for this disease. For all of these reasons a second edition of this book was clearly overdue. We would like to thank all the contributors to this book for the superb state-of-the-art overviews that they have provided. We would also especially like to thank the outstanding publishing team including Alan Burgess, Martin Lister, Karen Kennedy and Kath Burrow for the enthusiasm and sheer hard work that have turned this project into reality. Roger S Kirby John D McConnell John M Fitzpatrick Claus G Roehrborn Peter Boyle

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Page ix Foreword The editors of the second edition of Textbook of Benign Prostatic Hyperplasia have assembled a thoughtful group of authors who are experts in the field of benign prostatic hyperplasia and have produced the most comprehensive book on the topic that has been published. The chapters are concise, readable yet thorough, addressing all aspects of BPH. Particularly engaging are the chapters on medical management, where an expert who has personal experience with the drug addresses each specific treatment modality discussed. In a similar fashion, the surgical intervention options are discussed in detail. Moreover, the clinical chapters guide the clinician through appropriate diagnostic strategies, the limitations of clinical trials and then are filled with evidence-based data, citing where appropriate studies are missing. The basic science chapters are timely and review in a logical sequence all aspects of the development of the prostate, its innervation, and the response of the bladder to obstruction. These chapters should guide urologic investigators to the development of new strategies for both the prevention and treatment of BPH. Taken altogether, the text is a readable compendium on BPH, which will be enjoyed by all urologists, and others interested in the topic. E Darracott Vaughan Jr, MD

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Page xi List of Contributors Gregory S Adey MD Clinical Fellow in Surgery/Urology Harvard Medical School Brigham and Women’s Hospital Boston, MA 02115, USA Karl-Erik Andersson Department of Clinical Pharmacology Lund University Hospital 221 85 Lund, Sweden Edwin P Arnold MB ChB PhD FRCS FRACS Associate Professor, Department of Urology Christchurch Hospital Private Bag 4710 Christchurch, New Zealand Michael J Barry MD Chief, General Medicine Unit Massachusetts General Hospital Associate Professor of Medicine, Harvard Medical School 50 Staniford Street, 9th Floor Boston, MA 02114, USA Simon R J Bott Research Registrar, Institute of Urology and Nephrology UCL UCL Hospitals Trust Mortimer Street London W1T 3AA, UK David G Bostwick MD MBA Medical Director, Bostwick Laboratories 2807 N.Parham Road Richmond, VA 23294, USA Peter Boyle PhD Director, Division of Epidemiology and Biostatistics European Institute of Oncology via Ripamonti 435 20141 Milan, Italy Michael K Brawer MD Director of Northwest Prostate Institute Northwest Hospital Seattle, WA 98133, USA Reginald C Bruskewitz MD Professor of Surgery, Department of Surgery Division of Urology Clinical Science Center 600 Highland Avenue Madison, WI 53792, USA Eduardo I Canto Scott Department of Urology Baylor College of Medicine 6560 Fannin, Suite 2100 Houston, TX 77030, USA Cully C Carson MD FACS Rhodes Distinguished Professor Chief of Urology University of North Carolina 2140 Bioinformatics Building Chapel Hill, NC 27599–7235, USA Christopher R Chapple MD FRCS(Urol) FEBU file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_xi.html[09.07.2009 11:51:14]

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Consultant Urological Surgeon Department of Urology Royal Hallamshire Hospital Glossop Road Sheffield S10 2JF, UK James Choi MD College of Physicians and Surgeons Columbia University Columbia Presbyterian Medical Center 622 West 168th Street New York, NY 10004, USA

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Page xii Leland W K Chung PhD Professor of Urology and Cell Biology The University of Virgina Health System Molecular Urology and Therapeutics Program Box 422 Charlottesville, VA 22908, USA John S Dixon PhD Retired Darrel E Drachenberg MD FRCSC Urologic Oncologist, Assistant Professor of Surgery, Section of Urology University of Manitoba, St Boniface General Hospital 409 Tache Avenue, Room Z 3036 Winnipeg MB, R2H 2A6, Canada Kurt Dreikorn Urology Clinic St. Jurgen Str. 28205 Bremen, Germany Mark R Feneley MD FRCS(Eng) FRCS(Urol) Senior Lecturer, Institute of Urology and Nephrology University College London 48 Riding House Street London W1W 7EY, UK John M Fitzpatrick MCh FRCSI FC Urol (SA) FRCSGlas FRCS Consultant Urologist and Professor of Surgery Mater Misericordiae Hospital and University College Dublin 47 Eccles Street Dublin 7, Ireland Clare J Fowler FRCP Professor of Uro-Neurology, Institute of Neurology, UCL and National Hospital for Neurology and Neurosurgery Queen Square London WC1N 3BG, UK Michael R Freeman PhD Director, Urology Research, Children’s Hospital Boston Associate Professor, Department of Surgery Harvard Medical School Enders Research Laboratories, Rm. 1161 300 Longwood Avenue Boston, MA 02115, USA Cynthia J Girman Senior Director, Epidemiology Department Merck Research Laboratories 10 Sentry Parkway Blue Bell, PA 19422, USA Martin E Gleave MD FRCSC Associate Professor of Surgery University of British Columbia Division of Urology Vancouver Hospital and Health Sciences Center, D-9 2733 Heather Street Vancouver, BC, V5Z 3J5, Canada John A Gosling MB CHB MD FRCS Professor of Anatomy Division of Anatomy Stanford University CCSR Building file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_xii.html[09.07.2009 11:51:15]

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269 Campus Drive Stanford, CA 94305–5140, USA Keith Griffiths BSc MSc PhD DSc Formerly Tenovus Cancer Research Centre University of Wales College of Medicine Heath Park Cardiff CF14 4XX, Wales, UK Harry A Guess MD PhD Professor, Department of Epidemiology McGavran-Greenberg Hall, Room 2105B School of Public Health University of North Carolina at Chapel Hill Chapel Hill, NC 27599–7435, USA P Hegarty University College Hospital Galway, Ireland Edward F Ikeguchi Department of Urology College of Physicians and Surgeons Columbia University New York, NY 10004, USA

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Page xiii Alain Jardin MD Chef du Service D’Urologie Université Paris Sud Centre Hospitalier de Bicêtre Secteur P.Broca 78 rue Général Leclerc 94275 Le Kremlin-Bicêtre, Cedex, France Steven A Kaplan MD Herbert Irving Associate Professor of Urology J.Bentley Squier Urological Clinic College of Physicians and Surgeons, Columbia University Columbia Presbyterian Medical Center 622 West 168th Street New York, NY 10004, USA Lambertus A L M Kiemeney PhD Professor of Cancer Epidemiology Radboud University Medical Center PO Box 9001 NL-6500 HB, Nijmegen, The Netherlands Roger S Kirby MA MD FRCS (Urol) FEBU Professor of Urology 145 Harley Street, London W1G 6BJ, UK Natasha Kyprianou MD PhD Professor, Division of Urology Department of Surgery University of Kentucky Medical Center 800 Rose Street Lexington, KY 40536, USA Gary E Lemack MD Associate Professor of Urology Director of Neurourology University of Texas Southwestern Medical Centre 5323 Harry Hines Boulevard, J8.122 Dallas, TX 75390–9110, USA John D McConnell MD Professor of Urology, Department of Urology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, B11.300 Dallas, TX 75390–9131, USA Tom McNicholas MBBS FRCS FEBU Consultant Urological Surgeon The Lister Hospital Corey’s Mill Lane Stevenage, SG1 4AB, UK Chaidir A Mochtar MD Urologist, Department of Urology Academic Medical Center 1100 DE Amsterdam, The Netherlands Jørgen Nordling DrMedSci FEBU Professor of Urology, Department of Urology, H 123 Herlev Hospital University of Copenhagen 2730 Herlev, Denmark Michael P O’Leary MD MPH Associate Professor of Surgery, Harvard Medical School Senior Surgeon, Division of Urology Brigham and Women’s Hospital file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_xiii.html[09.07.2009 11:51:15]

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Boston, MA 02115, USA Kiaran J O’Malley MCh FRCS (Urol) FEBU Fellow in the Department of Uro-Neurology National Hospital for Neurology and Neurosurgery, and Fellow at the Institute of Urology Queen Square London WC1N 3BG, UK David Rickards FRCR, FFRDSA Consultant Uroradiologist University College Hospitals London The Middlesex Hospital London W1N 8AA, UK Claus G Roehrborn MD Professor and Chairman, Department of Urology The University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, J8.142 Dallas, TX 75390–9110, USA Claude C Schulman MD PhD Professor of Urology, Department of Urology Erasme Hospital University Clinics of Brussels 808 rue route de Lennik 1070 Brussels, Belgium

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Page xiv Jyoti Shah BSc MRCS MD DHMSA Urology SpR Kingston Hospital Galsworthy Road Kingston upon Thames, Surrey KT2 7QB, UK Ellen Shapiro MD Department of Urology New York University School of Medicine 150 E. 32nd Street, 2nd First Avenue New York, NY 10016, USA Shahrokh F Shariat Scott Department of Urology Baylor College of Medicine 6560 Fannin, Suite 2100 Houston, TX 77030, USA Kevin M Slawin MD Scott Department of Urology Baylor College of Medicine 6560 Fannin, Suite 2100 Houston, TX 77030, USA Gabe S Sonke MD PhD Resident in Internal Medicine Department of Internal Medicine University Medical Centre Utrecht 3508 GA Utrecht, The Netherlands Simon St Clair Carter FRCS Imperial College School of Medicine London University and Department of Urology Hammersmith Hospitals Trust London W12 0HS, UK Barry S Stein MD Professor and Chief, Division of Urology Brown University School of Medicine 2 Dudley Street, Suite 175–185 Providence, RI 02912, USA Mitchell S Steiner MD Department of Urology The University of Tennessee College of Medicine Memphis, TN 38163, USA Alexis E Te MD Associate Professor of Urology Director of the Prostate Center and Urodynamics Weill Medical College of Cornell University 1300 York Avenue, F918 New York, NY 10021, USA Kay Thomas Urology Registrar, Urology Department St George’s Hospital London SW17 0QT, UK Andrea Tubaro Department of Urology 2nd School of Medicine, “La Sapienza” University, and St Andrea Hospital 00189 Rome, Italy Atilla Turkes BSc, MSc, PhD Principal Clinical Scientist Department of Medical Biochemistry and Immunology file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_xiv.html[09.07.2009 11:51:16]

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University Hospital of Wales Heath Park Cardiff CF14 4XW, Wales, UK Michael G Wyllie BSc, PhD Pfizer Inc 235 East 42nd Street New York, NY 10017–5755, USA Alexandre R Zlotta MD Department of Urology University Clinics of Brussels Erasme Hospital 808 rue route de Lennik 1070 Brussels, Belgium

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Page 1 I Basic Science

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Page 3 1 Macro-anatomy of the prostate J S Dixon J A Gosling Introduction The prostate is shaped like an inverted pyramid and lies between the urinary bladder and the pelvic floor (Fig. 1.1). It is a fibromuscular glandular organ that surrounds the prostatic urethra. The prostate has a base and an apex, and anterior, posterior, and inferolateral surfaces. The base is the upper surface adjacent to the preprostatic urethra and bladder neck while the blunt apex is the lowest part. The anterior surface limits the retropubic space posteriorly and is connected inferiorly to the pubic bones by the puboprostatic ligaments. The inferolateral surfaces are clasped by the levator prostatae parts of the levator ani muscle, while the posterior surface lies in front of the lower rectum and is separated from it by the rectovesical fascia. The ejaculatory ducts pierce the posterior surface just below the bladder and pass obliquely through the gland for about 2 cm to open separately into the prostatic urethra about half way along its length on the verumontanum. A thin layer of connective tissue at the periphery of the prostate forms a ‘true’ capsule, outside which is a condensation of pelvic fascia forming the so-called ‘false’ capsule. A plexus of veins lies between these two capsules. Blood supply and lymphatic drainage The main arterial supply to the prostate gland is from the prostatic branch of the inferior vesical artery, with some small branches from the middle rectal internal pudendal vessels passing to the lower part. Occasionally, the middle rectal artery provides the major supply. The veins from the prostate gland form the prostatic venous plexus situated between the true capsule of the gland and the outer fibrous sheath. The lymph vessels from the prostate gland drain into the internal iliac nodes. The prostatic urethra The prostatic urethra is the widest and most dilatable part of the entire male urethra. It is about 3 cm long and extends through the prostate gland from base to apex. The prostatic urethra is divided into proximal and distal segments of approximately equal length by an abrupt anterior angulation of its posterior wall at the midpoint between prostate apex and bladder neck.1 The angle of deviation is approximately 35 degrees, but can be quite variable and tends to be greater in men with nodular

Figure 1.1 (a) Schematic diagram of a midline section through the male lower urinary tract. The lumen of the bladder and of the urethra is dilated and the right half of the trigone (T) is shown as a surface feature. The detrusor muscle (D) is in direct continuity with the deep trigone (DT). The superficial trigone (ST) extends inferiorly as far as the verumontanum. IS, internal sphincter. The external striated urethral sphincter (ES) surrounds the membranous urethra. (b) Viewed from in front the trigone (T) is represented as a surface feature on the luminal aspect of the trigonal detrusor thickening. D, detrusor muscle; IS, internal sphincter; PS, periurethral striated muscle; ES, distal or external striated urethral sphincter.

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Page 4 hyperplasia.2 The prostatic urethra lies nearer the anterior than the posterior surface of the prostate. It is widest in the middle and narrowest below, adjoining the membranous part. In cross-section it appears crescent shaped in outline with the convex side facing ventrally (Fig. 1.2). The characteristic crescent shape is due to the presence on the posterior wall of a narrow median longitudinal ridge formed by an elevation of the mucous membrane and its subjacent tissue, called the urethral crest. On each side of the crest lies a shallow depression termed the prostatic sinus, the floor of which is pierced by the openings of the prostatic ducts. About the middle of the length of the urethral crest, the colliculus seminalis (or verumontanum) forms an elevation on which the slit-like orifice of the prostatic utricle is situated. On each side of, or just within, this orifice are the openings of two ejaculatory ducts. The prostatic utricle is a blind-ending diverticulum about 6 mm long which extends upwards and backwards within the substance of the prostate. It develops from the paramesonephric ducts or urogenital sinus and, as a consequence, is a remnant of the system which forms the reproductive tract in the female. The preprostatic urethra is a short segment lying between the bladder neck and base of the gland and is surrounded by a sleeve of smooth muscle fibers, forming the preprostatic sphincter. Tiny ducts and abortive acinar systems are scattered along the length of the proximal urethral segment and arborize exclusively inside the confines of the preprostatic sphincter forming the periurethral gland region. The preprostatic sphincter is thought to function during ejaculation to prevent retrograde flow of seminal fluid from the distal urethral segment. It may also

Figure 1.2 A horizontal section through the human prostate gland. The prostatic urethra appears crescent shaped in outline. (H & E) have resting tone which maintains closure of the preprostatic urethra, thereby aiding urinary continence. The preprostatic sphincter is compact on the posterior aspect of the urethra, but anteriorly its fibers do not form complete rings but terminate within the tissue of the anterior fibromuscular stroma. Slender bundles of smooth muscle cells also occur in the proximal part of the urethral crest, extending as far as the prostatic utricle where they become continuous with the muscle coat of the ejaculatory ducts. Proximally, these muscle bundles are continuous with those extending from the superficial trigone along the posterior wall of the preprostatic urethra. Below the openings of the ejaculatory ducts the distal prostatic urethra possesses a thin coat of smooth muscle, consisting of both circularly and longitudinally orientated muscle bundles which are themselves continuous with the strands of smooth muscle pervading the prostate gland. The distal urethral segment is also surrounded by a sphincter formed of small-diameter (15–20 μ m), striated muscle fibers separated by connective tissue (Fig. 1.3), which represent a proximal extension of the external urethral sphincter (rhabdosphincter) located distal to the prostate apex. The sphincter within the prostate gland is incomplete posterolaterally where the semi-circular fibers anchor into the prostatic stroma. Histochemical studies3,4 have shown that the small-diameter striated muscle fibers are almost all of the slowtwitch type and that similar fibers lie on the inner aspect of the external urethral sphincter surrounding the membranous urethra. These fibers are believed to be important in the maintenance of urinary continence. The small-diameter fibers merge peripherally with larger-diameter

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Figure 1.3 Small-diameter striated muscle fibers, separated by connective tissue, surround the distal prostatic urethra. (Masson’s trichrome stain.)

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Page 5 fibers, two-thirds of which are of the slow-twitch type and one-third of the fast-twitch type. These larger-diameter fibers may be a proximal extension of the striated muscle surrounding the bulb of the penis and help to empty the urethra during ejaculation and at the end of micturition. Histologic structure of the prostate In 1912 Lowsley5 presented a detailed description of the anatomy of the human prostate gland, based on embryonic and fetal studies. However, his scheme of median and lateral prostatic lobes was found to be inadequate as a model for the anatomy of the adult human prostate. This early concept of prostatic structure was modified by the work of Franks6 and by the more recent studies of McNeal2,7–9 and Tissell and Salander.10,11 Although these latter authors used entirely different examination techniques, the results of their studies generally seem to coincide with those of McNeal. McNeal studied prostates obtained at autopsy from adults and infants and from which numerous sections were taken in different planes. From his observations McNeal has described four distinct regions, each of which arises from a different segment of the prostatic urethra (Fig. 1.4). The largest part is the anterior or ventral fibromuscular and nonglandular region, which forms the ventral surface of the gland and which constitutes about one-third of the entire prostate.

Figure 1.4 Diagram of a sagittal section of prostate to show anatomic subdivisions (redrawn from McNeal2). CZ, central zone; PZ, peripheral zone; TZ, transitional zone; V, verumontanum; FS, fibromuscular stroma; D, detrusor; P, preprostatic sphincter; ES, external sphincter; ST, superficial trigone; BL, bladder lumen; U, urethral lumen. The glandular prostate can then be subdivided into three zones, as follows: • A peripheral zone, representing about 70% of the glandular part of the prostate. This zone forms the lateral and posterior or dorsal part of the organ. It may be regarded as a funnel that distally constitutes the apex of the prostate and cranially opens to receive the distal part of the wedge-shaped central zone. The ducts of the peripheral zone open into the distal prostatic urethra. They extend mainly laterally in the coronal plane, with major branches that curve anteriorly and minor branches that curve posteriorly. • A central zone, comprising about 25% of the glandular prostate. This zone is wedge-shaped and surrounds the ejaculatory ducts with its apex at the verumontanum and its base against the bladder neck. Thus the central zone is, at least in its distal part, surrounded by the peripheral zone and its ducts open into the prostatic urethra, in close proximity to the ejaculatory ducts. The central zone, like the peripheral zone, has a funnel shape to accommodate the proximal segment of the urethra. Both funnels are incomplete ventrally, where their borders are held together by the fibromuscular stroma. • The smallest glandular part comprises only about 5–10% of the prostate and has been called a transitional zone. This zone consists of two independent small lobes whose ducts leave the posterolateral recesses of the urethral wall at a single point, just proximal to the point of urethral angulation and at the lower border of the preprostatic sphincter. The main ducts of the transitional zone extend laterally around the distal border of the sphincter and curve sharply anteriorly, arborizing towards the bladder neck immediately external to the preprostatic sphincter and fanning out laterally. The most medial ducts and acini of the transitional zone curve medially to penetrate into the sphincter. McNeal’s concept of prostate anatomy was later confirmed by Blacklock and Bouskill,12 although the presence of a transitional zone could not be confirmed by other workers.13 McNeal described distinct histologic differences between the central and peripheral glandular zones which might indicate a difference in their functions.8 In the peripheral zone and transitional zone, ducts file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_5.html[09.07.2009 11:51:18]

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and acini are usually 0.15 and 0.3 mm in diameter and have simple rounded contours that are not perfectly circular because of prominent undulations of the epithelial border. The

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Page 6 undulations reflect the presence of corrugations of the wall, which presumably provide for expansion of the lumina as secretory reservoirs. Central zone ducts and acini are distinctively larger than those of the peripheral zone and transitional zone—up to 0.6 mm in diameter or larger. They become progressively larger and more elaborate as the duct territories expand toward the prostate base. Acini are clustered into lobules around a central subsidiary duct while both ducts and acini are polygonal in contour. The corrugations within the walls are very prominent and frequently form into intraluminal ridges that partially subdivide acini. Glandular lobes in the central zone are separated by bundles of compact smooth muscle cells, but the ratio of epithelium to stroma is higher than in the peripheral and transitional zones. The more abundant peripheral zone stroma is loosely woven with randomly arranged smooth muscle bundles (Fig. 1.5). There is an abrupt contrast in stromal morphology which delineates the boundary between central zone and peripheral zone. However, the contrast between the peripheral and transitional zones is less obvious or consistent. The stroma of the transitional zone is composed of interlacing bundles of compact smooth muscle cells that blend with the adjacent stroma of the preprostatic sphincter and anterior fibromuscular stroma. According to McNeal,14 stromal distinctions are less evident in older prostates and may be obliterated by disease. Tissel and Salander,10,11using a microdissection technique, were able to distinguish two dorsal, two lateral, and two median lobes of the human prostate. The lobes are arranged in an onion pattern, with the median lobes lying centrally around the ejaculatory ducts and the lateral and

Figure 1.5 Irregularly shaped prostatic acini from the peripheral zone. Randomly arranged smooth muscle bundles lie in the prostatic stroma. (H & E) dorsal lobes forming the outer layers. Each of these three pairs of lobes was found to have its own histologic characteristics,15 which were subsequently confirmed by others.16 Compared with the histologic pattern of McNeal’s central and peripheral zones,7 the description of the histology of the medial lobe given by Salander et al.15 has obvious similarities with the central zone. Similarly, the dorsal-lateral lobes correspond to the peripheral zone. Thus the two descriptions by and large coincide, especially as McNeal has acknowledged that the peripheral zone might be subdivided into two zones. The establishment of distinct anatomic and histologic lobes or zones in the human prostate has led to studies of the relationship between prostatic disease and different parts of the gland, and also the hormonal dependence of individual lobes and zones. Benign prostatic hyperplasia largely arises in the preprostatic glandular tissue and the preprostatic urethra, and McNeal often found small nodules in this part of the organ. Furthermore, in almost half of the prostates studied by McNeal, small carcinomas, less than 0.1 cm3 in volume, were detected, most of which originated in the peripheral zone and only a few in the central zone. Inflammatory changes were also most often seen in the peripheral zone. The epithelium of the glandular prostate Within each zone of the prostate, the entire duct-acinar system, with the exception of the main ducts near the urethra, is lined by columnar secretory cells whose appearance is identical between ducts and acini. The secretory cells are separated from the basement membrane and prostatic stroma by a layer of basal cells. These cells are generally flattened and lie parallel to the basement membrane, with small dark-staining nuclei and little cytoplasm. These basal cells are often quite inconspicuous and may appear to be absent from some of the ducts and acini. They are considered to form the proliferative compartment of the prostate epithelium and divide to give rise to mature secretory cells.17

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Compared with other regions of the prostate, the secretory cells of the central zone have a darker, more prominently granular cytoplasm and each cell possesses a relatively large nucleus. The luminal epithelial border tends to be uneven with individual cells protruding into the lumen. The secretory cells of the peripheral zone, the transitional zone, and the periurethral glands have smaller nuclei, uniformly situated towards the base. The cytoplasm is pale-staining and the cells present a relatively smooth luminal border.14

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Page 7 In all zones of the prostate, the epithelium contains a small population of randomly scattered endocrineparacrine cells,18–20 that are rich in serotonin-containing granules and contain neuron-specific enolase.19 Subpopulations of these cells also contain a variety of peptide hormones such as somatostatin,20 calcitonin,21 and bombesin.21 These cells normally occur in the basal cell layer and often possess laterally spreading dendritic processes (Fig. 1.6). However, they do not often appear to extend as far as the luminal surface. Their precise function remains unknown, although they are assumed to have a paracrine function, possibly in response to neural stimulation, thereby regulating the secretory processes of the mature gland. They may also have a significant role to play during prostatic growth and differentiation. Spherical bodies called prostatic concretions (or corpora amylacea) normally occur in some of the prostatic acini. They vary greatly in size and may become calcified and exceed 1 mm in diameter. In sections they appear as concentric lamellated bodies which are believed to be condensations of prostatic secretory products. The transitional epithelium, which lines the prostatic urethra and extends for a variable distance into the main prostatic ducts, differs histologically from that which lines the urinary bladder and also differs from the lining of the female urethra. The transitional epithelial cells of the prostatic urethra and main ducts have relatively sparse cytoplasm with no evidence of maturation into luminal umbrella cells. Instead, the luminal surface is lined by a single layer of columnar secretory cells that appear identical to the secretory epithelium of the peripheral zone.

Figure 1.6 Endocrine-paracrine cells with dendritic processes frequently occur in human prostatic epithelium (bombesin immunocyto-chemistry). Innervation of the prostate gland The human prostate gland receives a dual autonomic innervation from both parasympathetic (cholinergic) and sympathetic (noradrenergic) nerves13,22–26 via the prostatic nerve plexus, i.e. that part of the pelvic autonomic plexus that lies adjacent to the prostate gland. The pelvic plexus (and hence the prostatic plexus) receives parasympathetic input from the sacral segments of the spinal cord (S2–S4) and sympathetic fibers from the hypogastric (presacral) nerves (T10–L2).27 These nerves ramify within the prostatic plexus which contains both cholinergic and noradrenergic nerve cell bodies. The autonomic nerves which supply the prostate (and also the seminal vesicles, urethra, and corpora cavernosae) arise from the pelvic plexus and travel together with the vascular supply. These neurovascular bundles approach the base of the prostate on its posterior aspect and generally lie in the same coronal plane as its rectal surface.28 Most of the nerve branches to the prostate leave the neurovascular bundles at a level just above the prostate base and extend medially within a layer of fatty tissue. The nerve branches in these superior pedicles fan out over the prostatic capsule, which contains many autonomic ganglia embedded in a layer of fat. Some nerve branches continue medially over the prostate base to supply the central zone, while others fan out distally and penetrate the capsule at a very oblique angle. A few nerve branches leave the neurovascular bundles at the apex of the prostate via two small inferior pedicles and penetrate the capsule directly. The neurovascular bundles continue over the anterolateral aspect of the prostate to innervate the erectile tissue of the penis (and possibly the external urethral sphincter). Within the prostatic parenchyma small nerve branches lie immediately adjacent to the walls of the ducts and acini, while other nerves form branching plexuses among the smooth muscle bundles of the stroma. file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_7.html[09.07.2009 11:51:19]

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According to Gosling,25 both cholinergic (Fig. 1.7) and noradrenergic nerves (Fig. 1.8) innervate the smooth muscle bundles of the prostatic stroma, while cholinergic nerves also innervate the smooth muscle of the capsule. It is well known that under sympathetic stimulation (such as occurs during ejaculation) prostatic fluid is expelled into the urethra.29 The importance of sympathetic nerves in the motor control of prostatic musculature has been demonstrated by in vivo,30,31 in vitro and clinical studies,32–34 and forms the basis of the therapeutic use of α-blockade in the medical management of benign prostatic hypertrophy. Although initial studies (in vitro) of prostatic capsule showed it to have a cholinergic component with an atropine-sensitive contractile response to nerve

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Figure 1.7 Acetylcholinesterase-positive nerve fibers lie at the base of the prostatic acini and also occur in association with the smooth muscle bundles of the prostatic stroma. Human prostate gland.

Figure 1.8 Formaldehyde-induced fluorescence preparation showing a profusion of branching noradrenergic nerves in association with smooth muscle bundles in the human prostate gland. The orange colored granules within the prostatic epithelial cells are autofluorescent lysosomes. stimulation,32 subsequent reports have failed to provide evidence that muscarinic cholinoceptor stimulation plays a significant motor role within the prostate.35,36 A decrease in the density of adrenergic and acetylcholinesterase-positive nerves has been reported in hyperplastic tissue in man.37 The human prostate gland is also supplied by nerves containing a variety of neuropeptides,13,38–41 such as vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY) (Fig. 1.9), substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SOM), and med- and eu-enkephalin (m-ENK and 1-ENK). As in other organs, it seems likely that at least some of these peptides coexist within the classical cholinergic and noradrenergic nerve fibers and serve as neuromodulators, neurotransmitters, or trophic factors. Both VIP and NPY are known to have

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Figure 1.9 Numerous neuropeptide Y (NPY)-immunoreactive nerve fibers lie at the base of these prostatic acini. Human prostate gland. motor functions elsewhere in the lower urinary and intestinal tracts. In the human urinary bladder, VIP produces a dose-related prolonged relaxation effect and is also a powerful vasodilator, whereas NPY is known as a pre- and postsynaptic modulator of adrenergic transmission. However, NPY is not only present in sympathetic nerves but can also occur in nonnoradrenergic nerves. Somatostatin, 1-ENK, and m-ENK have all been demonstrated in different minor populations of sympathetic nerves. In contrast, CGRP and SP are principally colocalized in sensory nerve fibers. SP is also known to produce contraction of detrusor and intestinal smooth muscle. CGRP is a potent inhibitor of SP degradation and also a potent vasodilator. It seems likely that SP and CGRP fulfill a primarily sensory neurotransmitter role within the prostate during ‘axon reflex’ activity.37 The presence of intrinsic autonomic ganglion cells has also been reported in the human prostate41 with a widespread distribution, occurring not only in the capsule but throughout the substance of the gland (Fig. 1.10). These ganglia contain both presumptive noradrenergic and cholinergic nerve cell bodies and, by analogy with intrinsic ganglia in other organs, it is likely that these nerve cells play an integrative and/or modulatory role in prostatic activity rather than acting as simple relay stations.41 Recently, nitric oxide (NO) has been implicated in the functional control of the human prostate, based on the immunohistochemical demonstration of nitric oxide synthase (NOS)-containing nerve fibers and ganglion cells within the prostatic stroma.42 These data have been interpreted as indicating that NO, serving as a neurotransmitter and as a paracrine factor, may modulate smooth muscle tone in the human prostate gland.

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Figure 1.10 An autonomic ganglion from the prostatic capsule containing both small DBHpositive (presumptive noradrenergic) and larger DBH-negative (presumptive cholinergic) nerve cell bodies. Human prostate gland. Neural control of prostatic secretion Numerous acetylcholinesterase-positive nerves lie at the base of the glandular acini of the prostate, forming a presumptive cholinergic secretomotor innervation,13,41 and it is well known that parasympathetic stimulation increases the rate of prostatic secretion.35 Immunohistochemical studies have shown that the subepithelial nerve fibers in the human prostate gland are rich in VIP,13,41,43 and thus VIP is considered to play a vital role in the regulation of secretory activity within the organ. VIP may also have an effect in the regulation of blood flow within the prostate, an increase in blood flow enhancing the secretory activity of the gland.43 Recently, NOS has been demonstrated in nerve fibers surrounding glandular acini in the human prostate gland, indicating the probable involvement of NO in the control of prostatic secretion.42,44The apparent co-localization of both VIP and NOS in the same subepithelial nerve fibers is highly suggestive of a cofunctional role for NO and VIP in the regulation of prostatic secretory activity.44 References 1. Glenister T W. The development of the utricle and of the so-called ‘middle’ or ‘median’ lobe of the human prostate. J Anat 1962; 96:443–455 2. McNeal J E. The prostate and prostatic urethra: a morphologic synthesis. J Urol 1972; 107:1008–1016 3. Elbadawi A, Mathews R, Light J K, Wheeler T M. Immunohistochemical and ultrastructural study of rhabdosphincter component of the prostatic capsule. J Urol 1997; 158:1819–1828 4. Ho K M T, McMurray G, Brading A F et al. Nitric oxide synthase in the heterogenous population of intramural striated muscle fibres of the human membranous urethral sphincter. J Urol 1998; 159:1091– 1096 5. Lowsley O S. The development of the human prostate gland with reference to the development of other structures at the neck of the urinary bladder. Am J Anat 1912; 13:299–349 6. Franks L M. Benign nodular hyperplasia of the prostate. A review. Ann R Coll Surg 1954; 14:92–106 7. McNeal J E. Regional morphology and pathology of the prostate. Am J Clin Pathol 1968; 49:347–357 8. McNeal J E. Origin and evolution of benign prostatic enlargement. Invest Urol 1978; 15:340–345 9. McNeal J E. Anatomy of the prostate: an historical survey of divergent views. Prostate 1980; 1:3–13 10. Tissell L E, Salander H. The lobes of the human prostate. Scand J Nephrol 1975; 9:185–191 11. Tissell L E, Salander H. Anatomy of the human prostate and its three paired lobes. In: Kimball F A, Buhl A E, Carter D B (eds). New approaches to the study of benign prostatic hyperplasia. New York: Alan R.Liss, 1984: 55–65 12. Blacklock N J, Bouskill K. The zonal anatomy of the prostate in man and in the rhesus monkey. Urol Res 1977; 5:163–167 13. Higgins J R A, Gosling J A. Studies on the structure and intrinsic innervation of the normal human prostate. Prostate 1989; Suppl 2:5–16 14. McNeal J E. Prostate. In: Sternberg S S (ed). Histology for pathologists. New York: Raven Press, 1992:749–763 15. Salander H, Johansson S, Tissel L G. The histology of the dorsal and medial prostatic lobes in man. Invest Urol 1981; 15:479–484 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_9.html[09.07.2009 11:51:20]

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16. Stegmayr B, Busch C, Fritjofsson A, Ronquist G. Biochemical and morphologic studies of the prostate gland in men subjected to radical cystectomy. Ups J Med Sci 1985; 90:139–143 17. Dermer G B. Basal cell proliferation in benign prostatic hyperplasia. Cancer 1978; 41:1857–1862 18. Cohen R J, Glezerson G, Taylor L F et al. The neuroendocrine cell population of the human prostate gland. J Urol 1993; 150:365–368 19. Di Sant’ Agnese P A, de Mesy Jensen K L, Churukian J. Human prostate endocrine-paracrine (APUD) cells: distributional analysis with a comparison of serotonin and neuron-specific enolase immunoreactivity and silver stains. Arch Pathol Lab Med 1985; 109:607–612 20. Di Sant’ Agnese P A, de Mesy Jensen K L. Somatostatin and/or somatostatin like immunoreactive endocrine-

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Page 10 paracrine cells in the human prostate gland. Arch Pathol Lab Med 1984; 108:693–696 21. Di Sant’ Agnese P A. Calcitonin-like immunoreactive and bombesin-like immunoreactive endocrineparacrine cells of the human prostate. Arch Pathol Lab Med 1986; 110: 412–415 22. Baumgartner H G, Falck B, Holstein A F, Owman C H, Owman T. Adrenergic innervation of the human testis, epididymis, ductus deferens and prostate. A fluorescence microscopic and fluorimetric study. Z Zellforsch 1968; 90: 81–95 23. Gosling J A, Thompson S A. A neurohistochemical and histological study of peripheral autonomic neurons of the human bladder neck and prostate. Urol Int 1977; 32: 269–276 24. Vaalasti A, Hervonen A. Autonomic innervation of the human prostate. Invest Urol 1980; 17:293–297 25. Gosling J A. Autonomic innervation of the prostate. In: Hinman F (ed). Benign prostatic hypertrophy. New York: Springer-Verlag, 1983:349–360 26. Vaalasti A, Hervonen A. Nerve endings in the human prostate. Am J Anat 1980; 157:41–47 27. Langley J N, Anderson H K. The innervation of the pelvic and adjoining viscera. VI anatomical observations. J Physiol (Lond) 1896; 20:372–406 28. Lepor H, Gregerman M, Crosby R, Mostofi F K, Walsh P C. Precise localization of the autonomic nerves from the pelvic plexus to the corpora cavernosa: a detailed anatomical study of the adult male prostate. J Urol 1985; 133: 207–212 29. Brushini H, Schmidt R A, Tanagho E A. Neurologic control of prostatic secretion in the dog. Invest Urol 1978; 15: 288–291 30. Donker P J, Ivanovici F, Noach E L. Analyses of the urethral pressure profile by means of electromyography and the administration of drugs. Br J Urol 1972; 44:180 31. Furuya S, Kumamoto Y, Yokoyama E et al. Alpha-adrenergic activity and urethral pressure profilometry in prostatic zone in benign prostatic hypertrophy. J Urol 1982; 128: 836 32. Caine M, Raz S, Zeighler M. Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol 1975; 47:193 33. Caine M. Clinical experience with α-adrenoceptor antagonists in benign prostatic hypertrophy. Fed Proc 1986; 45: 2604 34. Caine M. The present role of α-adrenoceptor blockers in the treatment of benign prostatic hypertrophy. J Urol 1986; 136:1 35. Smith E R, Lebeaux M T. The mediation of the canine prostatic secretion provoked by hypogastric nerve stimulation. Invest Urol 1970; 7:313–318 36. Hedlund H, Anderson K E, Larsson B. Alpha-adrenoceptors and muscarinic receptors in the isolated human prostate. J Urol 1985; 134:1291 37. Chapple C R, Crowe R, Gilpin S A et al. The innervation of the human prostate gland—the changes associated with benign enlargement. J Urol 1991; 146:1637–1644 38. Vaalasti A, Linnoila I, Hervonen A. Immunohistochemical demonstration of VIP, [Met5]- and [Leu5]enkephalin immunoreactive nerve fibres in the human prostate and seminal vesicles. Histochemistry 1980; 66: 89–98 39. Gu J, Polak J M, Probert L et al. Peptidergic innervation of the human male genital tract. J Urol 1983; 130:386–391 40. Adrian T E, Gu J, Allen J M et al. Neuropeptide Y in the human male genital tract. Life Sci 1984; 35:2643–2648 41. Crowe R, Chapple C R, Burnstock G. The human prostate gland: a histochemical and immunohistochemical study of neuropeptides, serotonin, dopamine-β-hydroxylase and acetylcholinesterase in autonomic nerves and ganglia. Br J Urol 1991; 68:53–61 42. Burnett A L, Maguire M P, Chamness S L et al. Characterization and localization of nitric oxide synthase in the human prostate. Urology 1995; 45:435–439 43. Tainio H. Peptidergic innervation of the human prostate, seminal vesicle and vas deferens. Acta Histochem 1995; 97:113–119 44. Block W, Klotz T, Loch C et al. Distribution of nitric oxide synthase implies a regulation of circulation, smooth muscle tone, and secretory function in the human prostate by nitric oxide. Prostate 1997; 33:1– 8

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Page 11 2 Embryology and development of the prostate E Shapiro M S Steiner Embryology of the prostate The terminal end of the hindgut is termed the ‘cloaca’, which is the Latin word for sewer. Septation of the cloaca by the urorectal septum begins at about 28 days of gestation.1 The rectum and primitive urogenital sinus (UGS) have formed by the 44th day of development. The primitive UGS proximal to the mesonephric duct develops into the vesicourethral canal, whereas the region distal of the mesonephric duct becomes the definitive UGS. The UGS adjacent to the bladder (pelvic urethra) is narrow and differentiates into the lower portion of the prostatic and membranous urethra.2 Embryologically, the cranial half of the pelvic urethra is derived from the endodermal UGS. Posteriorly, a component of mesonephric mesoderm originating from the bladder becomes incorporated into the pelvic urethra (superficial layer of the trigone). Later in development, this mesenchyme becomes smooth muscle that is continuous with the bladder (trigone). The caudal half of the pelvic urethra originates entirely from the UGS.3,4 At about the 10th week of gestation, the ductal network within the prostate develops from solid epithelial outgrowths, or prostatic buds. These prostatic buds evaginate from the endodermal UGS immediately below the bladder and penetrate into the Müllerian mesoderm which develops into the utricle and the mesonephric mesoderm, which develops into the ejaculatory ducts.5–9 The prostatic ducts rapidly lengthen, arborize, and canalize. By 13 weeks, 70 primary ducts are present and exhibit secretory cytodifferentiation.6,9 Prostate growth and development are dependent on androgen production by the fetal testes, which begins at about the eighth week of gestation.10–14 Unlike development of the Wolffian duct derivatives, which are dependent solely on testosterone, the differentiation of the UGS is dependent on the 5α-reduced form of testosterone, dihydrotestosterone (DHT). DHT is essential for the mediation of growth and development of the prostate from the pelvic portion of the UGS.12,15,16 Prostate morphology Much of our understanding of prostatic ductal development has been derived from the 1912 detailed anatomic descriptions of Lowsley.9 Lowsley serially sectioned the human fetal prostate and noted that, by 12 weeks, the branching ductal system consisted of five distinct groups. These lobes were termed the posterior, lateral (two), anterior, and middle lobes. The ducts of the posterior lobes originate from the floor of the prostatic urethra distal to the openings of the ejaculatory ducts and grow posteriorly. The epithelial buds of the two lateral lobes branch lateral to the verumontanum. The ducts of the middle lobe originate on the posterior urethra proximal to the openings to the ejaculatory ducts. The anterior lobe buds branch anterior to the verumontanum. The anterior lobe is prominent until the 16th week and then involutes to become an insignificant structure by 22 weeks. Although Lowsley’s work in the fetus was meticulous and precise, it does not explain the morphology of the adult prostate gland. The distinct boundaries between the five prostate lobes that Lowsley defined cannot be identified 2.5 months postnatally, nor do the five distinct lobes exist in the prepubertal and normal young adult prostate.5,17,18 Nonetheless, the terms posterior, lateral, middle, and anterior continue to be used to describe the lobes of the prostate, even though the middle and lateral lobes exist only in the aging male. Although Lowsley’s study emphasized the structural changes in the fetal prostate gland, Zondek and Zondek19 examined the continuous influence of maternal placental and fetal hormones on prostatic growth. The investigators noted periodic acid-Schiff (PAS)-positive staining in the prostate as early as 14 weeks of gestation, which correlates with secretion and growth activity in the fetus. The incidence and degree of PAS-positive reactions increase as fetal development progresses. Squamous metaplasia is found in the prostatic tubular epithelium at 22 weeks’ gestation and increases as the fetus matures. The squamous metaplasia resolves by acantholysis and exfoliation, resulting in the disappearance of most foci by birth. This process appears to depend upon a delicate balance of estrogen and testosterone. In congenital anomalies such as anencephaly, the fetus is exposed to excessive levels of circulating estrogen in the face of abnormally low testosterone production due to the absence of gonadotropin stimulation. The prostates of fetuses with this anomaly contain extensive squamous metaplasia and cyst formation.

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Page 12 Zondek and Zondek19 also examined tubular proliferation in the fetus. The fetal prostate is composed of only a few tubules widely separated by stroma. By 40 weeks, glandular epithelium proliferates and interspersed stromal elements decline. More recently Xia et al.20 qualitatively examined prostate growth, histogenesis, and secretory activity in 107 specimens from normal fetuses ranging in age from 20 weeks’ gestation to 1 month (postnatal). No sharply delineated ‘lobules’ were recognized. Two zones were identified, the inner submucosal zone (IZ) and the peripheral zone (PZ). The IZ was characterized by a concentric mass of fibromuscular connective tissue containing ducts at various stages of development. The PZ contained less concentrically organized fibromuscular connective tissue with secondary ducts, gland buds, and groups of acinar glands. The PZ was further divided into anterior, posterior, and two lateral regions. Three stages of development were also identified.20 During the bud stage (20–30 weeks), the buds at the ends of the ducts were simple, solid, and cellular and contained no lumen. Columnar cells were seen basally, and spindle-shaped cells were found near the bud center. The budtubule stage (31–36 weeks) was characterized by small collections of cellular buds and acini in both the PZ and IZ. In the acinotubular stage (37–42 weeks), distinct acinotubular gland clusters arise from the tubules with distinct lumina. Other investigators have noted that progression of ductal formation occurs, except in the periurethral zone. There, primitive rounded glands persist. Xia et al.20 also observed the presence of a glandular pattern in 25% of the fetal prostates, which resembled ‘budding’ atypical hyperplasia with ‘back-to-back’ glands, as described in the adult prostate. This pattern was seen as early as 24 weeks, but occurred more frequently in the 37- to 42-week gestational age glands. PAS staining intensity was directly related to gestational age, with the region of greatest staining activity in the lateral lobes of the PZ. Prostate-specific antigen (PSA) was identified in only 20% of the specimens, all of which were either older fetal or newborn glands. Squamous metaplasia was always found in association with the utricle and posterior wall of the urethra. Regions of involvement of the ducts with squamous metaplasia were variable. As the fetus progressed in gestational age, the areas of squamous metaplasia became less prominent. To date, this study is the most comprehensive examination of the embryologic development of the fetal prostate. Our understanding of prostate development has evolved from Lowsley and Venero’s concept of five lobes and the organized progression of ductal budding to zonal histogenesis (IZ and PZ). These studies focus primarily on the ductal development of the gland. Popek et al.21 examined development of the epithelium and also the qualitative morphologic changes that occur in the mesenchyme or stroma during development. They observed that the primitive mesenchyme is initially very loose, with the epithelium budding into the stroma. As the ductal network progresses, the loose peripheral primitive mesenchyme is replaced by concentrically organized smooth muscle bundles around acini. The stroma does not under-go a change to smooth muscle in the periurethral region. Two distinct smooth muscle bands are also noted; one is in association with the anterior fibromuscular stroma and one surrounds the utricle and ejaculatory ducts and is continuous with the smooth muscle of the seminal vesicles. Skeletal muscle is also seen peripherally in association with the prostatic capsule. Muscle-specific actin staining was noted as early as week 16, but mesenchymal expression was more notable by week 22. Prostate-specific acid phosphatase staining was seen in the larger ducts and cannulated acini by 17 weeks. PSA was generally absent in ductal and acinar cellular cytoplasm but was detected in areas of squamous metaplasia by 32 weeks. Shapiro et al.22 reported the application of computer image analysis that adapts Weibel’s multipurpose test grid and line intersect stereologic analysis to quantify the relative amounts of stroma and epithelium in prostate tissue. The original gray-density computer image analysis discriminated between the epithelial and stromal elements of prostatic tissue sections stained with hematoxylin and eosin (H & E). Shapiro et al.23 recently developed a new technique for quantifying the cellular elements of the prostate. The technique involves double immunoenzymatic staining and computer assisted color image analysis. The epithelium and smooth muscle were labeled with rabbit anti-desmin and a mouse antihuman prostatic acid phosphatase (PSAP), respectively. A rabbit peroxidase-anti-peroxidase complex was linked to the rabbit anti-desmin by a secondary antibody to rabbit antibody. The peroxidaseantiperoxidase complex was stained brown using the chromogen DAB. A mouse alkaline phosphataseanti-alkaline phosphatase (APAAP) complex was linked to the mouse anti-PSAP by a secondary antibody to mouse antibody. The APAAP complex was labeled using the chromogen fast red. The epithelium, glandular lumen, smooth muscle, and connective tissue stained red, colorless, dark brown, and light brown, respectively, using the double immunoenzymatic staining technique. The thresholds for the computer assisted color image analysis were set to file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_12.html[09.07.2009 11:51:21]

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Page 13 discriminate between the different staining properties of the prostatic cellular elements. Literature examining the morphometry of the prepubertal prostate is scarce.24 The only comprehensive study of prostatic morphometry in the prepubertal male has recently been reported by Shapiro et al.25 Quantitative morphometric studies were performed on pediatric and other nonhyperplastic prostate specimens obtained from 45 males ranging in age from 2 days to 40 years. The entire group was stratified based upon age into categories reflecting the neonatal, childhood, peri-pubertal, adolescent, and young adult period. Double immunoenzymatic staining using anti-actin and anti-PSAP was used to label the tissue components.23 Color image analysis demonstrated age-related changes in the density of smooth muscle that appear to parallel serum testosterone levels that vary due to the postnatal testosterone surge (age 30–60 days) and the rise in testosterone at the onset of puberty.12–14 A progressive decrease in smooth muscle area density throughout childhood, prepuberty and puberty was observed (Fig. 2.1). The density of smooth muscle significantly increased following puberty and throughout adolescence and early adulthood. There was a concomitant increase in connective tissue from the neonatal period throughout childhood, prepuberty, and puberty and a decrease after puberty and throughout adolescence and early adulthood. Since the changes in smooth muscle and connective tissue were inversely related, the per cent contribution of the stromal compartment to the total gland remained constant. No significant changes were seen in the epithelium or glandular lumen during these periods. The stromal to epithelial ratio remains constant from birth to age 40 in nonhyperplastic glands and is similar to those in asymptomatic and symptomatic benign prostatic hyperplasia (BPH) tissues (Table 2.1). These morphometric observations suggest that BPH is not a unique stromal process.25 These studies demonstrate that the stromal compartment is a dynamic structure, and the relationship between changes in cellular content and hormone milieu may be important to our understanding of growth of the prostate from birth to age 40 and the subsequent development of BPH. In addition to these observed dynamic changes in morphometry, the early testosterone surge in the young infant may be a critically important ‘imprinting’ event that may have an impact on the gland’s propensity for future abnormal prostatic growth and disease. Hormonal imprinting has been studied in the rat.26 Naslund and Coffey27 showed that early hormonal surges are requisite for normal adult prostate growth in the rat and that an alteration in the normal endocrine events that occur shortly after birth can have significant and permanent effects on the androgen sensitivity and growth of the adult

Figure 2.1 Bar graph illustrating the smooth muscle (SM), connective tissue (CT), and their combined components or stromal compartment of the prostate gland in groups I–V (From Shapiro E, Perlman E, Hartanto V et al. Morphometric analysis of pediatric and nonhyperplastic prostate glands: evidence that BPH is not a unique stromal process. Prostate 1997; 33:180. Reprinted by permission of Wiley-Liss, Inc. a division of John Wiley and Sons, Inc.)

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Page 14 Table 2.1 Per cent area density of the histologic components of the prostate. (From Shapiro E, Perlman E, Hartanto V et al. Morphometric analysis of pediatric and non-hyperplastic prostate glands: evidence that BPH is not a unique stromal process. Prostate 1997; 33:179. Reprinted by permission of Wiley-Liss, Inc. a division of John Wiley and Sons, Inc.)

*p<0.05. SM, smooth muscle; CT, connective tissue; E, epithelium; L, glandular lumen. prostate. These hormonal surges are thought to affect prostatic growth by altering the properties of the prostatic stem cells. The absolute number of these stem cells is important because it ultimately determines the size of the gland. Therefore, hormonal events occurring before puberty can imprint or program the prostatic size, androgen sensitivity, and function and maintenance of the stem cells. In order to elucidate further the growth and development of the fetal prostate, Shapiro et al. (unpublished data) step-sectioned fetal prostates of 9.5–40 weeks’ gestation to determine the macroscopic growth rate and quantitative morphometry using color image analysis. Three-dimensional reconstruction of the fetal prostate gland has been performed to define the structural changes throughout the gland in the smooth muscle, connective tissue, and urethral lumen, as well as to define ductal budding and morphogenesis (Shapiro et al., unpublished data). Preliminary observations indicate that the mean cross-sectional area (csa) of the fetal prostate increases significantly in early gestation (Shapiro et al., unpublished data): at gestational age 9.5 weeks, 11.5 weeks, 13.0 weeks, and 16.5 weeks the csa is 0.42 mm2, 1.20 mm2, 1.96 mm2, and 4.95 mm2, respectively. The histologic composition of these prostates has been determined using double immunoenzymatic staining and color assisted computer image analysis.23 We have shown that the connective tissue comprises a significant component (approximately 65%) of the fetal gland (gestational age 9.5–16.5 weeks), while the smooth muscle component during these early weeks of prostatic development comprises only 25%. The epithelium and lumen together represent about 5–10% of the gland. Although the morphometry of the older fetus has yet to be determined, the stromal compartment of the neonate/infant gland (age 0–1 year) is known to be slightly smaller (80%), and is composed of almost 50% smooth muscle and 30% connective tissue. This again denotes dynamic changes in the stromal compartment during fetal development. Timms et al.28 investigated ductal budding and branching patterns in the developing prostate using threedimensional computer-assisted serial section reconstruction. He studied fetal mice and rats and also examined two human fetuses (crown-rump length 70 mm and 100 mm). Timms showed that ventral, lateral, and dorsal lines of epithelial buds follow a ventro-dorsal and cranial-caudal axis. His findings suggest that prostate ductal budding exhibits patterns compatible with the current concept of zonal anatomy.29–32 McNeal29–32 described the zonal anatomy of the prostate based on examination of the gland in different planes of section. The urethra divides the prostate into an anterior fibromuscular and posterior glandular portion and is the primary anatomic reference point. The urethra has a 35-degree angulation. The point of angulation divides the urethra into proximal and distal segments of about equal length (Fig. 2.2). Two principal regions of the glandular prostate are the PZ (approximately 75% of the total glandular volume) and the central zone (CZ) (approximately 25% of the total volume). The CZ and its ductal orifices are in close association with the ejaculatory ducts and their orifices near the verumontanum in the distal urethral segment, which extends from the prostatic apex to the verumontanum. The PZ ducts enter the urethra separately from those of the CZ and are in association primarily with the distal urethral segment. The CZ morphology is composed of ducts that branch into large, irregularly contoured acini, whereas the PZ ducts branch into small, round, regular acini.31–33 The epithelial cells in the CZ have granular cytoplasm and enlarged nuclei located at various levels from the basement membrane, whereas the epithelial cells of the PZ

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Page 15 have clear cytoplasm and small, dark nuclei located uniformly along the basal aspect of the basement membrane. The stroma of the CZ is long and compact and closely associated with the acini, whereas that of the PZ is random, with loose interconnections. These morphologic histologic differences between the PZ and CZ may be explained by the different embryonic origins. The ejaculatory ducts traverse the center of the CZ, and the epithelium of the CZ is similar to that of the seminal vesicle, suggesting a Wolffian duct origin. The PZ presumably is derived from the UGS. The transitional zone (TZ) accounts for less than 5–10% of the glandular volume and is closely related to the proximal urethral segment.31,32,34 The cylinder of the striated muscle surrounding the proximal urethral segment is termed the ‘preprostatic sphincter’, which prevents retrograde ejaculation. Lateral to this sphincter are two small lobes that are histologically similar to the PZ. The stroma of the TZ is dense and compact. The TZ is

Figure 2.2 Sagittal diagram of distal prostatic urethral segment (UD), proximal urethral segment (UP), and ejaculatory ducts (E) showing their relationships to a sagittal section of the anteromedial nonglandular tissues (bladder neck (bn), anterior fibromuscular stroma (fm), preprostatic sphincter (s), distal striated sphincter (s)). These structures are shown in relation to a three-dimensional representation of the glandular prostate (central zone (CZ), peripheral zone (PZ), transitional zone (TX)). Arrows indicate the coronal plane (C) along the distal urethral segment, which is the plane of greatest extent of glandular prostate, and the oblique coronal plane (OC) along the proximal urethral segment. (From McNeal J E. Normal histology of the prostate. Am J Surg Pathol 1988; 12:619, with permission.) adherent to the external aspect of the periprostatic sphincter, and its glands penetrate the sphincter, whereas the peripheral fibers of the sphincter penetrate the TZ stroma. The periurethral region of the prostate comprises less than 1% of the total glandular volume (Fig. 2.3).31,32 This region contains tiny ducts arising from the proximal urethral segment that are embedded in the periurethral smooth muscle. The periurethral glands are histologically similar to those of the PZ and TZ. This is not unexpected since the TZ and the periurethral gland region have a common embryonic urogenital sinus origin and are the sites of origin of BPH (Fig. 2.4). Hyperplastic nodules develop as early as the fourth decade. Periurethral nodules are stromal and resemble embryonic mesenchyme, where-as TZ nodules are glandular. Nodule genesis is focal and occurs randomly within areas of susceptibility. The initial abnormality in nodule genesis may be spontaneous reversion of a clone of stromal cells to the embryonic state. Growth potential can then be mediated through coordinated stromal-epithelial interactions. This postulation is supported by qualitative observations of ductal development that is tangential to nodule borders. These ducts may show epithelial hyperplasia and budding of new branches on only the duct wall facing the center of the nodule. These eccentric effects suggest that an induction or interaction is occurring on only one side of the duct.

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Figure 2.3 Oblique coronal plane of prostate subdivided by the preprostatic sphincter (S) into the transitional zone (T) and periurethral region (U). Main transitional zone ducts arise from the urethra at the base of the verumontanum (V) and pass around the distal border of the sphincter as they arborize toward the bladder. P, peripheral zone of glandular prostate. (From McNeal J E. Origin and evolution of benign prostatic enlargement. Invest Urol 1978; 15:340–343, with permission.)

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Figure 2.4 Prostate with few nodules superimposed on an oblique coronal diagram. Centers of glandular nodules are plotted and lie primarily within the transitional zone (T), especially near or within the sphincter (S). Stromal nodules are plotted on the right. They are fewer in number and are often periurethral (U) or in the medial sphincter. (b) Prostate with many nodules and diffusely enlarged transition zone. Glandular nodules (left) are generally located within the transitional zone. Stromal nodules (right) occur primarily in the periurethral region. (From McNeal J E. Origin and evolution of benign prostatic enlargement. Invest Urol 1978; 15:340–343, with permission.) The hallmark of embryonic development is the formation of new architecture. It seems logical that the development of BPH nodules, which is repressed until the fourth or fifth decade of life, may be a ‘reawakening of embryonic capabilities’ in the adult. Stromal-epithelial interactions in prostate development The formation of new ductal acinar architecture of BPH deviates from that in the normal development of most organs.31,35 First, the acinar development of the prostate should be completed during puberty. The prostate is the only organ that demonstrates new growth as part of the aging process. Also, the ductal system in BPH forms differently from that of the embryonic prostate. The ducts of the embryonic prostate branch parallel and away from each other rather than toward each other, as seen in BPH nodules. Although the specific biochemical factors initiating new growth of the prostate are unknown, there is increasing evidence that stromal cells are intimately involved.36–38 The inductive role of the stromal cells in the adult prostate resulting in new nodule formation, is, as mentioned above, thought of as (an embryonic reawakening’. These investigations by Cunha15,39–50 have examined the interaction between epithelium and mesenchyme, as well as the androgenic mediation of the events that result in prostatic growth and development. Stromal and epithelial interactions that occur in the developing prostate are androgen dependent.51 Chemical or surgical castration of the fetus during the critical periods of sexual development results in the inhibition of development of the prostate and other male accessory sex glands.52–60 During the postnatal period, androgen remains important for prostate growth, as castration at this time will inhibit growth and development.51,61,62 Although the fetal testis elaborates testosterone, it is DHT that is the active intracellular androgen responsible for prostatic morphogenesis. The enzyme 5αreductase has been localized in the UGS and external genitalia of humans.12,16,44,63,64 Inhibition of this enzyme in the male rat results in feminization of the external genitalia and urethra and the partial inhibition of prostatic development.65 Although DHT is important for prostatic growth, the developing prostate may be responsive to exceedingly low levels of DHT or other androgens.65 Also, some aspects of postnatal prostatic growth may be independent of androgens, as castration in the rat during this

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period does not completely inhibit prostate development.51,61,62 This suggests that other nonandrogen growth factors such as peptide growth factors are capable of mediating arborization and growth of prostatic ducts. The 5α-reductase deficiency syndrome is a form of autosomal recessive male pseudohermaphroditism characterized by severe penoscrotal hypospadias, a blind vaginal pouch, and normal testes with normal epididymes, vasa deferentia, and seminal vesicles.66,67 The ejaculatory ducts terminate in the blindending vagina, and the prostate is small or undetectable. The phenotypic appearance is female without breast development. The selective effects of testosterone and DHT are defined since the defect in virilization during embryogenesis is limited to the UGS and the anlage of the external genitalia. Testicular feminization syndrome (Tfm) results in complete failure of the prostate to develop.68 Androgen receptors are defective or absent. The Wolffian ducts undergo degeneration. The external genitalia are

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Page 17 feminized despite normal testosterone levels. Testicular feminization and 5α-reductase deficiency syndromes provide clinical models for understanding the profound effect of DHT on prostate morphogenesis. Analysis of tissue recombinant experiments utilizing Tfm mice has demonstrated the role of stromalepithelial interactions.69 These mice have defective androgen receptors and fail to develop prostates. When tissue recombinant constructed of wild-type mesenchyme and Tfm epithelium are exposed to physiologic androgen levels as a result of grafting of the recombinants into intact male hosts, normal prostatic morphogenesis ensues.42,48,70 When the Trm mesenchyme is used with either the Tfm or the wild-type epithelium, the prostate does not form. These studies suggest that the mesenchyme is the actual target which elaborates other local growth factors that mediate androgen effects on the epithelium. The importance of DHT in prostate development is further supported by the presence of DHT receptor binding sites in wildtype UGS,71–74 since these binding sites are absent in the Tfm urogenital mesenchyme.48 The rat and mouse models of prostate development47,75,76 have delineated the lobar and ductal development, hormonal receptor status, and sex steroid requirements for growth. In the rodent, prostatic morphogenesis continues from late fetal life until sexual maturity.47 In these rodent species, the prostatic ducts are organized and encapsulated into individual lobes which emerge centrally from the urethra and extend peripherally before branching. Microdissections of these glands have shown a compound ductal system lacking true acini.75 Each of the four paired lobes has a distinct ductal branching pattern. The ducts are lined with a pseudostratified columnar secreting epithelium and each duct is surrounded by a layer of smooth muscle.77–81 Along the basement membrane are nonsecretory basal epithelial cells which may function as reserve or stem cells capable of differentiation. The epithelial morphology varies along the proximal-distal axis of the ducts, accompanied by differences in the function of these cells. Plasma membrane proteins,47 secretory proteins,82 and proteins governing cell death and degeneration82–84 are differentially expressed in specific regions along the duct. The stroma in these rodent models consists of fibroblasts, smooth muscle cells, blood vessels, connective tissue, nerve terminals, and lymphatics with an extracellular matrix of collagen.85 The stroma is subdivided into periacinar and interacinar stroma.86 The periacinar stroma constitutes several layers of smooth muscle separated from the ductal epithelium by the basal lamina.78,87 Endocrinology of prostatic development Development of the prostate is androgen dependent11,12,14,36,47,88 and DHT is the active intracellular androgen. Castration of neonatal mice inhibits continued growth and development, while some aspects of neonatal growth may be androgen independent.47,62,89 In rodents, androgen receptors (ARs) are expressed prenatally in the mesenchyme but not in the epithelium.71–74 At the end of the first postnatal week, the epithelial ARs appear when duct canalization occurs.71 The timetable and distribution of AR expression have been further studied by Cooke et al.90 They showed that functional fetal mouse ARs (capable of ligand binding) are present on gestational days 13– 14 in the UGS and Wolffian duct mesenchyme, but not in the epithelium. At this early time, only AR mRNA is present in the epithelium. When functional epithelial ARs appear, they do so in a cranial-caudal direction in the Wolffian duct and UGS over the late fetal/early neonatal periods. Since differentiation, growth, and early morphogenesis of the UGS and Wolffian duct structures are androgen dependent, early androgen effects must be mediated through the ARs of the mesenchyme of these structures.90 Cunha’s tissue recombinant experiments47,48 demonstrate prostatic development when normal UGS mesenchyme (UGM) and Tfm UGS epithelium are grafted into a male host. A critical paracrine relationship exists between the mesenchyme and epithelium during androgen-dependent morphogenesis. Regional differences in androgen sensitivity have been demonstrated along the ductal axis.75,82,84 The proximal duct is relatively androgen independent, while the distal duct tips are highly androgen dependent. Prins et al.91 have shown no differences in functional AR levels and 5α-reductase levels along the ducts in the 15-, 30-, or 100-day-old-rat. Recent investigations by Prins and Birch,92 using antibodies to rat ARs have shown that in the rat the basal epithelium expresses ARs as early as day 1. These ARs may act as direct targets of androgen effects of the epithelium during prostate development, even though initial epithelial AR induction may be an androgen-dependent process mediated by AR+ mesenchyme during late fetal life. Luminal epithelium does not appear until day 5–10. When present, it stains intensely for ARs. Also, periductal mesenchyme shows differentiation into smooth muscle by day 3–5. These smooth muscle cells are also strongly AR+, while the interductal fibroblasts show fewer AR+ file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_17.html[09.07.2009 11:51:23]

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Page 18 cells. These smooth muscle cells may be important targets for androgen-mediated morphogenesis. Prins92,93 also examined the effects of neonatal estrogen exposure on the development of the ARs. Estrogen receptors (ERs) have been shown to be strongly expressed in the rat prostate94 and mouse prostate mesenchyme.95 While the stroma is strongly ER+, the prostate smooth muscle is weakly to negatively staining after differentiatThere are no ERs in the epithelium of the prostate. Brief ing from mesenchyme. Fibroblasts remain strongly ER+. exposure to neonatal estrogen will downregulate ARs and permanently alter their expression, as well as retard ductal development.92,93 Smooth muscle development is generally unaffected, as is the development of basal cells. Estrogenization does not inhibit epithelial cell differentiation (determined by the appearance of luminal cell cytokeratins) completely, indicating that initiation of cytodifferentiation precedes elevated AR expression rather than increasing AR triggering cytodifferentiation. These experiments suggest that functional differentiation is dependent on AR expression in epithelial cells. The ventral prostate epithelial cells express prostate binding protein only after cytodifferentiation of distal duct tips occurs where AR immunostaining was seen. These studies support previous observations by Donjacour and Cunha96 using tissue recombinant experiments. Although UGM from normal mice instructively induced prostate morphology in wild-type, as well as the Tfm urinary tract epithelium, tissue recombinants of UGM and Tfm bladder or urethral epithelium cannot produce complete prostate cytodifferentiation or secretory proteins. Epithelial ARs are, therefore, important to the final states of morphogenesis and the initiation of prostate secretory activity. Tissue recombinant experiments have also been used to examine epithelial-mesenchymal interactions on the differentiation and organization of prostatic smooth muscle.97 Experiments combined adult prostatic epithelium (PRE) with UGM or seminal vesicle mesenchyme (SVM) or bladder epithelium (BLE) with UGM or SVM. Prostatic ducts developed in all tissue recombinants when UGM was used with either epithelium. Smooth muscle cells also organized into sheets resembling prostate. When SVM was combined with either epithelium, the prostatic ducts were surrounded by thick smooth muscle cells resembling seminal vesicle. The smooth muscle was unorganized in grafts of SVM or UGM. These experiments suggest that male urogenital gland mesenchyme dictates spatial organization, but smooth muscle differentiation is induced by epithelium. Urothelium may also direct the organization of smooth muscle tissue, since urothelium is thought to be a potent inducer of smooth muscle differentiation. Cunha and Donjacour47 have shown that the proximal segments of prostatic ducts near the urethra express urothelial membrane antigen and have associated thick layers of smooth muscle cells surrounding them. Role of growth factors in prostatic development Peptide growth factors may be direct mediators of androgen action and responsible for mediating the epithelial-mesenchymal microenvironment through either autocrine or paracrine pathways.98–101 These growth factors are regulated by androgens, suggesting that androgens may only indirectly influence growth. Peptide growth factors are part of a large family of proliferating and differentiating regulatory factors and may be important in prostate growth. Almost a decade ago, Norman et al.102 combined mouse UGM with an adult prostate epithelial duct tip. The mesenchyme induced ductal proliferation and arborization of adult epithelium, which demonstrated that the adult prostate has the potential for new growth by ‘reawakening’ of early prostatic embryonic mesenchymal-epithelial interactions.28–32,47 These findings that adult prostate treated with androgens does not grow, but embryonic mesenchyme is effective in inducing growth of adult prostate, suggest that the mesenchyme may elaborate other local factors that stimulate adult prostatic growth. Peptide growth factors are those local factors most likely responsible for mediating mesenchymal and epithelial interactions important for prostate development, since: • Peptide growth factors are expressed in either mesenchymal or epithelial components of developing prostate.47,49,103 • Isolated prostatic, epithelial, and stromal cells respond to peptide growth factors in vitro.49,104 • Prostatic mesenchymal and epithelial cells express specific membrane receptors for peptide growth factors.105–107 • Neutralizing antibodies for a peptide growth factor or its receptor inhibit biological effects.108–111 • Overexpression of peptide growth factors in transgenic mice perturbs prostatic growth and development.112–114 • Androgens directly influence the expression of peptide growth factors by prostate cells.111,115,116

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Page 19 • Androgen production is modulated by peptide growth factors.117,118 Epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), and transforming growth factor β (TGFβ) family members have been found in normal prostate.36,119–122 The interplay between the stimulatory growth factors (EGF, TGFα, IGF, and FGF) and inhibitory growth factors (TGFβ1–3) regulates the epithelial and mesenchymal interactions responsible for prostatic development.123 Although TGFα and EGF utilize the same EGF receptor to enhance prostate cell proliferation. TGFα is preferentially expressed during periods of prenatal and postnatal prostate epithelial development.124 TGFα appears to stimulate prostatic ductal proliferation during development since overproduction of TGFα in prostates from TGFα transgenic mice resulted in prostatic ductal hyperplasia.114 Interestingly, FGF family members are mitogenic for both prostatic epithelial and mesenchymal cells.108,125,126 Perhaps the strongest evidence for their role in the embryonic reawakening of mesenchymal and epithelial interactions leading to prostatic growth is based on transgenic mice that over produce int-2, which is FGF-like growth factor.112,113 These int-2 transgenic mice exhibit exuberant prostatic hyperplasia with prostates up to 20-fold larger than control animals. The prostatic hyperplasia was similar to human BPH.112,113 Another FGF family member, KGF, is unique as it is produced by stromal cells but stimulates only epithelial growth.127 Similarly, IGF appears to stimulate prostatic epithelial proliferation selectively.128 This suggests that peptide growth factors can specifically influence either epithelial or mesenchymal cells during prostatic development. TGFβ family members have multifunctional biological properties. TGFβ inhibits normal prostatic epithelial growth, but stimulates prostatic mesenchymal cells.123 Steiner (unpublished data) has performed preliminary studies focusing on defining the important factors on prostate development. He has utilized TGFβ1 transgenic mice which overexpress TGFβ1.129,130 Overexpression of TGFβ1 alters prostate development by decreasing prostate ductal branching and increasing smooth muscle surrounding the acinar ducts (Steiner, unpublished data).112–114 Moreover, the anterior prostate had evidence of only primary ductal branching—the involuted or ‘aborted’ ductal branching—as seen in the development of distal ductal tips in androgen-deprived animals (Steiner, unpublished data). The effects of androgens on growth factors have generally been investigated in adult rats when glandular growth is minimal.49 This is the case for studies with TGFβ, which have shown that, following castration, there is a cascade of events, one of which is a marked increase in the level of TGFβ1 mRNA expression and TGFβ1 receptor binding sites in the rat ventral prostate.111,116,131 TGFβ1 has also been shown to inhibit normal proliferation of prostatic epithelial cells in culture. Foster and Cunha101 have recently investigated the role of TGFβ1 during prostate development. Rat anterior prostate is grown in vitro in a serum-free culture. The newborn rat anterior prostate consists of mesenchyme and unbranched epithelial buds. When testosterone is added for 6 days, there is ductal branching and morphogenesis. The trophic effects of testosterone and DHT can be inhibited by adding TGFβ1 to the culture medium. This inhibition occurs in a dose-dependent fashion. Thus, TGFβ plays a role in limiting ductal proliferation and arborization as well as stimulating mesenchymal cell growth (smooth muscle). Peptide growth factors appear to be the direct mediators of androgen action. Following androgen withdrawal, the production of stimulatory peptide growth factors EGF, IGF, and FGF by prostate cells decreases, whereas there is an increase in the expression of the inhibitory peptide growth factor TGFβ1 and TGFβ1 receptors.115,120,132,133 The net effect of these peptide growth factor alterations is prostatic involution. Androgen replacement re-establishes normal EGF, IGF, and FGF levels and suppresses TGFβ1, and the prostate regrows towards its original size.123 Peptide growth factors may be the embryonic inducers that initiate adult prostate growth. FGF and TGFβ family members have been implicated in the development of BPH.123 Mori et al.134 have reported that basic FGF (bFGF) and TGFβ2 mRNA are elevated in human BPH. Moreover, extracts of human BPH contain bFGF-like activity that enhances growth of human prostate epithelial cells and prostate-derived fibroblasts in culture.108 TGFβ is known to stimulate production of bFGF mRNA and protein in prostatederived stromal cells.135 Thus, a stromal BPH nodule may be formed when bFGF and TGFβ2 both stimulate stromal proliferation. The degree of interplay between TGFβ2 and bFGF will have differential effects on prostatic epithelial-stromal interactions, resulting in varying amounts of stromal and glandular hyperplasia.

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Page 20 Evidence that peptide growth factors contribute to human fetal prostate development Although the precise cellular and molecular mechanisms remain unclear, androgens and peptide growth factors appear to mediate the mesenchymal and epithelial interactions needed for normal prostate morphogenesis. The stroma of the developing prostate, which is thought to be the target of androgen stimulation, elaborates factors that induce glandular proliferation.39 The androgen receptor is expressed prenatally in the mouse prostatic mesenchyme, but not in the epithelium.136 Based on these observations, Tenniswood137 proposed that paracrine interactions between the androgen-receptorpositive mesenchyme and the androgen-receptor-negative epithelium may be mediated by a stromaderived growth factor capable of regulating epithelial cell proliferation. Prostate organ culture studies provide direct evidence for such interactions between stroma and epithelium; DHT promotes mitogenesis of stromal cells and stromal cells secrete fibroblast-derived soluble growth factors which stimulate epithelial proliferation.138 Peptide growth factors appear to be those soluble factors that mediate androgen effects on postnatal prostatic growth, but their role in prenatal prostate development is unknown. Nonetheless, experimental evidence examining the interactions of peptide growth factor members of the EGF and TGFβ families and androgens in prostate tissue has provided some mechanistic clues.139 Since EGF is under androgen control,132 and is required for epithelial cell proliferation in vitro, it may be one of the stroma-derived growth factors (SDGF).133 However, it is not known whether EGF is synthesized by the prostatic epithelial or stromal cells. Peptide growth factors have been shown to be regulated by androgens, suggesting that androgens may only indirectly influence prostate growth. One member of the EGF family, TGFα, is preferentially expressed during periods of pre- and postnatal prostate epithelial development.124 TGFβ is a multifunctional family, which generally inhibits growth of many types of epithelial cells and stimulates most mesenchymal cells.123 In transgenic mice, overexpression of TGFβ1 appears to alter prostate development by decreasing ductal branching and increasing smooth muscle surrounding the acinar ducts.113 Studies in rats have shown that castration is followed by a cascade of events including a downregulation of TGFα and a marked increase in TGFβ1 mRNA expression and TGFβ1 receptor binding sites in ventral prostate.111,116,131Finally, emerging studies have confirmed that some aspects of postnatal prostatic growth are androgen independent, as castration does not completely inhibit prostate development, supporting a role for peptide growth factors.51,62 Indirect evidence suggests that it is the interplay between stimulatory growth factors (TGFα) and inhibitory growth factors (TGFβ1–3) that regulates in part the mesenchymal and epithelial interactions responsible for prostate development. The exact interrelationship between androgens and peptide growth factors remains to be elucidated. Raghow et al.140 have performed studies that support the hypothesis that peptide growth factors may be the mediators of androgenic action in mesenchymal and epithelial interactions responsible for the early prostate development. Prostatic development is dependent not only on the presence of testosterone, but also on its conversion to DHT. Although testosterone production and Leydig cell hyperplasia begin at the eighth week of gestation,10,11 serum testosterone concentrations peak at about 13–16 weeks of gestational age, and gradually they decline to female testosterone levels.141 In vitro experimental evidence suggests that androgens may play only a permissive role, whereas peptide growth factors may be the direct mediators of androgen action. Prostate cell proliferation in vitro is dependent on EGF or βFGF, but not androgens.133 DHT has been shown to modulate the expression of TGFα, EGF, βFGF, and TGFβ in prostate.123 Organ culture studies have revealed that TGFβ1 can inhibit prostate ductal proliferation and branching morphogenesis. Moreover, βFGF can induce ductal proliferation independent of androgens.142 Hence, fetal prostate development may only be indirectly dependent on androgens, and peptide growth factors may be the direct mediators of androgen action. The expression of the enzyme 5α-reductase during the early phase (11–16.5 weeks) of fetal prostate development is confined to the prostatic mesenchyme and urothelium, with no detectable staining in the fetal prostatic epithelial cells.143 This pattern of expression is similar to human and rat male external genitalia and prostate differentiation, which is dependent upon local DHT formation early in gestation.66,67,144 In the adult rat prostate, George et al.145 have stated that 5α-reductase gene expression is under feed-forward control, in which product of the enzyme, DHT, stimulates the expression of the gene. However, no such feed-forward regulation of this enzyme was detected in the fetal rat prostate.146 Inhibition of the 5α-reductase enzyme in the male rat results in feminization of the external genitalia and urethra and partial inhibition of prostatic development. As previously discussed, in man, the 5α-reductase deficiency syndrome is recognized as male pseudohermaphroditism characterized by a small or file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_20.html[09.07.2009 11:51:25]

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Page 21 undetectable prostate.65,66 Consequently, 5α-reductase and DHT are critical for normal human prostate development.147 In humans, androgen receptor was initially present in the mesenchyme and urothelium, but with the fetal androgen surge, the prostatic epithelium had greater AR staining.143 This suggests that DHT is produced by the AR+ mesenchyme and affects the AR+ epithelial cells by paracrine signaling pathways. Similarly, in rodent prostate development, androgen receptors are expressed prenatally in the mesenchyme, but not in the epithelium.71–73 If the corresponding urogenital mesenchyme lacks AR, as in the testicular feminization (Tfm) syndrome, the prostate does not develop, whereas AR+ urogenital sinus mesenchyme was able to induce AR− Tfm epithelium to develop into epithelium.47 Hence, tissue recombinant experiments46,47 have demonstrated the critical paracrine relationship between the mesenchyme and epithelium during androgen-dependent morphogenesis. Donjacour and Cunha,51 in similar mouse tissue recombinant experiments, showed the importance of epithelial ARs to both prostate development and cytodifferentiation to secretory epithelium. Thus, the presence of ARs and DHT is necessary to stimulate mesenchymal elaboration of stromal factors. Raghow et al. have shown that some of those elaborated factors are members of the EGF and TGFβ families. TGFα, TGFβ1, and TGFβ3 were present in the mesenchyme at significant levels during the period of prostate development prior to the androgen surge (9.5–11.5 weeks).140 In contrast, TGFβ2 increased measurably only after 13 weeks, simultaneous with the peak of androgen production by the testes. These results suggest androgens modulate the differential expression of peptide growth factors during fetal prostate development.140 Furthermore, the presence of DHT with the appearance of 5α-reductase and AR+ epithelium was associated with the greatest intensity of immunostaining for TGFα and TGFβ3 in the epithelium during weeks 13–16.5 of gestation.140 Although TGFα, TGFβ1, and TGFβ3 were present initially in the mesenchyme, they later appeared in the epithelium during the androgen surge.140 Hence, it appears that initially DHT only indirectly influences prostatic epithelium by directly inducing the elaboration of mesenchymal factors that diffuse to affect the epithelium in a paracrine fashion. This is consistent with other investigators who have shown in developing rat prostate that the urogenital mesenchyme (UGM) induces epithelial ductal morphogenesis and epithelial androgen receptors, regulates epithelial proliferation, and specifies the expression of prostate-specific secretory proteins.45,148–151 The level of TGFβ1 was initially high during the early weeks of fetal prostate development, but then declined during the period of androgen surge, to the baseline low levels later at about 20 weeks.140 This reciprocal relationship between presence of DHT and TGFβ1 level seems to suggest downregulation of TGFβ1 by androgens during the period of active fetal prostate development. The downregulation of mesenchymal TGFβ1 by DHT following the androgen surge may be one of the ways mesenchyme induces epithelial differentiation during fetal prostate development. TGFβ is primarily a growth inhibitor and antagonizes other stimulatory growth factors; however, not much is known about the differential roles of the specific TGFβ isoforms. Raghow et al.140 have shown higher levels of TGFα and TGFβ3 in the prostatic epithelium during the period of androgen surge, suggesting DHT regulation of this TGFβ isoform in a manner similar to that of mitogenic growth factor TGFβ. TGFα was initially thought to be produced exclusively by transformed cells, but is now known to be present in rapidly growing normal tissues.152–156 Overexpression of TGFα in transgenic mice results in hyperplasia of the anterior prostate.114 Whereas TGFα has been shown to be a growth stimulator that may be critical in the cellular proliferation associated with prostatic growth, TGFβ3 may be an important factor in continued ductal elongation and morphogenesis. The role of TGFβ2 in the developing epithelium, however, remains unclear. In conclusion, the cascade of events starting with the onset of testosterone production by the fetal testes, the expression of functional androgen receptors, and the conversion of testosterone to DHT by 5α-reductase all modulate the differential expression of peptide growth factors in both prostatic mesenchyme and the epithelial cells.140 All the data taken together support the role of peptide growth factors as local mediators that, by autocrine and paracrine pathways, may be directly responsible for mesenchymal and epithelial interactions leading to human fetal prostate development. Further studies are required in the growing prostate to elucidate the differences in growth factor expression in the growing versus the normal growth-quiescent adult prostate. Recent advances in prostate development Shapiro et al.157 studied prostate development in human male fetuses with myelomeningocele (MMC) at 20 weeks’ gestational age. Immunohistochemical staining was performed using Masson’s trichrome and antibodies to smooth and skeletal muscle actin. S-100 protein for

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Page 22 Schwann cell localization and neurofilament protein was also used. These studies demonstrated a marked decrease in the peripheral neural innervation to the prostate in MMC. Trichrome and smooth muscle actin staining also showed that smooth muscle in MMC specimens was less well differentiated. Prostatic size, ductal morphogenesis, and smooth muscle were decreased when compared to controls. At the level where the ejaculatory ducts enter into the prostatic urethra, the mean cross-sectional area was 6.79 mm2 and 11.91 mm2 in the MMC and normal prostate, respectively. Control prostates showed smooth muscle surrounding acini which subsequently become cannulated. In MMC prostates, smooth muscle was absent in the periphery where ductal branching and formation of acini normally occur. They concluded that there is a global defect in the development of smooth muscle in MMC prostate at 20 weeks’ gestation. Since the peripheral nerve density was diminished in the MMC prostate, an intact nervous system may be important in the smooth muscle and ductal morphogenesis of the developing prostate. Xue et al.158 examined chromogranin-A and serotonin immunostaining in 42 prostates, from fetuses at 12–38 weeks’ gestation, infants, prepubertal males and young adults. They determined the staining neuroendocrine (NE) cell index by evaluating the number of epithelial cells and NE cells in tissue sections. They determined that, from 13 weeks’ gestation, NE cells were detected in the prostate. By 20 weeks, all prostates contained NE cells. NE cells were identified mainly in the acinous/ductal regions, whereas most budding tips were devoid of NE cell staining. There were no significant differences found between any of the age groups studied. This study suggests that NE cells may have a role in differentiation and ductal morphogenesis. The NE cells are preferentially distributed in the acinous/ductal region, which may imply a paracrine function during secretory differentiation of exocrine epithelial cells. Cytokeratins have been used to identify various epithelial cells. In 1991, Sherwood et al. identified cytokeratins associated with the basal and luminal epithelia of the human prostate.159 Monoclonal anticytokeratin 8.12 was shown to exhibit immunoactivity with basal but not luminal epithelia. There was no 8.12 antibody staining since prostate cancer tissues are devoid of basal cells. Epithelia of 30 and 36 weeks’ gestation prostates contained only basal cells, whereas both luminal and basal cells were noted in 7-month- and 1-year-old juvenile prostates. This finding has suggested a stem cell function for the prostatic basal cells. Xue et al.160 recently examined keratin expression in the developing human prostate. Samples from five fetuses (of 17, 19, 27, 32, and 38 weeks’ gestation), three infants, three prepubertal males, and one 11-year-old male were studied. They found that, in the early stages of prostate development, cells with an intermediate keratin phenotype can be identified. There were large numbers of these cells, which suggests a hierarchical pathway of cellular differentiation from basal to luminal cells. Intermediate cells were identified by their coexpression of antibodies to RC K103, which recognizes K5 found in basal cells and K18 which is found in luminal cells. In this study there was a variable differentiation-specific keratin in the immature prostate. Their keratin phenotype was K14/K5/K18, which is similar to that of spindleshaped basal cells in the adult prostate.17,18 Interestingly, the luminally located cells were partially positive for 34-βE12 and RCK103, which both stain for basal cells, and almost all contained K18. This suggests that luminally located cells are not fully differentiated and that they still have basal cell and intermediate cell characteristics. Bierhoff et al.161 examined morphological analogies of fetal prostate stroma and nodular stromal proliferates in BPH. The fetal prostates ranged in age from 12 to 40 weeks of gestation. They showed that the developing fetal prostate stroma consists of immature mesenchymal cells up to 17 weeks of gestation, followed by fibroblastic and fibromuscular stromal cells up to week 25 of gestation and predominantly smooth muscle cells until the end of gestation. Stromal nodules occur as immature mesenchymal, fibroblastic, fibromuscular, and smooth muscular, suggestive of a maturational process. The fetal prostate stroma and the stromal nodules present with an increasing degree of maturation, a similar vascular pattern, and a similar occurrence of CD3 (2 lymphocytes), CD20 (B lymphocytes), CD68 (macrophages), S100, and neuron-specific enolase-positive cells. These data suggest that ontogenic processes are recapitulated in the development of stromal nodules in BPH, supporting the idea of the reawakening of fetal processes in BPH. Summary The fetal prostate represents the most proliferative state of the prostate. Over the past 5 years, a great deal has been learned about the molecular events associated with fetal prostate development. Unraveling the mechanisms of fetal prostate growth and development is likely to have important implications for understanding the mechanism giving rise to BPH and prostate cancer, two important diseases of aberrant growth of the prostate. file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_22.html[09.07.2009 11:51:26]

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Page 23 References 1. Stephens F D. Congenital malformations of the urinary tract. New York: Praeger, 1993 2. Hamilton W J, Mossman H W. The urogenital system. In: Human embryology: prenatal development of form and function, 4th edn. New York: Macmillan, 1976:201 3. McNeal J E. The prostate and prostatic urethra: a morphologic synthesis. J Urol 1972; 107:1008 4. McNeal J E. Development and comparative anatomy of the prostate. In: Grayhack J T, Wilson J D, Scherbenske MJ (eds). Benign prostatic hyperplasia. Bethesda: DHEW Publication No NIH 76–1113, Washington: US Government Printing Office, 1976:1 5. Johnson F P. The later development of the urethra in the male. J Urol 1920, 4:447 6. Kellokumpu-Lehtinen P. The histochemical localization of acid phosphatase in human fetal urethral and prostatic epithelium. Invest Urol 1980; 17:435–440 7. Kellokumpu-Lehtinen P. Development of sexual dimorphism in human urogenital sinus complex. Biol Neonate 1985; 48:157 8. Kellokumpu-Lehtinen P, Santti R, Pelliniemi L J. Correlation of early cytodifferentiation of the human fetal prostate and leydig cells. Anat Rec 1980; 196:263–273 9. Lowsley O S. The development of the human prostate gland with reference to the development of other structures at the neck of the urinary bladder. Am J Anat 1912; 13:299–346 10. Pointis G, Latreille M T, Cedard L, Gonado-pituitary relationships in the fetal mouse at various times during sexual differentiation. J Endocrinol 1980; 86:48 11. Resko J A. Androgen secretion by the fetal and neonatal Rhesus monkey. Endocrinology 1978; 87:680 12. Siiteri P K, Wilson J D. Testosterone formation and metabolism during male sexual differentiation in the human embryo. J Clin Endocrinol Metab 1974; 38:113 13. Weniger J P, Zeis A. Sur la secretion prococe de testosterone par le testicule embryonnaire de souris. Comp Rend Acad Sci Paris 1972; 275:1431 14. Winter J S D, Faiman C, Reyes F. Sexual endocrinology of fetal and perinatal life. In: Austin CR, Edward RG (eds). Mechanisms of sex differentiation in animal and man. New York: Academic Press, 1981:205 15. Cunha G R. Epithelio-mesenchyme interactions in primordial gland structures which become responsive to androgenic stimulation. Anat Rec 1972; 172:179 16. Wilson J D, Griffin J E, Leshin M et al. Role of gonadal hormones in development of the sexual phenotypes. Hum Genet 1981; 58:78 17. Franks L M. Benign nodular hyperplasia of the prostate. A review. Ann R Coll Surg Engl 1954; 14:92–106 18. Franks L M. Benign prostatic hyperplasia. Gross and microscopic anatomy. In: Grayhack J T, Wilson J D, Scherbenske M K (eds). Benign prostatic hyperplasia. NIAMDD Workshop Proceedings, 20–21 Feb, 1975. DHEW Publication No NIH 76–1113. Washington: US Government Printing Office, 1976:63–89 19. Zondek T, Zondek L H. The fetal and neonatal prostate. In: Goland M (ed). Normal and abnormal growth of the prostate. Springfield: CC Thomas, 1975:5–28 20. Xia T, Blackburn W R, Gardner W A. Fetal prostate growth and development. Pediatr Pathol 1990; 10: 527–537 21. Popek E J, Tyson R W, Miller G J, Caldwell S A. Prostate development in prune belly syndrome and posterior urethral valves: etiology of PBS—lower urinary tract obstruction or primary mesenchymal defect? Pediatr Pathol 1991; 11:1–29 22. Shapiro E, Hartanto V, Becich M L, Lepor H. The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic BPH. J Urol 1992; 147:1293 23. Shapiro E, Hartanto V, Lepor H. Quantifying the smooth muscle content of the prostate using double-immunoenzy-matic staining and color assisted image analysis. J Urol 1992; 147:1167–1170 24. Andrews G S. The histology of the human fetal and prepubertal prostates. J Anat 1951; 85:44–54 25. Shapiro E, Perlman E, Hartanto V et al. Morphometric analysis of pediatric and non-hyperplastic prostate glands: evidence that BPH is not a unique stromal process. Prostate 1997; 33:177–182 26. Rajfer J, Coffey D S. Sex steroid imprinting of the immature prostate: long-term effects. Invest Urol 1978; 16: 186–190 27. Naslund M J, Coffey D S. The differential effects of neonatal androgen, estrogen, and progesterone on adult rat prostate. J Urol 1986; 136:1136–1140 28. Timms B G, Mohs T J, Didio L J A. Ductal budding and branching patterns in the developing prostate. J Urol 1994; 151:1427–1432 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_23.html[09.07.2009 11:51:26]

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McNeal McNeal McNeal McNeal

J J J J

E. E. E. E.

The zonal anatomy of the prostate. Prostate 1981; 2:35–49 The prostate gland: morphology and pathology. Monogr Urol 1983; 4:3 The prostate gland: morphology and pathobiology. Monogr Urol 1988; 9:3 Normal histology of the prostate. Am J Surg Pathol 1988; 12:619

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Page 24 33. Egevad L. Cytology of the central zone of the prostate. Diagn Cytopathol 2003; 28:239–244 34. Zlotta A R, Djavan B, Damoun M et al. The importance of measuring the prostatic transition zone: an anatomical and radiological study. BJU Int 1999; 84:661–666 35. Islam M A, Kato H, Hayama M. Are neuroendocrine cells responsible for the development of benign prostatic hyperplasia? Eur Urol 2002; 42:79–83 36. Crescioli C, Villari D, Forti G et al. Des (1–3) IGF-I-stimulated growth of human stromal BPH cells is inhibited by a vitamin D(3) analogue. Mol Cell Endocrinol 2002; 198: 69–75 37. Farnsworth W E. Prostate stroma: physiology. Prostate 1999; 38:60–72 38. Niu Y, Xy Y, Zhang J et al. Proliferation and differentiation of prostatic stromal cells. BJU Int 2001; 87:386–393 39. Cunha G R. The role of androgens in the epithelio-mesenchymal interactions involved in prostatic morphogenesis in embryonic mice. Anat Rec 1972; 175:87 40. Cunha G R. Support of normal salivary gland morphogenesis by mesenchyme derived from accessory sexual glands of embryonic mice. Anat Rec 1972; 173:205 41. Cunha G R. Epithelial-stromal interactions in development of the urogenital tract. Int Rev Cytol 1976; 47: 137–194 42. Cunha G R, Lung B. The possible influences of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild-type and androgen-insensitive (Tfm) mice. J Exp Zool 1978; 205:343 43. Cunha G R, Chung L W K, Shannon J M, Reese B A. Stromal-epithelial interactions in sex differentiation. Biol Reprod 1980; 22:19–43 44. Cunha G R, Chung L W K. Stromal-epithelial interactions: induction of prostatic phenotype in urothelium of testicular feminized (Tfm/y) mice. J Steroid Biochem 1981; 14:1317 45. Cunha G R, Chung L W K, Shannon J M et al. Hormoneinduced morphogenesis and growth: role of mesenchy-mal-epithelial interaction. Recent Prog Horm Res 1983; 39:559–598 46. Cunha G R, Donjacour A A. Stromal-epithelial interactions in normal and abnormal prostatic development. Prog Clin Biol Res 1987; 239:251–272 47. Cunha G R, Donjacour A A, Cooke P S et al. The endocrinology and developmental biology of the prostate. Endocr Rev 1987; 8:388 48. Cunha G R, Donjacour A A. Mesenchymal-epithelial interaction in the growth and development of the prostate. In: Lepor H, Ratliff TL (eds). Urologic oncology. Boston: Kluwer Academic, 1989:159 49. Cunha G R, Alarid E T, Turner T et al. Normal and abnormal development of the male urogenital tract: role of androgens, mesenchymal-epithelial interactions, and growth factors. J Androl 1992; 13:465 50. Cunha G R, Hayward S W, Wang Y Z. Role of stroma in carcinogenesis of the prostate. Differentiation 2002; 70: 473–85 51. Donjacour A A, Cunha G R. The effect of androgen deprivation on branching morphogenesis in the mouse prostate. Dev Biol 1988; 128:1 52. Burns R K. Role of hormones in the differentiation of sex. In: Young WC (ed). Sex and internal secretions. Baltimore: Williams & Wilkins, 1961:76 53. Elger W, Graf K J, Steinbeck H et al. Hormonal control of sexual development. Adv Biosci 1974; 13:41 54. Greene R R. Hormonal factors in sex inversion. The effects of sex hormones on embryonic sexual structures of the rat. Biol Symp 1940; 9:105 55. Greene R R, Burrill M W, Ivy A C. The effects of estrogens on the antenatal sexual development of the rat. Am J Anat 1939; 67:305 56. Jost A. Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Recent Prog Horm Res 1953; 8: 379–418 57. Neumann F, Elger W, Steinbeck H. Antiandrogens and reproductive development. Phil Trans R Soc Long (Biol) 1970; 25:179 58. Neumann F, Graf K J, Elger W. Hormone-induced disturbances in sexual differentiation. Adv Biosci 1974; 13:71 59. Raynaud A, Frilley M. Destruction de cerveau des embryos de souris au treizieme jour de la gestation, par irradiation au moyen des rayon X. Comp Rend Soc Biol 1947; 141:658 60. Wilson J D. Androgens. In: Hardman J G, Limbird LE (eds). Goodman & Gilman’s The pharmacological basis of therapeutics, 10th edn. New York: McGraw-Hill, 2001: 1441–1458 61. Lung B, Cunha G R. Development of seminal vesicles and coagulating glands in neonatal mice 1: The morphogenetic effects of various hormonal conditions. Anat Rec 1981; 199:73 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_24.html[09.07.2009 11:51:27]

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62. Price D. Normal development of the prostate and seminal vesicles of the rat with a study of experimental postnatal modifications. Am J Anat 1936; 60:79 63. Sherwood J B, McConnell J D, Vazquez D J et al. Heterogeneity of 5 alpha-reductase gene expression in benign prostatic hyperplasia. J Urol 2003; 169:575–579 64. Steers W D. 5 Alpha-reductase activity in the prostate. Urology 2001; 58 Suppl 6:17–24 (discussion 24) 65. Imperato-McGinley J, Binienda Z, Arthur A et al. The development of a male pseudohermaphroditic rat using an

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Page 25 inhibitor of the enzyme 5α reductase. Endocrinology 1985; 116:807 66. Imperato-McGinley J, Guerrero L, Gautieer T et al. Steroid 5α-reductase deficiency in man. An inherited form of pseudohermaphroditism. Science 1974; 186:1213 67. Walsh P C, Madden J D, Harrod M J et al. Familial incomplete male pseudohermaphroditism type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974; 291:944 68. Griffin J E, Wildon J D. Disorders of sexual differentiation. In: Walsh P C, Gittes R F, Perlmutter A D et al. (eds). Campbell’s urology, 5th edn. Philadelphia: WB Saunders, 1986:1819 69. Ohio S. Major sex determining genes. New York: Springer-Verlag, 1979:1–140 70. Lasnitzki I, Mizuno T. Prostatic induction and interaction of epithelium and mesenchyme from normal wild-type and androgen-insensitive mice with testicular feminization. J Endocrinol 1980; 85:423 71. Shannon J M, Cunha G R. Autoradiographic localization of androgen binding in the developing mouse prostate. Prostate 1983; 4:367–673 72. Shannon J M, Cunha G R, Vanderslice K D. Autoradiographic localization of androgen receptors in the developing urogenital tract and mammary gland. Anat Rec 1981; 199:232 73. Takeda H, Mizuno T, Lasnitzki I. Autoradiographic studies of androgen-binding sites in the rat urogenital sinus and postnatal prostate. J Endocrinol 1985; 104:87–92 74. Wasner G, Hennermann I, Kratochwil K. Ontogeny of mesenchymal androgen receptors in the embryonic mouse mammary gland. Endocrinology 1983; 113:1771 75. Sugimura Y, Cunha G R, Donjacour A A. Morphogenesis and histologic study of castration-induced degeneration and androgen-induced regeneration in the mouse prostate. Biol Reprod 1980; 22:19–43 76. Hayashi N, Sugimura Y, Kawamura J et al. Morphological and functional heterogeneity in the rat prostate gland. Biol Reprod 1991; 45:308–321 77. Bazer G T. Basal cell proliferation and differentiation in regeneration of the rat ventral prostate. Invest Urol 1979; 17:470 78. Ichihara I, Pelliniemi L J. Ultrastructure of the basal cell and the acinar capsule of rat ventral prostate. Anat Anz 1975; 138:355 79. Dahl E, Kjaerheim A, Tveter K. The ultrastructure of the accessory sex organs of the male rat. 1. Normal structure. Z Zellforsch 1973; 137:345 80. Timms B G, Chandler J A, Sinowatz F. The ultrastructure of basal cells of rat and dog prostate. Cell Tissue Res 1976; 173:542 81. Rowlatt C, Franks L M. Myoepithelium in mouse prostate. Nature 1964; 202:707 82. Lee C, Sensibar J, Dudek S et al. Prostatic ductal system in rats: regional variation in morphological and functional activities. Biol Reprod 1990; 43:1079–1086 83. Sensibar J, Griswold M, Sylvester S et al. Prostatic ductal system in rats: regional variation in localization of an androgen-repressed gene product, sulfated glycoprotein-2. Endocrinology 1991; 128:2091–2102 84. Rouleau M, Legert J, Tenniswood M. Ductal heterogeneity of cytokeratins, gene expression, and cell death in the rat ventral prostate. Mol Endocrinol 1990; 4:2003–2013 85. Aumuller G. Morphologic and endocrine aspects of prostatic function. Prostate 1983; 4:195 86. English H F, Drago J R, Santen R J. Cellular response to androgen depletion and repletion in the rat ventral prostate; autoradiography and morphometric analysis. Prostate 1985; 7:41 87. Brandes D. Fine structure and cytochemistry of male accessory organs. In: Brandes D (ed). Male accessory sex organs: structure and function. New York: Academic Press, 1974:18 88. Marker P C, Donjacour A A, Dahiya R, Cunha G R. Hormonal, cellular, and molecular control of prostatic development. Dev Biol 2003; 253:165–174 89. Berry S, Isaacs J T. Comparative aspects of prostatic growth and androgen metabolism with aging in the rat versus the dog. Endocrinology 1984; 114:511 90. Cooke P S, Young P, Cunha G R. Androgen receptor expression in developing male reproductive organs. Endocrinology 1991; 128:2867 91. Prins G, Cooke P, Birch L et al. Androgen receptor expression and 5α reductase activity along the proximal-distal axis of the rat prostate duct. Endocrinology 1992; 130: 3066–3073 92. Prins G S, Birch L. The developmental pattern of androgen receptor expression in rat prostate lobes is altered after neonatal exposure to estrogen. Endocrinology 1995; 136:1303–1314 93. Prins G. Neonatal estrogen exposure induces lobe-specific alterations in adult rat prostate and androgen receptor expression. Endocrinology 1992; 130:3703–3714 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_25.html[09.07.2009 11:51:27]

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94. Sar M, Welsch F. Oestrogen receptor alpha and beta in rat prostate and epididymis. Andrologia 2000; 32:295–301 95. Cooke P S, Young P, Hess R A, Cunha G R. Estrogen receptor expression in developing epididymis, efferent ductules, and other male reproductive organs. Endocrinology 1991; 128:2874–2879 96. Donjacour A A, Cunha G R. Assessment of prostatic protein secretion in tissue recombinants made of urogenital sinus mesenchyme and urothelium from normal or andro-

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Page 26 gen-insensitive mice. Endocrinology 1993; 132: 2342–2350 97. Cunha G R, Battle E, Young P et al. Role of epithelial-mesenchyme interaction in the differentiation and spatial organization of visceral smooth muscle. Epithelial Cell Biol 1992; 1:76–83 98. Aaronson S A, Bottaro D P, Miki T et al. Keratinocyte growth factor: a fibroblast growth factor family member with unusual target cell specificity. Ann NY Acad Sci 1991; 638:62–77 99. Nilsen-Hamilton M. Transforming growth factor-β and its actions on cellular growth and differentiation. Curr Top Dev Biol 1990; 24:95–136 100. Partanen A M. Epidermal growth factor and transforming growth factor-α in the development of epithelial-mesenchymal organs of the mouse. Curr Top Dev Biol 1990; 24:31–55 101. Cunha G R. Role of mesenchymal-epithelial interactions in normal and abnormal development of the mammary gland and prostate. Cancer 1994; 74:1030–1043 102. Norman J T, Cunha G R, Sugimura Y. The induction of new ductal growth in adult prostatic epithelium in response to an embryonic prostatic inductor. Prostate 1986; 8:209–220 103. Steiner M S, Barrack E R. Transforming growth factor-β1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol Endocrinol 1992; 6:15 104. Mansson P E, Adams P, Kan M, McKeehan W L. Heparinbinding growth factor gene expression and receptor characteristics in normal rat prostate and two transplantable rat prostate tumors. Cancer Res 1989; 49:2485 105. Connolly J M, Rose D P. Production of epidermal growth factor and transforming growth factor-α by the androgenresponsive LNCaP human prostate cancer cell line. Prostate 1990; 16:209 106. Story M T, Livingston B, Baeten L et al. Cultured human prostate-derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor. Prostate 1989; 15:355 107. Wilding G, Zugmeier G, Knabbe C, Flanders KC, Gelmann E. Differential effects of transforming growth factor beta on human prostate cancer cells in vitro. Mol Cell Endocrinol 1989; 62:79 108. McKeehan W L, Adams P S. Heparin-binding growth factor/prostatropin attenuates inhibition of rat prostate tumor epithelial cell growth by transforming growth factor type beta. In Vitro Cell Dev Biol 1988; 24:243 109. Wilding G, Valverius E, Knabbe C, Gelmann E P. Role of transforming growth factor-α in human prostate cancer cell growth. Prostate 1989; 15:1 110. Shain S A, Lin A L, Koger J D, Karaganis A G. Rat prostate cancer cells contain functional receptors for transforming growth factor-beta. Endocrinology 1990; 126:818 111. Kyprianous N, Isaacs J T. Identification of a cellular receptor for transforming growth factor-beta in rat ventral prostate and its negative regulation by androgens. Endocrinology 1988; 123:2124 112. Muller W J, Lee F S, Dickson C et al. The int-2-gene product acts as an epithelial growth factor in transgenic mice. EMBO J 1990; 9:907 113. Tutrone R F, Ball R A, Ornitz D M et al. Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model. J Urol 1993; 149:633 114. Sandgren E P, Luetteke N C, Palmiter R D et al. Overexpression of TGFα in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia and carcinoma of the breast. Cell 1990; 61:1121 115. Katz A E, Benson M C, Wise G J et al. Gene activity during the early phase of androgen-stimulated rat prostate regrowth. Cancer Res 1989; 49:5889 116. Kyprianou N, Isaacs J T. Expression of transforming growth factor-beta in the rat ventral prostate during castration-induced programmed cell death. Mol Endocrinol 1989; 3:1515 117. Avallet O, Vigier M, Perrard-Sapori M H, Saez J M. Transforming growth factor beta inhibits Leydig cell functions. Biochem Biophys Res Commun 1987; 146:575 118. Lin T, Blaisdell J, Haskell J F. Transforming growth factorbeta inhibits Leydig cell steroidogenesis in primary culture. Biochem Biophys Res Commun 1987; 146:387 119. Steiner M S. The role of peptide growth factors in the prostate. A review. Urology 1993; 42:99 120. Fiorelli G, DeBellis A, Longo A et al. Insulin-like growth factor-1 receptors in human hyperplasia prostate tissue: characterization, tissue localization and their modulation by chronic treatment with a gonadotropin-releasing hormone analog. J Endocr Metab 1991; 72:740 121. Kimura G, Kasuya J, Giannini S et al. Inhibition of IGF-II-stimulated growth of prostate cancer cells by IGF-I receptor-specific monoclonal antibody and antisense oligonucleotide of IGF-II messenger RNA. J Urol 1994; 151: 367A (abstract) file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_26.html[09.07.2009 11:51:28]

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122. Saez C, Gonzalez-Baena A C, Japon M A et al. Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride. Prostate 1999; 40:83–88 123. Steiner M S. Review of peptide growth factors in benign prostatic hyperplasia and urologic malignancy. J Urol 1995; 153:1085 124. Taylor T B, Ramsdell J S. Transforming growth factor-α and its receptor are expressed in the epithelium of the rat prostate gland. Endocrinology 1993; 133:1306

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Page 27 125. McKeehan W L, Adams P S, Fast D. Different hormonal requirements for androgen-independent growth of normal and tumor epithelial cells from rat prostate. In Vitro Cell Dev Biol 1987; 23:147 126. Smith E P, Russell W E, French F S, Wilson F M. A form of basic fibroblast growth factor is secreted into the adluminal fluid of the rat coagulating gland. Prostate 1989; 14: 353 127. Marchese C, Rubin J, Ron D et al. Human keratinocyte growth factor activity on proliferation and differentiation of human keratinocytes: differentiation of human keratinocytes: differentiation response distinguishes KGF from EGF family. J Cell Physiol 1990; 144:326 128. Iwamura M, Sluss P M, Casamento J B, Cockett A T K. Insulin-like growth factor I: action and receptor characterization in human prostate cancer cell lines. Prostate 1993; 22:243 129. Matsui Y, Halter S A, Holt J T et al. Development of mammary hyperplasia and neoplasia in MMTVTGF alpha transgenic mice. Cell 1990; 61:1147 130. Halter S A, Dempsey P, Matsui Y et al. Distinctive patterns of hyperplasia in MMTV-TGFα transgenic mice. Characterization of mammary gland and skin proliferations. Am J Pathol 1992; 140:1131 131. Martikainen P, Kyprianou N, Isaacs J T. Effect of transforming growth factor-beta 1 on proliferation and death of rat prostatic cells. Endocrinology 1990; 127:2963–2968 132. Hiramatsu M, Kashimata M, Minami N et al. Androgenic regulation of epidermal growth factor in the mouse ventral prostate. Biochem Int 1988; 17:311 133. McKeenhan W L, Adams P S, Rosser M P. Direct mitogenic effects of insulin, epidermal growth factor, glucocorticoid, cholera toxin, unknown pituitary factors and possibly prolactin, but not androgen, on normal rat prostate epithelial cells in serum-free, primary cell culture. Cancer Res 1984; 44:1998 134. Mori H, Maki M, Oishi K et al. Increased expression of genes for basic fibroblast growth factor and transforming growth factor type beta 2 in human benign prostatic hyperplasia. Prostate 1990; 16:71 135. Story M T, Hopp K A, Meier D A et al. Influence of transforming growth factor β1 and other growth factors on basic fibroblast growth factor level and proliferation of cultured human prostate-derived fibroblasts. Prostate 1993; 22:183 136. Takeda H, Chang C. Immunohistochemical and in-situ hybridization analysis of androgen receptor expression during the development of the mouse prostate gland. J Endocrinol 1991; 129:83 137. Tenniswood M. Role of epithelial-stromal interactions in the control of gene expression in the prostate: an hypothesis. Prostate 1986; 9:375 138. Chang S M, Chung L W K. Interaction between prostatic fibroblast and epithelial cells in culture: role of androgen. Endocrinology 1989; 125:2719 139. Story M T. Polypeptide modulators of prostatic growth and development. Cancer Surv 1991; 11:123 140. Raghow S, Shapiro E, Steiner M S. Immunohistochemical location of TGF-α during early human fetal prostate development. J Urol; in press 141. Reyes F I, Boroditsky R S, Winter J S D et al. Studies on human sexual development. II. Fetal and maternal serum gonadotropin and sex steroid concentrations. JCEM 1973; 38:612 142. Alarid E T, Cunha G R, Young P et al. Evidence for a possible organ- and sex-specific role of bFGF in the development of the fetal mammalian reproductive tract. Endocrinology 1991; 129:2148 143. Shapiro E, Tang R, Wang B et al. The expression of 5α-reductase and the androgen receptor in the human fetal prostate. J Urol 1996; 155:534 (abstract) 144. George F W, Peterson K G. 5α-Dihydrotestosterone formation is necessary for embryogenesis of the rat prostate. Endocrinology 1988; 122:1159 145. George F W, Russell D W, Wilson J D. Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5α-reductase. Proc Natl Acad Sci USA 1991; 88:8044 146. Bermann D M, Tian H, Russell D W. Expression and regulation of steroid 5α-reductase in the urogenital tract of the fetal rat. Mol Endocrinol 1995; 9:1561 147. Imperato-McGinley J, Gautier T, Zirinsky K. Prostate visualization studies in males homozygous and heterozygous for 5α reductase deficiency. J Clin Endocrinol Metab 1992; 75:1022 148. Cunha G R, Donjacour A A. Mesenchymal-epithelial interaction in the growth and development of the prostate. In: Lepor H, Ratliff T L (eds). Urologic oncology. Boston: Kluwer Academic Publishers, 1989 149. Hayward S W, Baskin L S, Haughney P C et al. Epithelial development in the rat ventral prostate, anterior prostate and seminal vesicle. Acta Anat 1996; 155:81 150. Hayward S W, Baskin L S, Haughney P C et al. Stromal development in the ventral prostate, anterior prostate and seminal vesicle of the rat. Acta Anat 1996; 155:94 151. Takeda H, Suematso N, Mizuno T. Transcription of prostatic steroid binding protein (PSBP) gene is induced by epithelial-mesenchymal interaction. Development 1990; 110:273 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_27.html[09.07.2009 11:51:28]

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152. Coffey R J, Derynck R, Wilcox J N et al. Production and auto-induction of transforming growth factor-β in human keratinocytes. Nature 1987; 328:817

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Page 28 153. Derynck R, Lindquist P B, Bringman T S et al. Expression of the transforming growth factor-alpha gene in tumor cells and normal tissue. Cancer Cells 1989; 7:297 154. Lee D C, Rochford R M, Rodaro G J et al. Developmental expression of rat transforming growth factor-α mRNA. Mol Cell Biol 1985; 5:3644 155. Samsoonder J, Kobrin M S, Kudlow J E. Transforming growth factor-a secreted by untransformed bovine anterior pituitary cells in culture. J Biol Chem 1986; 261: 14 408–14 413 156. Skinner M K, Takacs K, Coffey R J. Transforming growth factor-a gene expression and action in the seminiferous tubule. Peritubular cell-Sertoli cell interactions. Endocrinology 1989; 124:845 157. Shapiro E, Seller M J, Lepor H et al. Altered smooth muscle development and innervation of the lower genitourinary and gastrointestinal tract of the human male fetus with myelomeningocele. J Urol 1998; 160:1047 158. Xue Y, Smedts F, van der Laak J et al. The neuroendocrine cell in the developing human prostate. J Urol 1999; 161: 56 (abstract # 209) 159. Sherwood E R, Theyer G, Steiner G et al. Differential expression of specific cytokeratin polypeptides in the basal and luminal epithelia of the human prostate. 1991; 18: 303 160. Xue Y, Smedts F, Debruyne F M J, de la Rosette J, Schalken J A. Identification of intermediate cell types by keratin expression in the developing human prostate. Prostate 1998; 34:292 161. Bierhoff E, Walljasper U, Hofmann et al. Morphological analogies of fetal prostate stroma and stromal nodules in BPH. Prostate 1997; 31:234

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Page 29 3 Molecular control of prostatic growth A Turkes K Griffiths Introduction Our knowledge and understanding of the endocrine, biochemical, and molecular processes implicated in the pathogenesis of prostatic disease are rapidly growing. Although it would now be recognized that symptomatic clinical benign prostatic hyperplasia (BPH), associated with bladder outlet obstruction, is not a premalignant condition that leads to the development of prostatic cancer, current thought tends to be directed to the possibility that the earlier stages in the natural history of BPH, essentially related to epithelial cell hyperplasia and microscopic BPH, may well give rise to transition zone cancer.1 Prostatic enlargement associated with bladder outlet obstruction is generally the end result of dysfunctional growth regulatory mechanisms within the gland, that can result in the development of a benign stromal adenoma (Fig. 3.1). It is also clear from our understanding that the clinical manifestations of symptomatic BPH are generally recognized in men over the age of 50 years. Indeed, the aging factor is considered a risk factor relating to the disease. Also now accepted, is the evidence that a large proportion of men in their later years will have some degree of prostate enlargement,2,3 often causing bladder outlet obstruction that requires surgical intervention. Moreover, as life expectancy is extended around the world, it would be expected that the proportion of men requiring a transurethral prostatectomy will consequently increase, and it is currently predicted that in the USA, for example, a man of 40 years of age now has a 30% chance of under-going such surgical treatment in his lifetime.4 Twenty-five years ago, approximately 10% could be expected to have surgery.5 Although surgery in the form of transurethral resection of the prostate offers effective therapy for bladder outlet obstruction, the extensive and increasing use of medical treatment, α-blockers and 5αreductase inhibitors, for the management of BPH is now well

Figure 3.1 Obstruction to urinary flow.

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Page 30 recognized. The use of 5α-reductase inhibitors suppresses the conversion of testosterone to 5αdihydrotestosterone (DHT), the principal ‘active androgen’ within the prostate gland. Concurrently, intense research activity is attempting to improve understanding of the molecular processes through which DHT influences prostatic growth and function.6,7 It is noteworthy that clinical BPH occurs during a period of time when testicular function is declining and the concentrations of testosterone in plasma (Fig. 3.2), and also in saliva (Fig. 3.3), are falling with increasing age.8,9 Despite this, most of the related evidence tends to indicate that androgens are implicated in the pathogenesis of the disease. Early castration, or hypopituitarism, appears to prevent the development of BPH. Furthermore, the enlarged prostate regresses following castration or after the administration of luteinizing hormone-releasing hormone (LH-RH) treatment, or after treatment with anti-androgens.10 Plasma hormones, the prostate, and aging Although the prostate grows and functions within a multihormonal environment, responding to a range of regulatory factors, the functional activity of the human gland is primarily dependent on the maintenance of normal concentrations of plasma testosterone. Approximately 90–95% of the 6–7 mg testosterone that is produced daily and appears in the plasma is synthesized by the Leydig cells of the testes,11,12 under the control of LH. The remainder originates in the adrenal gland, either by direct synthesis and secretion or from its production by the peripheral metabolism of the adrenal androgens, the C19 steroids dehydroepiandrosterone (DHA), DHA sulfate, or androstenedione, by muscle and adipose tissue (Fig. 3.4). The concentration of testosterone in the spermatic vein is approximately 75 times higher than that in the peripheral venous plasma. LH secretion by the pituitary

Figure 3.2 Decline in the concentration of testosterone in plasma with increasing age. (Data from Riad-Fahmy et al. 8)

Figure 3.3 Range of salivary testosterone concentrations in a large population of males of different ages. The salivary steroid concentration represents the plasma levels of free, nonprotein-bound, biologically active steroid moiety. The concentrations decline significantly with age.

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Figure 3.4 Testosterone (T) production by the human male. LH, luteinizing hormone; RH, releasing hormone; ACTH, adrenocorticotropic hormone; SHBG, sex hormone-binding globulin. gland is controlled by LH-RH, a decapeptide released by the hypothalamus in a pulsatile manner, thereby promoting a similar, corresponding pulsatile secretion of LH. Both the androgens and estrogens are involved in negative feedback control processes in order to regulate LH synthesis and secretion.13 In man, approximately 30% of the plasma estrogens are synthesized and secreted by the testes,14,15with the major proportion, however, being produced by the peripheral aromatization of androstenedione and testosterone (Fig. 3.5).16 The secretion of the adrenal androgens is controlled by adrenocorticotropic hormone (ACTH), although prolactin may exercise a synergistic influence with ACTH. Testosterone would be considered the most important plasma androgen, but it is the concentration of the free, nonprotein-bound form (Fig. 3.6) which is generally accepted as the biologically active moiety that enters the prostate target cells. The free testosterone level normally provides a reasonable indicator of the androgenic status of the male. In the plasma of the younger man,17–20 approximately 57% of the testosterone is specifically and avidly bound to sex hormone-binding globulin (SHBG), with about 40% less well bound to albumin. A smaller amount, 1%, is bound to corticosteroid-binding globulin (CBG) and approximately 2% constitutes the free fraction (Fig. 3.6). The estrogens are similarly bound to SHBG with, again, approximately 2% in the free fraction. SHBG is synthesized and secreted by the liver by processes regulated to some extent by estrogens, with the thyroid hormones and insulin also implicated.21–23 The decline in testicular function with age would generally be considered to be of primary testicular origin.9 Although plasma levels of LH rise in the elderly man, there is also an impaired testicular response to LH and, moreover, a decreasing number of Leydig cells with increasing age, with a consequent fall in plasma testosterone concentrations (Fig. 3.2). Aging generally increases SHBG levels, giving rise to a corresponding reciprocal decrease in the free testosterone concentration. Therefore, although the total plasma testosterone level of an 80-year-old man is approximately 30–40% of that of a 25-year-old, the free concentration represents only 15–20% of that of the younger man (Fig. 3.6). The ‘active’ androgenic steroid hormone within the prostate gland is DHT,24,25 synthesized from testosterone by the 5α-reductase enzyme system located on the nuclear membrane of prostatic cells file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_31.html[09.07.2009 11:51:30]

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(Fig. 3.7). It is interesting that testosterone and DHT are also synthesized from the adrenal androgens within prostatic tissue (Fig. 3.8),26,27 and this particular source of DHT has been implicated by some in the progression of disseminated prostatic cancer after primary endocrine therapy such as castration or the administration of LH-RH analogs.28–30 Studies in animals certainly suggest that the adrenal steroids can influence prostatic growth and function,31 but they cannot restore the size nor maintain the morphology of the prostate of the castrated rat. The significance of the role of the adrenal androgens in the normal prostate has yet to be clarified and, at present, there are few if any data from man to indicate that they are involved in the pathogenesis of BPH. Of interest and rarely considered is that certain of the metabolites of DHT, the 5α-androstanediols, and androst-5-ene-3β,17β-diol, a metabolite of DHA, elicit weak estrogenic effects32 by binding to the estrogen receptor protein (ER) and promoting certain biological responses similar to, but weaker than those effected by estradiol (Fig. 3.8). There is some controversy as to the precise changes in the endocrine status of the male as he ages.6,7,33,34 It is reported that as testicular function declines with

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Figure 3.5 Production of estrogens by the human male: E1, estrone; E2, estradiol-17 β; T, testosterone; LH, luteinizing hormone; ACTH, adrenocorticotropic hormone; DHA, dehydroepiandrosterone; S, sulfate; A, androstenedione; SHBG, sex hormone-binding globulin.

Figure 3.6 Factors concerned with the levels of free, nonprotein-bound steroid hormone in plasma that is considered to be the biologically active moiety that enters the target cell E2, estradiol-17 β; T, testosterone; SHBG, sex. hormone-binding globulin; CBG, corticosteroidbinding globulin.

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Figure 3.7 A simple representation of the intracellular processes relating to the binding of DHT (D) to the androgen receptor (AR) and to the dimerization of the DHT-AR complex when binding to the hormone response elements (HRE), the nucleotide recognition sequences on the genome. T, testosterone; TF, transcription factors binding to the DNA adjacent to the DHT-AR complexes. increasing age, there is a corresponding increase in the rate of peripheral aromatization35,36 such that the levels of estradiol in plasma rise relative to those of testosterone. The SHBG binding capacity is reported to increase in the elderly (Fig. 3.9),18,37 possibly in response to the elevated estrogenic status in the older man, the consequent effect seen as an increased ratio of the plasma free estradiol to free testosterone. The aging prostate is therefore subjected to a changing estrogen/androgen balance that would be expected to influence the amounts of the steroid hormones that are transferred into the prostate cell. It is generally accepted that the free steroid is transferred into the prostate cell by a process of passive file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_33.html[09.07.2009 11:51:31]

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diffusion, although there is still much to understand about

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Figure 3.8 Metabolism of the adrenal androgens by the human prostate gland to produce DHT. The DHT is further metabolized to the 5α-androstanediols, which can elicit weak estrogenic effects by association with the ER. E2, estradiol-17 β; T, testosterone; DHA, dehydroepiandrosterone. these biological mechanisms, with reports that the testosterone-SHBG complex specifically binds to receptors on the cell membrane (Fig. 3.10) to activate signal transduction systems.38 Extrinsic and intrinsic factors The prostate gland is androgen dependent and a source of testosterone is necessary for the growth, development, and function of the gland.39 It is, however, the intraprostatic androgen, DHT, a metabolite of testosterone, that preferentially binds to the androgen receptor (AR) as a DHT-AR complex, it associates with specific hormone response elements (HREs) on the genome and, in association with other transcription factors (TFs), modulates the expression of androgen-responsive genes (Fig. 3.7). The molecular biochemistry by which steroid hormone receptor complexes associate with their specific recognition sequences within the promoter region of responsive genes is now better understood.40,41 DHT is essential for prostate growth7,42 and exercises an important role in the regulation of gene activity. It is now recognized that the biological effects of such extrinsic factors on the prostate gland are mediated by various peptide growth-regulatory factors. These growth factors, which are produced by the gland, influence

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Figure 3.9 Diagram illustrating changes that have been recognized in the endocrine status of the middle-aged man. Declining testicular function and decreasing testosterone (T) output are associated with increased peripheral aromatization of adrenal androgens. The elevated estradiol (E2) levels have been implicated in the increased sex hormone-binding globulin (SHBG) binding capacity and the resultant changes in the free E2/free T ratio in plasma, the overall effect giving rise to an enhanced estrogenic influence on the prostate gland. prostate function by promoting inter- and intracellular signaling between and within cell populations, through paracrine, autocrine, and intracrine effects (Fig. 3.11). Paradoxically, therefore, it appears that DHT is essential to but not directly responsible for cellular proliferation and it is the intrinsic growth factors such as epidermal growth factor (EGF), keratinocyte growth factor (KGF), insulin-like growth factors (IGF-I and -II), and fibroblast growth factors (FGFs), which are mitogenic and directly stimulate proliferation. Lee et al.43 highlighted these prostatic interrelationships (Fig. 3.12).

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Figure 3.10 Simple representation of the reported cell membrane receptor that is activated by the testosterone (T)—sex. hormonebinding globulin (SHBG) complex. to promote intracellular cyclic adenosine monophosphate (cAMP) production. E2, estradiol-17 β. Stromal-epithelial interrelationship It is now recognized that the stromal elements of the prostate gland play an important role in regulating various aspects of growth and function.44–47 Essentially, DHT-mediated effects on the stromal compartment produce growth stimulatory factors which induce signal transduction pathways within the epithelial cells and thereby promote growth and differentiation (Fig. 3.13). Considerable interest currently centers on KGF, one of the FGF family and sometimes referred to as FGF-7, which would seem a particularly important growth-promoting factor in the prostate.48–53 It is produced by stromal fibroblasts and exercises a paracrine mitogenic effect on epithelial cells through an FGF receptor protein (FGF-R) localized on the cell membrane. The receptor, FGF-R2-exonIIIb, is a splice variant of the FGFR2(bek) gene, which preferentially recognizes KGF.54 The growth-inhibitory factor, transforming growth factor β (TGFβ), inhibits this action of KGF on the epithelium; however, KGF has no effect on stromal cell proliferation. In contrast, FGF-2, sometimes referred to as basic FGF (bFGF), elicits an autocrine mitogenic action on prostatic stromal cells,55–57 but has no effect on epithelial cells. FGF-2 promotes stromal growth through the FGF-R1 that is encoded by the FGF-R1(flg) gene, normally localized only in the stromal compartment. Both epithelial and stromal cells produce FGF-2,57 however, and it is particularly relevant that an elevated expression of FGF-2 has been associated with BPH.58

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Figure 3.11 A simple representation of factors involved in the regulation of prostatic growth.

Figure 3.12 Extrinsic and intrinsic growth regulatory factors.

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Figure 3.13 Relationship between stromal and epithelial compartments of the prostate gland. DHT, dihydrotestosterone; TGF, transforming growth factor; FGF, fibroblast growth factors; KGF, keratinocyte growth factor. There is accumulating evidence that the FGF family is intimately involved with the growth-regulatory processes of the prostate. The family currently consists of ten members, FGF-1 to FGF-10, sharing 30– 55% amino acid sequence homology, which interact with high-affinity tyrosine kinase receptors encoded by four distinct genes. Alternative splicing, however, generates numerous receptor isoforms and markedly increases the complexity of the ligand-receptor interactions. Acidic FGF (FGF-1) and basic FGF (FGF-2) were the first to be characterized and have been extensively investigated. As described, FGF-2 and FGF-7 may have a role in the induction of BPH. FGF-8 mRNA, on the other hand, has been reported to be overexpressed in 22 (71%) of 31 human prostate cancers studied, significantly correlating with grade, but rarely in BPH.59 Seven protein isoforms of FGF-8 exist and were shown to have different transforming potentials in NIH3T3 cells.60 The FGF-8b isoform has been identified in androgenindependent DU 145 cells61 and could well be implicated in cancer progression. As the rat prostatic Dunning tumors progressed to androgen independence, there was a switch in the expression of FGF-R2 from the IIIb isoform to the IIIc isoform,62 and the latter is preferentially associated with FGF-2. Also noteworthy is that FGF-8 also binds with high affinity to FGF-R2exonIIIc and FGF-R3exonIIIc.63 It remains to be determined whether the interaction of FGF-8 with FGF-R2exonIIIc is important with regard to hormone-refractory prostate cancer in man. It has been reported that FGF-R3exonIIIc is the most prevalent isoform in both the normal prostate gland and in primary prostatic epithelial cell cultures.64 The significance of this report in relation to FGF-8 has yet to be evaluated. The predominant localization of the ‘classical’ estrogen receptor (ERα) in the stromal compartment of the human prostate65 and the promotion of stromal hyperplasia by estrogen66 suggest that estradiol as well as DHT may be synergistically implicated in the production of FGF-2 (Fig. 3.13). Overall, homeostasis and the maintenance of the fine balance between cell proliferation and cell death are the result of complex interactions between growth-stimulatory factors and growth-inhibitory factors (Fig. 3.14), modulated by steroid hormones, with the proteins encoded by the growth-suppressor genes such as the p53 and retinoblastoma (Rb) genes also exercising a role in normal growth regulation. Differences in both epithelial and stromal cell function within the ductal system of the prostate gland As our understanding of the growth regulatory processes of the prostate gland increases, so does the realization that the system is, indeed, complex. The human prostate gland is a branched glandular structure, with 40 to 50 ductal

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Figure 3.14 A simple illustration of growth-regulatory balance modulated by steroid hormones. TGF, transforming growth factor; FGF, fibroblast growth factors; EGF, epidermal growth factor; KGF, keratinocyte growth factor; IGF, insulin-like growth factors. systems, each duct lined with epithelial cells and embedded in a matrix of stromal components.67,68 The studies of Chung Lee et al.69,70 and of Tenniswood et al.71,72 have highlighted the complexity of the interaction between stromal and epithelial compartments. Essentially, there is a regional variation in the functional activity of epithelial cells in different regions of the rat ductal system that relates to corresponding differences in the stromal elements. These regions are described as proximal, intermediate, and distal (Fig. 3.15) relative to their distance from the urethra. The epithelial cells in the distal region are actively proliferating, those in the intermediate segment, the major component, are differentiated and secretory, while those in the proximal region are associated with programmed cell death, or apoptosis. It is perceived that TGFβ, produced by the smooth muscle-like cells prevalent in the underlying stroma in the proximal region, will exercise a prominent role in promoting cell death,73,74 a process that DHT will restrain. DHT and KGF will be predominant in the distal region promoting epithelial cell proliferation. A balance between the influence of DHT, TGFβ, and KGF in the intermediate segment will promote epithelial cell differentiation and a secretory function (Fig. 3.15). The proximal region exclusively expresses the castration-induced protein testosterone-repressed prostate message-2 (TRPM-2), or clusterin, the protein associated with apoptosis and produced under androgen-deprived conditions. These studies also imply a migration of epithelial cells from the distal proliferative region, along the duct, to the proximal segment where apoptosis prevails. These locally regulated cell-cell interactions, with regional heterogeneity in stromal-epithelial interrelationships, must now be recognized. The cells are all exposed to the same level of circulating androgen, yet the different patterns of cellular behavior suggest a variable androgenic stimulus to the cells. The different cell responses relating to the production and action of growth regulatory factors must be seen as pivotal to prostatic growth control. There is also regional stromal heterogeneity,75 with multiple layers of smooth muscle cells in the proximal region and a single layer underlining the distal epithelial cells. TGFβ, directly implicated in apoptosis, is located in the stromal elements, but particularly in the actin-positive smooth muscle cells of the proximal region. Fibroblasts are reported to be evenly distributed throughout the stromal compartment.76,77 It is important to note, however, that in tissue culture, smooth muscle cells and fibroblasts appear to be somewhat interchangeable, which can lead to problems of interpretation of studies of cells in culture. It is also important to note that receptors for both androgen and estrogen have been identified in smooth muscle cells and in fibroblasts,78,79 with estrogens stimulating smooth muscle growth.80–83

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Figure 3.15 Regional variation in the functional activity of epithelial cells. TGF, transforming growth factor; FGF, fibroblast growth factors; KGF, keratinocyte growth factor; DHT, dihydrotestosterone. (Adapted from references 69 and 72.) Intra- and intercellular signaling pathways The interrelationship between the stromal and epithelial compartments of the prostate would appear to be pivotal to the growth regulatory processes of the gland. Our understanding of the inter- and intracellular signaling pathways between and within cells, and the associated intrinsic growth regulatory factors that control these pathways, is rapidly attaining a highly sophisticated and comprehensive level. The basis of our understanding has, to date, been centered on the more simple relationship between glandular epithelial cells and the muscle cells and fibroblasts of the stromal compartment. The prostatic neuroendocrine cells are also located within the epithelial compartment, being basally orientated (Fig. 3.16) and morphologically, either the ‘open type’, with apical processes extending to the lumen, or the ‘closed type’, both having long dendritic processes extending under and weaving between adjacent epithelial cells.84 There is speculation regarding their role, but it generally would be considered to encompass the regulation of cell growth and differentiation as well as neuroendocrine, endocrine, and exocrine secretion.85,86 They are specialized, differentiated cells that contain and secrete: • The biogenic amine, serotonin; • Bombesin/gastrin-releasing peptide; • The chromogranin family of polypeptides; • The calcitonin family of peptides; • Somatostatin; • Parathyroid hormone related protein (PTHrP); • Thyroid-stimulating hormone (TSH)-like peptide; • Human chorionic gonadotropin (HCG)-like peptide. Although the high levels of calcitonin, bombesin, and somatostatin in semen suggest that these peptides are directly secreted by the neuroendocrine cells, little is known about the intercellular autocrine and paracrine local regulatory mechanisms by which the neuroendocrine cells interrelate with the neighboring cells.87 This may involve interaction between neuroendocrine cells, factors produced by the stromal compartment, extrinsic, blood-borne endocrine agents, or an input from the nervous system (Fig. 3.16). There is speculation that neuroendocrine cells are implicated in the focal development of BPH.87 Bombesin, for example, a well-established growth

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Figure 3.16 Morphology of the neuroendocrine cells of the epithelial compartment and some of the intrinsic factors implicated in the interaction between stromal and epithelial compartments of the prostate gland. TGF, transforming growth factor; KGF, keratinocyte growth factor; TSH, thyroid-stimulating hormone; PTH, parathyroid hormone; hCG, human choriogonadotropin; VEGE, vascular endothelial growth factor. factor in the lung in association with small cell carcinoma, also exercises a mitogenic effect on prostatic cancer cell lines.88–91 There are similar reports that calcitonin92 and PTHrP93 elicit similar effects. The serotonin antagonist pindobind inhibits the proliferation of human prostatic PC3 cancer cells in vitro and in vivo,94 suggesting that serotonin may have mitogenic effects within the prostate. Focal neuroendocrine cell differentiation is virtually ubiquitous in carcinoma of the prostate84 and the extent of neuroendocrine cell proliferation correlates with poor prognosis. A report from the Tenovus Cancer Research Centre,95 relating to the production of TGF-α and vascular endothelial growth factor (VEGF) by neuroendocrine cells of the human prostate (Fig. 3.17), is of particular interest. The expression of TGF-α, which mediates its biological action through the EGF receptor, is generally associated with the proliferation of human prostatic cancer cells96,97 and VEGF is now recognized as a powerful promoter of angiogenesis (Fig. 3.18). It is well accepted that once a tumor attains a volume of approximately 2 mm, an improved new blood supply is required for continued growth.98–100 The production of VEGF by the neuroendocrine cells of the tumor may well be a factor associated with the promotion of angiogenesis and cancer progression. Prostatic neuroendocrine cells do not express AR95 and appear to be terminally differentiated, postmitotic cells,101 although the proliferation markers PCNA and Ki-67 and the ‘anti-apoptopic factor’ Bcl-2102 are expressed by neighboring cells. Serotonin is mitogenic in certain tissues103 and, permissively with androgens, may regulate epithelial cell proliferation.104,105 Synergistically with other growth factors, it may exercise an important paracrine role in promoting smooth muscle106 and fibroblast107 mitogenesis. It has been proposed,87,108 therefore, that the production of peptides by neuroendocrine cells may be implicated in the focal pathogenesis of BPH and the early biological changes implicated in early transition zone carcinogenesis. In relation to this, the studies of O’Malley et al.109 indicate that dopamine activates steroid hormone receptors in the absence of steroid, raising the possibility that other biogenic amines such as serotonin may elicit similar responses. It would be presumed that dopamine constitutively activates gene expression through the interaction between the N-terminal A/B activation domains of the AR1 and adjacent coactivators associated with their particular recognition sequences on the genome. In considering the complex interplay between the populations of cells that constitute the microenvironment of

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Figure 3.17 Localization and expression of vascular endothelial growth factor (VEGF) by the neuroendocrine cells of the human prostate gland. Neuroendocrine cells are classically recognized by the expression of chromagranin. the human prostate, the basal cells must not be forgotten. These cells, by their very nature, are less differentiated than the luminal cells and are confined to the base of the epithelium (Fig. 3.19). The cytokeratins, intermediate filament proteins and thereby components of the cytoskeleton, are found in epithelial cells and Schalken et al.110 have demonstrated that their pattern of expression varies according to cell type and degree of differentiation. At least 20 different members of the keratin family are expressed in specific combinations in the various types of epithelial cells, and epithelial phenotypes can be recognized in relation to cell differentiation and function.110 With cytokeratin patterns as markers, Schalken et al.110 showed that withdrawal of androgen reduced the population of luminal epithelial cells, whereas the basal cells were unaffected. The luminal cell number increased appropriately, following testosterone administration. The results suggest a hierarchical relationship between basal and luminal cells, with the basal cells acquiring simple keratins and losing their complex components during differentiation, a concept promulgated by Isaacs and Coffey.111 The stem cell model, essentially relating to the pathogenesis of BPH,111,112 describes a biological system in which the total cell population of the prostate is determined by the number of stem cells. These cells are capable of extensive self-renewal and maintain their proliferative capacity despite any marked change or decrease in the total cell population of the gland.

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Figure 3.18 Promotion of angiogenesis by the vascular endothelial growth factor (VEGF) in neuroendocrine cells. FGF, fibroblast growth factor.

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Figure 3.19 Interrelationship between various cell types, based on keratin phenotypes and differential expression. As depicted by J.Schalken. However, to explain the capacity of the prostate to restore its total cell number after castration and subsequent administration of androgen, Isaacs112 suggested that prostatic cell renewal is not the unique responsibility of this limited number of stem cells. As well as extensive stem cell renewal, it is considered that other ‘amplifying cells’ which originate from stem cells are capable of limited proliferation and are present, with stem cells, in the involuted prostate gland after castration. Despite a limited proliferative capacity, the consequent effect would be seen as an extensive amplification of the total cells produced,112 essentially, a 32-fold increase in cell number on administration of androgen. Prostatic growth would, therefore, result not from any major increase in the rate of stem cell renewal, but from the proliferation of these preexisting amplifying cells. During androgen deprivation, they would independently maintain themselves, but still retain androgen sensitivity. The terminally differentiated ‘transit cells’ formed from this pool of amplifying cells and which equate to the differentiated luminal cells have only limited capacity to proliferate and are androgen dependent. They make up the major proportion of the prostate cell population and are the cells which are lost on androgen withdrawal. Therefore, the earlier stages in epithelial cell proliferation could result from either an increase in stem cell number or from a greater capacity of the amplifying or transit cells to proliferate before cell death or apoptosis. The keratin phenotyping studies of Schalken110 and others113,114 provide a valuable insight into the pathogenesis of prostatic disease and into the complex interrelationships that exist between the various populations of cell types. The balance between cell proliferation and apoptosis In normal tissues, the fine balance between the rate of cell proliferation and that of cell death is tightly controlled. Throughout life, the prostate gland responds to certain extrinsic endocrine signals as it develops during the fetal and prepubertal phases and during the rapid period of growth following adolescence. After attaining its adult size in the early twenties, and with the establishment of homeostasis, the prostate gland normally maintains this size until the age of 50, after which time abnormal growth, both benign and cancerous, is often manifest, presumably because of a disturbance in the regulatory factors controling the balance (Fig. 3.20). The precise nature of the factors that regulate this balance and the genetic or epigenetic factors which are implicated in any imbalance still remain to be determined. Such factors and processes which may exercise an important influence on this homeostatic balance include the various intrinsic growth-regulatory factors and their associated signaling processes, cell cycle regulatory control, damage to DNA, senescence of the cell replication process and the ‘cell death’ genes. However this imbalance occurs, whether it be through an increased rate of cell replication or a decreased rate of cell death, the consequence is an accumulation of

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Figure 3.20 The balance between cell proliferation and cell death in the prostate. prostate cells and an associated growth of the gland. The kinetics of the balance are now being precisely defined in terms of a dynamic interplay between the growth-stimulatory processes and those responsible for growth restraint. The signaling processes that are associated with the cell cycle, and which influence both cell growth and cell death, now constitute one of the most active and particularly exciting fields of scientific research currently being followed, investigations that will have a major impact on our understanding of prostatic growth regulation.115,116 DNA synthesis and cell cycle control The prostatic cell is generally in a quiescent or nongrowing state, that is referred to as G0. The influence of the extrinsic steroid hormones and their interaction with the intrinsic growth regulatory factors which activate cell signaling processes can stimulate a cell to grow and initiate the active phase of the cell cycle, referred to as G1. Once the cell completes this G1 phase it commences DNA synthesis, the S phase of the cycle (Fig. 3.21). Once the DNA has been replicated there is a secondary phase, G2, during which the cell prepares for cell division or mitosis. It is during the mitotic M phase of the cycle that the mitotic spindle of the cell separates into two sets of chromosomes, after which the nucleus reorganizes and the cell cycle is then complete. Clearly, knowledge of the complex processes that regulate the cell cycle is fundamental to understanding prostatic growth control. There are many specific check-points at the interfaces between the various phases of the cycle which determine progression into the next phase. These checkpoints, or decision points as they are called, are controlled by the interaction of a variety of regulatory proteins, referred to as cyclin-dependent kinases (CDKs), which have the capacity to stimulate or suppress the activity of various growth suppressors, by promoting their phosphorylation. Figure 3.21 illustrates the transition of a cell in G0 resting phase to the process of either cell growth or cell death. The cyclin-dependent kinases represent a series of at least seven regulatory enzymes, referred to as CDK2 and CDK4 to CDK7, with their location and the phase in which they influence the cell cycle delineated in Fig. 3.21. They are activated at various points in the cell cycle. An example of the regulatory activity of the cyclindependent kinases involves the activation of a particular specific cell cycle ‘brake’ or growth suppressor protein, the retinoblastoma (Rb) protein. In its nonphosphorylated state, Rb serves as a checkpoint, or brake, between the G1 and S phases of the cell cycle. Activation of the Rb protein through its phosphorylation by a cyclin kinase removes its braking capacity and thereby allows the cell to progress from the G1 phase of the cycle into the S phase, with the resultant initiation of DNA synthesis and promotion of prostatic growth. There are other examples of cyclin-dependent kinase activation involving other cell cycle suppressors. The p15, p16, p21, and p27 proteins are

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Figure 3.21 Regulatory factors in the different phases of the cell cycle. CDC, cell-division cycle; ICE, interleukin converting enzyme; CDK, cyclin-dependent kinases; TGF β-R, transforming growth factor-β receptor; TRPM-2, testosterone-repressed prostate message2; ODC, ornithine decarboxylase. all cycle-independent kinase inhibitors and it is noteworthy that p21 appears to be upregulated by p53. An increased expression of p53 after DNA damage will introduce a brake on the cell cycle, allowing the cell to correct for the damaged DNA. If the p53 protein is damaged, lost, or downregulated, the particular checkpoint is ineffective, allowing uncontrolled growth of the cell, enhanced genetic instability, and DNA damage, cellular characteristics which are inherited by the daughter cells. Control of cell death Also illustrated in Fig. 3.21 are the perceived regulatory checkpoints in the cell-death cycle.115 A celldeath cycle checkpoint D1, a phase analogous to G1 of the cell-growth cycle, is associated with events that occur before DNA fragmentation. The cell-death phase D1 is further subdivided into A and B regions, both of which are regulated by a range of different factors, including interleukin-converting enzyme (ICE), calcium, TGFβ, a particular DNA nuclease, and the TRPM-1 gene, which upregulate this phase of the death cycle. The D1 phase is downregulated through activation of the ornithine decarboxylase (ODC) gene, CDK2, and a cyclin. The next phase of the death cycle, the F phase, is the period of DNA fragmentation and nuclear degradation. During the last D2 phase of the death cycle, which follows DNA fragmentation, the cell finally undergoes nuclear destruction and phagocytosis. The entire cycle has been termed apoptosis, a process which is clearly characterized by significant morphological and biochemical events within the cell. The p53 protein is a regulatory protein that, in certain tissues, is implicated in the control of the celldeath cycle, as is the principal brake of the apoptosis cycle, the bcl-2, a 26-kDa protein. When available and activated, bcl-2 represses the processes associated with cell death. Abnormal, elevated rates of cell death result from a mutation in the bcl-2 gene or from suppression of gene expression. The bcl-2 protein is inhibited from acting as a brake on apoptosis by its association with another protein, referred to as bax, which is a member of a family of celldeath-inducing proteins that have been identified. The bax gene is upregulated by the p53 protein. These interrelationships are simply illustrated in Fig. 3.22. It has been reported that nine out of nine hormonerefractory prostate tumors, or their metastases, expressed bcl-2.116 The bcl-2 gene is also overexpressed in the lesions of preneoplasia referred to as prostatic intraepithelial neoplasia (PIN). Androgen-dependent LNCaP cells, transfected with a vector containing the bcl-2 protooncogene, were resistant, in vitro, to agents which

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Figure 3.22 A simple illustration of the interrelationship between myc, bcl-2, and apoptosis. EGF, epidermal growth factor; FGF, fibroblast growth factor; KGF, keratinocyte growth factor; IGF, insulin-like growth factor. promoted apoptosis.117 Complementary studies in vivo117 showed that when these transfected cells were introduced into nude mice, they developed into larger tumors than the controls and were also resistant to androgen withdrawal, thereby relating bcl-2 expression to the androgenindependent state.118 Quite clearly, the biological processes concerned with the expression and activation of bax and, thereby, the consequent inhibition of bcl-2 and its influence on cell death, must exercise a fundamentally important role in the regulation of prostatic growth. Telomerase and aging: relationship to prostate growth Telomerase and the activity of the telomerase enzyme have recently been recognized as important factors related to growth regulation within the prostate.119–121 The Hayflick phenomenon indicates that cells can undergo only a finite number of cell divisions before they senesce and subsequently destruct through the processes of apoptosis. Cells that do not senesce are termed immortal and, as such, can be established as cell lines in culture. Mortal cells shorten their telomeres, small pieces of DNA located on the ends of chromosomes, with each cell cycle until they become unstable.119 The biological clock that counts each cell division and brings about cell senescence is thus controlled through the telomeres. Each time a cell progresses through a complete cell cycle and divides, it loses a small amount of the telomeric DNA. The repetitive, accumulative loss of these small DNA fragments acts as a ‘mitotic clock’ counting the cell cycles. After approximately 50 doublings, these cells will senesce and die. Telomerase is an enzyme that is concerned with this process on a small template made of RNA that it uses to replace the telomeres after each cell division. If the telomerase is inactive, or depleted from the cell, the telomeres will shorten. If present, the telomeres are relengthened after each cell cycle and immortality can be attained. Studies show that telomerase is a stem-cell marker in the ventral lobe of the rat prostate120 and it is suggested121 that telomerase activity is an effective means of distinguishing benign and malignant growth of the prostate gland (Fig. 3.23). The complex interrelationship between the intrinsic factors within the prostate gland The integrated response of the various populations of cells within the prostate to signaling language, reading sense from the many messages induced by the wide range of growth regulatory factors, as well as those initiated by the extrinsic endocrine factors that impact on the gland, is very clearly a finely tuned and complex interactive system.

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Figure 3.23 Telomerase and the immortality of cells. (Adapted from reference 121.)

Figure 3.24 Tyrosine-specific protein kinase and intracellular signaling pathways. MAPK, mitogen-activated protein kinase; MEK, mitogenactivated protein kinase kinase; TK, tyrosine kinase; KGF, keratinocyte growth factor; Grb2-mSOS, growth factor receptor binding proteinmammalian son-of-sevenless complex; RAF-1, serine-threonine protein kinase; P, protein; PK, protein kinase.

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Page 47 As our understanding of these signaling pathways develops, the information that accumulates provides a greater insight into the potential consequences of their impairment and their relationship to the pathogenesis of prostate disease. Cells which respond to external stimuli such as those induced by KGF or FGF-2 depend not only on the presence of cell membrane-localized receptor proteins (Fig. 3.24), but on the particular activity of the signal transduction pathways, as well as the intracellular structural matrix of the target cell. The nuclear matrix is the cell type-specific framework that is implicated in the organization of DNA and in the biological processes concerned with the regulation of gene transcription.122,123 There is a specific association between the components of the nuclear matrix and steroid hormone receptors in the regulation of gene expression by steroids.124 Fundamental to the hormone responsiveness of the prostate gland is the interrelationship between the signaling pathways inducing biological responses through steroid receptors and those activated by the binding of the peptide growth-regulatory factors to the cell membrane receptors. As described earlier, it would now appear that the mitogenic paracrine effect of DHT on the prostate epithelial cells is mediated by peptide growth-stimulatory factors, probably KGF (FGF-7), produced by the smooth muscle cells of the stromal compartment of the gland. The mitogenic signals are initiated by the association of the growth factor with the external domain of receptors on the cell membrane. Through a tyrosine-specific protein kinase (TK) situated on the intracellular domain of the receptor, the binding of the peptide triggers a cascade of intracellular signaling events (Fig. 3.24) that ultimately lead to the activation of proto-oncogenes and gene transcription.125,126 Such signals could activate the c-myc, c-fos , and c-jun proto-oncogenes, all encoding proteins that are normally involved in normal growth-regulatory processes within the prostate gland and which are referred to as transcription factors (TFs). As well as encoding for transcription factors, proto-oncogenes would also encode for growthregulatory factors and their corresponding membrane receptor proteins, as well as for the many and various components of the signal transduction pathways. The current evidence therefore suggests that the androgenic effect on the prostate is at least partly mediated through the production of these mitogenic growth factors, with the target cells responding by expressing and activating a range of transcription factors that exercise a role in growth regulation. The Fos and Jun proteins, either as Fos/Jun heterodimers, or as Jun/Jun homodimers, are components of the AP-1 transcription factor that associates with the AP-1 recognition sequences on the genome (Fig. 3.25) characterized by the –TGACTCA– nucleotide

Figure 3.25 Diagrammatic representation of the concept of cross-talk between signaling pathways. DHT (D), dihydrotestosterone; AR, androgen receptor; TK, tyrosine kinase; GR, glucocorticoid receptor; RAR, retinoic acid receptor; Vit. D3R, vitamin D3 receptor. file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_47.html[09.07.2009 11:51:38]

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Page 48 sequence,127,128 with the interaction between the two proteins on the genome representing a specific interaction between the ‘leucine zipper’ structural domains of the proteins.129 The spatial disposition of the HREs or androgen response elements alongside AP-1 recognition sites in juxtaposition along the promoter region of an androgen responsive gene (Fig. 3.25) would therefore lead to functional interaction or synergism.130–132 Such interaction could be referred to as ‘cross-talk’ between signaling pathways. It has been reported that the binding of the ARs to particular androgen response elements is favored in the presence of NF-1 and NF-3 nucleotide consensus sequences.133 Also recognized is that the association of either the NF-1 transcription factor134 or the ER135 with the genome changes the spatial orientation of the DNA due to ‘bending’ of the DNA strands. It would seem that such interactions between the androgen receptor and the genome facilitate an easier accessibility for the transcription factors to their recognition sites.40 The concept of cross-talk is illustrated by experiments with estrogen responsive MCF-7 breast cancer cells in culture,96 to which EGF had been added (Fig. 3.26).

Figure 3.26 Interaction between steroid receptor protein and growth factor signaling pathways. EGF, epidermal growth factor; TKI, tyrosine-specific protein kinase inhibitor. Addition of a tyrosine-specific protein kinase inhibitor (ZM 252868, Zeneca, Alderly Edge, Macclesfield, UK) inhibited cell proliferation in a dose-dependent manner in the presence of EGF. The ZM 252868 specifically inhibits the mitogenic action of EGF and TGFα, the latter modulating cell proliferation through the EGF-R. Addition of the pure anti-estrogen ICI 182780, also in the presence of EGF, similarly suppressed cell proliferation in a dosedependent way, suggesting that the steroid receptor protein, either directly or indirectly, is necessary for the biological action of the growth factor. Little is known about the sensitivity of this type of interaction, nor of the concentrations of DHT-AR necessary to support growth factor signaling. Equally important is whether AR, in the absence of DHT, has the capacity constitutively to sustain basal levels of signaling. It would seem that although the prostate responds to a wide range of growth-regulatory factors,44,97 DHT appears to ‘fine tune’ these regulatory systems through the influence of the DHT-AR on the genome. Possibly the sensitivity of these systems is greater than hitherto had been appreciated, with probably an even greater sensitivity conferred on cancer cells.96 AR expression is maintained in most androgen-resistant cancers of the prostate,136 and it may be that under these circumstances the presence of AR confers a growth advantage, even in the presence of extremely low concentrations of androgen. The N-terminal (A/B) domain of the AR (Fig. 3.7) contains a ligand-independent transcription-activating file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_48.html[09.07.2009 11:51:38]

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function referred to as TAF-1. This domain also includes various homopolymeric stretches of amino acids, including 17 to 29 repeating glutamine residues and a 24-glycine stretch, and it has been suggested that it is the interaction of these homopolymeric stretches with other proteins such as the transcription factors that allows them to influence transcription,137,138 with the amino acids between 141 and 338 essential for TAF-1 transcription activation. The complexity of these interrelationships is further emphasized in Fig. 3.25, which illustrates how other proteins probably interact with AR, either as co-activators or co-repressors, to influence gene transcription.139,140 The potential interaction of the retinoic acid receptor, the glucocorticoid receptor, and the 1,25dihydroxyvitamin D3 (1,25-diOHvitD3) receptor that can interact with the Fos/Jun heterodimer complex to restrain transcription activity has been simply portrayed.141 It is clear that impairment of the growth-regulatory balance can lead to cellular hyperplasia with consequent genetic instability and subversion of the normal processes of growth restraint. Moreover, proto-oncogenes that

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Page 49 become dysfunctional through point mutations, deletions, amplification, or other changes that alter the structure or influence the expression of these growth regulatory genes can induce carcinogenesis. With the constant search for new therapeutic regimens, the potential of the tyrosine-specific tyrosine kinase inhibitors is obvious, and innovative drugs, essentially analogs of retinoic acid and 1,25diOHvitD3, may also have particular value. The place of glucocorticosteroids within the complex multihormonal environment of the prostate, with regard to growth control, may require re-assessment. The complexity of the stromal-epithelial interaction As stated, the interrelationship between stromal and epithelial compartments of the prostate gland would appear pivotal to growth regulation. The regional functional heterogeneity of the ductal system of the rat prostate,70–72 together with the different cell populations of the gland (Fig. 3.27), emphasizes the complexity of the system.44 In relation to the regional heterogeneity in the functional activity of the epithelial cells of the human ductal network, Fig. 3.28 diagrammatically represents certain functional differences between various regions of the rat prostatic ducts, with high epithelial proliferation reported in the distal segments and apoptosis in the proximal region. Animal studies45,46,142 indicate that the adult prostatic epithelium responds to inductive signals from the mesenchyme in a manner similar to that observed during fetal prostatic branching morphogenesis and development. Studies by Schalken et al.143 directed attention to the relative importance of this branching in the adult human prostate, using immunocytochemistry to reconstruct the morphological transition along the prostatic ductal structure. The glandular networks showed continuous transitions in morphology and immunoreactivity, with identification

Figure 3.27 The complex interrelationship between stromal and epithelial elements of the human prostate gland. TSH, thyroid-stimulating hormone; PSA, prostate-specific antigen; TGF, transforming growth factor; KGF, keratinocyte growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factors; IGF-BP, IGF-binding protein; DHT, dihydrotestosterone; T, testosterone; E2, estradiol.

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Page 50 of branch-like acini in the adult human prostate with unique phenotypic characteristics comparable with the developing prostate and the distal segments of the rat prostatic ducts (Fig. 3.28). These cells were characterized by a basal cell keratin phenotype, bcl-2 expression in all cells and a higher labeling index, seen from MIB-1 staining, when compared to mature glands. Intracellular E-cadherin expression was also prominent, as was an enhanced tenascin-C immunoreactivity, relating to active stromal-epithelial interaction. 144–148 Tenascin is a glycoprotein of the extracellular matrix which has been recognized as an essential factor for the modulation of the stromal-epithelial interactions which are reported in relation to wound healing of the skin, embryogenesis, and oncogenesis in other organs. It is of interest that Shalken et al. found that the expression of tenascin was enhanced in association with the newly formed epithelial components in the developing prostate and in the budding ductal tips.147,148 Tenascin expression was also found to be correlated with the grade of prostatic cancer, inversely relating to the expression of laminin and the relative disruption of the basement membrane. There was increasing expression of tenascin, from the levels associated with normal and BPH tissue through to those found in low- and high-grade PIN, in which the immunostaining was comparable with levels in ‘moderate grade’ tumors. These new and innovative studies from the laboratory of Schalken do much to support the concept of a regional heterogeneity of epithelial-stromal interaction and associated functional response within the human prostate, similar to that proposed by Chung Lee and Tenniswood70–72 for the ductal system of the rat. Growth regulatory factors implicated in the stromal-epithelial interaction The growth factors, together with the cells implicated in their production, which are intimately concerned in the interrelationship between stromal and epithelial elements of the human prostate gland, have been diagrammatically depicted earlier (Figs. 3,13, 3.15, and 3.27), with attention directed to KGF (FGF-7), FGF-2, and TGFβ.44

Figure 3.28 Comparison of prostatic branching morphogenesis between man and rat.

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Page 51 The current picture suggests a greater degree of complexity, even without consideration of the regional variability in function. The neuroendocrine cells are now seen to be playing a significant role in growthregulatory mechanisms and are possibly implicated in the focal pathogenesis of BPH. Their presence in association with cancer predicts an unfavorable prognosis.149 Although our knowledge concerning the function of these cells as well as their interrelationship with other cells is still limited, it is accepted that they represent a highly differentiated and specialized epithelial cell. Their keratin phenotype relates to that of the luminal epithelial cells. From a study of the ductal budding and branching patterns in the developing prostate, Timms et al.150 reemphasized the concept151 that the regional organization of the prostatic complex is determined by the regional heterogeneity of mesenchymal induction, with particular specific mesenchymal effects induced along a budding axis. This influence of stromal heterogeneity on growth and differentiation of the prostate gland, effects which are ‘imprinted’ on the gland during fetal life by the action of the various steroid hormones, is fundamentally important and relates to subsequent predisposition of various regions of the prostate to disease.150 This is discussed further in the following section that considers the role of estrogens on the prostate. Estrogens and the prostate Previous studies have centered on the ‘aging factor’ that relates to the pathogenesis of BPH and is seen primarily as an endocrine function. Essentially, the increasing prevalence of focal epithelial hyperplasia developing into nodular hyperplasia from the early twenties through to the late forties (Fig. 3.29) has been considered ‘androgen driven’ (Fig. 3.30). Estrogens, as well as androgens, have been seen to be implicated in the development of the adenoma associated with bladder outlet obstruction—a benign growth, which in most cases is predominantly composed of stromal elements, primarily muscle cells. This estrogenic stimulus is considered to be based on the consequence of a falling level of circulating testosterone sometime after the age of 50,44 relative to a sustained concentration of estrogen in the plasma (Fig. 3.31). Within the prostate, Krieg et al.152 have demonstrated a shift towards a higher estrogen/DHT ratio, with increasing age. With regard to the ‘imprinting role’ of estrogens on the fetal prostate in utero,150,153 Timms et al.153 reported that a physiological, 50% increase in the estradiol concentration within the male mouse fetus, produced from a maternal silastic implant, resulted in the development of an enlarged adult prostate gland, with a 6-fold increase in

Figure 3.29 The well-accepted growth profile of the human prostate and data showing the increased prevalence of microscopic BPH, epithelial hyperplasia, that is recognized in men as they age from the mid-twenties to later life.

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Figure 3.30 Diagrammatic illustration of the natural history of clinical BPH that causes bladder outlet obstruction. DHT, dihydrotestosterone.

Figure 3.31 The endocrine status of men at ‘mid-life’. The declining testicular function and associated fall in plasma testosterone (T) relative to the sustained level of circulating estrogen from the aromatase activity of adipose tissue increases the free estradiol (E2)/free testosterone ratio in the plasma. The free steroid, bound to neither plasma sex hormone-binding globulin (SHBG) nor albumin, is seen as the biologically active moiety in the plasma. 17 βOHSD, 17 beta hydroxy steroid dehydrogenase.

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Page 53 AR levels relative to controls. The implant increased the concentration of estradiol from 94 pg/ml to 146 pg/ml, the increase representing a difference of 0.1 pg/ml of free, biologically active estrogenic hormone, approximately 0.4 pmol/l. A 5-fold increase in the estradiol level of total serum, however, resulted in a smaller adult prostate gland. The results suggest that estrogens can modulate the action of androgens by enhancing the sensitivity of the prostate to androgen and, moreover, the effect is sustained throughout life, probably forming the basis of growth-regulatory dysfunction and disease in later years. It is of interest that the male mouse fetus, exposed to these physiological, small increases in estradiol levels, showed an immediate, significant increase in the number of prostate glands throughout the dorsal urogenital sinus, including the dorsocranial region. This region is considered homologous to the areas of the human prostate in which BPH originates.153 In relation to these studies, earlier investigations,154 directed to the estrogen levels in the plasma of pregnant black American women, indicated a 50% higher concentration of estradiol than in corresponding white women. The possible significance of these results in relation to the high prevalence of prostatic cancer in black American males is worthy of further investigation. It is certainly important to elucidate further the role of estradiol in the prostate gland, a plea voiced in many earlier venues.44,154,155 The recognition of the new estrogen receptor-β (ERβ) also emphasizes this need. Two reports156,157 have generated intense excitement in the field of endocrinology. The ER was cloned over a decade ago158 and it had been thought that only one receptor protein existed. These exciting reports describe a complementary DNA (cDNA) clone that encodes a new distinct, separate subtype of receptor, which is now referred to as ERβ. Of particular interest is that the human and rat ERß clones were recognized within cDNA libraries from the human testes and rat prostate. Interest now centers on the role of the ERβ. It is important to determine whether the ERβ has a similar biological role to that of the established estrogen receptor, now referred to as ERα. Their roles may be quite distinct, complementary, or antagonistic. Both have a high affinity for estradiol,159 although some estrogenic compounds show a preferential binding to ERβ. ERα predominates in the uterus, whereas ERβ is the major component in the prostate. Investigations with cDNA probes to ERβ identified cell-specific localization of ERβ in the secretory epithelial cells of the prostate,156 suggesting that ERβ may have a particular function in these cells. Previous reports44,65 have emphasized the exclusive localization of ER (ERα) in the stromal elements of the human prostate, with a predominance in the smooth muscle cells. The ERβ and ERα have very similar sequences of amino acids in the estrogen-binding domain of the protein, as well as in the DNA-binding domains, suggesting that they would associate with the same hormoneresponse elements on the genome. The N-terminal A/B regions and TAF-1 activation functions are, however, different, so that the cross-talk, or synergistic, functional interaction between the ERs and other cell-specific coactivators and -repressors in juxtaposition on the genome (Fig. 3.32) could be different for the ERβ relative to ERα within the prostate gland.160–164 Nucleotide recognition sequences may specifically interact with an ERα/ERβ heterodimer, for example, and it is now necessary to elucidate the molecular events associated with the role of ERβ in the prostate. The discovery of this new receptor for estrogens in the prostate gland will revitalize interest in the role of estrogens within the gland and their influence on growthregulatory processes. There will be renewed interest in the mechanism of action of the estrogens in general, but in particular, in relation to the new and novel ERß. There are many known biological roles for estradiol in nonreproductive systems, in particular on vascular tissue165 and bone. Some of the effects of estrogen on the vasculature relate to the production of nitric oxide, implicated in the proliferation of smooth muscle cells and also of prostacyclin and endothelin-1, factors concerned with the patency of the blood vessels. Within this context, the report from the third international consultation44 notes the presence of a specific plasma-membrane-located receptor for an estradiolZSHBG complex, that was found in the stromal elements of the human prostate. The estradiol-SHBG complex can induce intracellular signaling by promoting an 8-fold elevation in cAMP levels (Fig. 3.10). Nitric oxide (NO), a free radical associated with injury to tissue when reacting with the free radical superoxide, is now recognized as an important physiological regulator of certain endocrine systems. Nitric oxide is synonymous with endothelium-derived relaxing factor,166 which causes arterial vasodilatation.167 This nitrinergic system is assuming greater significance as studies develop. NOsynthase activation (Fig. 3.33) is concerned in LH-RH release from the hypothalamus168 and is recognized as a mediator of smooth muscle relaxation,169 and the neural NO-synthase is implicated in penile erection.170 Estradiol is believed to influence the L-arginine-NO-cGMP axis (Fig. 3.33) in

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Figure 3.32 Potential interrelationship between the estrogen-binding domain of the receptor proteins and the genome. E, estradiol; ER, estrogen receptor; KGF, keratinocyte growth factor. the promotion of parturition. Some consideration of the role of estrogens in relation to smooth muscle contractions within the prostate and in the maintenance of urinary flow will be of interest. NO generation may be involved in innervation.171 Studies with the rat insulinoma RINm5F cell line172 suggest that the induction of the NO-synthase may exercise a particular influence on the processes of apoptosis. The role of estrogens in relation to apoptosis in the prostate gland has not, as yet, been precisely determined, but recent important investigations by Kyprianou et al.173 indicate that the α1-adrenoceptor blocker doxazosin increased the apoptopic indices in both stromal muscle cells (15%) and epithelial cells (6%) of the prostates of men treated for BPH. The effect on the muscle cells was sustained for 12 months. The doxazosin was reported to relieve the symptoms of BPH in association with the induced smooth muscle cell apoptosis, together with stromal degeneration and diminished α-smooth muscle actin expression, molecular changes that appear to underlie the therapeutic response to α1-blockade. It has been suggested174 that the reaction between NO and superoxide that gives rise to the toxic peroxy nitrite (Fig. 3.33) may also be part of the natural process of apoptosis, by which phagocytes engulf and destroy foreign proteins, with ‘apoptopic genes’ encoding free radical scavengers.175,176 Anti-estrogenic therapeutic options related to the management of BPH In earlier reports,6,7,44 discussion has been directed to the potential benefits of anti-estrogen therapy for the management of the patient with clinical BPH. The use of the anti-estrogen tamoxifen suggested that the treatment caused stromal hyperplasia because of the estrogen agonistic properties of the drug, although dosage may not have been appropriate for the male. The use of an aromatase inhibitor alone was reported to be ineffective,177 although it could be thought that effective treatment should be directed to the withdrawal of both estrogens and androgens. A new and innovative approach, which may help to provide a greater understanding of the effect of decreasing the concentration of estrogens in the plasma of men with

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Figure 3.33 The concept of nitric oxide as a ‘second messenger’, whereby steroid hormones are implicated in its effect on muscle contractility and possibly in apoptosis. BPH, is the use of the compound mepartricin (SPA: Societa Prodotti Antibiotici SpA, Milan). Mepartricin, marketed under the trade name Ipertrofan, is a semisynthetic derivative of a polyene antibiotic isolated from a Streptomyces aureofaciens culture, existing as a mixture of two similar heptaenes (Fig. 3.34). In the doses used clinically, mepartricin is not systemically absorbed after oral administration and is well tolerated. Essentially, mepartricin irreversibly binds within the intestine, with the various estrogenic steroids, thereby interfering with the enterohepatic system that leads to the reabsorption of steroids from the gut (Fig. 3.35). In a manner similar to that pertaining to vegetarians on a high-fiber diet, there is an increased excretion of fecal estrogens as mepartricin-steroid complexes. The consequence of taking mepartricin, therefore, is a decrease in the concentration of estrogens in plasma, through the interruption of the enterohepatic recirculation of estrogens. The increased excretion of fecal estrogens and the consequent decline in plasma levels has been demonstrated in experimental animals after administration of mepartricin.178,179 In a controlled study of patients with BPH, treated with mepartricin for 30 days, a significant decrease in the concentrations of estradiol, estrone, and estriol has been reported.180,181 Short-term, double-blind, and openlabel studies have shown the clinical efficacy of mepartricin. A dose of 40 mg mepartricin daily, in placebocontrolled, double-blind clinical studies of up to 180 days,181 produced significant symptomatic improvement in patients with BPH, improving urinary flow rate and residual urine volume. Following the guidelines recommended by the International Consultation on BPH,182 mepartricin-treated patients were reported to experience a significant 39% decline in the International Prostate Symptom Score (I-PSS) after 6 months’ treatment. This simple and apparently effective form of therapy, that has no side-effects and none of the possible difficulties that could be associated with the more intrusive treatment involving anti-estrogenic drugs, may well help to increase our understanding of the role of estrogens in the prostate and, moreover, possibly in association with

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Figure 3.34 The structure of mepartricin.

Figure 3.35 Some steroid metabolic changes involved in the enterohepatic circulation, with interchange of sulfate (S) and glucuronide (G) residues on the estrogens. E1, estrone; E2, estradiol; E3 estriol. anti-androgen therapy, offer a new, innovative approach to the management of BPH. BPH: hereditary predisposition The concepts discussed in this chapter clearly emphasize the complexity of prostatic growth control. The etiology of BPH is undoubtedly multifactorial and, although the two principal risk factors relate to aging and functional testes, evidence continues to accumulate to suggest that a familial history of BPH may also constitute a risk factor. The evidence indicates a predisposing genetic element in patients with early onset BPH and that ‘DNA abnormalities’ may contribute to the pathogenesis of the disease. DNA fingerprinting has demonstrated a high frequency of genomic alterations in prostate tissue from patients with

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Page 57 BPH relative to normal human tissue.183,184 Molecular abnormalities in the DNA sequences relating to the growth suppressor gene p53 have been identified in approximately 40% of BPH tissue when analyzed at this genetic locus and abnormal nucleotide methylation patterns are also present185. BPH can be genetically induced in transgenic mice by activation of the int-2 gene.186,187 Sanda et al.,188 in a case-control study of familial clustering of clinical BPH, identified a family history of BPH as a major risk factor for the development of the disease that required surgical intervention at an early age. Of interest was that the male relatives of men who developed this early onset BPH had a 66% cumulative lifetime risk of prostatectomy for BPH compared to a 17% risk among the control group. The data provided evidence of a dominant Mendelian transmission of a genetic allele and are supported by observations of a higher concordance of BPH among monozygotic twins when compared to their dizygotic counterparts.189 In a corresponding study,190 it was reported that familial BPH was characterized by a larger prostate size, but normal concentrations of serum testosterone and a normal response to 5α-reductase inhibitors. The authors suggest that the hereditary factors relating to BPH may influence the prostate through androgen-independent processes. In relation to this concept, Doehring et al.191 demonstrated that these larger prostates of young men with ‘hereditary BPH’ are associated with higher stromal/epithelial ratios. Diet and prostate disease: the concept of prevention The relationship of diet to prostate disease has been the subject of a recent major review.192,193 From the marked differences in the incidence of both prostate and breast cancer between the East and the West (Fig. 3.36), it was not difficult to direct attention to fat and animal products, which can provide up to 40% of the total caloric intake in some North American people, as possible causative factors. Recently, however, an alternative concept has emerged to suggest that constituents of the Asian diet may restrain the processes of carcinogenesis.193 Studies of people migrating from Japan and China, through Hawaii, to mainland USA indicate that the migrants, in one or two generations, show a mortality rate for prostate cancer that comes close to that of the indigenous American people, thereby highlighting a possible influence of dietary factors.194,195 Interest now centers on isoflavonoids, flavonoids, and lignans, products of vegetables, fruit, whole grains, and soya, that are metabolized by the gut microflora to give rise to compounds such as enterolactone, daidzein, and

Figure 3.36 Incidence of breast and prostate cancer in countries from the East and West.

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Page 58 genistein (Fig. 3.37), weak plant estrogens, referred to generally as the phytoestrogens. As weak estrogens, such compounds could act as ‘natural tamoxifen-like’ factors that could, like tamoxifen, which is also a weak estrogen agonist, restrain the early processes associated with breast carcinogenesis by their antagonistic anti-estrogenic effect. Estrogenic substances in plants The presence in plants of nonsteroidal substances with estrogenic activity has been recognized for some time and many hundreds of plants manifest some degree of estrogenic activity.196,197 Soya bean and red clover are members of the leguminosae family and are a major source of isoflavonoids.197–199 Soya is consumed daily in large amounts in a number of forms in China and Japan and in Asia generally. Many foods of plant origin contain varying amounts of isoflavonoids, flavonoids, and lignans (Fig. 3.38). Some of these polyphenolic phytoestrogens possess weak estrogenic activity and therefore the potential for exerting an influence on hormone-dependent cancers such as those of the breast and prostate.200 Soya beans contain the glycoside conjugates of the isoflavonoids genistein and daidzein, which can be metabolized by gut bacteria to the aglycones. Genistein can be further metabolized to the nonestrogenic p -ethylphenol and daidzein is converted to the estrogenic isoflavan, equol. The aglycones and their metabolites are then absorbed and appear in blood and urine, primarily as glucuronide conjugates and also as sulfates.200 Daidzein and genistein were isolated from soya beans more than 70 years ago201 and 100 g fat-free soya beans may yield up to 300 mg genistein.202 Generally, the presence of isoflavonoids in plants is limited to legumes, although they have recently been identified in beer and bourbon203,204 and may be more widely distributed than was previously thought. Lignans are another group of polyphenolic plant compounds.197,205 The plant precursors, matairesinol and secoisolariciresinol, are metabolized after ingestion by intestinal microflora to give rise to the weakly estrogenic enterolactone and enterodiol, respectively. The lignans are absorbed from the gut to appear in blood and other body fluids.200 The lignans are widely distributed in nature and precursors are found in many cereals, grains, fruits, and vegetables, but the richest source is linseed (flaxseed) and other oilseeds such as sesame.206 Isoflavonoids and lignans are normal constituents of body fluids and have been identified in most animal200 and human body fluids by gas chromatography-mass spectrometry (GC-MS).207 They are present in urine,208,209 plasma,210 saliva,211 and semen.212 Analysis of expressed prostatic fluid found that enterolactone and equol were constituents,211 suggesting that dietary estrogens can accumulate in the prostate.

Figure 3.37 The structure of certain phytoestrogens.

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Page 59 The levels of isoflavonoids are high in the urine and plasma (Fig. 3.39) of the Japanese and Chinese,207,213,214 whose traditional foodstuffs contain large amounts of soya in the form of bean curd (tofu), soya bean milk, miso, and tempeh. The concentration of lignans is high in the urine of vegetarians,209 whose diet contains whole-grain cereals, vegetables, and fruits. In Western subjects fed 40 g soya daily, the urinary excretion of equol was found to increase 1000-fold above control levels.199,215 The concentrations of flavonoids in plasma and urine of different populations have yet to be determined and present an obvious program for future research. However, as tea, fruit, and vegetables are the principal sources of flavonoids, it is probable that Asians, with their high consumption of tea, and vegetarians have significant circulating levels of these compounds. Whether such phytoestrogens could restrain prostate carcinogenesis through their influence on the physiological actions of estrogens in the growth-regulatory events of the prostate is controversial.216 These compounds, however, exercise other influences on cell biology. The following are some of the reported properties of the phytoestrogens:

Figure 3.38 Sources of phytoestrogens.

Figure 3.39 Comparative mean concentrations of isoflavonoids, genistein, and daidzein in normal British and Japanese subjects.

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Page 60 • Inhibition of 5α-reductase activity;217,218 • Inhibition of aromatase activity;219,220 • Inhibition of tyrosine-specific protein kinases;221,222 • Inhibition of angiogenesis;223,224 • Influence on free radicals as antioxidants;225,226 • Influence on the topoisomerase enzymes;227–230 • Inhibition of tumorigenesis in experimental animals.231–234 The imprinting influence of estrogens in utero on the male fetal prostate, biological actions whose consequences are often manifest later in life, may also be influenced by such dietary factors. These steroid-imprinting effects would seem of particular importance in determining the subsequent growth patterns of the gland as it develops and their influence is sustained throughout life. Acknowledgment The authors are grateful to Mr David Griffiths, CompGraphics, Cardiff, who owns the copyright for the illustrations in this chapter. The authors also acknowledge the work and support of the committee concerned with the regulation of prostatic growth, which was part of the recent International Consultation on BPH, held in Paris in 2000. Some of the conclusions and illustrations in the report of the committee are included in this chapter. References 1. Griffiths K, Cockett A T K, Coffey D S et al. Regulation of prostate growth. In: Denis L J, Cockett A T K, Chatelein C et al. (eds). The fourth international consultation on BPH. Paris: SCI Press, 1998:85–128 2. Garraway W M, Collins G N, Lee R J. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991; 338:469–471 3. Barry M J, Beckley S, Boyle P et al. Importance of understanding the epidemiology and natural history of BPH. In: Cockett A T K, Aso Y, Chatelain C et al. (eds). The first international consultation on benign prostatic hyperplasia (BPH). Paris: SCI Press, 1991:13–21 4. Glynne R J, Campion E W, Bouchard G R, Silbert J E. The development of benign prostatic hyperplasia among volunteers in the normative aging study. Am J Epidemiol 1985; 121:78–90 5. Lytton B, Emery J M, Harvard B M. The incidence of benign prostatic obstruction. J Urol 1968; 99:639–645 6. Griffiths K, Akaza H, Eaton C L et al. Hormones, growth factors and benign prostatic hyperplasia (BPH). In: Cockett A T K, Aso Y, Chatelain C et al. (eds). The first consultation on benign prostatic hyperplasia (BPH). Paris: SCI Press, 1991:25–49 7. Griffiths K, Akaza H, Eaton C L et al Regulation of prostatic growth. In: Cockett A T K, Khoury S, Aso Y et al. (eds). The second international consultation on benign prostatic hyperplasia (BPH). Paris: SCI Press, 1993:49–75 8. Riad-Fahmy D, Read G F, Walker R F, Griffiths K. Steroids in saliva for assessing endocrine function. Endocr Rev 1982; 3:367–395 9. Vermeulen A, Deslypere J P, Meirleir K. A new look at the andropause: altered function of the gonadotrophs. J Steroid Biochem 1989; 32:163–165 10. Schroeder F H, Westerhof M, Bosch R J L H, Kurth K H. Benign prostatic hyperplasia treated by castration or the LH-RH analogue buserelin: a report on six cases. Eur Urol 1986; 12:318–321 11. Baird D T, Uno A, Melby J C. Adrenal secretion of androgens and oestrogens. J Endocrinol 1969; 45:135–136 12. Lipsett M B. Steroid secretion by the human testis. In: Rosemberg E, Paulsen C A (eds). The human testis. New York: Plenum Press, 1970:407–421 13. Santen R J, Bardin C W. Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiological mechanisms. J Clin Invest 1973; 52: 2617–2628 14. Longcope C, Widrich W, Sawin C T. The secretion of estrone and estradiol-17ß by human testis. Steroids 1972; 20:439–448 15. Baird D T, Galbraith A, Fraser I S, Newsam J E. The concentration of oestrone and oestradiol-17α in spermatic venous blood in man. J Endocrinol 1973; 57:285–288 16. McDonald P C. Origin of estrogen in man. In: Grayhack J T, Wilson J D, Schebenske M J (eds). Benign prostatic hyperplasia, NIAMDD Workshop Proceedings. DHEW Publication No (NIH) 76–1113. Bethesda: NIH, 1976: 191–193 17. Vermeulen A, Rubens R, Verdonck L. Testosterone secretion and metabolism in male senescence. J Clin Endocrinol Metab 1972; 34:730–735 18. Vermeulen A, Van Camp A, Mattelaer J, De Sy W. Hormonal factors related to abnormal growth of file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_60.html[09.07.2009 11:51:44]

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the prostate. In: Coffey D S, Isaacs J T (eds). Prostate cancer. UICC Technical Report Series, Vol 48. Geneva: UICC, 1979:81–92 19. Vermeulen A. Testicular hormone secretion and aging in males. In: Grayhack J T, Wilson J D, Scherbenske M J (eds). Benign prostatic hyperplasia. NIAMDD Workshop Proceedings. NIH Publication No (NIH) 76–1113. Bethesda: NIH, 1976:177–182 20. Rubens R, Dhont M, Vermeulen A. Further studies on Leydig cell function in old age. J Clin Endocrinol Metab 1974; 39:40–45

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Page 61 21. Rosner W. The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances. Endocr Rev 1990; 11:80–91 22. Loukovaara M, Carson M, Adlercreutz H. Regulation of production and secretion of sex hormonebinding globulin in HepG2 cell cultures by hormones and growth factors. J Clin Endocrinol Metab 1995; 80:160–164 23. Mousavi Y, Adlercreutz H. Genistein is an effective stimulator of sex hormone-binding globulin production in hepatocarcinoma human liver cancer cells in culture. Steroids 1993; 58:301–304 24. Bruchovsky N, Wilson J D. The intranuclear binding of testosterone and 5α-androstan-17ß-ol-3-one by rat prostate. J Biol Chem 1968; 243:5953–5960 25. Bruchovsky N, Wilson J D. The conversion of testosterone to 5α-androstan-17ß-ol-3-one by rat prostate in vivo and in vitro. J Biol Chem 1968; 243:2012–2021 26. Harper M E, Pike A, Peeling W B, Griffiths K. Steroids of adrenal origin metabolized by human prostatic tissue both in vivo and in vitro. J Endocrinol 1974; 60:117–125 27. Harper M E, Peeling W B, Griffiths K. Adrenal androgens and the prostate. In: Motta M, Serio M (eds). Hormonal therapy of prostatic disease: basic and clinical aspects. Netherlands: Medicom Europe, 1988:81–104 28. Labrie F, Dupont A, Belanger A. New approach in the treatment of prostatic cancer: complete instead of partial withdrawal of androgens. Prostate 1983; 4:579–594 29. Labrie F, Dupont A, Belanger A. Spectacular response to combined antihormonal treatment in advanced prostate cancer. In: Labrie F, Prouix L (eds). Endocrinology, international congress series. Amsterdam: Excerpta Medica, 1984:450–453 30. Denis L J. Controversies in the management of localised and metastatic prostatic cancer. Eur J Cancer 1991; 27: 333–341 31. Muntzing J. The androgenic action of adrenal implants in the ventral prostate of adult, castrated and oestrogentreated rats. Acta Pharmacol Toxicol (Kbh) 1971; 30: 203–207 32. Nicholson R I, Davies P, Griffiths K. Interaction of androgens with oestradiol-17ß receptor proteins in DMBA-induced mammary tumours—a possible oncolytic mechanism. Eur J Cancer 1978; 14:439–445 33. Griffiths K, Davies P, Harper M E et al. The etiology and endocrinology of prostatic cancer. In: Rose D (ed). Endocrinology of cancer. Vol 2. Boca Raton: CRC Press, 1979:1–55 34. Griffiths K, Davies P, Eaton CL et al. Cancer of the prostate: endocrine factors. In: Clarke JR (ed). Oxford reviews of reproductive biology. Vol 9. Oxford: Oxford University Press, 1987:192–259 35. MacDonald P C, Grodin J M, Siiteri P K. Dynamics of androgen and estrogen secretion. In: Baird D T, Strong J A (eds). Control of gonadal steroid secretion. Baltimore: Williams & Wilkins 1972:157–167 36. Kley H K, Nieschlag E, Bidlingmaier F, Kruskemper H L. Possible age-dependent influence of estrogens on the binding of testosterone in plasma of adult men. Horm Metab Res 1974; 6:213–221 37. Baker H W G, Burger H G, De Kretser D M et al. Changes in the pituitary-testicular system with age. Clin Endocrinol (Oxf) 1976; 5:349 38. Hryb D J, Kahn M S, Romas N A, Rosner W. Solubilization and partial characterization of the sex hormone-binding globulin receptor from human prostate. J Biol Chem 1989; 264:5378–5383 39. Bruchovsky N, Lesser B, VanDoorn E, Craven S. Hormonal effects on cell proliferation in rat prostate. Vit Horm 1975; 33:61–102 40. Truss M, Beato M. Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocr Rev 1993; 14:459–479 41. Wiseman H, Duffy R. New advances in the understanding of the role of steroids and steroid receptors. Biochem Soc Trans 2001; 29:205–209 42. Imperato-McGinley J, Guerro L, Gautier T, Peterson R E. Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 1974; 186: 1213–1215 43. Lee C, Kozlowski J M, Grayhack J T. Intrinsic and extrinsic factors controlling benign prostatic growth. Prostate 1997; 31:131–138 44. Griffiths K, Coffey D, Cockett A T K et al. The regulation of prostatic growth. In: Cockett ATK, Khoury S, Aso Y et al. (eds). The third international consultation on benign prostatic hyperplasia. Paris: SCI, 1996:73–115 45. Cunha G R, Chung L W K, Shannon J M et al. Hormoneinduced morphogenesis and growth: role of mesenchymal-epithelial interactions. Rec Prog Horm Res 1983; 39: 559–595 46. Chung L W K, Cunha G R. Stromal-epithelial interactions: II Regulation of prostatic growth by embryonic urogenital sinus mesenchyme. Prostate 1983; 4:503–511 47. Franks L M, Riddle P N, Carbonell A W, Gey G O. A comparative study of the ultrastructure and lack file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_61.html[09.07.2009 11:51:45]

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Page 62 proliferation of human prostatic epithelial cells. J Urol 1991; 145:475 50. Sugimura Y, Cunha G R, Haywood S et al. Keratinocyte growth factor (KGF) is a mediator of testosterone induced prostatic development. J Urol 1994; 151:381 51. Alarid E T, Rubin J S, Young P et al. Keratinocyte growth factor functions in epithelial induction during seminal vesicle development. Proc Natl Acad Sci USA 1994; 91: 1074–1078 52. Culig Z, Hobixch A, Cronauer M V et al. Androgen receptor activation in prostatic tumour cell lines by insulin-like growth factor I, keratinocyte growth factor and epidermal growth factor. Cancer Res 1994; 54: 5474–5478 53. Guo L, Degenstein L, Fuchs E. Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev 1996; 10:165–175 54. Miki T, Bottaro D P, Fleming T P et al. Determination of ligand-binding specificity by alternate splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci USA 1992; 89:246–250 55. Story M T, Livingstone B, Baeten L et al. Cultured human prostate-derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor. Prostate 1989; 15:355–365 56. Mansson P E, Adams P, Kan M, McKeehan W L. Heparinbinding growth factor gene expression and receptor characteristics in normal rat prostate and two transplantable rat prostate tumors. Cancer Res 1989; 49:2485–2494 57. Sherwood E R, Fong C J, Lee C, Kozlowski J M. Basic fibroblast growth factor: a potential mediator of stromal growth in the human prostate. Endocrinology 1992; 130: 2955–2963 58. Lawson R K. Etiology of benign prostatic hyperplasia. In: Lepor H, Lawson RK (eds). Prostate diseases. Philadelphia: Saunders, 1993:89–95 59. Leung H Y, Dickson C, Robson C N, Neal D E. Overexpression of fibroblast growth factor-8 in human prostate cancer. Oncogene 1996; 12:1833–1835 60. MacArthur C A, Lawshe A, Shankar D B et al. FGF-8 isoforms differ in NIH3t3 cell transforming potential. Cell Growth Diff 1995; 6:817–825 61. Schmitt J F, Hearn M T, Risbridger G P. Expression of fibroblast growth factor-8 in adult rat tissues and human prostate carcinoma cells. J Steroid Biochem Mol Biol 1996; 57:173–178 62. Yan G, Fukabori Y, McBride G et al. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol Cell Biol 1993; 13:4513–4522 63. MacArthur C A, Lawshe A, Xu J et al. FGF-8 isoforms activate receptor splice variants that are expressed in mesenchymal regions of mouse development. Development 1995; 121:3603–3613 64. Ittman M, Mansukhani A. Expression of fibroblast growth factors (FGFs) and FGF receptors in human prostate. J Urol 1997; 157:351–356 65. Krieg M, Bartsch W, Thomsen M, Voigt K D. Androgens and estrogens: their interaction with stroma and epithelium of human benign prostatic hyperplasia and normal prostate. J Steroid Biochem 1983; 19:155–161 66. Habenicht U F, El Etreby M F. Selective inhibition of androstenedione-induced prostate growth in intact beagle dogs by a combined treatment with the antiandrogen cyproterone acetate and the aromatase inhibitor 1-methyl-androsta-1, 4-diene-3, 17-dione. Prostate 1989; 14: 309–322 67. Rohr H P, Bartsch G. Human benign prostatic hyperplasia: a stromal disease? New perspectives by quantitative morphology. Urology 1980; 16:625–633 68. McNeal J E. Normal histology of the prostate. Am J Surg Pathol 1988; 12:629–633 69. Lee C, Sensibar J A, Dudek S M et al. Prostatic ductal system in rats: regional variation in morphological and functional activities. Biol Reprod 1990; 43:1079–1086 70. Sensibar J A, Griswold M D, Sylvester S R. Prostatic ductal system in rats: regional variation in localisation of an androgen-repressed gene product, sulfated glycoprotein-2. Endocrinology 1991; 128:2091–2102 71. Wong P, Pineault J, Lakins J N et al. Genomic organisation and expression of the rat TRPM-2 (clusterin) gene, a gene implicated in apoptosis. J Biol Chem 1993; 268: 5021–5031 72. Rouleau M, Leger J, Tenniswood M P. Ductal heterogeneity of cytokeratins, gene expression and cell death in the rat ventral prostate. Mol Endocrinol 1990; 4:2003–2013 73. Kyprianou N, Isaacs J T. Expression of transforming growth factors in the rat ventral prostate during castration-induced programmed cell death. Mol Endocrinol 1989; 3:1515–1522 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_62.html[09.07.2009 11:51:45]

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74. Isaacs J T. Antagonistic effect of androgen on prostatic cell death. Prostate 1984; 5:545–557 75. Ichihara I, Kallio M, Pelliniemi L J. Light and electron microscopy of the ducts and their sub-epithelial tissue in the rat ventral prostate. Cell Tissue Res 1978; 192: 381–390 76. Lee C, Kozlowski J M, Grayhack J T. Etiology of benign prostatic hyperplasia. Urol Clin North Am 1995; 22: 237–246 77. Nemeth J A, Lee C. The prostatic ductal system in rats: regional variation in stromal organisation. Prostate 1996; 28:124–128

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Page 63 78. Cooke P S, Young P, Cunha G R. Androgen receptor expression in developing male reproductive organs. Endocrinology 1991; 128:2867–2873 79. Cooke P S, Young P, Hess R A, Cunha G R. Estrogen receptor expression in developing epididymis, efferent ductules and other male reproductive tissues. Endocrinology 1991; 128:2874–2879 80. Toney T W, Danzo BJ. Developmental changes in and hormonal regulation of estrogen and androgen receptors present in the rabbit epididymis. Biol Reprod 1988; 39: 818–828 81. Toney T W, Danzo B J. Androgen and estrogen effects on protein synthesis by the adult rabbit epididymis. Endocrinology 1989; 125:243–249 82. Bruengger A, Mariotti A, Rohr H P et al. Androgen and estrogen effects on guinea pig seminal vesicle muscle: a combined serological and biochemical study. Prostate 1986; 9:303–310 83. Steiner M S. Role of peptide growth factors in the prostate: a review. Urology 1993; 42:99–110 84. Di Sant Agnese P. Neuroendocrine differeniation in carcinoma of the prostate. Diagnostic, prognostic and therapeutic implications. Cancer 1992; 70:254–268 85. Larsson L I. On the possible existence of multiple endocrine, paracrine and neuroendocrine messengers in secretory cell systems. Invest Cell Pathol 1980; 3:73–85 86. Grube D. The endocrine cells of the digestive system: amines, peptides and modes of action. Anat Embryol 1986; 175:151–162 87. Cockett A T K, Di Sant Agnese P A, Gopinath P et al. Relationship of neuroendocrine cells of prostate and serotonin to benign prostatic hyperplasia. Urology 1993; 42: 512–519 88. Bologna M, Festuccia C, Muzi P et al. Bombesin stimulates growth of human prostatic cancer cells in vitro. Cancer 1989; 63:1714–1720 89. Aprikian A, Han K, Chevalier S et al. Bombesin specifically induces intracellular calcium mobilisation via gastrin-releasing peptide receptors in human prostate cancer cells. J Mol Endocrinol 1996; 16:297– 306 90. Wasilenko A, Cooper J, Palad A et al. Calcium signalling in prostate cancer cells: evidence for multiple receptors and enhanced sensitivity to bombesin/GRP Prostate 1997; 30:167–173 91. Han K, Viallet J, Chevalier S et al. Characterisation of intracellular calcium mobilisation by bombesinrelated neuropeptides in PC-3 human prostate cancer cells. Prostate 1997; 31:53–60 92. Ritchie C, Thomas K, Andrews L et al. Effects of the calciotrophic peptides calcitonin and parathyroid hormone on prostate cancer growth and chemotaxis. Prostate 1997; 30:183–187 93. Iwamura M, Wu G, Abrahamsson P A et al. Parathyroid hormone-related protein: a potential autocrine growth regulator in human prostate cancer cell lines. Urology 1994; 43:675–679 94. Abdul M, Anezinis P, Logothetis C, Hoosein N. Growth inhibition of human prostatic carcinoma cell lines by serotonin antagonists. Anticancer Res 1994; 14:1215–1220 95. Harper M E, Glynne-Jones E, Goddard L et al. Vascular endothelial growth factor (VEGF) expression in prostatic tumours and its relationship to neuroendocrine cells. Br J Cancer 1996; 74:910–916 96. Griffiths K, Morton M S, Nicholson R I. Androgens, androgen receptors, antiandrogens and the treatment of prostate cancer. Eur Urol 1997; 32 (Suppl 3): 24–40 97. Isaacs J T, Cussenot O, Jankevicius F et al. Growth regulation of normal and malignant prostatic cells. In: Murphy G, Denis L, Chatelain C et al. (eds). First international consultation on prostate cancer. Paris: SCI, 1996:31–81 98. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990; 82:4–6 99. Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235:442–447 100. Weidner N, Carroll P R, Flax J et al. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993; 143:401–409 101. Bang Y, Pirnia F, Fang W et al. Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP Proc Natl Acad Sci USA 1994; 91:5330– 5334 102. Segal N, Cohen R, Huffejee Z, Savage N. Bcl-2 protooncogene expression in prostate cancer and its relationship to the prostatic neuroendocrine cell. Arch Pathol Lab Med 1994; 118:616–618 103. Seuwen K, Poiyssegur J. Serotonin as a growth factor. Biochem Pharmacol 1990; 39:985–990 104. Kinghorn E M, Bate A S, Higgins S J. Growth of rat seminal vesicle epithelial cells in culture: neurotransmitters are required for androgen-regulated synthesis of tissuespecific secretory proteins. Endocrinology 1987; 121: 1678–1688 105. Tutton B J, Barkla D H. Biogenic amines as regulators of the proliferative activity of normal and neoplastic intestinal epithelial cells. Anticancer Res 1987; 7:1–12 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_63.html[09.07.2009 11:51:46]

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106. Nemecek G M, Coughlin S R, Handley D A, Moskowitz M A. Stimulation of aortic smooth muscle cell mitogenesis by serotonin. Proc Natl Acad Sci USA 1986; 83: 674–678 107. Seuwen K, Magnaldo I, Pouyssegue J. Serotonin stimulates DNA synthesis in fibroblasts acting through 5-HT1B receptors coupled to G-protein. Nature 1988; 335: 254–256

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Page 64 108. Cockett A T K, Di Sant Agnese P A, Gopinath P et al. Relationship of neuroendocrine cells of prostate and serotonin to benign prostatic hyperplasia. Adult Urol 1993; 42:512–519 109. Power R F, Mani S K, Codina J et al. Dopaminergic and ligand-independent activation of steroid hormone receptors. Science 1991; 254:1636–1639 110. Verhagen A P M, Aalders T W, Ramaekers F C S et al. Differential expression of keratins in the basal and luminal compartments of rat prostate epithelium during degeneration and regeneration. Prostate 1988; 13:25–38 111. Isaacs J T, Coffey D S. Etiology and disease process of benign prostatic hyperplasia. Prostate 1989; 2 (Suppl 2): 33–50 112. Isaacs J T. Control of cell proliferation and cell death in the normal and neoplastic prostate: a stem cell model. In: Rodgers C H, Coffey D S, Cunha G R et al. (eds). Benign prostatic hyperplasia. Vol II, NIH Publication No. 87–2881. Bethesda: NIH, 1987:85–94 113. Bonkhoff H, Stein U, Remberger K. Multidirectional differentiation in the normal, hyperplastic, and neoplastic human prostate: simultaneous demonstration of cell-specific epithelial markers. Hum Pathol 1994; 25:42–46 114. Bonkhoff H, Remberger K. Differentiation pathways and histogenetic aspects of normal and abnormal prostatic growth: a stem cell model. Prostate 1996; 28:98–106 115. Denmeade S R, Lin S X, Isaacs J T. The role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer. Prostate 1995; 28: 251–265 116. Colombel M, Symmans F, Gil S et al. Detection of the apoptosis-suppressing oncoprotein bcl-2 in hormone refractory human prostate cancers. Am J Pathol 1993; 143:390–400 117. Raffo A J, Perlman H, Chen M W et al. Overexpression of bcl-2 protects prostate cancer from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res 1995; 55:4438–4445 118. McDonnell M L, Troncoso P, Brisbay S M et al. Expression of the proto-oncogene bcl-2 in prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 1992; 52:6940–6944 119. Kim N W, Hruszkewyez A M. Telomerase activity modulation in the prevention of prostate cancer. Urology 2001; 57 (Suppl 1): 148–153 120. Sommerfeld H, Meeker A K, Piatyszek M A et al. Telomerase activity: a prevalent marker of malignant human prostate tissue. Cancer Res 1996; 56:218–222 121. Sommerfeld H, Meeker A K, Posadas E M, Coffey D S. Frontiers in prostate cancer: telomeres and chaos. Cancer 1995; 75:2027–2035 122. Robinson S I, Small D, Idzerda R et al. The association of transcriptionally active genes with the nuclear matrix of the chick oviduct. Nucl Acid Res 1983; 11:5113–5130 123. Nickerson J A, He D, Fey E G, Penman S. The nuclear matrix. In: Strauss P R, Wilson S H (eds). The eukaryotic nucleus: molecular biochemistry and macromolecular assemblies, Vol 2. Caldwell: Telford Press, 1990 124. Barrack E R, Coffey D S. The specific binding of oestrogens and androgens to the nuclear matrix of sex hormone responsive tissues. J Biol Chem 1980; 255:7265–7275 125. Aaronson S. Growth factors and cancer. Science 1991; 254:1146–1153 126. Weinberg R A. The molecular basis of oncogenes and tumor suppressor genes. Ann NY Acad Sci 1995; 758: 331–338 127. Curran T, Bravo R, Muller R. Transient induction of c-fos and c-myc is an intermediate consequence of growth factor stimulation. Cancer Surv 1985; 4:655–681 128. Jones N. Transcriptional regulation by dimerisation: two sides to an incestuous relationship. Cell 1990; 61:9–11 129. Landschultz W H, Johnson P F, McKnight S L. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science 1986; 240: 1759–1764 130. Diamond M I, Miner J N, Yoshinaga S K, Yamamoto K R. Transcription factor interactions: selections of positive and negative regulation from a single DNA element. Science 1990; 249:1266–1272 131. Schule R, Muller M, Kaltschmidt C, Rentawitz R. Many transcription factors interact synergistically with steroid receptors. Science 1988; 242:1418–1420 132. Shemshedini L, Knauthe R, Sassone-Corsi P et al. Cell specific inhibitory and stimulatory effects of fos and jun on transcription activation by nuclear receptors. EMBO J 1991; 10:3839–3849 133. Griffiths K, Davies P, Eaton C L et al. Endocrine factors in the initiation, diagnosis and treatment of prostate cancer. In: Voigt K D, Knabbe C (eds). Endocrine dependent tumors. New York: Raven Press, 1991:83–130 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_64.html[09.07.2009 11:51:46]

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134. Sabbah M, Le Recousse S, Redeuilh G, Beaulieu E E. Estrogen receptor-induced binding of the xenopus vitellogenin A2 gene hormone response element. Biochem Biophys Res Commun 1992; 185:944–952 135. Nardulli A M, Shapiro D J. Binding of the estrogen receptor DNA-binding domain to the estrogen response element induces DNA binding. Mol Cell Biol 1992; 12: 2037–2042 136. Chodak G W, Krane D M, Puy L A et al. Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate. J Urol 1992; 147:798–803

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Page 65 137. Gerber H P, Seipel K, Georgiev O et al. Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 1994; 263:808–811 138. Jenster G, van der Korput H A G M, Trapman J, Brinkmann A G. Identification of two transcriptional activation units in the N-terminal domain of the human androgen receptor. J Biol Chem 1995; 270:7341– 7346 139. Beato M, Herrlich P, Schutz G. Steroid hormone receptors: many actors in search of a plot. Cell 1995; 83: 851–857 140. Mangelsdorf D J, Evans R M. The RXR heterodimers and orphan receptors. Cell 1995; 83:841–850 141. Saatcioglu F, Claret F X, Karin M. Negative transcriptional regulation by nuclear receptors. Semin Cancer Biol 1994; 5:347–359 142. Sugimura Y, Cunha G R, Donjacour A A et al. Whole mount autoradiography study of DNA synthetic activity during postnatal development and androgen-induced regeneration in the mouse prostate. Biol Reprod 1986; 34: 985–995 143. Xue Y, Schalken J A, Miller G J et al. Immunohistochemical determination of in vivo distribution of branching patterns in human adult prostate. J Urol 1996; 155:332A 144. Lightner V A. Tenascin: does it play a role in epidermal morphogenesis and homeostasis? J Invest Dermatol 1994; 102:273–277 145. Mackie E J, Chiquet Ehrismann R, Pearson C A et al. Tenascin is a stromal marker for epithelial malignancy in the mammary gland. Proc Natl Acad Sci USA 1987; 84: 4621–4625 146. Shiraishi T, Kato H, Komada S et al. Tenascin expression and postnatal development of the human prostate. Int J Dev Biol 1994; 38:391–395 147. Xue Y, Umbas R, Aalders T et al. Tenascin expression in human prostate: is tenascin involved in tissue homeostasis? Urol Res 1995; 23:246 148. Xue Y, Ruijter E, Aalders T et al. Tenascin expression in prostatic intraepithelial neoplasia (PIN): is tenascin expression associated with tissue remodelling in prostatic neoplastic transformation? Urol Res 1995; 23:283 149. Weinstein M H, Partin A W, Veltri R W, Epstein J I. Neuroendocrine differentiation in prostate cancer: enhanced prediction of progression after radical prostatectomy. Hum Pathol 1996; 27:683–687 150. Timms B G, Mohs T J, Didio L J A. Ductal budding and branching patterns in the developing prostate. J Urol 1994; 151:1427–1432 151. Norman J T, Cunha G R, Sugimura Y. Induction of new ductal growth in adult prostatic epithelium in response to an embryonic prostatic inductor. Prostate 1986; 8: 209–220 152. Krieg M, Nass R, Tun S. Effect of aging on endogenous level of 5α-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate (BPH). J Clin Endocrinol Metab 1993; 77:375–381 153. Vom Saal F S, Timms B G, Montano M M et al. Prostate enlargement in mice due to fetal exposure to a low dose of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci USA 1997; 94:2056–2061 154. Griffiths K. Les oestrogenes et la prostate. In: Khoury S, Chatelain C (eds). Urologie. Paris: FIIS, 1988:308–332 155. Prins G S, Birch L. The developmental pattern of androgen receptor expression in rat prostate lobes is altered after neonatal exposure to estrogen. Endocrinology 1995; 136:1303–1314 156. Kuiper G G J M, Enmark E, Pelto-Huikko M et al. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996; 93:5925–5930 157. Mosselman S, Polman J, Dijkema R. ERß: identification and characterisation of a novel human estrogen receptor. FEBS Lett 1996; 392:49–53 158. Green S, Walter P, Kumar V et al. Human oestrogen receptor cDNA sequence, expression and homology to verb-A. Nature 1986; 320:134–139 159. Kuiper G G J M, Carlsson B, Grandien J et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and ß. Endocrinology 1997; 138:863–870 160. Berry M, Metzger D, Chambon P. Role of the two activating domains of oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the antioestrogen 4-hydroxytamoxifen. EMBO J 1990; 9: 2811–2818 161. Tzukerman M T, Esty A, Santiso-Mere D et al. Human estrogen receptor transactivational capacity is determined by both cellular and promoter-context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol 1994; 8:21–30 162. Kraus W L, McInerny E M, Katzenellenbogen B S. Ligand-dependent, transcriptionally productive file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_65.html[09.07.2009 11:51:47]

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association of the amino- and carboxy-terminal regions of a steroid hormone nuclear receptor. Proc Natl Acad Sci USA 1995; 92:12314–12318 163. Montano M M, Muller V, Trobaugh A, Katzenellenbogen B S. The carboxy-terminal F domain of the human estrogen receptor: role in the transcriptional activity of the receptor and the effectiveness of antiestrogens as estrogen antagonists. Mol Endocrinol 1995; 9:814–825 164. Katzenellenbogen J A, O’Malley B W, Katzenellenbogen B S. Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a base for the cell- and promoter-specific action of these hormones. Mol Endocrinol 1996; 10:119–131

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Page 66 165. Iafrati M D, Karas R H, Aronovitz M et al. Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nature Med 1997; 3:545–548 166. Palmer R M J, Ferrige A G, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327:524–526 167. Bulkley G B. Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function. Lancet 1994; 344:934–936 168. Moretto M, Lopez F J, Negro-Vilar J. Nitric oxide regulates luteinizing hormone-releasing hormone secretion. Endocrinology 1993; 133:2399–2402 169. Moncada S. Nitric oxide: discovery and impact on clinical medicine. J R Soc Med 1999; 92:164–169 170. Rajfer J, Aronson W J, Bush P A et al. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to noradrenergic, noncholinergic neurotransmission. N Engl J Med 1992; 326:90–94 171. Shaw R I, Papka R E, McNeill D L, Yee J A. NADPH-diaphorase positive nerves and the role of nitric oxide in CGRP relaxation of uterine contraction. Peptides 1993; 14:637–641 172. Suarez-Pinzon W L, Strynadka K, Schulz R, Rabinovitch A. Mechanisms of cytokine-induced destruction of rat insulinoma cells: the role of nitric oxide. Endocrinology 1994; 134:1006–1010 173. Kyprianou N, Litvak J P, Borkowski A et al. Induction of prostate apoptosis by doxazosin in benign prostatic hyperplasia. J Urol 1998; 159:1810–1815 174. Sarafian TA, Bredesen DE. Is apoptosis mediated by reactive oxygen species? Free Radic Res 1994; 20:1–6 175. Klebanoff S J. Oxygen metabolites from phagocytes. In: Gallin J I, Goldstein I M, Snyderman R (eds). Inflamation: basic principles and clinical correlates, 2nd edn. New York: Raven Press, 1992:541– 588 176. Hibbs J B, Taintor R R, Vavrin Z, Rachlin E M. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 1988; 157:87–94 177. El Etreby M F, Habenicht U F. The function and the role of aromatase inhibitors in the treatment of BPH. In: Kurth K, Newling DWW (eds). Benign prostatic hyperplasia. New York: Wiley-Liss, 1994:209– 230 178. Del Vecchio S, Ulissi A. Faecal elimination of steroids in rats after oral administration of mepartricin. J Int Med Res 1990; 18:468–478 179. Shakutou S, Bandoh K, Yoshinaka Y et al. Effect of mepartricin, a polyene macrolide agent, on fecal excretion and serum concentration of estrogen and number of prostatic estrogen receptors in immature rats. Prostate 1999; 38: 17–27 180. Lotti T, Mirone V, Prezioso D et al. Observations on some hormone fractions in patients with BPH treated with mepartricin. Curr Ther Res 1988; 44:402–406 181. Denis L, Pagano F, Nonis A et al. Double-blind, placebocontrolled trial to assess the efficacy and tolerability of mepartracin in the treatment of BPH. Prostate 1998; 37: 246–252 182. McConnell J, Bartsch G, Debruyne F et al. Hormonal treatment of benign prostatic hyperplasia. In: Cockett A T K, Aso Y, Chatelain C et al. (eds). First international consultation on benign prostatic hyperplasia. Paris: SCI, 1991:179–191 183. White J J, Neuwirth H, Miller CD, Schneider EL. DNA alterations in prostatic adenocarcinoma and benign prostatic hyperplasia: detection by DNA fingerprint analyses. Mutat Res 1990; 237:37–43 184. de Vere White R W, Gumerlock P H, Chi S G, Meyers F J. p53 Tumor suppressor gene abnormalities are frequent in human prostatic tissues. J Urol 1993; 149:376A 185. Bedford M T, van Helden P D. Hypomethylation of DNA in pathological conditions of the human prostate. Cancer Res 1987; 47:5274–5276 186. Muller W J, Lee F S, Dickson C et al. The int-2 gene product acts as an epithelial growth factor in transgenic mice. EMBO J 1990; 9:907–913 187. Tutrone R F, Ball R A, Ornitz D M et al. Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model. J Urol 1993; 149:633–639 188. Sanda M G, Beaty T H, Stutzman R E et al. Genetic susceptibility of benign prostatic hyperplasia. J Urol 1994; 152:115–119 189. Partin A W, Page W F, Lee B R et al. Concordance rates for benign prostatic disease among twins suggest hereditary influence. Urol 1994; 44:646–650 190. Sanda M G, Doehring C B, Binkowitz B et al. Clinical and biological characterization of familial benign prostatic hyperplasia. J Urol 1997; 157:876–879 191. Doehring C B, Sanda M G, Partin A W et al. Histopathologic characterization of hereditary benign file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_66.html[09.07.2009 11:51:48]

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prostatic hyperplasia. Urology 1996; 48:650–653 192. Griffiths K, Adlercreutz H, Boyle P et al. Nutrition and cancer. Oxford: Isis Medical Media, 1996 193. Griffiths K, Denis L J, Turkes A. Oestrogens, phytooestrogens and pathogenesis of prostatic disease. London: Martin Dunitz, 2002 194. Haenzel W, Kurihara M. Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. J Natl Cancer Inst 1968; 40:43–68 195. Shimizu H, Ropp R K, Bernstein L et al. Cancers of the breast and prostate among Japanese and white immigrants in Los Angeles County. Br J Cancer 1991; 63:963–966

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Page 67 196. Bradbury R B, White D C. Oestrogens and related substances in plants. Vit Horm 1954; 12:207–233 197. Price K R, Fenwick G R. Naturally occurring oestrogens in food—a review. Food Add Contam 1985; 2:73–106 198. Verdeal K, Brown R R, Richardson T, Ryan D S. Affinity of phytoestrogens for estradiol-binding proteins and effect of coumestrol on growth of 7, 12-dimethylbenz(a) anthracene-induced rat mammary tumors. J Natl Cancer Inst 1980; 64:285–290 199. Axelson M, Sjovall J, Gustafsson B E, Setchell K D R. A dietary source of the non-steroidal oestrogen equol in man and animals. J Endocrinol 1984; 102:49–56 200. Setchell K D R, Adlercreutz H. Mammalian lignans and phytooestrogens. Recent studies on their formation, metabolism and biological role in health and disease. In: Rowland IR (ed). Role of gut flora in toxicity and cancer. London: Academic Press, 1988:315–345 201. Walz E. Isoflavon- und Sapogenin-Glucoside in Sojahispida. Justus Liebigs Annal Chem 1931; 489: 118–155 202. Coward L, Barnes N C, Setchell K D R, Barnes S. Genistein, daidzein, and their β-glycoside conjugates: antitumor isoflavones in soybean foods from American and Asian diets. J Agric Food Chem 1992; 41:1961–1967 203. Rosenblum E R, Campbell I M, Van Thiel D H, Gavaler J S. Isolation and identification of phytoestrogens from beer. Alcoholism Clin Exp Res 1992; 16:843–845 204. Van Thiel D H, Galvao-Teles A, Monteiro E et al. The phytoestrogens present in de-ethanolised bourbon are biologically active: a preliminary study in postmenopausal women. Alcoholism Clin Exp Res 1991; 15:822–823 205. Rao C B S (ed). The chemistry of lignans. Waltair, India: Andra University Press and Publications, 1978:1–377 206. Thompson L U, Robb P, Serraino M, Cheung F. Mammalian lignan production from various foods. Nutr Cancer 1991; 16:43–45 207. Pumford S L, Morton M M, Turkes A, Griffiths K. Determination of the isoflavonoids genistein and daidzein in biological samples by gas chromatography-mass spectrometry. Anal Clin Biochem 2002; 39:281–292 208. Grace P B, Taylor J I, Botting N P et al. Quantification of isoflavones and lignans in urine using gas chromatography/mass spectrometry. Anal Biochem 2003; 315: 114–121 209. Adlercreutz H, Fotsis T, Bannwart C et al. Determination of urinary lignans and phytoestrogen metabolites, potential antiestrogens and anticarcinogens, in urine of women on various habitual diets. J Steroid Biochem 1986; 25: 791–797 210. Morton M S, Wilcox G, Wahlquvist M L, Griffiths K. Determination of lignans and isoflavonoids in human female plasma following dietary supplementation. J Endocrinol 1994; 142:251–259 211. Finlay E M H, Wilson D W, Adlercreutz H, Griffiths K. The identification and measurement of phytooestrogens in human saliva, plasma, breast aspirate or cyst fluid, and prostatic fluid using gas chromatography-mass spectrometry. J Endocrinol 1991; 129 (Suppl): 49 212. Dehennin L, Reiffsteck A, Joudet M, Thibier M. Identification and quantitative estimation of a lignan in human and bovine semen. J Reprod Fert 1982; 66: 305–309 213. Adlercreutz H, Honjo H, Higashi A et al. Urinary excretion of lignans and isoflavonoid phytoestrogens in Japanese men and women consuming traditional Japanese diet. Am J Clin Nutr 1991; 54:1093–1100 214. Adlercreutz H, Markkanen H, Watanabe S. Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 1993; 342:1209–1210 215. Setchell K D R, Borriello S P, Hulme P et al. Nonsteroidal oestrogens of dietary origin: possible roles in hormonedependent disease. Am J Clin Nutr 1984; 40:569–578 216. Turkes A, Denis L, Griffiths K. Can diet reduce the risk of prostate cancer? In: Bowsher W (ed). Challenges in prostate cancer. Oxford: Blackwell Science, 2000:3–18 217. Evans B A J, Griffiths K, Morton M. Inhibition of 5α-reductase and 17ß-hydroxysteroid dehydrogenase in genital skin fibroblasts by dietary lignans and isoflavonoids. J Endocrinol 1995; 147:295–302 218. Hiipakka R A, Zhang H Z, Dai W et al. Structure-activity relationships for inhibition of human 5alpha-reductase by polyphenols. Biochem Pharmacol 2002; 63:1165–1176 219. Adlercreutz H, Bannwart C, Wahala K et al. Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens. J Steroid Biochem Molec Biol 1993; 44: 147–153 220. Brueggemeier R W, Gu X, Mobley J A et al. Effect of phytoestrogens and synthetic combinatorial file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_67.html[09.07.2009 11:51:48]

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libraries on aromatase, estrogen biosynthesis, and metabolism. Ann NY Acad Sci 2001; 948:51–66 221. Akiyama T, Ishida J, Nakagawa S et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987; 262:5592–5595 222. Scholar E M, Toews M L. Inhibition of invasion of murine mammary carcinoma cells by the tyrosine kinase inhibitor genistein. Cancer Lett 1994; 87:159–162 223. Fotsis T, Pepper M, Adlercreutz H et al. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA 1993; 90:2690–2694 224. Myoung H, Hong S P, Yun P Y et al. Anti-cancer effect of genistein in oral squamous cell carcinoma with respect to angiogenesis and in vitro invasion. Cancer Sci 2003; 94: 215–220

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Page 68 225. Rice-Evans C A, Miller N J, Bolwell P G et al. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radical Res 1995; 22:375–383 226. Wei H, Zhang X, Wang Y, Lebwohl M. Inhibition of ultraviolet light-induced oxidative events in the skin and internal organs of hairless mice by isoflavone genistein. Cancer Lett 2002; 185:21–29 227. McCabe M J Jr, Orrenius S. Genistein induces apoptosis in immature human thymocytes by inhibiting topoisomerase-II. Biochem Biophys Res Comm 1993; 194: 944–950 228. Constantinou A, Mehta R, Runyan C et al. Flavonoids as DNA topoisomerase antagonists and poisons: structure-activity relationships. J Nat Prod 1995; 58: 217–225 229. Messina M J, Persky V, Setchell K D R, Barnes S. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer 1994; 21:113–130 230. Salti G I, Grewal S, Mehta R R et al. Genistein induces apoptosis and topoisomerase II-mediated DNA breakage in colon cancer cells. Eur J Cancer 2000; 36:796–802 231. Lamartiniere C A, Zhang J X, Cotreneo M S. Genistein studies in rats: potential for breast cancer prevention and reproductive and development toxicity. Am J Clin Nutr 1998; 68 (Suppl 6): 1400S-1405S 232. Zhou J R, Mukherjee P, Gugger E T et al. Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis. Cancer Res 1998; 58:5231– 5238 233. Cohen L A, Zhao Z, Pittman B, Scimeca J A. Effect of intact and isoflavone-depleted soy protein on NMU-induced rat mammary tumorigenesis. Carcinogenesis 2000; 21:925–935 234. Jin Z, MacDonald R S. Soy isoflavones increase latency of spontaneous mammary tumors in mice. J Nutr 2002; 132: 186–190

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Page 69 4 Molecular aspects of bening prostatic hyperplasia M R Freeman M E Gleave L W K Chung Introduction Despite research on benign prostatic hyperplasia (BPH) undertaken by a large number of laboratories and spanning nearly a century,1,2 the molecular mechanisms underlying the age-related enlargement of the prostate, and the cellular basis of BPH symptoms, are still obscure. In the last decade, however, there has been an explosive growth of new knowledge on molecular aspects of cellular growth control, the function of secreted and cell surface proteins, the regulatory role of the extracellular matrix, pathways of transmission of external signals to the cell interior and to the cell nucleus, and the mechanics of cell cycle regulation. Although much of this research has been carried out in other organ systems or in artificial models, increases in new findings using prostate-growth models in recent years have also provided important clues about potential mechanisms of prostatic neoplasia. There is now strong evidence that biochemical mediators sequestered or originating from within the prostatic connective tissue play a crucial role in the functional state and the growth potential of the mature gland. In the prostate and in other organ systems, both diffusible (soluble) and solid-state (insoluble) mediators are involved in tissue interactions responsible for differentiative change as well as changes in patterns of cell growth. The identification of some of these regulatory molecules, and in some cases the discovery of their specific functional roles, suggest the possibility that BPH occurs as a result of aberrant cellular interactions resulting from alteration in expression, localization, and function of cytokines and growth factors as well as insoluble regulatory molecules comprising the connective tissue matrix. In this review we provide an overview of the concept of stromal-(mesenchymal-) epithelial interaction as it pertains to development and growth of the prostate. We attempt to integrate findings from more classical studies of tissue and cell recombination with recent results from molecular investigations of cell regulation by soluble regulatory factors and the extracellular matrix (ECM). The objective of this treatment is to provide a framework for the development of testable hypotheses of the molecular processes underlying the clinical dilemma of BPH, with the ultimate goal of devising novel and effective therapies for this common neoplasm. Stromal-epithelial interactions in prostatic functional differentiation and growth The prostate gland is composed of two histologically distinct tissue compartments, a branching acinarductal epithelium and fibromuscular stroma. Morphometric analyses have demonstrated that each compartment (when luminal spaces are considered part of the epithelial compartment) makes up about one-half of the glandular volume of the human prostate.3 Each of these tissue elements is further comprised of a variety of cell types, including secretory and basal epithelial cells, smooth muscle cells, undifferentiated fibroblasts, vascular endothelial networks, nerve bundles, and inflammatory cell infiltrates. Each of these specialized cells can be further grouped by histologic criteria into distinct subcompartments, such as simple columnar vs pseudostratified epithelium, and vascular and connective smooth muscle. However, a precise categorization of all of the specialized cells in the prostate awaits the identification of more informative molecular markers than we have presently. None of the specialized cell types found within the human prostate has yet been thoroughly characterized in molecular terms. The prostatic stroma provides a supporting matrix for the ductal epithelial cells, which synthesize, concentrate, and secrete the components of the prostatic fluid into the ductal lumina. In addition, the connective-smooth-muscle compartment mediates the contractions which expel the prostatic secretions from the gland. There is strong evidence from experimental models that the stromal and epithelial compartments communicate with each other, and that prostatic growth and functional differentiation, both during development and in the adult, are dependent on regulatory signaling between them. The development of the prostate occurs in response to inductive signals originating from the endodermal urogenital sinus mesenchyme. In tissue recombination experiments, in which mouse fetal urogenital sinus (UGS) is microdissected into epithelial (UGE) and mesenchymal (UGM) components, prostatic growth, morphogenesis, and functional differentiation occur when homotypic (prostatic) or certain types of heterotypic epithelia are recombined with UGM and implanted under the kidney

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Page 70 capsule of a syngeneic or athymic host.4–10 Under these conditions, reconstituted prostatic tissue is formed, with histomorphologic and immunohistochemical evidence of normal glandular architecture and secretory functions. Prostatic morphogenesis does not occur in the absence of UGM, or in the presence of noninductive heterotypic mesenchymes, indicating a high degree of tissue or developmental specificity underlying the morphologic outcome of these experiments.11 These tissue-specific inductive mechanisms are highly conserved in evolution, as demonstrated by the capability of human fetal bladder epithelium to differentiate into ductal structures lined by columnar epithelium in response to heterotypic recombination with mouse UGM.7 It is now well established that fetal prostatic development and morphogenesis is absolutely dependent on inductive signals originating from the mesenchymal compartment. This is consistent with similar findings in other organ systems.8,12 Remarkably, however, the ability of adult epithelia to respond functionally to these inductive signals has also been demonstrated for adult prostatic, seminal vesicle, ureter, and bladder epithelium.4,5,9,10,13–15 These studies have demonstrated directly that adult urogenital epithelia maintain the capability to respond to stromal mediators of growth and differentiation. This conclusion is consistent with the hypothesis, first proposed by McNeal,16 that benign prostatic growth occurring later in life in humans is the result of a ‘reawakening’ of the inductive potential of the prostatic stroma. There is general agreement that BPH is mediated in part by gonadal androgens. Boys castrated prepubertally do not develop BPH.17 The prostate is an androgendependent organ and circulating androgens are required for maintenance of prostatic function in adulthood and for embryonic and fetal prostatic development.18 The rat prostate, which is primarily a parenchymal organ with an epithelial:stromal ratio of 5:1, loses approximately 80% of its cellular content after castration.19 Based on a variety of studies of prostatic dependence and response to androgens, the epithelial compartment appears to be more sensitive to the effects of androgen withdrawal than the stromal compartment. This correlates with the observation that high-affinity androgen receptors are more abundant in the adult prostatic epithelium than in the neonatal prostatic stroma or in the mature prostate of the adult20,21 However, during fetal prostatic development, androgen receptors are expressed exclusively in the mesenchyme,21,22 indicating that androgen-mediated effects on development of prostatic epithelial ductal growth and morphogenesis are proximally regulated by androgenreceptor-mediated mechanisms confined initially to the mesenchymal compartment. This was demonstrated most dramatically by recombination experiments in which androgen-receptor-deficient bladder epithelium (Tfm/y) was recombined heterotypically with androgen-receptorpositive UGM, resulting in dramatic growth and prostatic functional differentiation in the epithelium.9,23–25 These results demonstrate that mesenchyme-mediated regulation of epithelium is not only permissive, in which epithelial glandular morphogenesis occurs in cells previously committed to expressing a prostatic phenotype. In addition, these findings indicate that mesenchymal-epithelial interactions can also be instructive, in which epithelium previously directed to a distinct, nonsecretory, nonglandular lineage is nevertheless capable of expressing a heterotypic, secretory phenotype specified by the adjacent mesenchyme. Studies on androgen receptor localization in these reconstituted prostatic tissues have confirmed the absence of androgen receptors in the epithelial compartment, and the presence of androgen receptors (identified by binding analyses revealing the presence of functional, high-affinity androgen-binding sites) in the mesenchyme.24,25. A critical role for the mesenchyme in prostatic development parallels studies on the mechanisms of hormonally-induced regression of the mammary gland, in which steroid hormone-mediated degenerative responses in the parenchyma are mediated by the mesenchyme.12,26,27 Similarities between the prostate and mammary gland in cellular and molecular mechanisms of organ function are of interest in the study of prostatic disease because of the functional, structural, and endocrinological similarities between these two organs.11 The tissue specificity of inductive mesenchymal-epithelial interactions was demonstrated by tissue recombination experiments in which mammary gland and preputial gland mesenchyme were each capable of eliciting dramatic growth and cytodifferentiation of mammary epithelium in vivo, while other mesenchymes (vaginal, uterine, UGS, genital tubercle) were either incapable of inducing growth, or induced an aberrant histomorphologic architecture.8 There is also experimental evidence that the epithelial tissue compartment is capable of directing events in neighboring mesenchyme. Tissue recombination experiments similar to those described above have recently provided evidence that spatial organization of urogenital smooth muscle involves critical, tissuespecific paracrine mediation from the neighboring epithelium.28 The potential for stromal mediation of neoplastic growth has also been demonstrated with experimental

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Page 71 models. Chung and collaborators have presented results of a series of studies using cell recombination techniques which show that the presence of stromal cells greatly enhances neoplastic growth of immortalized epithelial cells or adenocarcinoma cells in vivo.15,29–34 In these experiments, carcinomas or carcinosarcomas are created experimentally in syngeneic or athymic rodent hosts by in vivo injection of epithelial cells in a co-inoculum with homotypic or heterotypic fibroblasts cultured in vitro. Tumorigenic potential and tumor growth rate are subsequently measured directly. Initially, Chung et al.29 demonstrated the potential for tumorigenic rat prostate fibroblasts to evoke neoplastic growth in vivo of nontumorigenic rat prostate-derived epithelial cells. Subsequent studies demonstrated the potential for heterotypic fibroblasts to accelerate the growth of human prostate, breast, bladder, and kidney carcinoma cells when co-inoculated subcutaneously in athymic hosts.30 Using the androgenreceptor-positive LNCaP cell line, which expresses the androgen-regulated prostate-specific proteinase, prostate-specific antigen (PSA), Gleave et al.32 demonstrated the capability of prostate and bone fibroblasts, but not lung and kidney fibroblasts, to induce PSAsecreting tumors in vivo. In this study, LNCaP tumors grew preferentially in male hosts, suggesting a role for androgens in fibroblast-mediated acceleration of epithelial tumor growth. An inductive role for the organ-specific microenvironment in prostate tumor growth was also shown in studies where LNCaP tumors were generated within prostatic tissue by orthotopic inoculation into mouse dorsal prostate.33 In these studies, PSA-secreting tumors did not form when LNCaP cells were injected under the renal capsule or under the skin, even when higher numbers of tumor cells were injected at these ectopic sites. The capability for mouse prostate to serve as a preferred site for growth of human prostate tumor cells also suggests that inductive stromal influences on prostate tumor growth are evolutionarily conserved. Intraprostatic implantation of human prostate tumor cells has also been demonstrated to result in enhanced rates of tumor metastasis to distant sites,35 consistent with the idea that the prostatic environment contains regulatory factors which can enhance tumor development and progression to the metastatic state. In contrast to the above studies, which demonstrate the capability of stromal cells to promote normal and neoplastic growth of prostatic epithelial cells, mesenchyme has also been shown to induce differentiation of transplantable rat prostatic tumors carried in animals for decades. UGM was able to induce glandular, secretory, and biochemical differentiation of androgen-sensitive, well-differentiated Dunning prostatic tumors, but not the poorly differentiated, androgen-independent Dunning and Noble prostatic tumors.36,37 This induction of histomorphologic and functional differentiation in a tumor of nearly historic origin (the Dunning tumor has been passaged in animals continuously for over 30 years) is likely to be tissue-specific, based on the failure of neonatal bladder mesenchyme to induce differentiation of tumor in Dunning tumor-bladder mesenchyme chimeras.37 These studies are consistent with reports from other laboratories demonstrating the capability of embryonic tissues to induce the differentiation of a variety of neoplasms, including embryonal carcinoma,38 colon carcinoma,39 neuroblastoma,40 and mammary carcinoma.41 Induction of carcinoma cell differentiation by stroma provides an intriguing contrast to the growth-promoting role of fibroblasts in carcinomas created by in vivo injections of single cell suspensions. These differences illustrate the limitations of model systems in extrapolating directly to the clinical situation. However, they also provide clear demonstrations of the potential for in vivo growth of tumors to be altered in drastic ways by the stromal microenvironment. The role of soluble growth factors The results presented above are consistent with the hypothesis that mesenchyme-derived paracrine factors direct growth, branching morphogenesis, and secretory function of prostatic epithelium during critical phases of prenatal and adult life. A common assumption is that enlargement of tissues occurs as a result of the paracrine activity of one or more growth factors, soluble polypeptides belonging to a spectrum of gene families which stimulate proliferation of cells in culture. This is partly correct, but nevertheless it is a highly oversimplified assumption. Most of the molecules identified as growth factors by functional criteria using in vitro systems actually show a wide range of biological activities in cell culture, depending on the experimental conditions or on the cell types used for analysis. Further, for many of these factors, evidence from in vivo systems indicates that their roles in development, tissue homeostasis, or wound repair may be distinctly different or even unrelated to the control of cell growth per se. Basic fibroblast growth factor (historically abbreviated bFGF, but more recently known as FGF-2) is a pleoitropic polypeptide capable of stimulating the proliferation of a variety of cultured cells,42 including human prostate stro mal cells.43 FGF-2 also induces endothelial cell growth in vitro, initiates neovascularization in vivo, and is an

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Page 72 important tumor angiogenesis factor. FGF family members are important mediators of mesoderm patterning, organ growth and differentiation, and bone formation,44 however, from in vitro studies of FGFs alone, it would have been difficult to predict these important developmental roles for this growth factor family. The reader is directed to a comprehensive review on growth factors in relation to prostatic and urological neoplasia for an overview.45 The pleiotropic nature of most growth factors makes it difficult to construct hypotheses regarding the potential role of one single growth factor on specific forms in BPH. Although the prostatic volume enlarges in benign hyperplasia in humans, physiologic changes such as remodeling of the microvasculature46 and relative increases in the nonmuscular (fibroblastic) compartment of the prostatic stroma3 have also been reported. These and other findings in experimental systems suggest that BPH is a complex physiologic process involving growth and remodeling of tissue architecture, and involving bladder outlet obstruction as well as bladder dysfunction.47 Individual growth factors might therefore play multiple roles while other growth factors, although present, may play no functional role in BPH. Studies of growth factor localization and function in human and rodent prostatic tissues have been less common than studies with cultured cell lines. To date, few differences between growth factor levels in human BPH and normal prostatic tissue have been reported. In some reports, where investigators used mRNA expression techniques to examine growth factor or growth factor receptor levels, no differences between normal and BPH tissues were found.48,49 One of the best studied examples of a single factor that is capable of mediating a wide range of distinct activities in vitro and in vivo is transforming growth factor β1 (TGFβ1). TGFβ1 is a member of a family of growth and differentiation factors which includes the related but genetically distinct isoforms TGFβ2 and TGFβ3 in mammals, and a variety of other molecules such as Mullerian inhibiting substance (involved in masculinization during fetal development), activins, inhibins, and bone morphogenetic proteins.50 The identification of TGFβ-related molecules as mediators of cell differentiation exemplifies the role of growth factors in normal developmental processes unrelated to cell growth. TGFβ1 is a potent mitogen for fibroblasts and other mesenchymal cell types, but may also be the most important physiologic inhibitor of epithelial cell proliferation. TGFβ1 also regulates extracellular matrix biosysnthesis and degradation, is a potent immunosuppressor, and can stimulate cells to undergo apoptosis. Carcinoma cells, including prostate tumor cells, often lose their normal pattern of growth inhibition in response to TGFβ1.51,52 The TGFβ insensitivity of carcinoma cells is thought to be an important mechanism of tumor expansion during malignant progression. TGFβ1 may also enhance the invasive potential of tumor cells,53 thereby promoting malignant progression by a mechanism not directly related to an absence of its normal growthinhibitory function. It is clear from studies of the diverse biological activities of TGFβ1, and of a host of other growth factors belonging to different gene families, that the physiologic activities of specific growth factors in vivo are dependent on the temporal and spatial context in which they act. It has been proposed that alteration in the functional status of TGFβ1 in prostatic tissue may play a role in BPH. Although TGFβ1 can positively regulate prostate stromal cell growth, it also upregulates the production of FGF-2, an autocrine growth factor for prostate stromal cells.43,54 Therefore, this growth factor axis, which consists of mechanisms for both positive and negative effects on stromal cell proliferation, could be altered during the natural history of BPH to favor expansion of the stromal compartment. TGFβ1 has been found in human seminal plasma, suggesting that it is a secretory product of the normal prostate gland.55 Enforced expression of TGFβ1 in vivo in reconstituted mouse prostate by retroviral transfection resulted in proliferative abnormalities in the epithelial and stromal compartments, but with no overall change in tissue growth.56 Elevation of TGFβ isoform accumulation has been observed in human prostate cancer and in rodent prostatic tumors.57–59 Human and rat prostate cell lines and normal and neoplastic tissues also express TGFβ-like bone morphogenetic protein mRNAs.60 In the developing mouse prostate, TGFβ-1, -2, and -3 isoforms were detected in UGM, with expression levels appearing higher in UGM than in UGE.61 During development, highest levels of TGFβ1 were found at epithelial—mesenchymal interfaces in areas of active epithelial branching morphogenesis, suggesting a role for the growth factor in morphogenesis of the ductal network and in epithelial differentiation. Expression of the TGFβ1 isoform was retained, predominantly in the mesenchyme, in the adult. Expression patterns of TGFβ isoforms in development have also suggested a role for these factors in mesenchymal-epithelial interactions outside of the developing urogenital tract.62 The potential for TGFβ isoforms to regulate smooth muscle cell physiology63 suggests the possibility that TGFβ-related factors may be physiologic regulators of prostatic smooth muscle cells in vivo. An indirect role for TGFβ in tissue growth can also be inferred

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Page 73 from studies in which TGFβ has been shown to upregulate production of angiogenic factors by vascular smooth muscle cells.64 Increases in TGFβ receptor mRNA have been reported in BPH patients treated with finasteride, suggesting the involvement of the TGFβ axis in the glandular atrophy seen histologically with long-term 5α-reductase inhibition.65 FGF-like factors were identified early on as major intraprostate mitogens, based on functional tests.66 FGF-like activity is detectable at significant levels in normal human and rodent prostate and in prostatic fluid.67,68 The FGF gene family contains multiple, structurally similar, but functionally distinct factors, which bind and activate multiple classes of cell-surface receptors in a cell-typespecific fashion. The functional roles of the FGF family members are still not well defined, a problem that grows more complex because a variety of new FGF receptor ligands have been discovered in recent years. Seventeen members of the FGF family have been found at this writing,44 but only a few have been extensively studied. FGF-1 (‘acidic’ FGF) and ‘basic’ bFGF/FGF-2 (‘basic’ FGF) are members of a distinct subclass of the FGF family because these polypeptides, unlike other FGFs, lack a secretion signal at their amino termini. Most FGFs are thought to be secreted into the extracellular space by a conventional protein secretory pathway. However, FGF-1 and FGF-2 bind to high-affinity receptors displayed on the cell surface. Therefore, the physiologic context and the regulatory signals mediating the secretion of these two factors remain unclear. Wounding and cell death, which cause damage to cell membranes, may result in the release of the normally intracellular FGF-1 and FGF-2 into the extracellular space, thereby making these factors available to their cognate receptors.69,70 These observations provide a logical bridge between studies designed to define the circumstances in which apoptotic cell death occurs in the prostate and mechanisms of growth factor action and intercellular communication. Keratinocyte growth factor, an FGF-family member (KGF/FGF-7), is significant in terms of identifying mechanisms of stromal-epithelial interaction in the prostate because, unlike other members of the FGF family, cell-surface KGF receptors are expressed exclusively by prostatic epithelial cells while KGF itself is a product exclusively of prostatic stromal cells.71 Consequently, KGF may be involved in stromalmediated hormonal regulation of prostatic epithelium. Such soluble factors have long been predicted to exist, based on results of tissue recombination experiments described above. A neutralizing anti-KGF antibody inhibited androgen-dependent seminal vesicle and prostate growth and ductal branching morphogenesis in organ culture, and exogenously applied KGF was able to substitute in part for androgens in cell differentiation and maturation in this system.72 These results provide direct evidence for a role for stromal-derived KGF in hormone-dependent growth and epithelial differentiation in two organs known to require mesenchymal-epithelial interactions for normal development. KGF may be one of the long-sought ‘andromedins’, peptide mediators of androgenic signaling in the male accessory sex glands. However, the findings of more recent studies contradict this view. Nemeth et al.73 did not find an association between levels of KGF expression and hormonally mediated growth or tissue regression in the rat ventral prostate. Thomson et al.74 found that variations in KGF and KGF receptor levels in the developing rat seminal vesicle and prostate reflected variations in the mesenchyme/epithelial ratio rather than regulation by androgen. On the other hand, the KGF promoter has been demonstrated to be regulated by androgen,75 consistent with the hypothesis that KGF synthesis might be regulated by androgen directly through the stromal compartment. Targeting of KGF to the mouse prostate epithelium, a manipulation that created an autocrine instead of a paracrine signaling loop, resulted in epithelial hyperplasia and disorganized smooth muscle architecture. These results demonstrate that KGF has the capability to promote hyperplastic cell growth in the prostate. More studies are needed to clarify the potential role of this important mitogen in mechanisms of prostate cell growth. In the Dunning prostate tumor model, fetal UGM, when recombined with poorly differentiated Dunning tumor pieces, induced the differentiation of the adenocarcinoma cells consistent with a reversion of the malignant phenotype.36,37 These observations suggest that neoplastic growth of the Dunning tumor cells can be controlled by their connective tissue environment. McKeehan and coworkers have determined that, in the Dunning model, a transition from a stromal-dependent, nonmalignant form of tumor growth to a stromal-independent, malignant form is accompanied by a switch in FGF receptor isoforms.76 This switch is the result of an alternative mRNA splicing event in which the FGF-receptor-2 (FGFR2) iso form containing the IIIb region of the third immunoglobulin-like loop domain, a segment of the extracellular FGF binding region, is replaced by the alternative IIIc region. This confers a change in FGF ligand receptor responsitivity by the cells, resulting in an inability to respond to KGF (a ligand for the IIIb form of the FGFR2 receptor). Because this switch in receptor expression is also

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Page 74 accompanied by an up-regulation of the FGF-2 gene as well as genes for several other FGF receptors, these data suggest that loss of regulation by stromal-derived KGF, possibly accompanied by acquisition of cellular responsiveness to other FGF-like factors, may accompany progression to a state of uncontrolled, stromal-independent growth in prostatic tumors. Additional evidence indicates that FGF-like factors are involved in BPH. One of the first demonstrations of the possibility for growth factors to induce hyperplastic growth in the male reproductive tract was the creation of a transgenic mouse line expressing the int-2/FGF-3 growth factor targeted to the mammary gland and, fortuituously, to the male accessory sex glands. Expression of this oncoprotein in male mice results in an androgensensitive epithelial/glandular hyperplasia histologically similar to human and canine BPH.77 Originally thought to be prostatic overgrowth, subsequent studies by Donjacour et al. indicated that the abnormal tissue expansion in these animals actually occurs in the ampullary gland and the seminal vesicle, which are derived from the Wolffian duct, but not the prostate, which is derived from the urogenital sinus.78 Interestingly, however, these investigators also demonstrated that prostatic overgrowth is not seen in these animals despite the fact that the FGF-3 transgene is in fact expressed in the dorsolateral prostate. This finding suggests that growth factors capable of causing BPH-like tissue expansion can exhibit exquisite, and highly unexpected, tissue specificity. Because of the limited availability of ‘normal’ prostate tissue, i.e. from young men, there is still very limited evidence from published studies implicating alterations in levels of a specific regulatory polypeptide in BPH. However, Begun et al.68 used a sensitive radioimmunoassay to measure levels of FGF-2 accumulation in a significant series of normal prostatic tissue and BPH glands. The BPH tissue showed 2–3-fold elevation of this growth factor in comparison to the histologically normal glands, a result that is consistent with the hypothesis that BPH coincides with increased levels of resident growth factors in the gland. Stroma-derived FGF-2 may originate or preferrentially localize to stromal smooth muscle cells,79 which may be the primary interstitial cell type involved in stromal-epithelial interactions in the normal prostate. FGF-2 accumulation in human prostatic tissue may not be regulated directly by androgens,80 consistent with the possibility that paracrine signaling through different tissue compartments is involved in growth factor homeostasis. The identification of other stromal-derived prostatic growth factors, in addition to members of the FGF family, will be of great interest. These potentially include hepatocyte growth factor/scatter factor (HGF/SF) and plateletderived growth factor (PDGF) isoforms, which may be physiologic mitogens for normal and neoplastic prostate epithelial cells, prostatic fibroblasts and/or smooth muscle cells.34 HGF/SF, a paracrine factor produced by prostate and bone fibroblasts, was found to be a potent mitogen that supports anchorage-independent growth of prostate epithelial cells, an activity mediated by c-Met, the cell surface HGF/SF receptor and a known proto-oncoprotein.81,82 HGF/SF is also a key paracrine growth factor stimulating vascular endothelial cell growth and tubulogenesis,83 and serves as a survival factor that prevents programmed cell death in response to cytotoxic insults such as chemotherapy, radiation therapy, and other forms of cell stress.84 c-Met was found to be prevalently expressed by the basal cells (stem cells) in the normal human prostate gland81 and its expression is negatively regulated by androgen.82 Immunohistochemically, c-Met was found to be expressed by a majority of prostate cancers, including early stages of neoplasm, such as prostatic intraepithelial neoplasia (PIN);81 c-Met, however, was expressed infrequently in BPH tissues.81 Activation of HGF/SFc-Met downstream signaling may enhance mitogenesis, motogenesis, morphogenesis, and angiogenesis of both tumor and normal cells that could play a role in intiating the benign and malignant growth of prostate tumors. Platelet-derived growth factor (PDGF) isoforms are potent fibroblast and smooth-muscle-cell mitogens. PDGFs could conceivably drive proliferation of most of the cells in the fibromuscular prostatic stroma (e.g. nondifferentiated fibroblasts and smooth muscle cells). Stromal cells derived from human prostate tissue were shown to express high-affinity receptors for the PDGF-BB isoform and demonstrated an increased proliferative response to exogenous PDGF-BB.85 Several abnormalities in the insulin-like growth factor (IGF) axis have been identified in cultured human stromal cells derived from BPH specimens when compared to stromal cells derived from histologically normal specimens. Cohen et al.86 found evidence for enhanced expression of IGF-II and diminished expression of IGF-binding protein 5, a stoichiometric regulator of IGF activity. A subsequent study from the same group demonstrated enhanced expression of the IGF-II gene and enhanced expression of the IGF receptor type 1 (IGF1R) specifically in stromal cell strains from BPH patients.87 These data suggest that IGF activity might be enhanced in BPH stroma relative to normal due to both increases in stromal growth factor and receptor synthesis and localization as file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_74.html[09.07.2009 11:51:52]

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Page 75 well as release of inhibitory control over growth factor function. IGF-II levels were shown to positively correlate with dihydrotestosterone (DHT) levels in human BPH tissue,88 suggesting the possibility that IGF-II is a mediator of androgen-dependent stromal-epithelial interaction. Increases in circulating levels of IGF-I have been shown to be associated with prostate cancer but were not seen in BPH.89 The EGF family in humans now contains six members known to activate the canonical EGF receptor (ErbB-1): EGF, transforming growth factor α (TGFα), amphiregulin, heparin-binding EGF-like growth factor (HB-EGF), betacellulin, and epiregulin. Additional EGF-like factors bind and activate three additional EGF-receptor (EGFR)-related tyrosine kinases (ErbB-2/Neu, ErbB-3, and ErbB-4). The soluble receptor ligands which do not activate the EGF-R by direct ligand binding are known collectively as the neu differentiation factors (NDFs) or heregulins,90 which bind to ErbB-3 and ErbB-4, but not ErbB-2 and ErbB-1/EGF-R. Cross-talk between the ErbB receptor isoforms occurs in a variety of cells and results in context-dependent signaling, initiated by the clustering of downstream activating molecules at the cytoplasmic side of the activated receptor complex.91 Because of the physiologic importance of the EGFR, and the well-known capability of the ErbB family of molecules to be involved in control of growth regulation, EGF-like factors and their cognate receptors are good candidates for mediators of stromalepithelial interaction in urogenital tissues. At this writing, any or all of the above factors might potentially be involved in growth regulation in the prostate. EGF-like activities have been detected in the intact prostate and in prostatic secretions.92 EGF is likely to be the predominant growth factor in this family in the prostatic fluid, based on direct, quantitative measurement and comparison of EGF levels (which are high) with TGFα levels (which are comparatively low).93 EGF localized specifically in the periurethral region of the prostate has been linked recently to BPH and may be under regulation by androgen.94 TGFα has been detected in the human prostate by immunologic and molecular techniques95–97 and is probably primarily an epithelial cell product, although expression in the stroma has also been reported.98 The ErbB-2/c-Neu and ErbB-3 proteins have also been identified in human benign hyperplastic and carcinomatous prostatic tissue and altered expression of these molecules in tissues may provide some prognostic information, suggesting a functional role in prostatic disease.99,100 Recent evidence suggests signaling downstream from ErbB-2/c-Neu activation intersects and ‘superactivates’ the androgen response pathway in prostatic cells.101 In some cells, survival signals activated by EGF are transmitted into the cell by ErbB-3 via ErbB-1/ErbB-3 receptor dimerization. This mechanism of cell survival regulation by ErbB-1/ErbB-3 dimerization has recently been shown in LNCaP prostate carcinoma cells.102 ErbB receptors can also be ‘transactivated’ by signaling molecules known to regulate smooth muscle cell growth. Recently, the pressor peptide angiotensin II has been shown to be capable of transactivating ErbB1 and ErbB2 receptors in human prostate stromal cells.103 Another EGF receptor ligand, heparin-binding EGFlike growth factor (HB-EGF), was recently identified as a product predominantly of interstitial and vascular smooth muscle cells in the human prostate104 (Fig. 4.1). HB-EGF binds and activates the EGF receptor with a potency similar to EGF and TGFα, however this growth factor is also a more effective smooth muscle mitogen than either EGF or TGFα, suggesting a potentially specialized role in the muscle compartment. Adam et al.105 identified the EGF receptor ligand, amphiregulin, as a second smooth-muscle-derived growth factor in the human prostate, whose expression appears to be coordinately regulated with HB-EGF in a manner that is distinct from other ErbB receptor ligands. Amphiregulin and HB-EGF share a similar domain structure and a nearly identical affinity for heparin and heparin sulfate proteoglycans. Amphiregulin and HB-EGF are coordinately expressed in the human prostate and are probably coordinately regulated.104 The EGF receptor is localized exclusively to the (normal and malignant) epithelial cell compartments in the prostate,98,105 suggesting that the HB-EGF and amphiregulin-EGF receptor interaction is a directional signaling mechanism linking the prostatic smooth-muscle compartment with the epithelium. Hayward et al. have proposed, on the basis of microscopic observations of prostatic tissue and on analogies to other organs, such as the uterus, that the most important stromal-epithelial interaction under normal circumstances in the prostate is a smooth-muscle cell-epithelial interaction.106 These findings suggest that directional signaling between prostatic smooth muscle and epithelium may involve specialized members of the EGF family. Potentially important components of the prostatic stroma which have not been studied extensively are inflammatory cell infiltrates, including lymphocytes and monocyte-derived macrophages. Extensive infiltration of human BPH tissues by chronically activated T cells has been reported to be common.107 The absence of granulocytes in these infiltrates suggests that mononuclear cell accumulation in the prostate is unlikely to be the result of

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Figure 4.1 Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized primarily in the interstitial and vascular smooth muscle cells of the adult human prostate (a), while the cognate receptor, the ErbB1/EGF receptor tyrosine kinase, is expressed exclusively by prostatic basal epithelial cells and some carcinoma cells (b). The synthesis of HB-EGF in the stromal compartment, with localization of the cognate receptor to the epithelial compartment, strongly suggests that this growth factor is involved in a directional signaling mechanism between the smooth muscle cells and ductal epithelial cells. For more information see references 104 and 105. infection (reaction to foreign antigens). Peripheral blood T cells, in the absence of a requirement for a Tcell-receptor-mediated stimulus, have recently been shown to produce and secrete three heparin-binding growth factors: HB-EGF and FGF-2,108 as well as vascular endothelial growth factor (VEGF), a potent angiogenic factor and endothelial cell mitogen.109 All of these factors could exert potent mitogenic effects on endothelial cells and promote the formation of neovascular networks. VEGF synthesis was also recently identified as a product of T cells infiltrating human prostate and bladder cancers.109 Human tumor-derived lymphocytes were shown to produce bioactive HB-EGF and FGF-2 capable of stimulating the growth of breast and ovarian tumor cells as well as smooth-muscle cells and fibroblasts.110 These results suggest that T cells have the capability to secrete potent epithelial, vascular, and stromal mitogens into the interstitial tissues in a fashion that is not dependent on active immunoregulatory (Tcell-receptor-dependent) signals. Within the context of BPH, this could mean that T-cell infiltrates, not functioning as part of a sustained immunologic reaction but present in significant numbers, might contribute directly to stromal as well as glandular hyperplasia. In this context, it is intriguing to note that marked differences in acute and chronic inflammation exist between the prostate gland and the seminal vesicles; the latter seldom undergo neoplastic transformation, as opposed to the former, where frequent benign and malignant growth is observed. The role of the extracellular matrix The potential role of the extracellular matrix (ECM) in the promotion of neoplastic growth in vivo has been demonstrated in model systems in which isolated matrix, such as the basement membrane-like matrix from the EHS sarcoma, promotes growth of tumor cells, including human prostatic carcinoma cells, into athymic hosts.111–113 These studies may be analogous to the previously mentioned experiments in which carcinomatous growth can be promoted by co-inoculating epithelial tumor cells with heterotypic or homotypic fibroblasts, a source of extracellular matrix (ECM). In prostate-tumor models, stroma or ECM has been found to have promotional29–31,33 or suppressive36,37 effects on the malignant phenotype of carcinoma cells, indicating the dramatic potential for the connective tissue environment to direct or alter the natural course of epithelial tumors. Freeman et al.114 demonstrated that long-term cell contact with basement-membrane ECM increased cell motility and invasive properties, and resulted in stably altered patterns of gene expression in a poorly differentiated prostatic tumor line. These data suggest that cell association with specific matrices has the potential to induce hyperplastic, and even malignant, growth of epithelial cells in vivo. What is occurring at the molecular level that can explain how seemingly simple contextual cues can dramatically regulate cell growth and malignant phenotype? The ECM is capable of sequestering soluble regulatory

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Page 77 molecules such as growth factors, and releasing them during degradative or inflammatory conditions, where they become available to cognate cell-surface receptors. Heparin-binding growth factors, such as FGF-2, can accumulate at significant levels in ECM, particularly in basement membranes.115 Some matrix components, such as heparin sulfate proteoglycans (HSPGs), appear to be specialized to bind and store heparin-binding growth factors in extracellular sites.116 Certain membrane-bound HSPGs also appear to be required on cell surfaces for the presentation of bound growth factors to receptors, thereby acting as co-receptors for cell activation by growth factors.117,118 This may be a general mechanism for cell activation by growth factors with a high affinity for heparin, where intimate, specialized contacts between growth factor ligand, cell-surface receptor, and HSPGs activate the receptor. Heparin-binding growth factor interaction with HSPGs is also likely to be highly specific, with some interactions resulting in significant biological responses in target cells, while others do not The isoform of the cell surface CD44 proteoglycan (the hyaluronic acid receptor) containing the so-called V3 region is modified with heparin sulfate and binds two heparin-binding growth factors, FGF-2 and HB-EGF, but does not bind the heparinbinding growth factor amphiregulin.119 This is an interesting and unexpected observation because amphiregulin and HB-EGF have nearly identical affinity for heparin, as determined by heparin affinity chromatography. Heparinlike molecules are likely to be co-receptors for EGF receptor activation by amphiregulin and HB-EGF, as is the case for other heparin-binding growth factors. The CD44 family of proteoglycans has been implicated in regulation of inflammation and malignant progression. The V3-containing CD44 isoform is expressed on keratinocytes, monocytes, and dendritic cells in inflamed skin tissue. When depleted of heparin sulfate, the V3 region failed to promote downstream receptor tyrosine kinase c-Met phosphorylation upon interaction with its heparin-binding ligand, HGF/SF120 These observations indicate that heparin-sulfate-containing proteoglycans are likely to be highly specialized for presentation of particular growth factor subsets to high-affinity cell-surface receptors. This mechanism of growth factor regulation likely occurs in a context-dependent or tissuespecific manner. The observations discussed above indicate that HSPG components of the ECM are critical regulators of cellular interaction, in that they coordinate growth factor localization and presentation to cell-surface receptors. Interestingly, in epithelial-mesenchymal culture models of cell differentiation, formation of HSPGs at the basement membrane interface has been found to be dependent on the presence of both epithelial and stromal cells.121 Formation of HSPG-containing matrices can be controlled directly by heterologous matrix-cell interactions.122 These observations suggest the importance of heterotypic cellcell interactions in the establishment of connective tissue networks that regulate tissue differentiation and function. Remodeling of the ECM during tumorigenesis or inflammation may alter the normal homeostasis of these growth factor-ECM interactions, resulting in the alteration of the proliferative state of cells. Matrix remodeling occurs by release of matrix-degrading enzymes, such as serine/threonine proteases, cysteine proteases, and metalloproteinases from parenchymal, interstitial, and inflammatory cells. Alteration of the normal balance between matrix synthesis and degradation occurs in response to proliferative signals and may be mediated by matrixassociated growth factors such as TGFβ1, which control synthesis of ECM components as well as specific ECM degradative mechanisms involving proteases and protease inhibitors.123 Matrix has also been proposed to be a storage site for growth factors involved in the sustained elevation of local proteolysis.124 Metastatic tumor cells appear to stimulate their own growth and movement through matrix by releasing HSPG-degrading enzymes (heparinases), an activity which also presumably releases pleiotropic HSPG-resident growth factors, such as FGF-2.125 Are growth factors likely to be the major growth-promoting elements of the ECM? The matrix was once considered to be an inert scaffold of insoluble material serving to anchor cells to each other and to connective tissues. It is now clear, however, that the ECM is a dynamic structure linking a complex network of extracellular signals to cytoplasmic and nuclear locations within cells, mediated in part by ECM receptors, the heterodimeric α and β integrin isotype families. The large ECM proteins such as collagens I, III, and IV, fibronectin, and laminin consist of arrays of distinct multidomain structures with diverse functions. These molecules bind specifically to each other, either directly or by mutual interaction with other glycoproteins and glycosaminoglycans. The complexity of the ECM in most tissues is formidable. As an example, the abundant interstitial collagens I and III represent only two out of a family of structurally related molecules with at least 19 members.126 Cells make contact with specific matrices using cellsurface receptors known as integrins.127 Integrins belong file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_77.html[09.07.2009 11:51:54]

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Page 78 to a large family of multifunctional, heterodimeric transmembrane proteins that bind specific matrix sites on their extracellular face and components of the cytoskeleton in the cell interior. Extracellular ligands which bind integrins include ECM glycoproteins, cellular adhesion molecules, thrombolytic proteins, and components of the complement cascade. Integrins provide a functional link between the outside and the inside of the cell by serving as mechanical connectors between the ramifying ECM scaffolds and their associated molecules, the intracellular cytoskeletal systems, and the cell nucleus. Regulatory signals are transmitted to the cell interior through this network.128 Cytoplasmic proteins involved in intracellular cell signaling events are recruited to protein complexes containing integrins following integrin binding to extracellular ligands. Subsequent to binding ligand, integrins typically cluster on the cell surface, resulting in amplification and transmission of mechanochemical information to the cell interior. Extracellular signals can alter a variety of cellular activities, such as growth, migration, invasion, and differentation, through ligand-receptor interactions with specific integrins.129,130 The complexity of these signals is made plain by the fact that most integrins can be demonstrated by biochemical techniques to specifically bind multiple ligands, in some cases as many as seven or more. Therefore, integrins appear to be unusually permissive regulatory proteins with respect to ligand binding and activation resulting from protein-protein interaction. A variety of integrins bind the large ECM glycoproteins, such as fibronectin (bound by αvβ1, α3β1, and α4β1 integrins) and laminin (bound by α1β1, α2β1, α3β1, α6β1, α7β1, and α6β4 integrins). Signal transduction through ECM receptors, resulting in changes in cellular physiology reminiscent of signals through membrane-bound growth factor receptors, has been demonstrated for a number of specific integrins.130–132. Integrins are thus capable of ‘out-side-in’ signaling in addition to their role as structural connecting sites. Non-integrin matrix receptors capable of cell regulation have also been identified.133 Because many of the ligands for the more than 30 known integrins have been identified, and many are in fact matrix molecules rather than growth factors or cytokines, it is clear that important cellular events are mediated directly by cell contact with matrix. This would include cell adhesion molecules connected to the matrix and soluble molecules sequestered within the matrix. It is also clear that cellular interactions with purified matrices can transmit signals to the cell nucleus and regulate the expression of specific genes.130,134,135 Alterations of integrin expression on the surface of tumor cells have been shown to result in some of the abnormal cell behavior associated with malignant transformation. Therefore, the ECM itself is an important regulator of cellular physiology and the notion that connective tissue and basement membrane elements are mere support structures is definitively not valid. Basement membrane matrices are particularly potent at eliciting dramatic behavioral changes within cells, at least in cell culture.136 Morphogenesis and differentiation of isolated lactogenic mammary epithelial cells into secretory acini occur in culture on basement-membrane gels.135,137 These multicellular structures resemble milk-producing acini in vivo. There is now extensive evidence that this differentiation event is mediated in large part by cell interaction with basement-membrane ECM. How does the ECM control cell growth? The mechanisms appear to be diverse and complex. For over 20 years it has been known that transformed, growth-factor-independent cells frequently lose the ability to contact components of the ECM,138 suggesting that adhesive interactions with extracellular sites may be required for normal growth control. This possibility has been confirmed with the identification of adhesion-dependent intracellular regulators of cell cycle progression.139,140 Growth control by the ECM can be negative or positive. Consistent with observations showing a loss of cell-surface ECM, particularly fibronectin, correlating with an increase in malignant properties, overexpression of the fibronectin receptor, α5β1 integrin, can suppress the tumorigenic phenotype and partly suppress growth of cells in culture.141 A dramatic and potentially clinically significant example of negative growth regulation by integrins is the finding that synthetic or immunologic antagonists to the αvβ3 integrin, expressed on microvascular endothelial cells undergoing angiogenesis, induce endothelial cell apoptosis and resultant loss of blood vessels.142 This regression of the microvasculature can culminate in tumor regression. Positive growth regulation by integrins appears to involve temporal coordination between integrin signaling mechanisms and growth factor receptor interactions. An in-vitro system in which this interplay between ECM and growth factors has been studied in some detail is the formation of capillary tubes from pure endothelial cell cultures, a process which may mimic angiogenesis in vivo. This complex morphogenetic process, which involves intricate cell movements and interactions as well as differentiative change, is dependent on both soluble as well as insoluble extracellular signals.143 Tumor growth is dependent on angiogenesis and remodeling of the microvasculature is a common feature of growing solid

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Page 79 tumors. Evidence for microvascular remodeling in human BPH has been reported.46 Growth-factor-mediated signaling systems regulating cell proliferation can be dependent on appropriate matrix-dependent cues from the extracellular environment. In mammary epithelial cells, the TGFβ1 gene, in contrast to the gene for the related isoform TGFβ2, responds to cell contact with basement membrane ECM by downregulation.135 This suggests that growth factor synthesis by cells is dependent on, and controlled by, cell-ECM contact. These findings also imply that disruption of the basement membrane ECM as a consequence of malignant growth may result in the upregulation of TGFβ1, a potent pleiotropic factor capable of stromal remodeling, immunosuppression, and stimulation of angiogenesis. As described above, TGFβ isoforms have been implicated by several laboratories in human prostatic disease.54–59 Because TGFβ regulates the connective tissue environment, aberrant stromal localization of TGFβ1 in experimental and human prostate carcinoma suggests that this growth factor may remodel the prostatic stroma during neoplastic growth. A generalizable mechanism for cell regulation by growth factors and ECM, which probably applies to growth control as well as cell differentiation, is that chemomechanical signals provided by the ECM act in concert with soluble signaling molecules to regulate cell physiology and behavior. That is, ECM and growth factors may each be obligatory components of many regulatory pathways and act cooperatively to initiate, maintain, and redirect regulated cellular responses to extracellular cues. Purified matrices, proteolytic fragments of matrix molecules, and synthetic peptides corresponding to discrete domains of matrix molecules can initiate a variety of cellular responses in model systems in cell culture.144–147 These effects have been shown to be highly dependent on the molecular structure of individual matrix molecules and therefore the result of highly specific cell-matrix interactions. Culture of human-breast-carcinoma cells in collagen I gels results in activation of the latent form of matrix metalloproteinase 2 (MMP-2), a matrix-degrading enzyme whose expression pattern in human mammary tumors correlates well with prognosis and tumor grade.147 This appears to be a specific property of intact polymeric collagen I and not of laminin, fibronectin, collagen IV, or gelatin. This observation suggests an important role for interstitial collagen, frequently considered to be primarily a support structure in tissues, in the growth of solid tumors. Signals transmitted to cells through matrix are frequently found to be dependent on mechanical information presented to the cell by the threedimensional matrix structure.148 Roles for specific cell-ECM interactions in human BPH remain speculative at present. A variety of specific integrins have been identified in human prostatic tissue.149–152 Some of these molecules, such as the hemidesmosome-associated α6β4 integrin, which is localized to prostatic basal epithelia, are likely to perform similar matrix-adhesion functions in the prostate as in other organs. The α6β1 and α2β1 integrins, localized to acinar basement membranes in normal and hyperplastic prostatic tissue, appear to be localized in distinct patterns and expressed abnormally in organ-confined and metastatic carcinoma. In order to understand these and other descriptive observations, the downstream effectors of integrin signaling in the prostate will have to be identified. Integrins may be important inhibitors of cell proliferation through their ability to regulate the cell cycle machinery. The p27 (Kip1) cell cycle inhibitor has been shown to be a downstream effector of the β1C integrin in prostate carcinoma cells.152 Dramatic downregulation of p27(Kip1) in both the stromal and epithelial compartments was reported in BPH and human prostate cancer tissues,153,154 and p27 (Kip1) null mice developed hyperplastic prostates.154 These observations suggest the potential for large-scale alterations in cell-growth regulation via integrin-mediated signaling systems. Given the general dependence of prostatic growth on circulating androgens, a fertile area of investigation is the potential for synthesis and deposition of stroma-derived matrices to be regulated by dihydrotestosterone, the primary prostatic androgen. Tenascin, a mesenchymederived matrix glycoprotein, has been shown to appear in prostatic stroma in response to androgen deprivation.155 This hormonal-dependent expression of tenascin in the prostate may be associated with a low degree of epithelial differentiation. In human prostates, tenascin was detected in normal and hyperplastic tissue and prostatic carcinoma.156,157 Studies with the androgen-responsive human prostate cell line LNCaP indicate that effects of androgens on differentiated properties of prostatic cells can be mediated in part by cell-ECM contact in concert with soluble stromal-derived factors.158 Tumorigenic growth of LNCaP cells in vitro is enhanced by ECM and FGF-2.33,34 It is likely that differentiated functions of the adult prostate are dependent on regulatory networks maintained by epithelial-mesenchymal interactions using solid-state and soluble mediators. Although the best evidence for this hypothesis derives from studies of mammary epithelia in culture, limited numbers of co-culture

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Page 80 systems employing urogenital cells, especially testicular Sertoli cells and mesenchymal peritubular cells,159 support this view. Future directions The current experimental evidence suggests an important role for stromal-derived paracrine factors in prostatic development, maintenance of prostatic function, and benign and malignant prostatic growth. At present, however, we still have a limited understanding of the precise mechanistic nature of age-related benign prostatic growth. Experimental models suggest that soluble molecules produced by stromal cells, in concert with ECMassociated cell-signaling mechanisms (which may include mechanochemical signaling as well as biochemical mediation), may play a role. We are at a stage, however, where we are still identifying likely candidate BPH mediators, based on experiments using prostatic cells and tissues, experiments in other organ systems, and models involving specific molecules but which do not necessarily possess definable physiologic correlates or contexts. Hypotheses involving these candidate molecules have to be developed and experiments to test these hypotheses designed. We believe, however, that further studies designed to identify new soluble as well as insoluble stromal cell products will complement existing studies and provide additional insights. Alternatively, understanding the converging downstream signaling pathways in response to steroid hormones, peptide growth factors, and ECMs could also prompt the development of novel approaches to modulate prostate growth under pathophysiologic conditions.102 The ability to deliver transgenes specifically into the prostate, allowing the targeting of discrete prostatic compartments in rodents, is now possible.59,61,160,161 These technologies should enhance the power of traditional rodent experimental models. New methods of scanning the expressed genome for proteins synthesized differentially among normal and pathologic tissues, and which allow rapid cloning of their respective genes, will markedly increase the pace of discovery. The identification of prostatic genes regulated by androgens is already benefiting from these new technologies.162 The relative contribution of cell survival signals vs proliferative signals needs to be established,102 particularly since new evidence suggests that control of apoptosis, rather than increases in rates of cell division, may be critically important in the tissue expansion seen in BPH.163 The potential for molecular and cellular biologic intervention to affect human health problems has never been greater than it is today. It will be the obligation of the basic scientist and the clinician, working together, to apply this new technology in creative ways to discover the fundamental mechanisms, and devise simple and effective treatments, for BPH and other urologic diseases. References 1. Albarran J, Halle N. Hypertrophie et neoplasies epitheliades de la prostate. Ann Mal Org Genito-Urin (Paris) 1900; 17:113 2. Reischauer F. Die Entstehung der sogenannten Prostatahypertrophie. Virchows Arch [B] 1925; 256: 357–389 3. Deering R E, Bigler S A, King J et al. Morphometric quantitation of stroma in human benign prostatic hyperplasia. Urology 1994; 44:64–70 4. Chung L W K, Cunha G R. Stromal-epithelial interactions. II Regulation of prostatic growth by embryonic urogenital sinus mesenchyme. Prostate 1983; 4:503–511 5. Chung L W K, Matsura J, Runner M N. Tissue interaction and prostatic growth. I. Induction of adult mouse prostatic hyperplasia by renal urogenital sinus implants. Biol Reprod 1984; 31:155–163 6. Neubauer B L, Chung L W K, McCormick K A et al. Epithelial-mesenchymal interactions in prostatic development. II. Biochemical observations of prostatic induction by urogenital sinus mesenchyme in epithelium of the adult rodent urinary bladder. J Cell Biol 1983; 96:1671–1676 7. Cunha G R, Sekkingstad M, Meloy B A. Heterospecific induction of prostatic development in tissue recombinants prepared with mouse, rat, rabbit and human tissues. Differentiation 1983; 24:174–180 8. Cunha G R, Young P, Hamamoto S et al. Developmental response of adult mammary epithelial cells to various fetal and neonatal mesenchymes. Epithelial Cell Biol 1992; 1: 105–118 9. Donjacour A A, Cunha G R. Assessment of prostatic protein secretion in tissue recombinants made of urogenital sinus mesenchyme and urothelium from normal or andro gen-insensitive mice. Endocrinology 1993; 132:2342–2350 10. Hayashi N, Cunha G R, Parker M. Permissive and instructive induction of adult rodent prostatic epithelium by heterotypic urogenital sinus mesenchyme. Epithelial Cell Biol 1993; 2:66–78 11. Cunha G R. Role of mesenchymal-epithelial interactions in normal and abnormal development of the mammary gland and prostate. Cancer 1994; 74:1030–1044 12. Howlett A R, Bissell M J. The influence of tissue microenvironment (stroma and extracellular matrix) on the development and function of mammary epithelium. 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Page 81 13. Higgins S J, Young P, Brody J R, Cunha G R. Induction of functional cytodifferentiation in the epithelium of tissue recombinants. I. Homotypic seminal vesicle recombinants. Development 1989; 106:219–234 14. Norman J T, Cunha G R, Sugimura Y. The induction of new ductal growth in adult prostatic epithelium in response to an embryonic prostatic inductor. Prostate 1986; 8:209–220 15. Zhau H-Y E, Hong S J, Chung L W K. A fetal urogenital sinus mesenchymal cell line (rUGM): accelerated growth and conferral of androgen-induced growth responsiveness upon a human bladder cancer epithelial cell line in vivo. Int J Cancer 1994; 56:706–714 16. McNeal J E. Origin and evolution of benign prostatic enlargement. Investigative Urology 1978; 15:340–345 17. Wu C P, Gu F L. The prostate in eunochs. In EORTC Genitourinary Group Monograph 10—Urologic oncology: reconstructive surgery, organ preservation, and restoration of function. New York: Wiley-Liss Inc, 1992:249–255 18. Cunha G R, Donjacour A, Cooke P S et al. The endocrinology and developmental biology of the prostate. Endocrine Rev 1987; 8:338–362 19. Lee C. Physiology of castration-induced regression in rat prostate. In: Karr J P, Sandberg A A, Murphy G P. (eds). The prostate cell: structure and function, Part A. New York: Alan R. Liss 1981 20. Schleicher G, Stumpf W E, Drews U et al. (1985) Differential distribution of 3H dihydrotestosterone and 3H estradiol nuclear binding sites in mouse male accessory sex organs: an autoradiographic study. Histochemistry 1985; 82:453–461 21. Takeda H, Mizuno T, Lasnitzki I. Autoradiographic studies of androgen-binding sites in the rat urogenital sinus and postnatal prostate. J Endocrinology 1985; 104:87–92 22. Shannon J M, Cunha G R. Autoradiographic localization of androgen binding in the developing mouse prostate. Prostate 1983; 4:367–373 23. Cunha G R, Chung L W K. Stromal-epithelial interactions. I. Induction of prostatic phenotype in urothelium of testicular feminized (Tfm/y) mice. J Steroid Biochem 1981; 14:1317–1321 24. Thompson T C, Cunha G R, Shannon J M, Chung L W K. Androgen-induced biochemical responses in epithelium lacking androgen receptors: characterization of androgen receptors in the mesenchymal derivative of the urogenital sinus. J Steroid Biochem 1986; 25:627–634 25. Sugimura Y, Cunha G R, Bigsby R M. Androgenic induction of DNA synthesis in prostatic glands induced in the urothelium of testicular feminized (Tfm/y) mice. Prostate 1986; 9:217–225 26. Drews U, Drews U. Regression of mouse mammary gland anlagen in recombinations of Tfm and wild-type tissues: testosterone acts via the mesenchyme. Cell 1977; 10: 401–404 27. Kratochwil K, Schwartz P. Tissue interaction in androgen response of embryonic mammary rudiment of mouse: identification of target for testosterone. Proc Natl Acad Sci USA 1976; 73:4041–4044 28. Hayward S W, Haughney P C, Rosen M A et al. Interactions between adult human prostatic epithelium and rat urogenital sinus mesenchyme in a tissue recombination model. Differentiation 1998; 63:131–140 29. Chung L W K, Chang S M, Bell C et al. Co-inoculation of tumorigenic rat prostate mesenchymal cells with nontumorigenic epithelial cells results in the development of carcinosarcoma in syngeneic and athymic animals. Int J Cancer 1989; 43:1179–1187 30. Camps J L, Chang S M, Hsu T C et al. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci USA 1990; 87:75–79 31. Chung L W K. Fibroblasts are critical determinants in prostate cancer growth and dissemination. Cancer Metastasis Rev 1991; 263–274 32. Gleave M E, Hsieh J T, Gao C A, von Eschenbach A C, Chung L W K. Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res 1991; 51:3753 33. Gleave M E, Hsieh J T, von Eschenbach A C, Chung L W K. Prostate and bone fibroblasts induce human prostate cancer growth in vivo: implications for bidirectional tumor-stromal cell interaction in prostatic carcinoma growth and metastasis. J Urol 1992; 147:1151–1159 34. Chung L W, Li W, Gleave M E et al. Human prostate cancer model: roles of growth factors and extracellular matrices. J Cell Biochem Suppl 1992; 16H: 99–105 35. Stephenson R A, Dinney C P, Gohji K, et al. Metastatic model for human prostate cancer using orthotopic implantation in nude mice. J Natl Cancer Inst 1992; 84: 951 36. Chung, L W K, Zhau H, Ro J. Morphologic and biochemical alterations in rat prostatic tumors induced by fetal urogenital sinus mesenchme. Prostate 1990; 17:165–174 37. Hayashi N, Cunha G R, Wong Y C. Influence of male genital tract mesenchymes on differentiation of file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_81.html[09.07.2009 11:51:56]

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Dunning prostatic adenocarcinoma. Cancer Res 1990; 50:4747 38. Pierce G B, Aguilar D, Hood G, Wells R S. Trophectoderm in control of murine embyronal carcinoma. Cancer Res 1984; 44:3987–3996 39. Fukamachi H, Mizuno T, Kim Y S. Morphogenesis of human colon cancer cells with fetal rat mesenchymes in organ culture. Experientia 1986; 42:312 40. Podesta A H, Mullins J, Pierce G B, Wells R S. The neurula stage mouse embryo in control of neuroblastoma. Proc Nat Acad Sci USA 1984; 81:7608–7611

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Page 82 41. DeCrosse, Gossens C L, Kuzma J F. Breast cancer: induction of differentiation by embryonic tissue. Science 1973; 181:1057 42. Klagsbrun M. The fibroblast growth factor family: structural and biological properties. Prog Growth Factor Res 1990; 1:207–235 43. Story M T, Livingston B, Baeten L et al. Cultured human prostate-derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor. Prostate 1989; 15:355–365 44. Xu X, Weinstein M, Li C, Deng C. Fibroblast growth factor receptors and their roles in limb development. Cell Tissue Res 1999; 296:33–43 45. Steiner M S. Review of peptide growth factors in benign prostatic hyperplasia and urological malignancy J Urol 1995; 153:1085–1096 46. Deering R E, Bigler S A, Brown S A, Brawer M K. Microvascularity in benign prostatic hyperplasia. Prostate 1995; 26:111–115 47. Lepor H. Natural history, assessment of efficacy and nonsurgical treatment of BPH. In: Walsh P C (ed). Campbell’s urology, 7th edn. Philadelphia: WB Saunders, 1998: 1453–1477 48. Glynne-Jones E, Harper M E, Goddard L et al. Transforming growth factor beta 1 expression in benign and malignant prostatic tumors. Prostate 1994; 25: 210–218 49. Bonnet P, Reiter E, Bruyninx M. Benign prostatic hyperplasia and normal prostate aging: differences in types I and II 5-alpha-reductase and steroid hormone receptor messenger ribonucleic acid (mRNA) levels, but not in insulinlike growth factor mRNA levels. J Clin Endocrinol Metab 1993; 77:1203–1208 50. Bonewald L F. Regulation and regulatory activities of transforming growth factor beta. Crit Rev Euk Gene Expr 1999; 9:33–44 51. McKeehan W L, Adams P S. Heparin binding growth factor/prostatropin attenuates inhibition of rat prostate tumor epithelial cell growth by transforming growth factor type beta. In Vitro Cell Dev Biol 1988; 24:243 52. Wright J A, Turley E A, Greenberg A H. Transforming growth factor beta and fibroblast growth factor as promoters of tumor progression to malignancy. Crit Rev Oncogenesis 1993; 4:473–492 53. Mooradian D L, McCarthy J B, Komanduri K V, Furcht L T. Effects of transforming growth factor-beta 1 on human pulmonary adenocarcinoma cell adhesion, motility and invasion in vitro. J Natl Cancer Inst 1992; 84:523–527 54. Story M T, Hopp K A, Meier D A. Influence of transforming growth factor beta 1 and other growth factors on basic fibroblast growth factor level and proliferation of cultured human prostate-derived fibroblasts. Prostate 1993; 22:183–197 55. Lokeshwar B L, Block N L. Isolation of a prostate carcinoma cell proliferation-inhibiting factor from seminal plasma and its similarity to transforming growth factor beta. Cancer Res 1992; 52:5821–5825 56. Timme T L, Yang G, Rogers E et al. Retroviral transduction of transforming growth factor-beta 1 induces pleiotropic benign prostatic growth abnormalities in mouse prostate reconstitutions. Lab Invest 1996; 74: 747–760 57. Truong L D, Kadmon D, McCune B K et al. Association of transforming growth factor-beta 1 with prostate cancer: an immunohistochemical study. Hum Pathol 1993; 24: 4–9 58. Steiner M S, Barrack E R. Transforming growth factorbeta 1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol Endocrinol 1992; 6: 15–25 59. Merz V W, Miller G J, Krebs T et al. Elevated transforming growth factor β1 and β3 mRNA levels are associated with ras+myc-induced carcinoma in reconstituted mouse prostate: evidence for a paracrine role during progression. Mol Endocrinol 1991; 15:503–513 60. Harris S E, Harris M A, Mahy P et al. Expression of bone morphogenetic protein messenger RNAs by normal rat and human prostate and prostate cancer cells. Prostate 1994; 24:204–211 61. Timme T L, Truong L D, Merz V W et al. Mesenchymalepithelial interactions and transforming growth factorbeta expression during mouse prostate morphogenesis. Endocrinology 1994; 134:1039–1045 62. Millan F A, Denhez F, Kondaiah P, Akhurst R J. Embryonic gene expression patterns of TGF beta 1, beta 2 and beta 3 suggest different developmental functions in vivo. Development 1991; 111:131–143 63. Orlandi A, Ropraz P, Gabbiani G. Proliferative activity and alpha-smooth muscle actin expression in cultured rat aortic smooth muscle cells are differently modulated by transforming growth factor beta-1 and heparin. Exp Cell Res 1994; 214:528–536 64. Brogli E, Wu T, Namiki A, Isner J M. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia up-regulates VEGF expression only. Circulation 1994; 90: 649–652 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_82.html[09.07.2009 11:51:56]

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65. Saez C, Gonzalez-Baena A C, Giraldez J et al. Regressive changes in finasteride-treated human hyperplastic prostates correlate with an upregulation of TGF receptor expression. Prostate 1998; 37:84– 90 66. Mydlo J H, Bulbul M A, Richon V M et al. Heparin-binding growth factor isolated from human prostatic extracts. Prostate 1988; 12:343 67. Smith E P, Russell W E, French F S, Wilson E M. A form of basic fibroblast growth factor is secreted into the

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Page 83 adluminal fluid of the rat coagulating gland. Prostate 1989; 14:353 68. Begun F P, Story M T, Hopp K A et al. Regional concentration of basic fibroblast growth factor in normal and benign hyperplastic human prostates. J Urol 1995; 153: 839–843 69. Muthukrihnan L, Warder E, McNeil P. Basic fibroblast growth factor is efficiently released from a cytosolic storage site through plasma membrane disruptions of endothelial cells. J Cell Physiol 1991; 148:1–16 70. Ku P -T, D’Amore P. Regulation of basic fibroblast growth factor (bFGF) gene and protein expression following its release from sublethally injured endothelial cells. J Cell Biochem 1995; 58:328–343 71. De Bellis A, Crescioli C, Grappone C et al. Expression and cellular localization of keratinocyte growth factor and its receptor in human hyperplastic prostate tissue. J Clin Endocrinol Metab 1988; 83:2186– 2191 72. Sugimura Y, Foster B A, Hom Y K et al. Keratinocyte growth factor (KGF) can replace testosterone in the ductal branching morphogenesis of the rat ventral prostate. Int J Dev Biol 1996; 40:941–951 73. Nemeth J A, Zelner D J, Lang S, Lee C. Keratinocyte growth factor in the rat ventral prostate: androgen-independent expression. J Endocrinol 1998; 156:115–125 74. Thomson A A, Foster B A, Cunha G R. Analysis of growth factor and receptor mRNA levels during development of the rat seminal vesicle and prostate. Development 1997; 124:2431–2439 75. Fasciana C, van der Made A C, Faber P W, Trapman J. Androgen regulation of the rat keratinocyte growth factor (KGF/FGF7) promoter. Biochem Biophys Res Comm 1996; 220:858–863 76. Yan G, Fukabori Y, McBride G, Nikolaropolous S, McKeehan W L. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol Cell Biol 1993; 13: 4513–4522 77. Tutrone R F, Ball R A, Ornitz D M et al. Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model. J Urol 1993; 149:633–639 78. Donjacour A A, Thomson A A, Cunha G R. Enlargement of the ampullary gland and seminal vesicle, but not the prostate in int-2/Fgf-3 transgenic mice. Differentiation 1998; 62:227–237 79. Deshmukh N, Scotson J, Dodson A R et al. Differential expression of acidic and basic fibroblast growth factors in benign and prostatic hyperplasia identified by immunohistochemistry. B J U 1997; 80:869–874 80. Geller J, Sionit L R, Baird A et al. In vivo and in vitro effects of androgen on fibroblast growth factor2 concen trations in the human prostate, Prostate 1994; 25: 206–209 81. Pisters L L, Troncoso P, Zhau H E et al. C-Met protooncogene expression in benign and malignant human prostate tissues. J Urol 1995; 154:293–298 82. Humphrey P A, Zhu X, Zarnegar R et al. Hepatocyte growth factor and its receptor (c-met) in prostate carcinoma. Am J Pathol 1995; 147:386–396 83. Montesano R, Soriano J V, Malinda K M et al. Differential effects of hepatocyte growth factor isoforms and epithelial and endothelial tubulogenesis. Cell Growth Diff 1998; 9: 355–365 84. Fan S, Wang J-A, Yuan R-Q et al. Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents. Oncogene 1998; 17:131–134 85. Vlahos C J, Kriauciunas T D, Gleason P E et al. Plateletderived growth factor induces proliferation of hyperplastic human prostatic stromal cells. J Cell Biochem 1993; 52: 404–413 86. Cohen P, Peehl D M, Baker B et al. Insulin-like growth factor axis abnormalities in prostatic stromal cells from patients with benign prostatic hyperplasia. J Clin Endocrinol Metab 1994; 79:1410–1415 87. Dong G, Rajah R, Vu T et al. Decreased expression of Wilms’ tumor gene WT-1 and elevated expression of insulin growth factor-II (IGF-II) and type 1 IGF receptor genes in prostatic stromal cells from patients with benign prostatic hyperplasia. J Clin Endocrinol Metab 1997; 82: 2198–2203 88. Monti S, Di Silverio F, Lanzara S et al. Insulin-like growth factor-I and -II in human benign prostatic hyperplasia: relationship with binding proteins 2 and 3 and androgens. Steroids 1998; 63:362–366 89. Mantzoros C S, Tzonou A, Signorello L B et al. Insulinlike growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer 1998; 76: 1115–1118 90. Tzahar E, Levkowitz G, Karunagaran D et al. ErbB-3 and ErbB-4 function as the low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. J Biol Chem 1994; 269:25226–25233 91. Karunagaran D, Tzahar E, Liu N et al. Neu differentiation factor inhibits EGF binding. A model for trans-regulation within the ErbB family of receptor tyrosine kinases. J Biol Chem 1995; 270:9982–9990 92. Gregory H, Willshire I R, Kavanagh J P et al. Urogastroneepidermal growth factor concentrations in prostatic fluid of normal individuals and patients with benign prostatic hypertrophy. Clin Sci 1986; file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_83.html[09.07.2009 11:51:57]

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70:359 93. Gann P H, Chatterton R, Vogelsong K et al. Epidermal growth factor-related peptides in human prostatic fluid: sources of variability in assay results. Prostate 1997; 32: 234–240

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Page 84 94. Di Silverio F, Sciarra A, Monti S et al. Can the intraprostatic concentration of epidermal growth factor influence the variance of serum prostate specific antigen levels in patients with benign prostatic hyperplasia? J Urol 1999; 161:128–132 95. Ching K Z, Ramsey E, Pettigrew N et al. Expression of mRNA for epidermal growth factor, transforming growth factor-alpha and their receptor in human prostate tissues and cell lines. Mol Cell Biochem 1993; 126:151–158 96. Yang Y, Chisholm G D, Habib F K. Epidermal growth factor and transforming growth factor alpha concentrations in BPH and cancer of the prostate: their relationships with tissue androgen levels. Br J Cancer 1993; 67:152–155 97. Robertson C N, Robertson K M, Hrzberg A J et al. Differential immunoreactivity of transforming growth factor alpha in benign, dysplastic and malignant prostatic tissues. Surg Oncol 1994; 3:237–242 98. Leav I, McNeal J E, Ziar J, Alroy J. The localization of transforming growth factor alpha and epidermal growth factor receptor in stromal and epithelial compartments of developing human prostate and hyperplastic, dysplastic and carcinomatous lesions. Hum Pathol 1998; 29: 668–675 99. Zhau H-Y E, Wan D S, Zhou J et al. Expression of cerbB2/neu proto-oncogene in human prostatic cancer tissues and cell lines. Mol Carcinogenesis 1992; 5:320–327 100. Giri D K, Wadhwa S N, Upadhaya S N, Talwar G P. Expression of NEU/HER-2 oncoprotein (p185neu) in prostate tumors: an immunohistochemical study. Prostate 1993; 23:329–336 101. Yeh S, Lin H K, Kang H Y et al. From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci USA 1999; 96:5458–5463 102. Lin J, Adam R M, Santiestevan E, Freeman MR. The phosphatidylinositol 3′-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. Cancer Res 1999; 59: 2891–2897 103. Lin J, Freeman M R. Transactivation of ErbB1 and ErbB2 receptors by angiotensin II in normal human prostate stromal cells. Prostate 2003; 54:1–7 104. Freeman M R, Paul S, Kaefer M et al. Heparin-binding EGF-like growth factor in the human prostate: synthesis predominantly by interstitial and vascular smooth muscle cells and action as a carcinoma cell mitogen. J Cell Biochem 1998; 68:328–338 105. Adam R M, Borer J G, Williams B J et al. Amphiregulin is coordinately expressed with heparinbinding EGF-like growth factor in the interstitial smooth muscle of the human prostate. Endocrinology 1999; 140:5866–5875 106. Hayward S W, Cunha G R, Dahiya R. Normal development and carcinogenesis of the prostate: A unifying hypothesis. Ann NY Acad Sci 1996; 784:50–62 107. Theyer G, Kramer G, Assman I et al. Phenotypic characterization of infiltrating leukocytes in benign prostatic hyperplasia. Lab Invest 1992; 66:96–107 108. Blotnick S, Peoples G E, Freeman M R et al. T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: Differential production and release by CD4+ and CD8+ T cells. Proc Natl Acad Sci USA 1994; 91:2890–2894 109. Freeman M R, Schneck F X, Gagnon M et al. Peripheral blood T lymphocytes and T cells infiltrating human cancers express vascular endothelial growth factor: A potential role for T cells in angiogenesis. Cancer Res 1995; 55: 4140–4145 110. Peoples G E, Blotnick S, Takahashi K et al. T lymphocytes that infiltrate tumors and atherosclerotic plaques produce HB-EGF and bFGF: A pathologic role. Proc Natl Acad Sci USA 1995; 92:6547–6551 111. Passanti A, Isaacs J T, Haney J A et al. Stimulation of human prostatic carcinoma tumor growth in athymic mice and control of migration in culture by extracellular matrix. Int J Cancer 1992; 51:318–324 112. Fridman R, Kibbey M C, Royce L S et al. Enhanced tumor growth of both primary and established human and murine tumor cells in athymic mice after coinjection with Matrigel. J Natl Cancer Inst 1991; 83:769–774 113. Pretlow T G, Delmoro C M, Dilley G G et al. Transplantation of human prostatic carcinoma into nude mice in Matrigel. Cancer Res 1991; 51:3814–3817 114. Freeman M R, Bagli D J, Lamb C C et al. Culture of a prostatic cell line in basement membrane gels results in an enhancement of malignant properties and constitutive alterations in gene expression. J Cell Physiol 1994; 158: 325–336 115. Folkman J, Klagsbrun M, Sasse J et al. Heparin-binding angiogenic protein-basic fibroblast growth factor—is stored within basement membrane. Am J Pathol 1988; 130:393–400 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_84.html[09.07.2009 11:51:57]

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116. Bernfield M, Sanderson R D. Syndecan, a developmentally regulated cell surface proteoglycan that binds extracellular matrix and growth factors. Phil Trans R Soc London B 1990; 327:171–186 117. Yayon A, Klagsbrun M, Esko J D et al. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 1991; 64:841–848 118. Kan M, Wang F, Xu J et al. An essential heparin-binding domain in the fibroblast growth factor receptor kinase. Science 1993; 259:1918–1921

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Page 85 119. Bennett K L, Jackson D G, Simon J C et al. CD44 isoforms containing exon V3 are responsible for the presentation of heparin-binding growth factor. J Cell Biol 1995; 128: 687–695 120. van der Voort R, Taher T E I, Wielenga V J M et al. Heparan sulfate-modified CD 44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-met. J Biol Chem 1999; 274:6499–6506 121. Vachon P H, Durand J, Beaulieu J F. Basement membrane formation and re-distribution of the beta1 integrins in a human intestinal co-culture system. Anat Rec 1993; 235: 567–576 122. Austria M R, Couchman J R. Enhanced assembly of basement membrane matrix by endodermal cells in response to fibronectin substrata. J Cell Sci 1991; 99:443–451 123. Presta M, Maier JA, Rusnati M et al. Modulation of plasminogen activator activity in human endometrial adeno carcinoma cells by basic fibroblast growth factor and transforming growth factor beta. Cancer Res 1989; 48: 68–74 124. Flaumenhaft R, Moscatelli D, Saksela O, Rifkin DB. Role of extracellular matrix in the action of basic fibroblast growth factor: matrix as a source of growth factor for longterm stimulation of plasminogen activator production and DNA synthesis. J Cell Physiol 1989; 140:75–81 125. Vlodavsky I, Korner G, Ishai-Michaeli R et al. Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. Cancer Met Rev 1990; 9:203–226 126. Olsen B R. Morphogenesis: collagen it takes and bone it makes. Curr Biol 1996; 6:645–647 127. Hynes RO. Integrins: versatility, modulation and signalling in cell adhesion. Cell 1992; 69:11–25 128. Dedhar S. Integrins and signal transduction. Curr Opin Hematol 1999; 6:37–43 129. Sorokin L, Sonnenberg A, Aumailley M et al. Recognition of the laminin E8 cell-binding site by an integrin possessing the α6 subunit is essential for epithelial polarization in developing kidney tubules. J Cell Biol 1990; 111: 1265–1273 130. Werb Z, Tremble P M, Behrendtsen O et al. Signal transduction through the fibronectin receptor induces collagenase and stromolysin gene expression. J Cell Biol 1989; 109:877–889 131. Kornberg L J, Earp H S, Turner C E et al. Signal transduction by integrins: increased protein phosphorylation caused by clustering of β1 integrins. Proc Natl Acad Sci USA 1991; 88:8392–8395 132. Pelletier A J, Bodary S C, Levinson A D. Signal transduction by the platelet integrin αIIbβ3: induction of calcium oscillations required for protein-tyrosine phosphorylation and ligand-induced spreading of stably transfected cells. Mol Biol Cell 1992; 3:989–998 133. Mecham R P, Hinek A, Entwistle R et al. Elastin binds to a multifunctional 67kD peripheral membrane protein. Biochemistry 1989; 28:3716–3722 134. Schmidhauser C, Bissell M J, Myers C A, Casperson G F. Extracellular matrix and hormones transcriptionally regulate bovine β-casein in stably transfected mouse mammary cells. Proc Natl Acad Sci USA 1990; 87:9118–9122 134. Streuli C H, Schmidhauser C, Kobrin M et al. Extracellular matrix regulates expression of the TGFbeta 1 gene. J Cell Biol 1993; 120:253–260 135. Kleinman H K, McGarvey M L, Hassell J R et al. Basement membrane complexes with biological activity. Biochem 1986; 25:312–318 136. Streuli C H, Bailey N, Bissell M J. Control of mammary epithelial differentiation: basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity. J Cell Biol 1991; 115:1383–1395 137. Wagner D, Ivatt R, Destree A, Hynes R. Similarities and differences between fibronectins of normal and transformed hamster cells. J Biol Chem 1981; 256:11708–11715 138. Guadagno T M, Ohtsubo M, Roberts J M, Assoian R K. A link between cyclin A expression and adhesion-dependent cell cycle proliferation. Science 1993; 262:1572–1575 140. Symington B E. Fibronectin receptor modulates cyclindependent kinase activity. J Biol Chem 1993; 267: 25744–25747 141. Giancotti F G, Ruoslahti E. Elevated levels of the α5β1 integrin suppresses the transformed phenotype of Chinese hamster ovary cells. Cell 1990; 60:849–859 142. Brooks P C, Montogomery A M P, Rosenfed M et al. Integrin αVβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994; 79:1157–1164 143. Ingber D E, Folkman J. How does extracellular matrix control capillary morphogenesis? Cell 1989; 58:803–805 144. Turpeenniemi-Hujanen T, Thorgeirsson U P, Rao C N, Liotta L A. Laminin increases the release of type IV collagenase from malignant cells. J Biol Chem 1986; 261: 1883–1889 145. Graf J, Iwamoto Y, Sasaki M et al. Identification of an amino acid sequence in laminin mediating file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_85.html[09.07.2009 11:51:58]

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cell attachment, chemotaxis and receptor binding. Cell 1987; 48: 989–996 146. Sephel G C, Tashiro K-I, Sasaki M et al. Laminin A chain synthetic peptide which supports neurite outgrowth. Biochem Biophys Res Comm 1989; 162:821–829

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Page 86 147. Thompson E W, Yu M, Bueno J et al. Collagen induced MMP-2 activation in human breast cancer. Breast Cancer Res Treat 1994; 31:357–370 148. Hohn H P, Parker C R, Boots L R et al. Modulation of differentiation markers in human choriocarcinoma cells by extracellular matrix: on the role of a three-dimensional matrix structure. Differentiation 1992; 51:61–70 149. Bonkoff H, Stein U, Remberger K. Differential expression of alpha 6 and alpha 2 very late antigen integrins in the normal, hyperplastic and neoplastic prostate: simultaneous demonstration of cell surface receptors and their extracellular ligands. Hum Pathol 1993; 24:243–248 150. Knox J D, Cress A E, Clark V et al. Differential expression of extracellular matrix molecules and the alpha 6-integrins in the normal and neoplastic prostate. Am J Pathol 1994; 145:167–174 151. Nagle R B, Knox J D, Wolf C et al. Adhesion molecules, extracellular matrix, and proteases in prostate carcinoma. J Cell Biochem 1994; 19:232–237 152. Fornaro M, Tallini G, Zheng D Q et al. p27(kit1) acts as a downstream effector of and is coexpressed with the beta 1C integrin in prostatic adenocarcinoma. J Clin Invest 1999; 103:321–329 153. Guo Y, Sklar G N, Borkowski A, Kyprianou N. Loss of the cyclin-dependent kinase inhibitor p27 (Kip1) protein in human prostate cancer correlates with tumor grade. Clin Cancer Res 1997; 3:2269– 2274 154. Cordon-Cardo C, Koff A, Drobnjak M et al. Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J Natl Cancer Inst 1998; 90:1284–1291 155. Vollmer G, Michna H, Ebert K, Knuppen R. Androgen ablation induces tenascin expression in the rat prostate. Prostate 1994; 25:81–90 156. Ibrahim N, Lightner V A, Ventimiglia J B et al. Tenascin expression in prostatic hyperplasia, intraepithelial neoplasia, and carcinoma. Hum Pathol 1993; 24:982–989 157. Xue Y, Li J, Latijnhouwers A et al. Expression of periglandular tenascin-C and basement membrane laminin in normal prostate, benign prostatic hyperplasia and prostate carcinoma. Br J Urol 1998; 81:844–851 158. Fong J, Sherwood R, Braun J et al. Regulation of prostatic carcinoma cell proliferation and secretory activity by extracellular matrix and stromal secretions. Prostate 1992; 21:121–131 159. Verhoeven G, Swinnen K, Cailleau J et al. The role of cellcell interactions in androgen action. J Steroid Biochem Mol Biol 1992; 41:487–494 160. Greenburg N M, DeMayo F, Sheppard P C et al. The rat probasin promoter directs hormonally and developmentally regulated expression of a heterologous gene specifically to the prostate in transgenic mice. Mol Endocrinol 1994; 8:230–239 161. Foster B A, Evangelou A, Gingrich J A et al. Enforced expression of FGF-7 promotes epithelial hyperplasia whereas a dominant negative FGFR2iiib promotes the emergence of a neuroendocrine phenotype in prostate glands of transgenic mice. Differentiation 2002; 70: 624–632 162. Nelson P S, Gan L, Ferguson C et al. Molecular cloning a characterization of prostase, an androgenregulated serine protease with prostate-restricted expression. Proc Natl Acad Sci USA 1999; 96:3114– 3119 163. Kyprianou N, Tu H, Jacobs S C. Doxasosin and terasosin suppresss prostate growth by inducing apoptosis: clinical significance. J Urol 2003; 169:1520–1525

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Page 87 5 Human prostatic adrenoceptors K-E Andersson M G Wyllie Historical perspective The use of α1-adrenoceptor antagonists in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) stemmed from the pioneering studies of Marco Caine. The subsequent extensive use of these agents and the analysis of their overall clinical profile have contributed greatly to our understanding of the autonomic innervation of the prostate. Although the prostate, like most organs, receives a dual adrenergic/cholinergic innervation,1 the adrenergic innervation is of particular interest to the urologist because it is the prime determinant of the periurethral prostate smooth muscle tone. Bladder outlet obstruction in BPH is thought to consist of two components: a static component related to the physical mass of the prostate tissue impinging on the urethra, and a dynamic component related to prostate smooth muscle tone.2 As approximately one-third of the tissue within the prostate is fibromuscular,3,4 a reduction in tone might be expected to reduce prostatic urethral pressure and to improve obstructive symptoms. In this context, in the mid-1970s Caine demonstrated that the contractile response of prostate capsule adenoma (derived from patients undergoing retropubic prostatectomy) was mediated primarily by α-adrenoceptors.5 On the basis of these data and several animal studies, Caine postulated that specific blockade of prostate α1-adrenoceptors would reduce urethral resistance, thereby increasing flow and improving symptoms. Shortly there-after, he reported the first clinical data with the mixed α-antagonist, phenoxybenzamine.6 Although phenoxybenzamine was effective, this study did not demonstrate the predominant role of α1-adrenoceptors because the antagonist also has high affinity for the α2adrenoceptors found in the prostate neuroeffector synapse. However, several studies using moreselective α1-adrenoceptor antagonists, particularly prazosin, doxazosin, and terazosin, have subsequently demonstrated a key role for α1-adrenoceptors in the control of prostate smooth muscle tone. The clinical effectiveness of selective α1-adrenoceptor antagonists rather than mixed or α2-adrenoceptor antagonists has a sound scientific basis. In particular, α1-adrenoceptors are the prime determinants of smooth muscle tone, even though the densities of α1- and α2-adrenoceptors in the prostate are similar.7–10 These and other studies provided the rationale for the development and use of selective α1adrenoceptor antagonists. Although phenoxybenzamine was clinically effective, the incidence and severity of side-effects arising from interactions at sites other than the α1-adrenoceptors (primarily α2adrenoceptors) limited its use. Considerable improvements in tolerability have been made with the advent of the selective α1-adrenoceptor antagonists such as prazosin, terazosin, doxazosin, and tamsulosin, which are now the mainstay of therapy for LUTS/BPH. However, none of these agents was designed specifically to target the prostate, and actions at other sites/tissues, particularly within the vasculature, cause symptoms (such as dizziness and light-headedness) that may become apparent at the higher end of the clinical dose range. In the mid-1980s, understanding of the heterogeneity of α1-adrenoceptors appeared to offer an opportunity to target the prostatic α1-adrenoceptor selectively while minimizing activity at other sites. Heterogeneity of α1-adrenoceptors Over the last few years, considerable evidence for the multiplicity of α1-adrenoceptor subtypes has emerged, and it is only recently that the debate surrounding classification and terminology has been resolved (Fig. 5.1).11–13 The impact of nomenclature must be recognized when interpreting historical data, as conclusions have often been reached on the basis of different classification criteria. It is not surprising, therefore, that in the early 1990s, the characterization and definition of the α1-adrenocep-tor subtype that mediated contraction of human prostate smooth muscle varied according to the group undertaking the study. Major difficulties have arisen because of the difference between adrenoceptors classified in native tissues and those identified using molecular cloning. Current nomenclature now allows for the alignment of cloned and native α1-adrenoceptors (Table 5.1).11–13 This consensus in terminology for α1-adrenoceptors should, in theory, have facilitated the unambiguous identification of the α1-adrenoceptor subtype involved in the contractile response of the prostate in humans.

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Figure 5.1 Classification of adrenoreceptors. Table 5.1 Molecular and pharmacological properties of α1-adrenoceptor subtypes.   Pharmacologic designation (and clone subtype) 1A(α1A) 1B(α1B) 1D(α1D) Structure 466 aa, 7TM 515 aa, 7TM 560 aa, 7TM   Human, bovine, rat Human, hamster, Human, rat rat Human chromosomal C8 C5 C20 localization Distribution of mRNA Human: liver, heart, cerebral Human: aorta, Human: aorta, cerebral cortex, lung, prostate spleen, lung cortex, prostate   Rat: vas deferens, cerebral Rat: cerebral Rat: hippocampus, cortex, heart, submaxillary cortex, kidney, cerebral cortex, vas gland liver, heart deferens Tissues expressing Rat: submaxillary gland Rat: liver, spleen   homogeneous populations Rabbit: liver (radioligand binding) Human: liver Functional preparations Rat: kidney vasoconstriction; Rat: spleen Rat: aorta contraction vas deferens contraction contraction   Human: prostate     contraction? Selective antagonist RS 17053 Spiperone BMY 7378 aa, amino acid. Evidence for α1-adrenoceptor heterogeneity Although the first evidence of different α1-adrenoceptor subtypes (L, H and N) emerged from pharmacologic experiments,14 molecular biology has provided much of the impetus for research into subtypes. In particular, the heterogeneity of α1-adrenoceptors was originally suggested on the basis of radioligand binding to native rat tissues.15,16 Thereafter, findings using receptor binding and functional approaches have clearly demonstrated the existence of multiple α1-adrenoceptor subtypes. Two types of pharmacologically defined α1-adrenoceptors have been detected consistently in native tissues (Table 5.1): • The α1A subtype displays high affinity for the competitive agonists methoxamine and oxymetazoline, and the antagonists WB 4101, phentolamine, 5-methylurapidil (5-MU), and (+)-niguldipine, but is resistant to alkylation by chloroethylclonidine (CEC). • The α1B subtype displays considerably lower affinity for the agonists and antagonists listed above, but is sensitive to alkylation and inactivation by CEC.

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Page 89 Receptor cloning studies have revealed the existence of at least three subtypes of α1-adrenoceptors, encoded by distinct genes and located on different human chromosomes (Table 5.1).11 There is also functional evidence for further heterogeneity, particularly for a subtype with low affinity for prazosin.11,14,17,18 Distribution of α1-adrenoceptors in the prostate α1-Adrenoceptors have been characterized in homogenized prostate tissue (which consists of stromal, epithelial, and vascular elements) using iodinated or tritiated α1-antagonist radioligands, principally [3H]prazosin, [3H]tamsulosin, and [125I]iodo-4-hydroxyphenyl-ethylaminomethyl-tetralone (HEAT). Receptor autoradiography using [3H]prazosin indicated that the majority (85%) of α1-adrenoceptor binding sites are localized on the fibromuscular stroma, with a much lower density (15%) on glandular epithelium.19,20 In agreement with radioligand binding studies, molecular techniques also identify multiple α1adrenoceptor subtypes in human prostate tissue: mRNA transcripts for all three currently cloned α1adrenoceptors having been detected, either by reverse transcriptase-polymerase chain reaction of cDNA fragments or from human prostate cDNA libraries. Sequencing of full-length cDNAs shows a high degree of identity with other mammalian α1-adrenoceptor homologs. Stromal proteins21 and the density of stromal α1-adrenoceptors19,20,22 appear to be increased in BPH. α1-Adrenoceptors are found in the glandular epithelium23 and seem to be of the α1B subtype.24 Even though there may be regional differences in the binding to, and functional properties of, the prostatic α1-adrenoceptors,25–27 no significant regional differences in the contractile response to α1adrenoceptor agonists have been demonstrated.28 All three high-affinity α1-adrenoceptor subtypes identified in molecular cloning and functional studies (α1a/A, α1b/B, α1d/D) have been found in prostate stromal tissue.29–32 The α1a subtype is predominant, representing about 70% of the α1-adrenoceptor population.25,30,31,33 Among the four isoforms of the α1A-adrenoceptor recently identified (α1a/A-1, α1a/A-2, α1a/A-3, α1a/A-4), the α1a/A1 mRNA/protein was the most abundant.24 Nasu et al.34 suggested that there may be differences in subtype populations between normal and hyperplastic prostates. The numbers of α1a, α1b, α1d subtype mRNAs were found in the ratio 85:1:14 in samples from hyperplastic prostates, and in the ratio 63:6:31 in normal samples. The functional importance of this finding remains to be established. Walden et al.24 did not find any significant difference in the overall level of α1-adrenoceptor mRNA between normal and hyperplastic prostates; however, they demonstrated a difference in α1a-adrenoceptor subtype expression, with a reduced expression of α1b mRNA in both glandular and stromal hyperplasia. The sympathetic nervous system: the contractile effects of noradrenaline The identity of the α1-adrenoceptor subtype that mediates the contractile response to noradrenaline in the human prostate has been the subject of much analysis and debate (Fig 5.1). Activation of muscarinic receptors does not elicit contraction of human prostate tissue in vitro. It is well established that noradrenaline and phenylephrine mediate contractile responses almost exclusively via an interaction with α1-adrenoceptors, as the selective α2-agonists UK14304 and clonidine are relatively ineffective.8,9,35,36 The activities of a range of antagonists have confirmed unequivocally the role of αadrenoceptors in mediating contraction of prostate tissue. Several studies have tried to identify the α1-adreno ceptor subtype that mediates the functional response of human prostate tissue in vitro. However, several different conclusions have been reached across the early literature, mainly as a reflection of the limited pharmacologic tools available at the time and the various criteria applied to the classification of the functional response.19,25,31,32,37 Most of these early studies used competitive α1-adrenoceptor antagonists and the alkylating agent CEC. More recently, compounds that have different selectivity profiles for the various α1-adrenoceptor subtypes outlined above have been important in elucidating the predominant subtype that mediates the contractile responses of prostate smooth muscle in vitro. Classic pharmacologic analyses based on the estimation of the receptor affinities of a range of competitive α1-adrenoceptor antagonists suggest that α1A-adrenoceptors mediate functional responses. There is a clear correlation between the affinity of compounds for cloned human α1A-adrenoceptors and their corresponding efficacies against α1-mediated contractions of human prostate smooth muscle in vitro. Of particular interest are compounds such as 5MU, WB 4101, indoramin, and SNAP 1069 (Fig 5.2; Table 5.2),32,38–40 which have differing degrees of selectivity for the cloned α1A-subtype and exhibit functional affinity estimates consistent with their α1Abinding affinities. 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Figure 5.2 Correlation plots of the potency of prazosin (1), terazosin (2), indoramin (3), SNAP 1069 (4), 5-methylurapidil (5), SKF104856 (6), and RS 17052 (7) for cloned human and animal (RS 17053) α1A- (a), α1B- (b), and α1D- (c) adrenoceptors versus their potency at inhibiting α1-mediated contraction of the human prostate in vitro. There is a good correlation between functional α1-adrenoceptor affinity (pA2) on human prostate and binding affinity (pK1) for most, but not all, α1-adrenoceptor antagonists at the cloned α1A subtype. (Adapted from references 32 and 49.) Table 5.2 Binding affinities (pKI) for compounds at cloned human α1A-, α1B-, and α1Dadrenoceptors. Compound α1A α1B α1D Prazosin 9.7±0.20 9.6±0.14 9.5±0.10 Doxazosin 8.5±0.20 9.0±0.20 8.4±0.12 Alfuzosin 8.0±0.20 8.0±0.20 8.5±0.07 (+) Tamsulosin 8.4±0.06 7.0±0.08 8.1±0.04 (−) Tamsulosin 9.7±0.06 8.9±0.06 9.8±0.09 Indoramin 8.3±0.03 8.0±0.13 7.3±0.15 Phentolamine 8.1±0.09 7.1±0.15 7.8±0.03 WB 4101 9.3±0.10 8.2±0.16 9.2±0.06 5-Methylurapidil 8.5±0.009 6.8±0.13 7.8±0.09 Benoxathaln 8.9±0.23 7.8±0.14 8.6±0.12 SNAP 1069 7.8±0.19 7.6±0.18 6.8±0.20 Spiperone 7.6±0.42 8.8±046 8.1±0.03 Rec 15/2739 9.0±0.07 7.5±0.06 8.6±0.07 SL 89,0591 8.6±0.08 7.9±0.08 8.6±0.03 RS 17053 8.6±0.09 7.3±0.09 7.1±0.09 BMY 7378 6.7±0.10 6.7±0.11 8.7±0.10 Data from references 39 and 40.

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Page 91 accepted because of conflicting data generated using other compounds. In particular, the relatively low affinity exhibited by prazosin against α1-mediated contractile responses (pA2 estimated to be less that 9.0) is difficult to reconcile with the affinity for cloned α1A-adrenoceptors (pK I>9.5). On the basis of this and other results, the presence of another discrete functional receptor has been suggested.41 In addition, several studies have shown that the potency of 5-MU against noradrenaline-mediated contractions of the human prostate42,43 is intermediate between its affinities for α1A- and α1Badrenoceptors. This is consistent with the existence of a ‘non-α1A, nonα1B-adrenoceptor’.42 Other experimental compounds such as the highly selective and potent α1A-antagonist RS 17053 (α1A binding affinity=9.5) have been shown to be relatively weak antagonists in the human prostate (pA2=6.9).37 Taken together, these data suggest that the cloned α1A-adrenoceptor may not be identical to the α1adrenoceptor subtype that mediates the contractile responses of human prostate in vitro. In support of this conclusion, CEC attenuates the contractile response of human prostate,42,43 whereas other α1Aadrenoceptor-mediated functional responses are reported to be insensitive to CEC.11,16,42,44 This suggests that the response, or at least a component of the response, is not mediated by the α1Aadrenoceptor. However, it must be noted that the agonist response following alkylation of receptors with CEC can depend on a number of factors, including receptor reserve for the agonist, tissue type, species, and exposure time to CEC; thus, interpretation of comparative data is difficult. Although interpretation is difficult and the data are often confusing and contradictory, several lines of evidence link the α1A-adrenoceptor with the control of human smooth muscle contractility. Binding studies using either [125I]HEAT33 or [3H]prazosin45 indicate that these ligands label a single population of high-affinity α1-adrenoceptors in human and canine prostate homogenates. Competitive displacement of these radioligands by a wide range of competing compounds is consistent with an interaction at a single receptor that exhibits the characteristics of an α1A-adrenoceptor. Goetz et al.33 examined the profiles of more than 20 compounds: binding affinities determined against [125I]HEAT in human and canine prostate tissue homogenates correlated highly with affinities for the same compounds at cloned human α1Aa-adrenoceptors, but not with α1B or α1D subtypes. Similar conclusions were also reached by Testa et al.45 Although the majority of studies suggest the presence of a single population of binding sites, other binding studies suggest that at least two α1-adrenoceptor subtypes are detected in prostate homogenates. This is not, perhaps, surprising, given the composition of prostate-binding homogenates. However, as shown in Table 5.2, prazosin has similar affinity for all currently identified cloned receptors, yet several groups have reported that two receptors with differing affinities for prazosin (and some other compounds) can be identified in the human prostate. Prostate receptors that display different affinities for prazosin cannot be fully reconciled with the profile of prazosin at currently cloned α1-adrenoceptors. Muramatsu et al.41 showed that detection of these putative sites depends on the ability of certain compounds to differentiate between them—a component of [3H]prazosin binding is sensitive to agents such as phentolamine and 5-MU in competition studies. This is in contrast to other compounds such as prazosin and WB 4101, which appear to inhibit an additional component of the total number of sites labeled by [3H]prazosin. Similarly, in displacement studies using human,31 canine,46 and bovine47 prostatic α1-adrenoceptors, a few competing compounds have been found to be biphasic, suggesting that these drugs distinguish between two different α1-adrenoceptor subtypes on prostate membranes. In a comparative study, [3H] tamsulosin was found to label 75% of the sites in human prostate labeled by prazosin, suggesting that tamsulosin may have relatively low affinity for a subpopulation of the total sites identified by prazosin,48 although neither of these α1-antagonists discriminate between currently identified cloned α1-adrenoceptors. The key question is how the affinity of compounds (determined from radioligand binding) for those different sites relates to their functional affinity for noradrenalinemediated contractile responses, especially as binding homogenates contain more than purely stromal elements. In almost all published studies, for those compounds exhibiting high and low affinities for prostate binding sites (such as prazosin, WB 4101, oxymetazoline, and RS 17053), the low-affinity site has been claimed to be consistent with the identity of the functional α1A-adrenoceptor.31,41,49 Because the low binding and functional affinities exhibited by these compounds are not consistent with their profile at currently identified cloned α1-adrenoceptors, these data suggest the existence of a distinct subtype that is functionally predominant. If the prostate α1-adrenoceptor is not entirely consistent with its designation as a typical α1Aadrenoceptor, it appears to be at least closely related. However, exhaustive

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Page 92 attempts using homology-based molecular cloning have thus far failed to identify additional α1subtypes. Ford et al.17,49,50 suggested the possibility that multiple forms of the α1A-adrenoceptor mediate the noradrenaline-induced contraction of prostate smooth muscle. One candidate may be the receptor with low affinity for prazosin (the α1-adrenoceptor suggested by Muramatsu et al.41,51,52). This receptor has not been cloned, but it may represent a functional phenotype of the α1A-adrenoceptor and is often now referred to as either the α1L-adrenoceptor or the α1A/L-adrenoceptor.53 By and large, the pharmaceutical industry has worked on the assumption that selective targeting of the α1A-adrenoceptor subtype should result in an improved clinical profile over the currently used α1antagonists. Two novel α1-adrenoceptor antagonists, Ro 70–0004 and RS-100329, were shown to have a 50–126-fold selectivity for the α1A-adrenoceptor over the α1B and α1D subtypes in both cloned and native systems (Table 5.3).54 Several other companies are active in the area and have synthesized α1adrenoceptors with varying degrees of selectivity for the α1A-subtype.55–57 At least two of these have entered the clinic58,59 and should be sufficiently selective to enable the determination of the clinical value of selective targeting of the prostatic α1A-adrenoceptor in the treatment of LUTS/BPH. Prostatic α1A-adrenoceptors: non-contractile role The role of the α1B and α1D prostatic adrenoceptors, which comprise up to 30% of α1-adrenoceptor mRNA, is even more equivocal than that of the α1A subtype.60 One possibility, described in more detail in Chapter 30, is that these receptor subtypes could be involved in the regulation of prostate cell proliferation. Although there is clinical evidence to support this—normal clinical doses of doxazosin and terazosin stimulate apoptosis61–63—the precise role of the subtypes in this phenomenon is unknown. Indeed, as an effect on cell proliferation is not found at clinically effective concentrations of tamsulosin,64 the phenomenon may involve a mechanism that does not include α1-adrenoceptors.65 α2-Adrenoceptors In addition to α1-adrenoceptors, the presence of α2-adrenoceptors on human prostate tissue has been demonstrated. Radioligand binding studies clearly indicate the presence of α2-adrenoceptors, and autoradio graphy findings suggest an association with blood vessels and glandular epithelial cells.20 As noted above, selective α2-adrenoceptor agonists fail to contract human prostate smooth muscle in vitro. In addition, α2-adrenoceptor antagonists such as rauwolscine inhibit noradrenaline-mediated contractions at concentrations consistent with their affinity for α1- rather than α2-adrenoceptors. In addition, these compounds have no effect on field-stimulated contractions of human prostate at concentrations known to block α2-adrenoceptor-mediated responses. It is now well established that several α2-adrenoceptor antagonists, such as [3H]idazoxan, label non-α1, non-α2-adrenoceptors, which relate to the imidazoline structure of such compounds; these non-α1, non-α2 sites are referred to as nonadrenoceptor imidazoline binding sites. In human prostate, these distinct imidazoline sites are present at twice the density of α2-adrenoceptors, although as with α2-adrenoceptors, no functional role has been described. Caine66 suggested that α2-adrenoceptors may be involved in the effects of, for example, phenoxybenzamine in the treatment of BPH. If this is correct, it is most probably not by blockade of prostate α2-adrenoceptors. Table 5.3 Antagonist affinities of human cloned α1A-, α1B-, and α1D-adrenoceptors.   α1A α1B α1D Antagonist K1 pK B pK I pK B pK I pK B Ro 70–0004 8.9±0.1 8.6±0.1 7.1±0.1 6.7±0.1 7.2±0.1 7.1±0.1 RS-100329 9.6±0.1 9.6±0.1 7.5±0.1 7.8±0.2 7.9±0.1 7.9±0.1 Prazosin 9.0±0.1 8.7±0.1 9.9±0.1 9.6±0.1 9.5±0.1 9.6±0.3 Terazosin 10.0±0.1 10.5±0.1 9.7±0.1 9.4±0.2 9.4±0.1 9.8±0.3 Data from reference 54.

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Page 93 β-Adrenoceptors Several groups have demonstrated the presence of β-adrenoceptors in the human prostate using [3H]dihydroalprenalol binding studies.67,68 A consistent finding is that the number of β-adrenoceptor binding sites in BPH tissue is markedly lower than in corresponding control tissue. Tsujii et al.69 have studied the functional role of β-adrenoceptors in relation to these apparent differences in receptor density. Using tonically contracted prostate smooth muscle in vitro, it has been shown that the β-agonist isoprenaline causes a much larger relaxation in control tissue than in hyperplastic prostate tissue. These authors suggested, therefore, that a decrease in the number of β-adrenoceptors in hyperplastic tissue, with a concomitant reduction in β-adrenoceptor-mediated relaxation, might contribute to the increased dynamic tone of the prostate enveloping the urethra in men with clinical BPH. In vivo effects of α1-adrenoceptor antagonists The clinical profiles of a number of potent α1-antagonists clearly show that these agents are effective in reducing the symptoms of outlet obstruction, as both urinary flow and subjective symptom scores are improved.60 The pharmacology associated with the prostate α1-adrenoceptors that is now emerging clearly provides an opportunity for the development of drugs that are potent and selective for prostate α1-adrenoceptors, while producing fewer of the cardiovascular effects associated with other α1adrenoceptors. On this basis it is, therefore, desirable to profile the effects of putatively selective agents in vivo in models that allow the differentiation of prostate and blood pressure effects (Fig 5.3). Although such models may have some predictive value, they unfortunately also have limitations and the results may be both species- and assaydependent.69 In particular, there is currently no animal model that can reliably predict improvements in clinical symptoms. In summary, it should be possible to target the prostate selectively by optimizing affinity for the prostate adrenoceptor subtype while minimizing affinity at other sites. Drugs with this profile of action would be expected to reduce obstructive (voiding) symptoms, but may not necessarily decrease irritative (storage) symptoms, which may be attributed, at least in part, to extraprostatic α1-adreno ceptors. However, even a greater understanding of the role of extraprostatic α1-adrenoceptors in the generation of the symptoms of BPH, together with the pharmacology

Figure 5.3 Selectivity profile of doxazosin, terazosin, alfuzosin, and 5-methylurapidil (5-MU) in the anesthetized dog. Doxazosin, terazosin and alfuzoin are equally active on prostate pressure ( ) and blood pressure ( ); 5-MU, an α1A-selective compound, is approximately 30-fold prostate selective. of the prostatic adrenoceptors, may not be enough to lead to a new generation of drugs that will have additional benefits in the medical management of LUTS/BPH.70 References 1. Dail W G. Autonomic innervation of male reproductive genitalia. In: Maggi C A (ed). The autonomic nervous system. Vol 6. Nervous Control of the Urogenital System. London: Harwood Academic Publishers, 1993:69–101 2. Caine M. The present role of alpha adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol 1986; 136:1–4 3. Bartsch G, Muller H R, Oberholzer M, Rohr H P. Light microscopic stereological analysis of the normal human prostate and of benign prostatic hyperplasia. J Urol 1979; 112:487–491 4. McNeal J E. The zonal anatomy of the prostate. Prostate 1981; 2:35–39 5. Caine M, Raz S, Ziegler M. Adrenergic and cholinergic receptors in the human prostatic capsule and bladder neck. Br J Urol 1975; 47:193–202 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_93.html[09.07.2009 11:52:02]

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6. Caine M, Perlberg S, Meretyk S. A placebo-controlled double-blind study of the effect of phenoxybenzamine in benign prostatic obstruction. Br J Urol 1978; 50:551–554 7. Lepor H, Shapiro E. Characterization of alpha1 adrenergic receptors in human benign prostatic hyperplasia. J Urol 1984; 132:1226–1229 8. Hedlund H, Andersson E-E, Larsson B. Alpha-adrenoceptors and muscarinic receptors in the isolated human prostate. J Urol 1985; 134:1291–1298

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Page 94 9. Hieble J P, Caine M, Zalaznik E. In vitro characterization of the alpha-adrenoceptors in human prostate. Eur J Pharmacol 1985; 107:111–117 10. Shapiro E, Lepor H. Alpha2 adrenergic receptor in hyperplastic human prostate: identification and characterization using [3H]rauwolscine. J Urol 1986; 136:1038–1043 11. Hieble J P, Bylund D B, Clarke D E et al International Union of Pharmacology. X: Recommendation for nomenclature of α1-adrenoceptors: consensus update. Pharmacol Rev 1995; 47:267–270 12. Langer S Z. History and nomenclature of α1-adrenoceptor subtypes. Eur J Pharmacol 1999; 36 (Suppl 1): 2–6 13. Zhong H, Minneman K P. α1-adrenoceptor subtypes. Eur J Pharmacol 1999; 375:261–276 14. Muramatsu I, Ohmura T, Kigoshi S et al. Pharmacological subclassification of alpha 1-adrenoceptors in vascular smooth muscle. Br J Pharmacol 1990; 99:197–201 15. McGrath J C, Brown C M, Wilson V G. Alpha adrenoceptors: a critical review. Med Res Rev 1989; 9:407–533 16. Bylund D B. Subtypes of α1- and α2-adrenergic receptors. FASEB J 1992; 6:832–840 17. Ford W P D W, Arredondo N F, Blue D R et al. (N-[2] (2-Cyclopropylmethoxyphenoxy)ethyl-5-chloroa, a-dimethyl-1H-indole-3-ethanamine hydrochloride), a selective α1A-adrenoceptor antagonist, displays low affinity for functional α2-adrenoceptors in human prostate: implications for adrenoceptor classification. Mol Pharmacol 1996; 49:209–215 18. Leonardi A, Hieble J P, Guarneri L et al. Pharmacological characterization of the uroselective alpha-1 antagonist Rec 15/2739 (SB216469): role of the alpha-1L adrenoceptor in tissue selectivity, part I. J Pharmacol Exp Ther 1997; 281:1272–1283 19. Chapple C R, Aubry M L, James S et al. Characterization of human prostatic adrenoceptors using pharmacology receptor binding and localization. Br J Urol 1989; 63: 487–496 20. Kobayashi S, Tang R, Shapiro E, Lepor H. Characterization and localization of prostatic alpha1 adrenoceptors using radioligand binding on slide-mounted tissue section. J Urol 1993; 150:2002–2006 21. Bartsch G, Frick J, Ruegg I et al. Electron microscopic stereological analysis of the normal human prostate and of benign prostatic hyperplasia. J Urol 1979; 122:481–486 22. Yamada S, Ashizawa N, Ushijima H et al. Alpha-1 adrenoceptors in human prostate: characterization and alteration in benign prostatic hypertrophy. J Pharmacol Exp Ther 1987; 242:326–330 23. Kurimoto S, Moriyama N, Hamada K et al. Quantitative autoradiography of α1 adrenoceptors with [3H] tamsulosin in human hypertrophied prostate using computerized image analysis. Histochem J 1995; 27:1007–1013 24. Walden P D, Gerardi C, Lepor H. Localization and expression of the alpha1A-, alpha1B- and alpha1D-adrenoceptors in hyperplastic and non-hyperplastic human prostate. J Urol 1999; 161:635–640 25. Lepor H, Tang R, Shapiro E. The alpha-adrenoceptor subtype mediating tension of human prostatic smooth muscle. Prostate 1993; 22:301–307 26. Kurimoto S, Moriyama N, Hamada K, Kawabe K. Evaluation of histological structure and its effect on the distribution of alpha1-adrenoceptors in human benign prostatic hyperplasia. Br J Urol 1998; 81:388– 393 27. Moriyama N, Yamaguchi T, Takeuchi T et al. Semi-quantitative evaluation of alpha1A-adrenoceptor subtype mRNA in human hypertrophied and non-hypertrophied prostates: regional comparison. Life Sci 1999; 64: 201–210 28. Moriyama N, Miyata N, Yamaura H et al. Multidirectional contraction of human hypertrophied prostate. Gen Pharmacol 1994; 25:1459–1464 29. Hirawawa A, Horie K, Tanaka T et al. Cloning functional expression and tissue distribution of human cDNA for the α1a-adrenergic receptor. Biochem Biophys Res Commun 1993; 195:902–909 30. Price D T, Schwinn D A, Lomasney J W et al. Identification, quantification and localization of mRNA for three distinct alpha1 adrenergic receptor subtypes in human prostate. J Urol 1993; 150:546–551 31. Faure C, Pimoule C, Vallancien G et al. Identification of α1-adrenoceptor subtypes present in the human prostate. Life Sci 1994; 54:1595–1605 32. Forray C, Bard J A, Wetzel J M et al. The α1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human α1c subtype. Mol Pharmacol 1994; 45: 703–708 33. Goetz A S, Lutz M W, Rimele T J, Saussy D L Jr. Characterization of alpha1-adrenoceptor subtypes in human and canine prostate membranes. J Pharmacol Exp Ther 1994; 271:1228–1233 34. Nasu K, Moriyama N, Kawabe K et al. Quantification and distribution of alpha1-adrenoceptor subtype mRNAs in human prostate: comparison of benign hypertrophied tissue and non-hypertrophied tissue. Br file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_94.html[09.07.2009 11:52:02]

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J Pharmacol 1996; 119:797–803 35. Kitada S, Kumazawa J. Pharmacological characteristics of smooth muscle in benign prostatic hyperplasia and normal prostatic tissue. J Urol 1987; 138:158–160 36. Lepor H, Gup D I, Bavmann M, Shaprio E. Laboratory assessment of terazosin and α1-blockade in prostatic hyperplasia. Urology 1988; 32:21–26 37. Smith D J, Chapple C R, Marshall I et al. Human alpha 1C adrenoceptors: functional characterization in the human prostate. J Urol 1993; 149:434A

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Page 95 38. Kenny B A, Naylor A M, Carter A J et al. Effect of alpha 1 adrenoceptor antagonists on prostatic pressure and blood pressure in the anesthetized dog. Urology 1994; 44: 52–57 39. Kenny B A, Chalmers D H, Philpott P C, Naylor A M. Characterization of an alpha 1D-adrenoceptor mediating the contractile response of rat aorta to noradrenaline. Br J Phamacol 1995; 115:981–986 40. Kenny B A, Miller A M, Williamson I J et al. Evaluation of the pharmacological selectivity profile of alpha 1 adrenoceptor antagonists at prostatic alpha 1 adrenoceptors: binding, functional and in vivo studies. Br J Pharmacol 1996; 118:871–878 41. Muramatsu I, Oshita M, Ohmura T et al. Pharmacological characterization of α1-adrenoceptor subtypes in the human prostate: functional and binding studies. Br J Urol 1994; 74:572–578 42. Teng C H, Guh J H, Ko F N. Functional identification of α1-adrenoceptor subtypes in human prostate: comparison with those in rat vas deferens and spleen. Eur J Pharmacol 1994; 265:61–66 43. Chapple C R, Burt R P, Andersson P O et al. Alpha 1 adrenoceptor subtypes in the human prostate. Br J Urol 1994; 74:585–589 44. Ruffolo R R, Nichols A J, Stadel J M, Hieble J P. Structure and function of α-adrenoceptors. Pharmacol Rev 1991; 43:475–506 45. Testa R, Guarneri L, Ibba M et al. Characterization of α1-adrenoceptor subtypes in prostate and prostatic urethra of rat, rabbit, dog and man. Eur J Pharmacol 1993; 249: 307–315 46. Ohmura T, Sakamotos S, Hayashi H et al. α1-Adreno ceptor subtypes in the dog prostate. Urol Res 1993; 21: 211–215 47. Muruyama K, Tsuchihashi H, Baba S et al. α1-Adrenoceptor subtypes in bovine prostate. J Pharm Pharmacol 1992; 44:727–730 48. Yamada S, Tanaka C, Ohkura T et al. High-affinity specific [3H]tamsulosin binding to alpha 1adrenoceptors in human prostates with benign prostatic hypertrophy. Urol Res 1994; 22:273–278 49. Ford A P D W, Arredondo N F, Blue D R Jr et al. Do α1A(α1C) adrenoceptors (AR) mediate prostatic smooth muscle contraction in man? Studies with a novel selective α1A-adrenoceptor antagonist, RS 17053. Br J Pharmacol 1995; 115:24P 50. Ford A P, Daniels D V, Chang D J et al. Pharmacological pleiotropism of the human recombinant alpha1A-adrenoceptor: implications for alpha1-adrenoceptor classification. Br J Pharmacol 1997; 121:1127–1135 51. Muramatsu I, Ohmura T, Hashimoto S, Oshita M. Functional subclassification of vascular α1adrenoceptors. Pharmacol Commun 1995; 6:23–28 52. Muramatsu I, Taniguchi T, Okada K. Tamsulosin: alpha1-adrenoceptor subtype-selectivity and comparison with terazosin. Jpn J Pharmacol 1998; 78:331–335 53. Daniels D V, Gever J R, Jasper R J et al. Human cloned alpha1A-adrenoceptor isoforms display alpha1L-adrenoceptor pharmacology in functional studies. Eur J Pharmacol 1999; 370:337–343 54. Williams T J, Blue D R, Daniels D V et al. In vitro alpha1-adrenoceptor pharmacology of Ro 70–0004 and RS-100329 novel alpha1A-adrenoceptor selective antagonists. Br J Pharmacol 1999; 127:252–258 55. Meyer M D, Altenbach R J, Bai H et al. Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole αA-adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia. J Med Chem 2001; 44:1971–1985 56. Pulito V L, Li X, Varga S S et al. An investigation of the uroselective properties of four novel α1Aadrenergic receptor subtype-selective antagonists. J Pharmacol Exp Ther 2000; 294:224–229 57. Balle T, Andersen K, Soby K K, Liljefors T. α1-Adrenoceptor subtype selectivity. 3D-QSAR models for a new class of α1-adrenoceptor antagonists derived from the novel antipsychotic sertindole. J Mol Graph Model 2003; 21:523–534 58. Dutta S, Zhang Y, Daszkowski D J et al. Single- and multiple-dose pharmacokinetics of fiduxosin under nonfasting conditions in healthy male subjects. J Clin Pharmacol 2002; 42:540–546 59. Choppin A, Blue D R, Hegde S S et al. Evaluation of oral ro70–0004/003, an α1A-adrenoceptor antagonist, in the treatment of male erectile dysfunction. Int J Impot Res 2001; 13:157–161 60. Andersson K-E, Lepor H, Wyllie M G. Prostatic α1-adrenoceptors and uroselectivity. Prostate 1997; 30: 202–215 61. Kyprianou N, Allen I F, Wyllie M G. Induction of prostate apoptosis by doxazosin: alpha1adrenoceptor-dependent and -independent actionα Br J Pharmacol 1997; 22:283P 62. Chon J K, Borkowski A, Partin A W et al. Alpha 1-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia. J Urol 1999; 161:2002–2008 63. Glassman D T, Chon J K, Borkowski A et al. Combined effect of terazosin and finasteride on file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_95.html[09.07.2009 11:52:03]

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apoptosis, cell proliferation, and transforming growth factor-β expression in benign prostatic hyperplasia. Prostate 2001; 46:45–51 64. Partin J V, Anglin I E, Kyprianou N. Quinazoline-based alpha1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction. Br J Cancer 2003; 88:1615–1621

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Page 96 65. Kyprianou N. Doxazosin and terazosin suppress prostate growth by inducing apoptosis: clinical significance. J Urol 2003; 169:1520–1525 66. Caine M. Reflections on alpha blockade therapy for benign prostatic hyperplasia. Br J Urol 1995; 75:265–270 67. Yokoyama E, Furuya S, Kumamoto E. Quantitation of alpha1 and beta adrenergic receptor densities in the normal and hypertrophied prostate. Jpn J Urol 1985; 76: 525–327 68. Tsujii T, Azuma H, Yamaguchi T, Oshima H. A possible role of decreased relaxation mediated by αadrenoceptors in bladder outlet obstruction by benign prostatic hyperplasia. Br J Pharmacol 1992; 107:803–807 69. Hieble J P, Kolpak D C, McCafferty G P et al. Effects of alpha1-adrenoceptor antagonists on agonist and tiltinduced changes in blood pressure: relationship to uroselectivity. Eur J Pharmacol 1999; 373:51– 62 70. Wyllie M G. Uroselectivity: end of the road? BJU Int 2003; 92:141–142

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Page 97 6 The pathology of benign prostatic hyperplasia D G Bostwick Introduction Benign enlargement of the prostate (benign prostatic hyperplasia (BPH), nodular hyperplasia, or adenofibromyomatous hyperplasia (AFH)) consists of hyperplastic growth of the epithelium and fibromuscular tissue of the transition zone and periurethral area. Lower urinary tract symptoms (LUTS) are caused by obstruction of urinary flow through the prostatic urethra and interference with muscular sphincteric function. The relationship between prostate volume and clinical symptoms has not been established; however, some studies have identified a weak correlation between the two. This chapter describes the pathologic spectrum of BPH, including epithelial and stromal hyperplasia as well as a wide variety of other benign proliferative lesions. Usual epithelial and stromal hyperplasia At puberty, the increase in circulating androgens results in a rapid increase in prostatic growth.1 The normal adult prostate contains about 50% stroma, 30% acinar lumens, and 20% epithelium according to morphometric studies, Between 31 and 50 years, hyperplastic tissue grows exponentially, with a doubling time of 4.5 years.2 From 55 to 70 years, the doubling time for BPH is 10 years, decreasing to more than 100 years in men older than 70 years. The proliferative rate of the epithelium and stroma of BPH is much higher than that of the rest of the prostate (9 and 37 times higher, respectively).3 Pathogenesis of BPH The prevalence of histologic BPH increases rapidly from the fourth decade of life, and over 70% of men are affected by their seventh decade.4 The age-specific prevalence is remarkably similar in Western populations throughout the world (Fig. 6.1),5 although differences in cellular composition between some races have been observed.6 Epidemiologic studies have shown that the risk of undergoing prostatectomy for BPH is 4-fold greater in first-degree relatives of young men with BPH than in controls.7 The concordance rate for BPH among identical (monozygotic) twins is greater than among nonidentical twins (dizygotic), suggesting a hereditary influence in BPH.8 Development of BPH includes three pathologic stages: nodule formation, diffuse enlargement of the transition zone and periurethral tissue, and enlargement of nodules.9–11 In men under 70 years of age, diffuse enlargement predominates; in older men, epithelial proliferation and

Figure 6.1 Age-specific prevalence of BPH in autopsy specimens from human prostates according to country. (With permission from Bostwick et al.5)

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Page 98 expansile growth of existing nodules predominate, probably as the result of androgenic and other hormonal stimulation. This is accompanied by the clinical symptoms of LUTS and reduced peak urinary flow rates, which correlate with prostate volume and postvoid residual volume, and have also been linked to prostate-specific antigen (PSA) levels.12 The pathogenesis of BPH is uncertain, and multiple overlapping theories have been proposed, all of which may be operative.13,14 Essential to all are advancing age and the presence of circulating androgens. That regression of BPH can be reversibly induced by luteinizing hormonereleasing hormone (LHRH) agonists, and the lack of BPH in men deficient in dihydrotestosterone (DHT), indicate that androgens have at least an important supportive if not causative role in the development of BPH.15 Androgen/aging theory of BPH pathogenesis As men age, there is an increase in cumulative lipid peroxidation, resulting in an increase in tissue concentration of co-factors such as NAD and NADPH. This, in turn, increases 5α-reductase concentration (which is sensitive to changes in NADPH) and levels of prostatic DHT, which is reduced from testosterone by the enzyme. Two types of 5α-reductase have been identified—type 2 is the isoform predominantly active in the prostate, while type 1 is mainly located in the skin and liver. The increase in DHT ultimately induces epithelial and stromal growth, which culminates in BPH. The androgen/aging theory of BPH pathogenesis is supported by the consistent observation of high levels of DHT in patients with BPH, and the reduced levels of DHT, and BPH symptoms, with 5α-reductase inhibition.13 Estrogen theory of pathogenesis The ratio of plasma estrogen to testosterone increases with age, and this may result in excessive stromal growth because of the greater number of hormone receptors in the stroma compared with the epithelium. Investigation of the distribution of estrogen receptors alpha and beta (ERα and ERβ) revealed that ERα was only found in the stromal cells of the peripheral zone while ERβ was present in the stroma and the epithelium of both the peripheral and transition zones.16 This suggests a powerful influence of estrogen, acting through ERβ, on BPH development and helps explain why BPH is chiefly a stromal disease. Attempts to correlate the amount of BPH with serum hormone concentrations have yielded conflicting results,17 although testosterone and estrogen are clearly influential. Embryonic reawakening theory of pathogenesis McNeal10,11 suggested that the earliest lesion of BPH is a proliferation of epithelium, probably under the influence of DHT, with branching and budding due to ‘reawakening’ of the embryonic inductive potential of the prostatic stroma during adulthood. This theory accounts for the presence of the common fibroadenomatous nodules of BPH. Oxidoreductase theory of pathogenesis Abnormal activity of certain enzymes may cause BPH by promoting the retention of tissue DHT, resulting in higher DHT levels. Isaacs et al. found significantly lower concentrations of two enzymes which remove DHT from tissue (17β-hydroxysteroid and 3α-hydroxysteroid reductase) in BPH patients than in controls.1 Inflammation/growth factor theory of pathogenesis Inflammation and the release of locally produced growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factors (FGF), insulin-like growth factors and transforming growth factor beta (TGFβ) may play a role in the development of BPH due to effects on cell proliferation, apoptosis, and extracellular matrix turnover.18,19 FGF-7 and FGF-2 are overexpressed in hyperplastic prostate tissue in comparison to normal epithelium and transition zone tissue.20 There is a marked reduction in basic FGF level in BPH treated with finasteride in comparison with untreated BPH.21 Steiner et al.22 found that the number of T-cells in BPH is greater than that in the normal prostate, and these T-cells are preactivated and functionally capable of producing sufficient amounts of autocrine growth factors necessary for T-cell proliferation. Analysis of almost 4000 histologic BPH samples revealed that inflammation was present in over 40% of cases, with a correlation observed between this factor and prostate volume.23 Conversely, however, Helpap showed that there is no significant correlation between the amount of chronic inflammation and the extent of BPH.24 Pathology of BPH Grossly, BPH consists of variably sized nodules that are soft or firm, rubbery, and yellow-gray, and bulge from the cut surface upon transection (Fig. 6.2). If there is prominent epithelial hyperplasia in addition to stromal hyperplasia, the abundant luminal spaces create soft and grossly spongy nodules that ooze a pale-white watery fluid. If BPH is predominantly fibromuscular, there may be diffuse enlargement or numerous trabeculations without prominent file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_98.html[09.07.2009 11:52:04]

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Figure 6.2 Gross appearance of BPH. (a) Prostatic adenectomy specimen, with yellow nodules of BPH bulging from the gray-white fibromuscular stroma. (b) The rubbery nodules have replaced and expanded the transition zone, distorting and compressing the urethral lumen and adjacent prostate; the peripheral zone is compressed at the bottom and contains foci of adenocarcinoma which are subtle and appear pale yellow. (c) BPH and a large infarct. (d) A BPH nodule protrudes into the bladder lumen, acting as a ball valve with intermittent urinary obstruction. nodularity. Degenerative changes include calcification and infarction. BPH usually involves the transition zone, but occasionally nodules arise from the periurethral tissue at the bladder neck. Protrusion of bladder neck nodules into the bladder lumen is referred to as median lobe hyperplasia (Fig. 6.2). Rarely, hyperplastic nodules are present in the peripheral zone. Microscopically, BPH is invariably nodular, comprising varying proportions of epithelium, fibrous connective tissue, and smooth muscle. There are five types of nodules, including adenomyofibromatous (most common), fibromuscular, muscular (uncommon), fibroadenomatous, and stromal (Fig. 6.3). In practice, pathologists do not subclassify BPH histologically because of the wide variation in composition. Common associated findings include chronic inflammation, acinar atrophy, and luminal corpora amylacea and microcalculi. The transition zone is infrequently sampled by needle biopsy unless the urologist specifically targets this area or there is massive BPH, which compresses the peripheral zone. The diagnosis of BPH is often used by pathologists in reporting the findings in needle biopsy specimens when only normal benign peripheral zone tissue is present. However, such findings should be referred to as ‘benign prostate tissue’ as histologic biopsy results do not correlate with BPH, except when stromal nodules are present.25 We require the presence of at least part of a nodule for the diagnosis of BPH. Narrow 18-gauge biopsies virtually never contain the entire nodule unless it is very small and fortuitously sampled. Casual use of the term BPH for benign prostatic tissue may mislead the urologist into believing that a palpable nodule or hypoechoic focus of concern has been sampled and histologically evaluated; it is important for the pathologist to correlate the light

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Figure 6.3 Microscopic appearance of BPH. (a) Fibroadenomatous pattern of BPH, showing a circumscribed elongate nodule of glands and fibrous stroma. (b) Pure stromal nodule of BPH. (c) Edge of BPH nodule with infarct, note the presence of acute inflammation (left) and dilated glands with necrotic debris (right). (d) Section from giant BPH, this 16-year-old boy underwent suprapubic prostatectomy for massive enlarge-ment of the prostate. microscopic findings with the clinical impression, so communication with the urologist is vital. Vascular insufficiency probably accounts for infarction of BPH nodules, seen in up to 20% of resected cases (Fig. 6.3). The center of the nodule undergoes hemorrhagic necrosis, often with reactive changes in the residual epithelium at the periphery, including squamous metaplasia and transitional cell metaplasia. Peripheral zone BPH BPH sometimes protrudes from the transition zone into the peripheral zone, creating a palpable abnormality which may be clinically or radiographically mistaken for adenocarcinoma.26–28 Rarely, fibroadenomatous nodules originate in the peripheral zone and are spatially distinct from the transition zone29. These nodules are present in about 2% of radical prostatectomies with cancer and are of unknown etiology. Possible explanations include embryonic reawakening, similar to that proposed for transition zone BPH, parasitic nodule from the transition zone extending into the peripheral zone, and implantation of transition zone tissue in the peripheral zone during embryogenesis. There is no apparent relationship between peripheral zone BPH nodules and cancer. Giant BPH (giant prostatic hyperplasia) Prostatic enlargement due to BPH rarely exceeds 100 g, which occurs in only 4% of men over 70 years of age (Fig. 6.3).2 Giant BPH is arbitrarily defined as specimens over 200 g30 or 500 g;31 the lower threshold was suggested by Japanese authors,30 probably because BPH is rare in their country. The largest adenoma ever removed by suprapubic prostatectomy weighed 820 g, but the patient died of hemorrhage.32 Giant BPH tends to have the typical adenomyofibromatous pattern.

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Page 101 Morphometry of BPH: ratio of epithelium and stroma Numerous techniques have been used to study the ratio of epithelium and stroma in BPH, including light microscopy,33 computer-assisted digital image analysis,34,35 stereologic analysis,36 and texture analysis.37 The relative amounts of epithelium and stroma are 21.6–40% for epithelium and 60–78.4% for stroma, respectively, although this may differ between races.6 Japanese men have overall greater glandular lumen and lower stromal components as well as lower stroma to epithelium and stroma to glandular ratios than either Caucasian or African-American men. Mean per cent area densities of stroma and epithelium were 77.4 and 15.2%, compared to 84.2 and 12.1% for Caucasian men and 84.4 and 12.4% for African-American men, respectively. This may have a bearing on differences in PSA levels and overall clinical BPH prevalence. The clinical importance of the ratio of epithelium and stroma is that men with symptomatic BPH have a significantly higher proportion of stroma than men with asymptomatic BPH.34 It is likely that the predominant component of the BPH nodule determines the response to therapy: smooth musclepredominant nodules would respond to α-blockers, epithelial nodules to androgendeprivation therapy (LHRH agonists, steroid anti-androgens and 5α-reductase inhibitors) and fibrous nodules to surgery. Association of BPH and prostate cancer There are a number of similarities between BPH and cancer5 (Table 6.1). Both display a parallel increase in prevalence with patient age according to autopsy studies, although cancer lags by 15–20 years. Both require androgens for growth and development, and both may respond to androgendeprivation treatment. Most cancers arise in prostates with concomitant BPH, and cancer is found incidentally in a significant number (10%) of transurethral prostatectomy specimens. In addition, serum PSA levels have been shown to correlate with prostatic epithelial volume38 and it is thought that BPH may be related to prostate cancer arising in the transition zone. Increased levels of stromal components (smooth muscle cells and connective tissue) have been identified in the transition zone of BPH patients.39,40 Investigation of the stromal components of prostate cancer tissue showed a correlation between cancer in the peripheral zone and a decrease in smooth muscle cells and an increase in collagen fibers. As cancer grade increased, the ratios between the two became more pronounced.41 Although the exact association between prostate cancer and BPH remains undefined, low-grade carcinomas have been found to resemble BPH tissue in the transition zone.40 A proposed molecular marker for prostate cancer, α-methylacyl-CoA racemase (AMACR), which is found in prostatic intraepithelial neoplasia (PIN) and peripheral zone prostate carcinomas, has been observed in BPH tissue located adjacent to cancerous cells. Staining for the monoclonal antibody against AMACR (P504S), plus P63 or antikeratin 34β E12 antibodies revealed areas of transition from hyperplasia to carcinoma in some BPH nodules. This suggests that some BPH nodules containing AMACR may give rise to transitionzone carcinomas and that upregulation of AMACR occurs prior to neoplastic transformation. The findings also suggest that fatty acids, the oxidation of which AMACR is involved in, contribute to the development of carcinoma in the transition zone. Although BPH is not generally considered a premalignant lesion or a precursor of carcinoma, fastgrowing BPH has been linked to increased risk of clinical prostate cancer. Rapidly progressing BPH was found to be more common in men with noninsulin-dependent diabetes mellitus, hypertension, obesity, dyslipidemia, atherosclerosis, hyperuricemia, hyperinsulinemia, and elevated alanine aminotransferase (ALAT). The increased levels of pronounced clinical prostate cancer identified in these men may therefore arise as a function of insulin production.42 PSA levels have also been found to increase in a linear fashion alongside glandular proliferation and are significantly greater in cases of BPH with chronic prostatitis than BPH without chronic prostatitis. The relevance of these findings as regards risk of prostate cancer development, however, is as yet unknown.43 The optimal number of chips to submit for histologic evaluation from a transurethral resection specimen remains controversial, with some authors preferring partial sampling and others advocating complete submission even with large specimens, which would require many cassettes.44–47 The Cancer Committee of the College of American Pathologists recommends a minimum of six cassettes for the first 30 g of tissue and one cassette for every 10 g thereafter.48 Histologic variants of hyperplasia and associated benign lesions There is a wide morphologic spectrum of epithelial and stromal hyperplasia. Awareness of these variants is important in order to avoid misdiagnosis of adenocarcinoma (Table 6.2).

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Page 102 Table 6.1 Prostatic carcinoma: comparison based on anatomic site of origin*. Characteristic Transition zone cancer Peripheral zone cancer Incidence Stage T/a 75% — Stage T/b 79% — All stage T1 78% — All stages 24% 70% Origin In or near BPH Yes No Near Yes Yes Detection rate 78% — Pathologic features Tumor volume Usually small Small to large Tumor pattern Alveolar-medullary Tubular-scirrhous Tumor grade (Gleason) Usually 1 or 2 Usually 2, 3 or 4 Clear cell pattern Most cases Rare Stromal fibrosis Uncommon Common Associated putative premalignant changes AAH or PIN PIN Aneuploidy† 6% 31% Clinical behavior Extracapsular extension† 11% 44% Site of extracapsular extension extension Anterolateral and apical Lateral Average tumor size with extracapsular extension† 4.98cm3 3.86 cm3 Risk of stromal vesicle invasion† 0% 19% Risk of lymph node metastases Low High *Central zone cancers (5–10% of total) were excluded. TURP, transurethral resection of the prostate; AAH, atypical adenomatous hyperplasia; PIN, prostatic intraepithelial neoplasia. †Data from reference 49 for stage T1 and T2 cancers. Atrophy and postatrophic hyperplasia (postinflammatory hyperplasia; partial atrophy; postsclerotic hyperplasia) Atrophy is a common microscopic finding, consisting of small, distorted glands with flattened epithelium, hyperchromatic nuclei, and stromal fibrosis. It is usually idiopathic, and the prevalence increases with advancing age.23 At low magnification, atrophy may be confused with adenocarcinoma due to the prominent acinar architectural distortion. At high magnification, atrophy usually lacks nuclear and nucleolar enlargement, except in cases of postatrophic hyperplasia. Clusters of atrophic prostatic acini which display proliferative epithelial changes are referred to as postatrophic hyperplasia (PAH).50,51 PAH is at the extreme end of the morphologic continuum of acinar atrophy, which most closely mimics adenocarcinoma. This continuum varies from mild acinar irregularity with a flattened layer of attenuated cells with scant cytoplasm to that of PAH in which the lining cells are low cuboidal with moderate amounts of cytoplasm. There is no sharp division in this continuum between atrophy and PAH, challenging the utility of PAH as a distinct entity. However, the morphologic mimicry of PAH and carcinoma creates the potential for misdiagnosis, sometimes resulting in unnecessary prostatectomy.51 To avoid this potentially tragic misinterpretation, the pathologist should have an understanding of this extreme morphologic variant of atrophy. We believe that PAH is a diagnostic category for atrophic acini, which most closely mimic adenocarcinoma, recognizing that this is merely a descriptive term. PAH consists of a microscopic lobular cluster of five to 15 small acini with distorted contours reminiscent of atrophy (Fig. 6.4a). One or more larger dilated acini are usually present within these small round to oval clusters, and the small acini appear to bud off from the dilated acinus, imparting a lobular appearance to the lesion. The small acini are lined by a layer of cuboidal secretory cells with mildly enlarged nuclei with an increased nucleus-to-cytoplasmic ratio when compared with adjacent benign epithelial cells. The nuclei contain finely granular chromatin, and nucleoli are usually small, although mildly

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Page 103 Table 6.2 Histopathologic variants of BPH. Variant Microscopic features Usual location Postatrophic Atrophic acini with epithelial proliferative changes Easily mistaken for All zones hyperplasia adenocarcinoma owing to architectural distortion Stromal Stromal nodules in the setting of BPH with increased cellularity and Transition zone hyperplasia with nuclear atypia atypical giant cells Basal cell Proliferation of basal cells, two or more cells in thickness; may have Transition zone hyperplasia prominent nucleoli (atypical basal cell hyperplasia) or form a nodule (basal cell adenoma) Cribriform Acini with distinctive cribriform pattern, often with clear cytopasm. Transition zone hyperplasia Easily mistaken for proliferative acini of the central zone Atypical Localized proliferation of small acini in association with BPH nodule Transition zone adenomatous which architecturally mimics adenocarcinoma but lacks cytologic hyperplasia features of malignancy Sclerosing Circumscribed proliferation of small acini in in a dense spindle-cell Transition zone adenosis stroma without significant cytologic atypia. Usually solitary and microscopic Verumontanum Small benign acinar proliferation involving the verumontanum Verumontanum mucosal gland hyperplasia Hyperplasia of Rare benign lobular proliferation of small acini with colloid-like material All zones (very mesonephric in the lumens. May mimic nephrogenic metaplasia focally. Acini do not rare) remnants apparently express PSA or PAP PSA, prostate-specific antigen; PAP, prostatic acid phosphatase. enlarged nucleoli are focally present in 39% of cases. The cytoplasm is often basophilic or finely granular to clear, and luminal apocrine-like blebs are present in 33% of cases. Luminal mucin is occasionally present in PAH. Corpora amylacea are present in 75% of cases of PAH, but crystalloids are rarely if ever seen. The basal cell layer is usually present in PAH, but is often inconspicuous by routine light microscopy. Basal cell hyperplasia is rarely seen in foci of PAH. Immunohistochemical stains for high molecular weight keratin (antibody 34βE12) reveal a focally fragmented basal cell layer in some cases. Adjacent prostatic acini always show at least focal atrophy. Stromal changes are always present in PAH, ranging from smooth muscle atrophy to dense sclerosis with compression of acini. In cases with sclerosis, the acinar lumens are compressed and showed marked distortion. Subtyping of PAH into the lobular and postsclerotic subtypes is useful only to allow recognition of PAH and distinguish it from mimics such as low-grade adenocarcino ma, and we prefer not to subtype PAH. Also, PAH is often associated with patchy chronic inflammation; infrequently, dilated acini contain luminal neutrophils. PAH is distinguished from carcinoma by its characteristic lobular architecture, intact or fragmented basal cell layer, inconspicuous or mildly enlarged nucleoli, and adjacent acinar atrophy with stromal fibrosis or smooth muscle atrophy. Low-grade adenocarcinoma is the most important differential diagnostic consideration with PAH. PAH usually has a lobular pattern on low power, similar to Gleason pattern 2 and 3 adenocarcinoma. However, the lobular pattern is less distinct in cases with abundant stromal sclerosis, and there may be a pseudoinfiltrative growth pattern with fibrous entrapment of acini. Nucleolar changes are also useful in separating PAH and carcinoma, although some cases of low-grade carcinoma have only patchy large nucleoli or even micronucleoli. Mildly enlarged nucleoli may be present in PAH, but only focally, and the majority of cells have micronucleoli. The separation of PAH from carcinoma is most difficult in needle biopsy specimens in which only a portion of the lesion is sampled, and awareness of this entity assists in this distinction. In about half of the biopsies containing PAH, the lesion extends to the edge of the tissue core, indicating incomplete sampling.

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Figure 6.4 Variants of BPH. (a) Postatrophic hyperplasia, these distorted glands are embedded in sclerotic stroma in an area of atrophy. (b) Stromal hyperplasia with atypical giant cells. (c) Basal cell hyperplasia. (d) Atypical basal cell hyperplasia. (e) Basal cell adenoma. (f) Clear cell cribriform hyperplasia. (g) Atypical adenomatous hyperplasia. (h) Sclerosing adenosis.

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Page 105 Stromal hyperplasia with atypical giant cells Stromal hyperplasia with atypia consists of stromal nodules in the setting of BPH with increased cellularity and nuclear atypia (Fig. 6.4b).52,53 These may appear as solid stromal nodules (often referred to as atypical leiomyoma) or with atypical cells interspersed with benign glands. Stromal nuclei are large, hyperchromatic with smudged chromatin, and rarely multinucleated or vacuolated, with inconspicuous nucleoli. There are no mitotic figures and no necrosis. Stromal hyperplasia with atypia has no malignant potential, and the atypical cells are considered degenerative. Basal cell hyperplasia and basal cell proliferations There are three patterns of benign basal cell hyperplasia, including typical basal cell hyperplasia (Fig. 6.4c), atypical basal cell hyperplasia (Fig. 6.4d), and basal cell adenoma (Fig. 6.4e).54,55 Basal cell hyperplasia Basal cell hyperplasia consists of a proliferation of basal cells two or more cells in thickness at the periphery of prostatic acini (Fig. 6.4c).54–57 It sometimes appears as small nests of cells surrounded by a few concentric layers of compressed stroma, often associated with chronic inflammation. The nests may be solid or cystically dilated, and occasionally are punctuated by irregular rounded luminal spaces, creating a cribriform pattern. Basal cell hyperplasia frequently involves only part of an acinus, and sometimes protrudes into the lumen, retaining the overlying secretory cell layer; less commonly, there is symmetric duplication of the basal cell layer at the periphery of the acinus. The proliferation may protrude into the acinar lumen, retaining the overlying secretory luminal epithelium. Symmetric circumferential thickening of the basal cell layer is less frequent than eccentric thickening, and these changes do not result from tangential sectioning. The basal cells in basal cell hyperplasia (BCH) are enlarged, ovoid or round, and plump (epithelioid), with large pale ovoid nuclei, finely reticular chromatin, and a moderate amount of cytoplasm. Nucleoli are usually inconspicuous (less than 1 μ m in diameter) except in atypical BCH (see below). It is rarely associated with atypical adenomatous hyperplasia. Atypical BCH Atypical BCH is identical to BCH except for the presence of large prominent nucleoli (Fig. 6.4d). The nucleoli are round to oval and lightly eosinophilic. There is chronic inflammation in the majority of cases, suggesting that nucleolomegaly is a reflection of reactive atypia. A morphologic spectrum of nucleolar size is observed in basal cell proliferations, and only those with more than 10% of cells exhibiting prominent nucleoli are considered atypical.54 Basal cell adenoma Basal cell adenoma consists of a large, round, usually solitary, circumscribed nodule of acini with basal cell hyperplasia in the setting of BPH (Fig. 6.4e). The nodule contains uniformly spaced aggregates of hyperplastic basal cells which form small solid nests or cystically dilated acini. Condensed stroma is seen at the periphery of the nodule. In addition, stromal connective tissue traverses the adenomatous nodule, creating incomplete lobulation in some cases. Stroma is normal or slightly increased in density, and may be basophilic without myxoid change adjacent to cell nests. The basal cells in basal cell adenoma are plump, with large nuclei, scant cytoplasm, and usually inconspicuous nucleoli, although large prominent nucleoli are rarely observed. Many cells are cuboidal or ‘epithelioid’, particularly near the center of the cell nests, and some contain clear cytoplasm. Prominent calcific debris is often present within acinar lumens. Multiple basal cell adenomas are referred to as basal cell adenomatosis. Basal cell adenoma invariably arises in association with BPH, and appears to be a variant. Immunohistochemical findings Basal cell hyperplasia (typical and atypical forms) displays intense cytoplasmic immunoreactivity in virtually all of the cells with high molecular weight keratin 34βE12. Immunoreactivity for PSA, prostatic acid phosphatase (PAP), chromogranin, S-100 protein, and neuron-specific enolase is present in rare basal cells in the majority of cases. Role of basal cells Basal cells may act as ‘reserve’ cells, which are capable of dividing and replenishing the prostatic epithelium, including the ability to differentiate into other cell types such as secretory cells.58 Basal cells apparently retain the ability to undergo metaplasia, including squamous differentiation in the setting of prostatic infarction and myoepithelial differentiation in the setting of sclerosing adenosis. Epidermal growth factor receptors have been identified in basal cells

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Page 106 but not in secretory cells, suggesting that these cells play a role in growth regulation.59,60 Cribriform hyperplasia Cribriform hyperplasia, including clear cell cribriform hyperplasia, consists of a nodule composed of glands arranged in a distinctive cribriform pattern (Fig. 6.4f). The cells from such glands usually have pale to clear cytoplasm and small uniform nuclei with inconspicuous nucleoli.61,62 This lesion is distinguished from high-grade PIN and carcinoma by the lack of prominent nucleoli in acinar cells. Atypical adenomatous hyperplasia (adenosis) Atypical adenomatous hyperplasia (AAH) is a localized proliferation of small acini within the prostate that may be mistaken for carcinoma (Fig. 6.4g).63–65 Small acinar proliferations in the prostate form a morphologic continuum ranging from benign proliferations with minimal architectural and cytologic atypia to those in which the degree of atypia is such that they are easily recognized as welldifferentiated adenocarcinoma. The proliferations are distinguished easily at widely spaced points of the spectrum; however, no abrupt changes are apparent along the continuum. The greatest difficulty in distinguishing AAH from carcinoma is with lesions containing nucleoli intermediate in size between benign and malignant. To accommodate this borderline group, we recommend separating small acinar proliferations into AAH (probably benign) and atypical small acinar proliferations suspicious for, but not diagnostic of, malignancy (possibly benign, but having some features of carcinoma) (see below). AAH varies in incidence from 19.6% (transurethral resection specimens) to 24% (autopsy series in 20to 40-year-old men).65,66 It can be found throughout the prostate, but is usually present near the apex and in the transition zone and periurethral area.63 Separation of AAH and cancer AAH is distinguished from well-differentiated carcinoma by the following: (1) inconspicuous nucleoli, (2) infrequent crystalloids, and (3) fragmented basal cell layer as seen with basal cell-specific anti-keratin antibodies. All measures of nucleolar size allow separation of AAH from adenocarcinoma, including mean nucleolar diameter, largest nucleolar diameter, and percentage of nucleoli greater than 1 μ m in diameter. There is apparently wide-spread acceptance of Gleason’s criterion of nucleolar diameter greater than 1 μ m for separating well-differentiated cancer (Gleason primary grades 1 and 2) from other proliferative lesions.67 Despite the utility of these features, the absolute distinction between AAH and carcinoma is still problematic in some cases, particularly in those cases that are classified as atypical small acinar proliferations of uncertain significance. Other morphologic features are not useful in distinguishing AAH from adenocarcinoma, including lesion shape, circumscription, multifocality, average acinar size, variation in acinar size and shape, chromatin pattern, and the amount and tinctorial quality of the cytoplasm. Both lesions contain acidic mucin in the majority of cases.68,69 Immunohistochemistry of AAH Immunohistochemistry is often useful in the diagnosis of AAH. The basal cell layer is characteristically discontinuous and fragmented in AAH, but absent in cancer, a feature that can be demonstrated in routine formalin-fixed sections with basal cell-specific anti-keratin (high molecular weight keratin antibodies (34βE12)). Clinical significance of AAH Three significant unanswered questions remain regarding AAH. First, does ‘atypical small acinar proliferation of uncertain significance’ represent underdiagnosed adenocarcinoma? Six of eight cases in one study created considerable diagnostic discord among the participants.63 Critics could reasonably argue that the lack of concordance for this lesion indicates that it is not a distinct entity but merely a reflection of our uncertainty; also, the criteria for distinguishing this lesion from AAH and cancer may be difficult to apply in practice. Second, does Gleason primary grade 1 adenocarcinoma represent overdiagnosed adenocarcinoma? These lesions are uncommon; most would agree that Gleason primary grade 2 adenocarcinoma (infiltrating acini) is malignant, but what is the true biological potential of the circumscribed uniform proliferation of Gleason primary grade 1 adenocarcinoma? It is likely that many or most of the original grade 1 cancers would be classified today as AAH. Third, is AAH a precursor of adenocarcinoma? AAH has been proposed as a premalignant lesion of the prostate because of the following: increased incidence in association with carcinoma (15% in 100 prostates without carcinoma at autopsy, and 31% in 100 prostates with cancer at autopsy), topographic relationship with small-acinar carcinoma, age at peak incidence that precedes that of carcinoma, increasing silver-stained nucleolar organizer regions (AgNOR) count, increased nuclear area and

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Page 107 diameter, and a proliferative cell index that is similar to that of small-acinar carcinoma but significantly higher than that of normal and hyperplastic prostatic epithelium. Some authors claim that the link between cancer and AAH is an epiphenomenon and that the data are insufficient to conclude that AAH is a premalignant lesion.70,71 However, we have recently demonstrated allelic imbalances at microsatellite polymorphic markers on a number of chromosomes in 47% of cases of AAH.72 These genetic alterations are present frequently in high-grade PIN and cancer.73,74 AAH may be related to the subset of cancers that arise in the transition zone in association with BPH.5,74 Although the biological significance of AAH is slight, its light microscopic appearance and immunophenotype allow it to be separated from carcinoma. Atypical small acinar proliferation suspicious for malignancy The minimal criteria for prostatic adenocarcinoma are now sufficiently refined that we can separate out a category of suspicious foci which falls below the diagnostic threshold for malignancy. In 1.5–9.0% of prostate biopsies among unselected series75–81 there is a localized proliferation of small acini which is suspicious for carcinoma but falls below the diagnostic threshold. Atypical small acinar proliferation (ASAP) is most often due to the small size of the focus.76 The second most common reason for diagnosing ASAP is lack of definite cytologic evidence for cancer.76 In such cases, the pathologist appropriately should sign the case out as ‘atypical small acinar proliferation suspicious for but not diagnostic of malignancy (ASAP)’. We consider this a valid diagnostic category based on our ‘absolute uncertainty’ regarding the diagnosis. In such cases, the diagnosis of carcinoma cannot be made, but the possibility cannot be definitively excluded. In view of the serious consequences of the diagnosis of carcinoma, it is prudent to render the diagnosis of malignancy only when there is absolute confidence in the histologic findings. On the other hand, we discourage pathologists from using ASAP as a ‘wastebasket’ diagnosis without first having obtained intradepartmental consultation and, where appropriate, having performed an immunohistochemical stain for the presence of basal cells (keratin 34βE12) or obtaining deeper histologic sections. ASAP has a 38%,81 42%,82,83 45%,76 or 60%79 predictive value for cancer on repeat biopsy, at least equal to that of PIN. Repeat biopsy should be considered, sampling multiple sites of the prostate. Sextant biopsy or greater is best, since sampling only the side or sextant site initially diagnosed as ASAP would have missed cancer in 39% of patients whose cancer was detected exclusively at other sites.83 Sclerosing adenosis Sclerosing adenosis of the prostate, originally described as adenomatoid or pseudoadenomatoid tumor, consists of a benign circumscribed proliferation of small acini set in a dense spindle cell stroma (Fig. 6.4h).84–90 It is an incidental finding in transurethral resection specimens for BPH, present in about 2% of specimens; rare cases are associated with elevated serum PSA levels. Sclerosing adenosis is usually solitary and microscopic, but may be multifocal and extensive. The acini are predominantly well formed and small to medium in size, but may form minute cellular nests or clusters with abortive lumens. The cells lining the acini display a moderate amount of clear to eosinophilic cytoplasm, often with distinct cell margins. The basal cell layer may be focally prominent and hyperplastic, particularly in acini thickly rimmed by paucicellular hyalinized stroma. In some areas, the acini merge with the exuberant stroma composed of fibroblasts and loose ground substance. There is usually no significant cytologic atypia of the epithelial cells or stromal cells, but we have recently encountered several cases with moderate to severe cytologic atypia. Sclerosing adenosis can be distinguished from adenocarcinoma by its distinctive fibroblastic stroma which is rarely seen in carcinoma; benign cytology, with epithelial cells and stromal cells which lack the prominent nucleomegaly and nucleolomegaly is usually seen in prostatic carcinoma; hyalinized periacinar stroma occasionally seen in sclerosing adenosis; intact basal cell layer; frequent association with BPH; and immunophenotype of S-100 protein and actin immunoreactivity. The unique immunophenotype of sclerosing adenosis is a valuable diagnostic clue in distinguishing it from adenocarcinoma. Unlike normal prostatic epithelium or carcinoma, basal cells in sclerosing adenosis show positivity for S-100 protein and smooth muscle actin, reflecting their myoepithelial differentiation; consequently, sclerosing adenosis is considered a form of metaplasia. The basal cell layer is intact or fragmented in sclerosing adenosis, as demonstrated with immunohistochemical stains for high molecular weight keratin 34βE12, compared with absence of staining in carcinoma. PSA and PAP are present with secretory luminal cells. Acid mucin stain may also be of value in separating sclerosing adenosis from carcinoma; however, acid mucin is not specific for malignancy.

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Page 108 Ultrastructural studies confirm the presence of myoepithelial differentiation in sclerosing adenosis, with collections of thin filaments and dense bodies.86 Verumontanum mucosal gland hyperplasia This is an uncommon form of small acinar hyperplasia which mimics well-differentiated adenocarcinoma.91 It is invariably small, less than 1 mm, often multicentric, and limited anatomically to the verumontanum, utricle, ejaculatory ducts, and adjacent prostatic urethra and ducts. The acini are small and closely packed, with an intact basal cell layer, small uniform nuclei, and inconspicuous nucleoli. The basal cells display immunoreactivity for high molecular weight keratin and are S-100 protein negative. This lesion is rare in needle biopsies and is almost never sampled in transurethral resections because of the sparing of the verumontanum by this procedure. Hyperplasia of mesonephric remnants Hyperplasia of mesonephric remnants in the prostate and periprostatic tissues is a rare and benign mimic of adenocarcinoma which is usually identified in transurethral resection specimens. According to Gikas et al.,92 it shares many features with mesonephric hyperplasia of the female genital tract, including apparent infiltration of the stroma and neural spaces, lobular arrangement of small acini or solid nests lined by a single cell layer, prominent nucleoli, and eosinophilic intratubular material. Two histopathologic patterns have been described, both with a lobular pattern and cuboidal cell lining. One pattern consists of small acini which contain colloid-like material, reminiscent of thyroid follicles. The lining consists of a single layer of cuboidal cells without significant cytologic atypia. The second pattern consists of small acini or solid nests of cells with empty lumens, reminiscent of nephrogenic metaplasia. Unlike prostate cancer, the acini of prostatic mesonephric remnant contain a small amount of cytoplasm and this may be the most useful diagnostic finding. Also, the acini may be atrophic or exhibit micropapillary projections lined by cuboidal cells. Prominent nucleoli are occasionally observed, compounding the diagnostic confusion. The acini display immunoreactivity for keratin 34βE12, but not for PSA or PAP. One of the original cases was misdiagnosed as adenocarcinoma, resulting in unnecessary prostatectomy. Summary BPH is one of the most common diseases in elderly men, but its etiology and pathogenesis remain uncertain. The pathologic features of BPH are well defined and heterogeneous, and include varying amounts of epithelium, smooth muscle, and fibrous stroma. The correlation of pathologic findings and clinical symptoms is weak, although recent evidence suggests that men with symptomatic BPH have a significantly higher proportion of stroma than men with asymptomatic BPH. There is also increasing evidence of a relationship between BPH and the development of prostatic carcinoma. The tissue elements in BPH may respond differently to various forms of therapy. Numerous interesting and unusual pathologic variants of BPH have been described which mimic adenocarcinoma clinically and pathologically. References 1. Isaacs J T, Brendler C B, Walsh P C. Changes in the metabolism of dihydrotestosterone in the hyperplastic human prostate. J Clin Endocrinol Metab 1983; 56: 139–145 2. Berry S J, Coffey D S, Walsh P C, Ewing L L. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474–479 3. Claus S, Wrenger M, Senge T, Schulze H. Immunohistochemical determination of age related proliferation rates in normal and hyperplastic human prostates. Urol Res 1993; 21:305–308 4. Walsh P C. Benign prostatic hyperplasia. In: Walsh P C et al. (eds). Campbell’s urology, 6th edn. Philadelphia: W B Saunders, 1992:1007–1027 5. Bostwick D G, Cooner W H, Denis L et al. The association of benign prostatic hyperplasia and cancer of the prostate. Cancer 1992; 70:291–301 6. Aoki Y, Arai Y, Maeda H et al. Racial differences in cellular composition of benign prostatic hyperplasia. Prostate 2001; 49:243–250 7. Sanda M G, Beatty T H, Stautzman R E et al. Genetic susceptibility of benign prostatic hyperplasia. J Urol 1994; 151:115–119 8. Partin A W, Sanda M G, Page W F et al. Concordance rates for benign prostatic disease among twins suggest hereditary influence. Urology 1994; 44:646–650 9. Franks L M. Benign nodular hyperplasia of the prostate: a review. Ann R Coll Surg Engl 1954; 14:92– 106 10. McNeal J E. Origin and evolution of benign prostatic enlargement. Invest Urol 1978; 15:340–345

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Page 109 11. McNeal J E. The pathobiology of nodular hyperplasia. In: Bostwick DG ed. Pathology of the prostate. New York: Churchill Livingstone, 1990:31–36 12. Jacobsen S J, Girman C J, Lieber M M. Natural history of benign prostatic hyperplasia. Urology 2001; 58 (Suppl 1): 5–16 13. Geller J. Benign prostatic hyperplasia: pathogenesis and medical therapy. J Am Geriatric Soc 1991; 39:1208–1216 14. Djavan B, Remzi M, Erne B, Marberger M. The pathophysiology of benign prostatic hyperplasia. Drugs Today (Barc) 2002; 38:867–876 15. Peters C A, Walsh P C. The effect of nafarelin acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperplasia. N Engl J Med 1987; 17: 599–604 16. Tsurusaki T, Aoki D, Kanetake H et al. Zone-dependent expression of estrogen receptors alpha and beta in human benign prostatic hyperplasia. J Clin Endocrinol Metab 2003; 88:1333–1340 17. Partin A W, Oesterling J E, Epstein J I et al. Influence of age and endocrine factors on the volume of benign prostatic hyperplasia. J Urol 1991; 145:405–409 18. Gleason P E, Jones J A, Regan J S et al. Platelet derived growth factor (PDGF), androgens and inflammation: possible etiologic factors in the development of prostatic hyperplasia. J Urol 1993; 149:1586–1592 19. Eaton C L. Aetiology and pathogenesis of benign prostatic hyperplasia. Curr Opin Urol 2003; 13:7–10 20. Ropiquet F, Giri D, Lamb D J, Ittmann M. FGF7 and FGF2 are increased in benign prostatic hyperplasia and are associated with increased proliferation. J Urol 1999; 162: 595–599 21. Saez C, Gonzalez-Baena A C, Japon M A et al. Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride. Prostate 1999; 40:83–88 22. Steiner G, Gessl A, Kramer G et al. Phenotype and function of peripheral and prostatic lymphocytes in patients with benign prostatic hyperplasia. J Urol 1994; 151: 480–484 23. Di Silverio F, Gentile V, De Matteis A et al. Distribution of inflammation, pre-malignant lesions, incidental carcinoma in histologically confirmed benign prostatic hyperplasia: a retrospective analysis. Eur Urol 2003; 43: 164–175 24. Helpap B. Histological and immunohistochemical study of chronic prostatic inflammation with and without benign prostatic hyperplasia. J Urol Pathol 1994; 2:49–59 25. Viglione M P, Potter S, Partin A W et al. Should the diagnosis of benign prostatic hyperplasia be made on prostate needle biopsy? Hum Pathol 2002; 33:796–800 26. Egawa S, Ohori M, Uchida T et al. Nodular hyperplasia in the peripheral zone of the prostate gland. Br J Urol 1994; 74:520–521 27. Hamper U M, Sheth S, Walsh O C et al. Stage B adeno carcinoma of the prostate: transrectal US and pathologic correlation of nonmalignant hypoechoic peripheral zone lesion. Radiology 1991; 180:101–104 28. Oyen R H, Van de Voorde W M, Van Poppel H P et al. Benign hyperplastic nodules that originate in the peripheral zone of the prostate. Radiology 1993; 189:707–711 29. Ohori M, Egawa S, Wheeler T M. Nodules resembling nodular hyperplasia in the peripheral zone of the prostate gland. J Urol Pathol 1994; 2:223–233 30. Kawamura S, Takata K, Yoshia I, Matsui S. A case of giant prostatic hypertrophy. Hinyyyokika Kiyo 1984; 30: 1861–1866 31. Fishman J R, Merrill D C. A case of giant prostatic hyperplasia. Urology 1993; 42:336–337 32. Ockerblad N F. Giant prostate: the largest recorded. J Urol 1946; 56:81–82 33. Seppelt U. Correlation among prostate stroma, plasma oestrogen levels and urinary oestrogen excretion in patients with benign prostatic hypertrophy. J Clin Endocrinol Metab 1978; 47:1230–1234 34. Shapiro E, Becich M J, Hartanto V et al. The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostatic hyperplasia. J Urol 1992; 147:1293–1297 35. Costa P, Robert M, Sarrazin B et al. Quantitative topographic distribution of epithelial and mesenchymal components in benign prostatic hypertrophy. Eur Urol 1993; 24:120–123 36. Bartsch G, Muller H R, Oberholzer M, Rohr H P. Light microscopic sterological analysis of the normal human prostate and of benign prostatic hyperplasia. J Urol 1979; 122:487–491 37. Jardin A, Bensadoun A, Tranbaloc P. Constitution de l’adenome prostatique et profil hormonal. In: Legrain M, Chatelain C, eds. Seminaire d’Urologie. Paris: Masson, 1985:11 38. Fukatsu A, Ono Y, Ito M et al. Relationship between serum prostate-specific antigen and calculated epithelial volume. Urology 2003; 61:370–374 39. Chagas M A, Babinski M A, Costa W S, Sampaio F J. Stromal and acinar components of the file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_109.html[09.07.2009 11:52:10]

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transition zone in normal and hyperplastic human prostate. BJU Int 2002; 89:699–702 40. Leav I, McNeal J E, Ho S M, Jiang Z. Alpha-methylacylCO-A racemase (P504S) expression in evolving carcinomas within benign prostatic hyperplasia and in cancers of the transition zone. Hum Pathol 2003; 34:228–233

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Page 110 41. Zhang Y, Nojima S, Nakayama H et al. Characteristics of normal stromal components and their correlation with cancer occurrence in human prostate. Oncol Rep 2003; 10:207–211 42. Hammarsten J, Hogstedt B. Calculated fast-growing benign prostatic hyperplasia—a risk factor for developing clinical prostate cancer. Scand J Urol Nephrol 2002; 36: 330–338 43. Banu N A, Azim F A, Kamal M et al. Inflammation and glandular proliferation in hyperplastic prostates: association with prostate specific antigen value. Bangladesh Med Res Counc Bull 2001; 27:79– 83 44. Eble J N, Tejada E. Cost implications of sampling strategies for prostatic transurethral resection specimens: analysis of 549 cases. Am J Clin Pathol 1986; 85:382 45. Murphy W M, Dean P J, Brasfield J A et al. Incidental carcinoma of the prostate. How much sampling is adequate? Am J Surg Pathol 1986; 10:170–176 46. Rohr L R. Incidental adenocarcinoma in transurethral resection of the prostate. Partial versus complete microscopic examination. Am J Surg Pathol 1987; 11:53–58 47. Vollmer R T. Prostate cancer and chip specimens: complete versus partial sampling. Hum Pathol 1986; 17: 285–290 48. Henson D E, Hutter R V P, Farrow G M. Practice protocol for the examination of specimens removed from patients with carcinoma of the prostate gland. A publication of the Cancer Committee, College of American Pathologists. Arch Pathol Lab Med 1994; 118:779–783 49. Greene DR, Wheeler TM, Egawa S et al. Relationship between clinical stage and histological zone of origin in early prostatic cancer: morphometric analysis. Br J Urol 1991; 68:499–509 50. Franks L M. Atrophy and hyperplasia in prostate proper. J Pathol Bacteriol 1954; 68:617–621 51. Cheville J C, Bostwick D G. Post-atrophic hyperplasia of the prostate. A histologic mimic of prostatic adenocarcinoma Am J Surg Pathol 1995; 19:1068–1076 52. Eble J N, Tejada E. Prostatic stromal hyperplasia with bizarre nuclei. Arch Pathol Lab Med 1991; 115:87–89 53. Leong S S, Vogt P F, Yu G M. Atypical stroma with muscle hyperplasia of prostate. Urology 1988; 31:163–167 54. Devaraj L T, Bostwick D G. Atypical basal cell hyperplasia of the prostate: immunophenotypic profile and proposed classification of basal cell proliferations. Am J Surg Pathol 1993; 17:645–659 55. Grignon D J, Ro J Y, Ordonez N G et al. Basal cell hyperplasia, adenoid basal cell tumor, and adenoid cystic carcinoma of the prostate gland: an immunohistochemical study. Hum Pathol 1988; 19:1425–1433 56. Cleary K R, Choi H Y, Ayala A G. Basal cell hyperplasia of the prostate. Am J Clin Path 1983; 80:850–854 57. Dermer G B. Basal cell proliferation in benign prostatic hyperplasia. Cancer 1978; 41:1857–1862 58. Bonkhoff H, Stein V, Remberger K. Multidirectional differentiation in the normal, hyperplastic, and neoplastic human prostate: simultaneous demonstration of cell-specific epithelial markers. Hum Pathol 1994; 25:42–46 59. Maygarden S, Strom S, Ware J L. Localization of epidermal growth factor receptor by immunohistochemical methods in human prostatic carcinoma, prostatic intraepithelial neoplasia, and benign hyperplasia. Arch Pathol Lab Med 1992; 116:269–273 60. Mellon K, Thompson S, Charlton R G et al. p53, c-erbB-2 and the epidermal growth factor receptor in the benign and malignant and malignant prostate. J Urol 1992; 147: 496–499 61. Ayala A G, Srigley J R, Ro J Y et al. Clear cell cribriform hyperplasia of prostate. Am J Surg Pathol 1986; 10:665–672. 62. Frauenhoffer E E, Ro J Y, El-Naggar A K et al. Clear cell cribriform hyperplasia of the prostate: immunohistochemical and flow cytometric study. Am J Clin Pathol 1991; 95: 446–453 63. Bostwick D G, Srigley J, Grignon D et al. Atypical adenomatous hyperplasia of the prostate: morphologic criteria for its distinction from well-differentiated carcinoma. Hum Pathol 1993; 24:819–832 64. Bostwick D G, Algaba F, Amin M B et al. Consensus statement on terminology: recommendation to use atypical adenomatous hyperplasia in place of adenosis of the prostate. Am J Surg Pathol 1994; 18:1069–1070 65. Bostwick D G, Qian J. Atypical adenomatous hyperplasia of the prostate. Relationship with carcinoma in 217 whole-mount radical prostatectomies. Am J Surg Pathol 1995; 19:506–518 66. Brawn P N, Speights V O, Contin J U et al. Atypical hyperplasia in prostates of 20 to 40 year old men. J Clin Pathol 1989; 42:383–386 67. Gleason D F. Atypical hyperplasia, benign hyperplasia, and well-differentiated adenocarcinoma of the file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_110.html[09.07.2009 11:52:11]

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prostate. Am J Surg Pathol 1985; 9:53–67 68. Epstein J I, Fynheer J. Acidic mucin in the prostate: can it differentiate adenosis from adenocarcinoma? Hum Pathol 1992; 23:1321–1325 69. Goldstein N S, Qian J, Bostwick D G. Mucin expression in atypical adenomatous hyperplasia of the prostate. Hum Pathol 1995; 26:887–891 70. Epstein J I. Adenosis vs. atypical adenomatous hyperplasia of the prostate. Am J Surg Pathol 1994; 18:1070–1071 71. Srigley J R. Small-acinar patterns in the prostate gland with emphasis on atypical adenomatous hyperplasia and small-acinar carcinoma. Semin Diagn Pathol 1988; 5: 254–272

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Page 111 72. Cheng L, Shan A, Cheville J C et al. Atypical adenomatous hyperplasia of the prostate: a premalignant lesion? Cancer Res 1998; 58:389–391 73. Cunningham J M, Shan A, Wick M J et al. Allelic imbalance and microsatellite instability in prostatic adenocarcinoma. Cancer Res 1996; 56:4475–4482 74. Helpap B. The biological significance of atypical hyperplasia of the prostate. Virchows Arch A Pathol Anat Histol 1980; 387:307–317 75. Renshaw AA, Santis WF, Ritchie JP. Clinicopathologic characteristics of prostatic adenocarcinoma in men with atypical prostate needle biopsies. J Urol 1998; 159: 2018–2022 76. Iczkowski K A, MacLennan G T, Bostwick D G. Atypical small acinar proliferation of the prostate suspicious for malignancy in needle biopsies: histologic features and clinical significance in 33 cases. Am J Surg Pathol 1997; 21:1489–1495 77. Bostwick D G, Qian J, Frankel K. The incidence of high grade prostatic intraepithelial neoplasia in needle biopsies. J Urol 1995; 154:1791–1794 78. Weinstein M H, Epstein J I. Significance of high grade prostatic intraepithelial neoplasia on needle biopsy. Hum Pathol 1993; 24:624–629 79. Cheville J C, Reznicek M J, Clark J R et al. The focus of atypical glands suspicious for malignancy in prostate needle biopsy specimens: incidence, histologic features, and clinical follow-up of cases diagnosed in a community practice. Am J Clin Pathol 1997; 108:633–640 80. Hoedemaeker R F, Kraanse R, Rietbergen J B et al. Evaluation of prostate needle biopsies in a populationbased screening study: the impact of borderline lesions. Cancer 1999; 85:145–152 81. Orozco R, O’Dowd G, Kunnel B et al. Observations on pathology trends in 62,537 prostate biopsies obtained from urology practices in the United States. Urology 1998; 51:186–195 82. Iczkowski K A, Bostwick D G. Prostate biopsy 1999: strategies and significance of pathological findings. Semin Urol Oncol 1999; 17:177–186 83. Iczkowski K A, Bassler T J, Schwob V S et al. Diagnosis of ‘suspicious for malignancy’ in prostate biopsies: predictive value for cancer. Urology 1998; 51:749–758 84. Chen K T K, Schiff J J. Adenomatoid prostatic tumor. Urology 1983; 21:88–89 85. Collina G, Botticelli A R, Martinelli A M et al. Sclerosing adenosis of the prostate. Report of three cases with electronmicroscopy and immunohistochemical study. Histopathol 1992; 20:505–510 86. Grignon D J, Ro J Y, Srigley J R et al. Sclerosing adenosis of the prostate gland. A lesion showing myoepithelial differentiation. Am J Surg Pathol 1992; 16:383–391 87. Hulman G. ‘Pseudoadenomatoid’ tumor of prostate. Histopathol 1989; 14:317–323 88. Jones E C, Clement P B, Young R H. Sclerosing adenosis of the prostate gland. A clinicopathologic and immunohistochemical study of 11 cases. Am J Surg Pathol 1991; 15:1171–1180 89. Sakamoto N, Tsuneyoshi M, Enjoji M. Sclerosing adenosis of the prostate. Histopathologic and immunohistochemical analysis. Am J Surg Pathol 1991; 15:660–667 90. Young R H, Clement P B. Sclerosing adenosis of the prostate. Arch Pathol Lab Med 1987; 11:363– 366 91. Gagucas R J, Brown R W, Wheeler T M. Verumontanum mucosal gland hyperplasia. Am J Surg Pathol 1995; 19: 30–36 92. Gikas P, Del Buono E A, Epstein J I. Florid hyperplasia of mesonephric remnants involving prostate and periprostatic tissue: possible confusion with adenocarcinoma. Am J Surg Pathol 1992; 16:454–459

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Page 113 7 Bladder responses to obstruction G E Lemack J D McConnell Introduction The response of the bladder to infravesical obstruction varies with the duration, severity, and nature of the obstruction. Due to the inherent variability in this response, and the difficulty we, as clinicians, experience in accurately assessing these factors which affect the bladder response, a variety of symptoms may be associated with bladder outlet obstruction (BOO) in men with benign prostatic hyperplasia (BPH). Ultimately, the raised intravesical pressure caused by the combination of a fixed obstruction and the compensatory detrusor response to overcome that obstruction are thought to lead to a cascade of events resulting in changes in smooth muscle appearance and function, extracellular matrix (ECM) deposition, and detrusor innervation. The symptoms experienced and the functional effects uncovered during evaluation of BOO reflect the many changes occurring both within, and surrounding, detrusor smooth muscle cells. Response of the human bladder to obstruction—clinical studies Data collected from boys with congenital causes of outlet obstruction provide some of the best information on the natural response of the human bladder to BOO.1,2 Functionally, these boys are found to have a variety of bladder findings, including altered compliance, detrusor overactivity (DO), and myogenic failure, long after relief of obstruction, which typifies some of the most common findings seen after long-term BOO. In fact, the bladder dysfunction seen in these boys is thought to account for the incontinence that some will experience even after BOO relief. In adults, deciphering the effects of obstruction is often more difficult since the nature, duration, and severity are not always evident, and since changes in bladder function are commonly seen with aging, regardless of the presence of coexisting obstruction.3,4 In general, however, DO is found more often in men with BOO (in as many as 50–60% of patients), although there is no obvious link between the severity of obstruction and likelihood of finding DO.5 Similarly, overactivity dissipates after relief of obstruction in only 50–70% of cases, implying that the bladder dysfunction induced by BOO may be partially responsible for the symptom complex referred to as ‘prostatism’.6 While there are abundant data from animal studies that detrusor contractility suffers as a result of BOO, there is only indirect evidence from data collected among men with BPH to support this concept. Indeed, many men with BPH will be found to have hypocontractile bladders, although a direct association between the two entities has not been proven.7 Furthermore, it is clear that bladder decompensation does not always result from expectantly following men with urodynamically proven BOO who refused intervention.8 Nonetheless, some authors have argued that relative detrusor hypocontractility preoperatively can predict treatment failure after transurethral resection of the prostate (TURP).9 The physiologic alterations in bladder function underscoring the signs and symptoms associated with BOO are thought to occur as a result of a phenotypic modulation in the detrusor smooth muscle cell. Contractility and metabolism of smooth muscle cells, local ECM expression, and communication between neighboring cells are all affected. Together, these and other changes are thought to impact on the overall organ function by altering the ability of the bladder to store at low pressures, and empty effectively. The following discussion focuses on the animal models of partial bladder outlet obstruction which have provided the experimental data to support these concepts. Animal physiologic studies Animal models of partial bladder outlet obstruction have included rabbit,10 guinea pig,11 and rat,12 as well as fetal sheep and lamb models.13–14 Through the analysis of these and other models, the etiology of obstruction-induced bladder dysfunction has been clarified. Several pieces of evidence suggest that a relative ischemia in the detrusor layer is created by the raised intravesical pressures seen with BOO, and that the physiologic changes seen soon after obstruction reflect a response to that ischemia.15–17 It is clear, though, that the hypoxia of obstruction may not be evenly distributed throughout the bladder,18 and so the

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Page 114 impact on the various contractile properties may not necessarily be evenly distributed.19 Overall, several growth factors have been shown to be either enhanced (basic fibroblast growth factor) or suppressed (transforming growth factor beta) in the bladder,20 in association with the relative ischemia. It has also been shown that several proto-oncogenes appear to be temporally upregulated with obstruction. Changes in ECM deposition, and smooth muscle appearance, metabolism, contractility, and innervation, develop in conjunction with the ischemia experienced during BOO, and all contribute to the altered bladder function noted with infravesical obstruction (Fig. 7.1). Extracellular matrix changes A rapid increase in bladder weight is typical of almost all animal models of BOO, which may be as high as 8-fold depending on the severity and duration of obstruction. Among the changes in bladder wall architecture responsible for this rapid weight gain is a deposition of ECM proteins, largely collagen, both between and with smooth muscle fascicles (Fig.7.2). In some animal models, a dense subserosal deposition of collagen has been noted. Mature smooth muscle cells themselves are probably at least partially responsible for the collagen deposition, although it is likely that primitive mesenchymal cells can be transformed to myofibroblasts which are capable of synthesizing collagen.21 While total collagen content is increased after obstruction, its concentration is actually decreased, due to the tremendous smooth muscle hypertrophy. For this reason, some authors have suggested that the type of collagen may be a more important determinant of bladder function than the amount. In this regard, an increase in collagen type III has been noted in noncompliant human bladder tissue.22 Overall, it appears that altered collagen deposition, and particularly the subtype, affects the passive mechanical properties of the bladder, dramatically altering bladder wall stiffness.23 Changes in smooth muscle phenotype Smooth muscle hypertrophy appears to be the predominant histologic alteration seen following most forms of outlet obstruction, and is largely responsible for the tremendous increase in muscle mass seen in most models (Fig. 7.2).12 Interestingly, force production (measured either by whole bladder emptying or force generation per cross-sectional area of detrusor muscle strip) is reduced in association with this large increase in muscle mass.24 While a few authors have noted both smooth muscle and urothelial hyperplasia after BOO based on tritiated thymidine uptake studies, this is clearly not as universal a finding as hypertrophy. Ultrastructural changes in smooth muscle cells are also apparent in the obstructed bladder. Intermediate (adherens type) junctions, which provide physical

Figure 7.1 Cascade of events following bladder outlet obstruction resulting in bladder dysfunction. NGF, PVR, postvoid residual; UTI, urinary tract infection; Pdet, detrusor pressure

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Figure 7.2 (a) Trichrome stain of detrusor from control rabbit bladder (5.4×): green, collagen; red, smooth muscle. (b) Trichrome stain of detrusor from 6-week-obstructed rabbit bladder. Note thick collagen deposition between muscle fascicles, apparent increased size of individual muscle cells (hypertrophy), as well as increased fascicle size. coupling between neighboring cells, are altered after obstruction.25 The result is a loss of coordinated mechanical activity between cells. Additionally, abnormal protrusion junctions between adjacent cells seem to develop following BOO, which may cause aberrant electrical coupling. This ultrastructural finding may be the anatomic correlate for detrusor overactivity often seen in patients with BOO, although others have attributed this phenomenon to abnormal Na/K membrane pump activity26 or altered innervation. Changes in smooth muscle contractility Severity of infravesical obstruction appears to affect contractility to a greater extent than duration or type of obstruction. Mild obstruction has been shown to enhance the contractile response in some models, depending on the type of stimulation (cholinergic versus electrical field stimulation), while severe obstruction appears to universally decrease contractility. In many animal models, soon after obstruction there is an enhanced or supranormal contractile response, which diminishes with time and eventually leads to significant hypocontractility after longer durations of obstruction.12 In general, since in vitro muscle strip physiology studies may underestimate the emptying ability of the whole bladder, it appears likely that a significant impairment of normal micturition exists after 3–6 months of BOO. It also appears as though the detrusor response to adrenergic stimulation (relaxation in response to beta stimulation and contraction in response to alpha stimulation) is also blunted following severe BOO.27 Another interesting observation from obstructed bladders has been the finding of alternate stimulation pathways for smooth muscle. Normal bladders can be stimulated by cholinergic activation, electrical stimulation, or membrane depolarization, and in obstructed bladders a more prominent role for nonadrenergic noncholinergic (NANC) stimulation appears to be present (most typically purinergic). In addition, in most normal bladders, atropine will completely abolish cholinergically induced contractions, whereas in obstructed bladders, atropine resistance has been demonstrated.28 Thus, it appears as though alternate routes for smooth muscle stimulation may be present in obstructed bladders. Etiology for contractile dysfunction Contractile protein alterations: myosin and caldesmon protein studies Myosin light chain kinase, activated by the binding of calcium to calmodulin, phosphorylates the myosin light chain (MLC) which then activates cross-bridge cycling. Myosin and actin interactions follow, which result in shortening and force generation.29,30 Myosin is composed of two heavy chains (MHCs) and two pairs of MLCs. Four isoforms of smooth muscle (SM) MHC are produced by alternative splicing at the 5′ and 3′ ends of the primary transcript.31,32 SM1 or SM2 isoforms are produced by alternative splicing of a 39-base pair exon at the 3′ end (C terminal). The ratio of these isoforms appears to be developmentally regulated. The SM1 isoform predominates in dedifferentiated smooth muscle cells isolated in culture, and during fetal development in the rabbit bladder. In the normal adult rabbit bladder, however, there is a slight predominance of the SM2 isoform of MHC.33 Using Northern blot and S1 nuclease protection assays to study MHC expression in the obstructed rabbit bladder, it has been shown that there is both a downregulation in the

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Page 116 total MHC expression and a shift to SM1 expression with obstruction.34 A similar shift in isoform production has been found at the protein level as well.33 Two different isoforms, SMA and SMB, are derived from alternate splicing of a 21-base pair exon at the 5′ end (N terminal) near the region encoding the ATP pocket of the myosin molecule. Partial BOO also appears to affect the relative expression of these isoforms, with SMA predominating after BOO.35 These findings suggest that obstruction-induced hypertrophy produces a change in alternate splicing of the MHC gene product, downregulation of MHC expression, and is associated with a dedifferentiated state of the smooth muscle cell. Interestingly, changes in isoform expression induced by BOO may be reversible when contractility is restored by certain types of medical treatment for BPH.36 Caldesmon is another important regulatory protein in the smooth muscle cell; it both modulates contraction and maintains the ‘latch state’.37 Two isoforms of caldesmon exist within smooth muscle: a high-molecular weight form (h-form) is present in normal smooth muscle and a low-molecular weight form (l-form) is present in fibroblasts and smooth muscle cells in culture. Interestingly, studies have shown that obstruction induces expression of l-caldesmon, consistent with a reversion to a dedifferentiated state.38 Changes in smooth muscle metabolism Aerobic metabolism of glucose is primarily responsible for the ATP needed to drive contractile function in the normal bladder. Lowering the oxygen tension or decreasing the availability of glucose both lead to decreased force generation by forcing the detrusor to rely on more inefficient means of producing ATP In smooth muscle cells from obstructed bladders there is a decreased availability of ATP, perhaps due to a shift to anaerobic metabolism.39 In fact, it has been suggested that mitochondrial dysfunction is responsible for the hypocontractility seen in obstructed or ischemic bladders.40 Thus, the combination of increased metabolic demands due to outflow restriction and inefficient energy production probably contribute significantly to the hypocontractility seen with BOO. Alterations in calcium mobilization The interaction of calcium and calmodulin is required to initiate the sequence of events leading to muscle contraction. If intracellular calcium is not present in sufficient quantities, actin/myosin interactions cannot take place regardless of how much ATP is being generated. The smooth muscle cell can acquire calcium by mobilizing from intracellular stores in the sarcoplasmic reticulum (SR) or through extracellular influx. It has been demonstrated that obstruction appears to disrupt the normal mechanisms that trigger the release of calcium from SR stores.41,42 In fact, it has been suggested that alterations in contraction kinetics seen with BOO (i.e. time to achieve maximal tension) are directly influenced by the inability of the cell to mobilize calcium from the SR. Obstruction-induced alterations in bladder innervation Degeneration of axonal elements has been noted in obstructed bladders from humans and animals, which seems to corroborate the finding that electrically induced contractions are impaired in strips taken from these bladders.25,43 Denervation supersensitivity, a concept used to explain the finding of a supranormal response to cholinergic stimulation during in vitro muscle physiology studies and the clinical syndrome of DO, has been advocated by some authors on the basis of the histologic finding of neuronal loss.44 However, other authors have attributed DO to abnormal cell intercommunications. These authors suggest that, while neuronal degeneration may be present, it is not responsible for DO. Moreover, there is growing evidence from other animal models that nerve growth, not loss, is induced by BOO, and that these changes may be responsible for the clinical syndrome of urgency.45 Indeed, there is increased expression of the neurotropic factors, nerve growth factor (NGF)46 and brain-derived neurotrophic factor47 after BOO, both of which may contribute to the neural plasticity that accompanies BOO. Conclusions After partial bladder outlet obstruction in animal models there is a rapid increase in bladder weight that seems to be largely due to smooth muscle hypertrophy. Extracellular matrix deposition (largely collagen) also occurs which most likely affects the passive mechanical properties of the bladder, particularly compliance. Along with hypertrophy, the smooth muscle cell experiences changes in contractile protein expression to a more dedifferentiated pattern. Additional changes in energy metabolism, calcium regulation, and innervation, all seemingly induced by the ischemic state associated with BOO, are typical of the obstructed smooth muscle cell. As a result of these changes, smooth muscle hypocontractility may result and, at the organ level, bladder emptying eventually is impaired.

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Page 117 References 1. Bauer S B, Dieppa R A, Labib K K et al. The bladder in boys with posterior urethral valves: a urodynamic assessment. J Urol 1979; 121:769–773 2. Campaiola J M, Perlmutter A D, Steinhardt G F. Noncompliant bladder resulting from posterior urethral valves. J Urol 1985; 134:708–710 3. Andersen J T, Jacobsen O, Worm-Petersen J et al. Bladder function in healthy elderly males. Scand J Urol Nephrol 1978; 12:123–127 4. Andersen J T, Nordling J, Walter S. Prostatism I: the correlation between symptoms, cystometric and urodynamic findings. Scand J Urol Nephrol 1979; 13:229–236 5. Abrams P. Detrusor instability and bladder outlet obstruction. Neurourol Urodyn 1985; 4:317–320 6. Andersen J T. Prostatism III: detrusor hyperreflexia and residual urine: clinical and urodynamic aspects and influence of surgery on the prostate. Scand J Urol Nephrol 1982; 16:25–30 7. Kaplan S A, Bowers D L, Te A E et al. Differential diagnosis of prostatism: a 12-year retrospective analysis of symptoms, urodynamics and satisfaction with therapy. J Urol 1996; 155:1305–1308 8. George N J R, Fenely R C L, Robert J B M. Identification of the poor risk patient with ‘prostatism’ and detrusor failure. Br J Urol 1986; 58:290–295 9. Djavan B, Madersbacher S, Klingler C et al. Urodynamic assessment of patients with acute urinary retention: is treatment failure after prostatectomy predictable? J Urol 1997; 158:1829–1833 10. Saito M, Wein A J, Levin R M. Effect of partial outlet obstruction on contractility: comparison between severe and mild obstruction. Neurourol Urodyn 1993; 12: 573–583 11. Mostwin J L, Karim O M A, Van Koeveringe G. The guinea pig model of gradual urethral obstruction. J Urol 1991; 145:854–858 12. Saito M, Longhurst P A, Tammela T L J et al. Effects of partial outlet obstruction of the rat urinary bladder on micturition characteristics, DNA synthesis and the contractile response to field stimulation and pharmacologic agents. J Urol 1993; 150:1045–1051 13. Karim O M A, Cendron M, Mostwin J L et al. Developmental alterations in the fetal lamb bladder subjected to partial urethral obstruction in utero. J Urol 1993; 150:1060–1065 14. Nyirady P, Thiruchelvam N, Fry C H et al. Effects of in utero bladder outflow obstruction on fetal sheep detrusor contractility, compliance and innervation. J Urol 2002; 168:1615–1620 15. Finkbeiner A, Lapides J. Effect of distension on blood flow in dog’s urinary bladder. Invest Urol 1974; 12:210–212 16. Brading A F. Alterations in the physiological properties of urinary bladder smooth muscle caused by bladder emptying against an obstruction. Scand J Urol Nephrol 1997; 31 (Suppl): 51–58 17. Lemack G E, Burkhart F, Zimmern P E et al. Physiologic sequelae of partial infravesical obstruction in the mouse: role of inducible nitric oxide synthase. J Urol 1999; 161: 1015–1020 18. Levin R M, O’Connor L J, Leggett R E et al. Focal hypoxia of the obstructed rabbit bladder wall correlated with intermediate decompensation. Neurourol Urodyn 2003; 22:156–163 19. Schroder A, Uvelius B, Capello S A et al. Regional differences in bladder enlargement and in vitro contractility after outlet obstruction in the rabbit. J Urol 2002; 168: 1240–1246 20. Buttyan R, Jacobs B Z, Blaivas J G et al. Early molecular response to rabbit bladder outlet obstruction. Neurourol Urodyn 1992; 11:225–238 21. Buoro A, Ferrarese P, Chiavegato A et al. Myofibroblastderived smooth muscle cells during remodeling of rabbit urinary bladder wall induced by partial outflow obstruction. Lab Invest 1993; 69:589–602 22. Kaplan E P, Richier J C, Howard P S et al. Type III collagen messenger RNA is modulated in noncompliant human bladder tissue. J Urol 1997; 157:2366–2369 23. Damaser MS, Arner A, Uvelius B. Partial outlet obstruc tion induces chronic distension and increased stiffness of rat urinary bladder. Neurourol Urodyn 1996; 15:650–665 24. Levin R M, Longhurst P A, Monson F C et al. Effect of bladder outlet obstruction on the morphology, physiology, and pharmacology of the bladder. Prostate 1990; 3 (Suppl): 9–26 25. Elbadawi A, Yalla S, Resnick N M. Structural basis of geriatric voiding dysfunction. IV. Bladder outlet obstruction. J Urol 1993; 150:1681–1695 26. Seki N, Karim O M A, Mostwin J. The effect of experimental urethral obstruction and its reversal on changes in passive electrical properties of detrusor muscle. J Urol 1992; 148:1957–1961 27. Moore C K, Levendusky M, Longhurst P A. Relationship of mass of obstructed rat bladders and responsiveness to adrenergic stimulation. J Urol 2002; 168:1621–1625 28. van Koeveringe G A, Mostwin J L, van Mastrigt R et al. Effect of partial urethral obstruction of force file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_117.html[09.07.2009 11:52:14]

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development of the guinea pig bladder. Neurourol Urodyn 1993; 12: 555–571 29. Aksoy M O, Murphy, R A, Kamm, K E. Role of Ca2+ and myosin light chain phosphorylation in regulation of smooth muscle. Am J Physiol 1982; 242: C109–116

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Page 118 30. Kamm K E, Stull J T. Regulation of smooth muscle contractile elements by second messengers. Annu Rev Physiol 1989; 51:299–313 31. Rovner A S, Thompson M M, Murphy R A. Two different heavy chains are found in smooth muscle myosin. Am J Physiol 1986; 250:C861–870 32. Nagai R, Kuro-o M, Babij P et al. Identification of two different types of smooth muscle myosin heavy chain isoforms by cDNA cloning and immunoblot assay. J Biol Chem 1989; 264:9734–9737 33. Abernathy B B, Kadesky K T, McConnell J D. Myofilament protein alterations in the obstructed rabbit bladder. J Urol 1988; 139:195A 34. Cher M L, Abernathy B B, McConnell J D et al. Smooth muscle myosin heavy-chain isoform expression in bladderoutlet obstruction. World J Urol 1996; 14:295–300 35. Mannikarottu A, Disanto M E, Zderic S A et al. Regional variations of myosin II isoforms. The molecular motor for smooth muscle contraction in response to partial bladder outlet obstruction. J Urol 2003; 169:125 (abstract) 36. Gomes C M, Disanto M E, Horan P et al. Improved contractility of obstructed bladders after Tadenan treatment is associated with reversal of altered myosin isoform expression. J Urol 2000; 163:2008–2013 37. Sobue K, Kanda K, Tanaka T et al. Caldesmon: a common actin-linked regulatory protein in the smooth muscle and non-muscle contractile system. J Cell Biochem 1988; 337: 317–325 38. Lin V K, Lee I L, McConnell J D. Expression of 1-caldesmon in obstruction-induced bladder hypertrophy. J Cell Biol 1991; 115:1380a 39. Kato K, Lin A T-L, Haugaard N et al. Effects of outlet obstruction on glucose metabolism of the rabbit urinary bladder. J Urol 1990; 143:844–847 40. Lin A T L, Chen M T, Yang C H. Blood flow of the urinary bladder: effects of outlet obstruction and correlation with energetic metabolism. Neurourol Urodyn 1993; 149: 285–292 41. Saito M, Hypolite J A, Wein A J et al. Effect of partial outflow obstruction on rat detrusor contractility and intracellular free calcium concentration. Neurourol Urodyn 1994; 13:297–305 42. Levin R M, Yu H-J, Kim K-B et al. Etiology of bladder dysfunction secondary to partial outlet obstruction. Calcium disregulation in bladder power generation and the ability to perform work. Scand J Urol Nephrol 1997; 184 (Suppl): 43–50 43. Elbadawi A, Meyer S, Malcowicz S B et al. Effects of shortterm partial bladder outlet obstruction on the rabbit detrusor: an ultrastructural study. Neurourol Urodyn 1989; 8:89–116 44. Speakman M J, Bradin, A F, Gilpin C J et al. Bladder out-flow obstruction—a cause of denervation supersensitivity. J Urol 1987; 138:1461–1466 45. Steers WD, Ciambotti J, Etzel B et al. Alterations in afferent pathways from the urinary bladder of the rat in response to partial urethral obstruction. J Comp Neurol 1991; 310:401–410 46. Dupont M C, Persson K, Spitskergent D et al. The neuronal response to bladder outlet obstruction, a role for NGF. Adv Exp Med Biol 1995; 385:41–54 47. Zvara P, Kliment J, DeRoss A L et al. Differential expression of bladder neurotrophic factor mRNA in male and female rats after bladder outflow obstruction. J Urol 2002; 168:2682–2688

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Page 119 8 Molecular genetics of benign prostatic hyperplasia S F Shariat E I Canto K M Slawin Introduction The reported correlation between objective parameters of lower urinary tract function and subjective symptoms in patients diagnosed with BPH is variable. In contrast, the fact that prostate size increases with advancing age is widely accepted. The apparently inexorable growth of the prostate seems in most cases to be closely associated with the pathologic process of BPH. In fact, numerous studies have demonstrated that significant prostate growth does not occur in the absence of pathologic nodular hyperplasia. Therefore, given the observed ubiquity of age-dependent prostate growth, the high prevalence of pathologic BPH is not surprising. Autopsy studies have demonstrated that approximately 50% of men have histologic evidence of BPH by age 60, and 80% by age 80.1 This close association between prostate growth and pathologic BPH exists precisely because, to a large extent, prostate ‘growth’ is the direct consequence of this pathologic process, a process that eventually produces multiple, enlarging macroscopic nodules within the prostate. This reproducible progression of specific events begins with the formation of periurethral and transition zone stromal nodules, which is followed by convergent epithelial ingrowth and budding and branching morphogenesis within these micronodules, and culminates in the macroscopic enlargement of these ‘BPH’ nodules.2 Pathologic BPH occurs almost exclusively in the periurethral and transition zones of the prostate. The presence of nodular BPH within the peripheral zone is so rare, in fact, as to have been the subject of a case report.3 This highly orchestrated, spatially restricted, progression of events suggests that the pathophysiology of BPH is a genetically controlled process. It remains unclear whether this genetic program results directly from genetic alterations that develop within the cells of the prostate gland itself, or whether the host’s genetic makeup controls this process indirectly via effects on overall host physiology, e.g. hormonal milieu or genetically determined ‘susceptibility’ polymorphisms. The most likely explanation is that a combination of direct and indirect genetic mechanisms, as well as epigenetic factors, all play a role in the development and progression of pathologic BPH. Molecular basis of benign diseases The first discoveries of oncogenes and tumor suppressor genes in the 1970s confirmed that cancer is a genetic disease. Not unexpectedly, many of the key events associated with multistep carcinogenesis involve the alteration of genes directly involved in cell cycle regulation and signaling pathways directing cellular growth control within tumor tissues. Subsequently, molecular techniques first used to identify the genetic determinants of cancer have been used to demonstrate that many benign tumors and other benign diseases, once thought to be strictly due to environmental or other epigenetic causes, have a genetic basis as well For many types of benign tumors, specific genetic alterations have been identified within the genomic DNA of the tumor cells. Cytogenetic analysis of more than 2000 benign solid tumors has revealed the presence of a variety of specific chromosomal aberrations. Among these abnormalities, rearrangements of either 12q14–15 (HMGIC) or 6p21 (HMGIY) have been identified frequently within different types of benign mesenchymal tumors,4,5 including benign lipomas,6–8 uterine leiomyomas,9–12 pulmonary chondroid hamartomas,13–16 pleomorphic adenomas of the salivary glands,17,18 endometrial polyps,19–22 and breast fibroadenomas.23 Some of these benign tumor types exhibit pathologic and epidemiologic similarities to nodular BPH. For example, uterine leiomyomata, benign smooth muscle tumors of the female uterus, are the most commonly found pelvic tumors in women and the leading cause of hysterectomy. These tumors demonstrate abnormal expression of estrogen-regulated genes, indicating that the sex steroid, estrogen, likely plays a significant role in their pathophysiology.24,25 Similarly, the development of stromal nodules and the permissive requirement for androgens are prominent features in the pathophysiology of BPH. Uterine leiomyomata are characterized by the nonrandom involvement of at least four commonly altered cytogenetic regions: 12q14–15 abnormalities,11,12,26 7q deletions,27–29 3q deletions,30 or rearrangements involving 6p21.9–10 These and other similar findings from other extensive cytogenic studies of benign tumors have finally dispelled the myth that genetic alterations are associated solely with malignancy.

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Page 120 With the ‘genetic lens’ focused now on a wide variety of diseases, new associations linking common diseases to genetic determinants are routinely made. For example, up to 65% of the cases of type I diabetes mellitus have now been associated with susceptibility genes in the HLA region on chromosome 6p21, the insulin gene on chromosome 11p15, or with at least eight additional susceptibility genes currently under investigation.31 Similarly, a large number of susceptibility genes (e.g. the insulin receptor gene on chromosome 19p13,32,33 glycogen synthase gene,34,35 glucokinase gene,36,37 MODY genes,38 leptin gene,39 and several glucose transporter genes40,41 have been shown to contribute to type II diabetes mellitus. However, most investigators agree that a combination of genetic and environmental susceptibility factors act in concert to cause disease. While susceptibility to disease may be inherited, an environmental trigger often appears necessary to produce overt disease. BPH as a hereditary disease: results of genetic linkage analyses Over the past 5 years, efforts to identify genes and hereditary factors involved in the pathogenesis of BPH have escalated. One approach has been to define a hereditary form of BPH and then perform classical linkage analysis within families affected by the hereditary form of this disease in an attempt to identify genes responsible for hereditary BPH (Table 8.1). Genes responsible for the hereditary form of any disease, which is often characterized by an earlier age-of-onset and a more rapid progression, often play a role in nonhereditary, or ‘sporadic’ forms of the same disease. For example, alterations of the APC gene, found within the germline of families with hereditary familial adenomatous polyposis (FAP),42–46 are also found as somatic alterations in over 80% of both sporadic colon adenomas47 and sporadic (nonhereditary) colon cancers found within the general population.48–50 It has been difficult, however, to study BPH by these methods because of the complexity and diversity of criteria used to diagnose BPH. In addition to the broad spectrum of histologic findings in men with pathologic BPH,51,52 the poor correlation between lower urinary tract symptoms, prostate volume, bladder outlet obstruction, and indications for BPH surgery, has made it difficult, if not impossible, to select a homogeneous population of patients for study. Despite these caveats, Sanda et al. performed a case-control study of familial clustering of clinical BPH.53 They studied a subset of men in the youngest quartile (under age 64) with relative prostate volumes in the highest quartile (more than 37 g of tissue resected) selected from a cohort of 909 consecutive prostatectomy patients whose surgery was performed for histologically confirmed BPH. The families of these selected patients were compared to a control group of the families of both the patients’ spouses and the spouses of men who underwent radical prostatectomy during the same interval. Firstdegree male relatives of these young men with larger volume BPH were found to have a 4-fold greater risk of undergoing prostatectomy for BPH during their lifetime than males in control families (cumulative lifetime risk of 66% vs 17%, p =0.001), while brothers had a 6-fold increase in risk ( p =0.0089) compared to the brothers of controls. A segregation analysis, which examined for Mendelian and nongenetic models, suggested that Mendelian dominant inheritance of a high-risk gene accounted best for this familial aggregation of BPH. Doehring et al. studied the histopathologic features of 12 prostatectomy specimens from patients in this original study, and compared them to 35 age-matched control specimens, and 36 prostate weightmatched control specimens.54 They found that these specimens were characterized by a higher stromal/epithelial ratio than found in similar-sized prostates from older men with sporadic BPH, thus giving rise to speculation that the familial-associated form of BPH may be associated with a disproportionate increase in stromal elements. Previous reports had indicated that the proportion of epithelium increased with prostate size in older men undergoing prostatectomy for BPH (sporadic BPH patients).51,52,55–57 This analysis suggested that the familial form of BPH affects the stroma more than the sporadic form of BPH, and leads to a more proportionate increase in both stromal and epithelial elements than typically found in cases of sporadic BPH. Because only young patients with large-volume prostates who had undergone prostatectomy were selected for analysis, these initial studies were not designed to ascertain the true relationship between hereditary BPH (H-BPH), age of disease onset, and prostate volume, since a proportion of patients relegated to the control groups might also have had a hereditary form of the disease. Furthermore, since the clinical indications for proceeding to prostatectomy are often varied and somewhat arbitrary, the study population may have reflected these additional biases. A follow-up study by the same investigators attempted to correct these biases by defining familial BPH as that occurring in patients having three or more affected family members (including the proband), irrespective of patient age or prostate volume.58 BPH was defined in this study simply as ‘a history of BPH’ rather than a history

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Page 121 Table 8.1 Evidence of hereditary factors in benign prostatic hyperplasia (H-BPH). ReferencePatientsControls Population Results characteristics Sanda et 46 92 (spouses of Prostatectomy patients Risk factors of prostatectomy for BPH; al.53 cases and of Early age at onset (<64 •4-fold increase in age-specific risk for contemporary RRP years) relatives patients) Large prostate (>37 g •6-fold increase in risk for siblings. resected tissue) Suggests Mendelian dominant inheritance of hereditary BPH through a high-risk infrequent allele. Doehring 12 36 (age-matched) Mean age=59 years Stromal/epithelial ratio: et al.54 36 (prostateMean prostate •H-BPH group=2.6±1.4 weight-matched) weight=61 g •Controls (age)=2.7±1.7 •Controls (prostate weight)=1.7±0.9 Familial form of BPH is more of a stromal disease than sporadic, when controlling for prostate weight. Sanda et 69 345 Familial BPH-3 or more Familial BPH vs sporadic BPH: al.58 family members •Mean prostate volume: 82.7 vs 55.5ml (including the proband) North American phase •No differences noted in age, symptom III finasteride trial score, urinary flow rate, testosterone, patients dihydrotestosterone, or response to finasteride. Familial BPH is associated with large prostate size. Hereditary factors control prostate growth in familial BPH. Partin et 129 MZ   256 twin pairs; Relative risk for BPH=3.3 in monozygotic al.152 twins 112 DZ one ( n =231) or both Probability of BPH in a co-twin of an ( n =25) affected twin with clinical BPH (probandwise concordance rate); •25.7% for monozygotic (MZ) twins •8.5% for dizygotic (DZ) twins Concordance rate for BPH greater among MZ than DZ twins. Roberts 440 1679 Community-based, Cases with family history of ‘enlarged et al.61 Olmsted County, MN prostate’ vs controls Age range: 40–79 years Family history: a single •Moderate/severe urinary symptoms (odds relative, father or ratio 1.3) brother with enlarged •Impaired peak urinary flow rate (odds prostate ratio 1.3). Increased risk of developing BPH symptoms if relative is diagnosed at a younger age (odds ratio 2.5).

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Page 122 of prostatectomy. In an analysis of patients enrolled in the North American phase III finasteride clinical trial as the study population, 69 patients, categorized as having familial BPH, were compared to 345 control patients with respect to baseline prostate volume, patient’s age, maximum urinary flow rate, symptom score, serum prostatespecific antigen (PSA), and testosterone and dihydrotestosterone levels. Familial BPH was found to be associated with a larger baseline prostate volume (mean 82.7 ml vs 55.5 ml, p =0.001), but with similar mean age, symptom scores, flow rates, serum androgen levels, and serum PSA levels. Thus, while the hypothesis of their earlier studies that familial BPH was associated with larger prostate volumes was confirmed, no association with patient age was demonstrated, questioning the original notion that familial BPH was associated with younger patients. However, it is well known that the inclusion criteria for patients enrolled in the North American phase III finasteride clinical trial included ‘an enlarged prostate on digital rectal examination’.59 This resulted in a mean baseline prostate volume in enrolled patients of 59.9 ml, significantly higher than the baseline mean prostate volume of patients enrolled in other BPH medical therapy trials that did not include this criterion.60 As a consequence, the observations regarding familial BPH made in the study of Sanda et al. may not be applicable to a broader range of patients with BPH as defined by the presence of lower urinary tract symptoms or reduced flow rates. In a study of a broader-based population, not limited to patients treated medically or surgically for BPH, Roberts et al. examined the association between familial BPH and the severity of urinary symptoms within a large, carefully studied, community-based longitudinal cohort of men living in Olmsted County, MN.61 From the initially enrolled cohort of 2119 men, symptom assessment and bother scores were obtained via a self-administered questionnaire. In addition, family history of ‘an enlarged prostate’ was determined during a face-to-face interview, but self-reported family history was later validated using information from the medical records. Men with even a single affected first-degree relative were categorized as having a family history of BPH. The study found that the risk of moderate or severe urinary symptoms, or of an impaired peak urinary flow rate, was 1.3 times greater in men who had a family history of BPH than in men who did not. This risk was greater for men whose relatives were diagnosed at a young age (less than 60 years) and for men with an affected brother, than for men with an affected father. Although all of these studies vary in their methods and conclusions, taken in aggregate, they support the notion that men with a family history of BPH may be at increased risk for the development of symptomatic BPH, that the risk appears to be greater in men with younger affected relatives, and that they are more likely to have a larger prostate volume than men with no family history of BPH. Molecular genetics of BPH While evidence mounts that hereditary influences play a role in the pathogenesis of BPH, and most strongly supports a relationship with larger prostate volume, the identity of those genes that play a causal role in this process remains largely unknown. Investigators have taken different approaches in their attempts to identify these genes. Several groups have analyzed BPH specimens searching for genome-level or gross cytogenetic alterations. Others have selected specific genes in an approach known as candidate-gene analysis, looking for alterations in various oncogenes and tumor suppressor genes known to regulate cellular proliferation and apoptosis, processes that must play an integral role in prostate growth. Cytogenetic studies Cytogenetic studies have been instrumental in the characterization of many cancers. The study of chromosomal breakpoints in cancer tissue has led to the isolation and cloning of multiple cancerassociated genes.62 However, attempts to perform similar studies of solid tumors, such as BPH, have lagged because of the difficulty of performing and interpreting these studies. Most studies of BPH tissue, using techniques like flow cytometry (FCM) or image analysis for ploidy analysis,63 and fluorescent in-situ hybridization (FISH) to determine chromosomal numbers,64–66 have demonstrated that, for the most part, BPH cells have a normal complement of DNA. Some studies have demonstrated abnormal DNA content (aneuploidy) in samples obtained from nonmalignant prostate samples67,68 with large-volume prostates. However, the fact that many of the patients studied subsequently developed prostate cancer questions the association of aneuploidy with benign prostatic disease. Others have demonstrated the loss of chromosome Y,69–71 but only in shortterm primary cell cultures established from BPH samples rather than directly in BPH tissue, questioning whether these findings may have been an artifact of cell culture. Alternatively, the loss of the Y chromosome may be a general phenomenon of aging.72 Other abnormalities seen in BPH tissue, including trisomy 7,70,73 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_122.html[09.07.2009 11:52:17]

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Page 123 trisomy of chromosome 16,73 chromosome 1 rearrangements,71 and allelic loss on chromosomes 8p, 22q and 18q (DCC)74 have been described. However, most of these alterations seem to be rare and sporadic. More recently, sophisticated approaches, such as DNA fingerprinting analysis, have been utilized to scan the large numbers of independent genomic loci for genetic alterations. Two groups using this technique have detected genetic alterations in approximately 40% of the BPH samples examined.75,76 In contrast to these reports, a recent study using restriction landmark genomic scanning, a technique that searches for DNA amplification, deletion, or methylation at loci dispersed throughout the genome, detected only 64 out of thousands of ‘spots’ with altered intensity after examining 16 BPH specimens. The absence of apparent consistency or of correlation of patterns obtained from samples of hyperplastic and normal prostate, and the infrequent and random occurrence of these alterations, seemed to discount the notion that a single common genetic event underlies the development of BPH in most patients.77 However, these techniques examine only a small fraction of the 30–100000 genes that exist within the human genome and can identify only some of the types of alterations possible, leaving a large number of potentially important genes untested. In summary, no consistent patterns of genomic alterations in BPH samples have been identified. Analysis of candidate genes Since evidence suggests that changes in both cellular proliferation rate and apoptosis are associated with BPH, numerous investigators have undertaken a ‘candidategene’ approach, looking for alterations in various oncogenes (Table 8.2) and tumor suppressor genes (Table 8.3) that are known to regulate these processes that consequently may be altered in patients exhibiting BPH-associated prostate growth. Oncogenes Oncogene activation by amplification, overexpression, or mutation plays a central role in the pathogenesis of a large variety of tumors. The evidence gathered from numerous studies suggests that the activation of oncogenes, e.g. ras,78 c-myc, c-fos, c-sis, 79 or c-met, 80,81 does not appear to play an important role in the pathogenesis of BPH. However, most of these studies were performed primarily on prostate cancer specimens, with only small numbers of ‘BPH’ specimens studied as a control. In most cases, these control specimens were not selected using typical or rigorous criteria for BPH, e.g. presence of symptoms or prostate enlargement. Despite these caveats, the lack of oncogene activation in BPH may not be surprising, since numerous studies have failed to identify more than a minimal increase in cellular proliferation in BPH specimens.82,83 Some studies, however, have demonstrated overexpression of several selected proto-oncogenes. For example, increased expression of the oncoprotein bcl-2, which is a potent suppressor of apoptosis, has been detected within BPH tissue, limited to the basal cell compartment of the epithelium. Studies of tissue samples taken from nonmedically-treated BPH patients showed a dramatic increase in the number of cells expressing bcl-2 and in the intensity of staining among prostatic epithelial cells compared to tissue from normal prostate controls.84,85 In one of these studies, overexpression of bcl-2 was found to correlate negatively with the number of cells undergoing apoptosis ( r=0.7),85 suggesting that an abnormal increase in the expression of this anti-‘death’ protein might be involved in the growth deregulation of the prostatic epithelium that leads to BPH. Furthermore, the increased expression of this important anti-apoptotic gene has been found to correlate with a decreased apoptotic response to hormonal withdrawal in BPH tissue, but not in normal or cancerous prostate tissue.86 Expression and/or alteration of the c-erbB-2 gene (also known as her-2/neu),87,88 which encodes a growth-factorreceptor-like molecule that is 50% homologous to the epidermal growth factor receptor (EGFR or c-erbB-1), has also been evaluated in BPH samples by numerous investigators.89–92 While many of these studies have demonstrated increased staining for this growth factor receptor in BPH samples (from 0% to 89% of samples evaluated), none have demonstrated any alteration or amplification of the gene, as is commonly seen in some malignancies, such as breast,93,94 ovarian,95,96 gastric,97 colon,98 pulmonary,99,100 kidney,101 or urinary bladder cancer.102 In addition to oncogene activation, the loss of function of tumor suppressor genes has also been established as a primary mechanism whereby cells may escape growth control. Two of the most important tumor suppressor genes, p53 tumor suppressor gene and retinoblastoma susceptibility gene, play critical roles in regulating the cell cycle, proliferation, apoptosis, and DNA repair in tissues throughout the human body, making alterations of these genes important potential candidates in the pathogenesis of tissue growth disorders like BPH. Tumor suppressor genes p53 tumor suppressor gene Since p53 mutations are the most common genetic alteration found in file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_123.html[09.07.2009 11:52:17]

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Page 124 Table 8.2 Oncogenes in benign prostatic hyperplasia. OncogeneNo of MethodologyResults specimens Bcl-2 Kyprianou47 BPH IHC bcl-2 staining topologically restricted to the glandular epithelium et al.161 5 NP Four-fold decreased apoptosis in epithelium of BPH compared to NP Increase in number of cells (6-fold) expressing bcl-2 compared to NP ( p <0.02) Increased intensity of bcl-2 expression compared to NP Cardillo 26 BPH IHC bcl-2 staining topologically restricted to basal epithelial cell et al.86 16 biopsy compartment specimens In contrast to PCa and NP, androgen deprivation resulted in upregulation of bcl-2 expression and total absence of apoptosis in 19/26 (73%) BPH specimens Androgen ablation specimens exhibited more intense bcl-2 staining than preablation specimens Colombel 30 BPH IHC bcl-2 staining topologically restricted to glandular epithelium et al.85 10 NP Proliferation significantly greater and apoptosis lower in BPH compared to NP bcl-2 expression higher in BPH than in transition and peripheral zones of NP Percentage of bcl-2 positive cells correlates negatively with number of apoptotic bodies (r=0.7) in BPH samples c-erbB-2/HER-2 No mutation Zhau et 6 BPH IHC No expression in BPH and NP specimens as analyzed by Western blot al.162 5 NP Western blotand IHC Low frequency of mutations Ibrahim 35 PCa IHC Highest level in basal cell layers of BPH et al.89 with areas Expression significantly greater in BPH areas compared to PCa areas of BPH ( p <0.001) Gu et 10 BPH IHC 2/10 (20%) BPH specimens and 39/39 (100%) PCa stained positive al.163 39 PCa High frequency of mutations Mellon et 34 BPH IHC 6/34 (18%) strong positive and 9/34 (27%) weak positive staining in al.106 29 PCa the BPH specimens compared to 6/29 (21%) strong positive and 10/29 (35%) weak positive in the PCa specimens Ware et 13 BPH IHC 12/13 (92%) BPH specimens stained positive al.164 24 PCa 9/21 (43%) benign areas in PCa specimens stained positive Giri et 39 BPH IHC 35/39 (90%) BPH specimens stained positive from which 31% very al.91 3 NP strong positive 0% NP stained positive

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Page 125 Oncogene No of Methodology Results specimens Schwartz 30 BPH Semi19/30 (63%) mRNA overexpression in BPH samples et al.92 5 NP quantitativemRNA/RT-No DNA amplification of c-erb B-2 gene in BPH specimens PCR compared to NP specimens SemiquantitativeDNA/PCR c-mys, c-fos, c-sis Funa et 5 BPH in situ hybridization 3/5 (60%) BPH and 4/9 (44%) areas of BPH within PCa al.79 9 PCa specimens expressed c-fos mRNA 3/5 (60%) BPH and 4/8 (50%) areas of BPH within PCa specimens expressed c-sis mRNA 1/4 (25%) BPH and 2/8 (25%) areas of BPH within PCa specimens expressed c-myc mRNA Ras Anwar et 10 BPH DNA/PCR+ DNA 0/10 (0%) ras mutation in either BPH and NP al.78 10 NP hybridization c-met/HGF Pisters et 11 BPH IHC 2/11 (18%) BPH and 36/43 (84%) PCa samples ( p <0.0001) al.80 43 PCa stained positive for c-met protein Tsuka et 12 BPH RNA/RT-competitive c -met protein and mRNA levels weakly detected in BPH al.81 5 NP PCR specimens and similar to levels in NP specimens Western blot PCa, prostate cancer; NP, normal prostate; IHC, immunohistochemistry; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction.

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Page 126 Table 8.3 Tumor suppressors genes in benign prostatic hyperplasia. Tumor Methodology Results: No positive staining or mutations/No BPH samples examined suppressor (mutation frequency in %) genes p53 (presence of staining indicates abnormality) No mutation Mellon et IHC 0/34 (0%) al.106 Fan et IHC 0/10(0%) al.109 Henke et IHC 0% in areas of BPH within 71 PCa specimens al.107 Mottaz et IHC 0/13 (0%) positive staining and 0% positive staining in areas of BPH al.108 PCR-SSCP within 100 PCa 0/13 (0%) exon-specific mutation Low frequency of mutations Kallakury et PCR 1/20 (5%) mutation in exon 7 of benign cells near foci of high grade PCa al.165 Zhang et IHC 1/6(17%) al.110 deVere mRNA/RT-PCR 2/13(15%) White et al.125 Retinoblastoma gene (loss of expression indicates abnormality) deVere mRNA/RT-PCR 1/13 (8%) abnormal RB-1 expression White et al.125 Phillips et DNA/PCR 1/10 (10%) loss of heterozygosity located on intron 1 al.123 IHC 4/4 (100%) positive staining Kubota et mRNA/PCR+SSCP0/4 (0%) mutation al.124 P27KIP1 (loss of expression indicates abnormality) CordonIHC 0/14 (0%) stained positive for p27 protein in epithelial and stromal Cardo et mRNA in situ compartment al.128 hybridization 0/14 (0%) p27 KIP1 mRNA detectable in epithelial and stromal compartment In addition, p27 KIP1 null mice developed histologically hyperplastic glands (hypercellular acini of epithelial cells, and increase in fibromuscular stromal cells) PCR, polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction; IHC, immunohistochemistry; SSCP, single-stranded conformation polymorphism; TGGE, temperature gradient gel electrophoresis.

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Page 127 neoplasias,103,104 numerous investigators have extensively studied BPH tissues searching for a similar pattern of p53 alteration. Use of immunohistochemical techniques extends the half-life of mutant p53 protein105 and allows detectable staining of nuclei expressing mutant but not wild-type p53. However, cytoplasmic staining with nuclear exclusion has also been demonstrated in tissues harboring some specific mutations within the p53 tumor suppressor gene, e.g. codon 135val. Alternatively, more laborintensive techniques such as single-stranded conformational polymorphism (SSCP) analysis, temperature gradient gel electrophoresis (TGGE) analysis, or deoxyribonucleic acid (DNA) sequencing have been used to identify alterations directly within the cellular DNA of BPH tissue samples. Most studies using immunohistochemical staining for p53 protein using a number of different p53specific antibodies have not demonstrated any abnormal detectable staining in BPH tissues.106–109 Other investigators have found a very low frequency of abnormal staining in either BPH epithelium110 or within the cytoplasm of stromal cells (<1% to 5% of cells).111 In contrast, using techniques to examine the DNA (SSCP and/or DNA sequencing) directly, one group of investigators has described relatively high rates of p53 mutations (56% and 75% of the examined BPH specimens, respectively) in BPH tissue samples from patients without prostate cancer, who had undergone surgery for BPH.112,113 A more recent supportive study by Schlechte et al., using a more sensitive technique, TGGE of amplified p53 DNA, demonstrated p53 alterations in 19% of 153 BPH specimens evaluated.114 Furthermore, a similar evaluation of a small group of control specimens without evidence of either pathologic BPH or prostate cancer (one autopsy, six prostatitis) failed to demonstrate any p53 gene alterations. However, a significant proportion of the alterations detected by both groups of investigators were found upon DNA sequencing to be silent mutations, causing no alteration of the translated p53 protein, and neither group could consistently correlate the detection of alterations in the p53 tumor suppressor gene at the DNA level with abnormal p53 immunohistochemical staining in BPH samples. In contrast, the higher correlation between p53 mutations and positive immunohistochemical staining,112 as well as the significantly different distribution in the actual mutations detected in PCa versus BPH samples,114 suggests a possibly different role for p53 in these two diseases. The clinical and pathogenic consequences of p53 alterations in BPH remain in question and require further study. Retinoblastoma (Rb1) tumor suppressor gene Rb1, the first tumor suppressor gene isolated,115–117 is a very large gene located on chromosome 13q14. Rb1 plays a significant role in the pathogenesis of numerous human cancers,118 including breast,119 lung,120 and prostate cancer.121,122 Yet, in contrast to the abundance of research on p53, few studies have evaluated BPH specimens for alterations in RB1. Using immunohistochemistry for the Rb protein product, pRB, in which the absence of staining is associated with the abnormal loss of RB function, one study demonstrated normal nuclear staining in all areas of BPH within nine PCa samples and in four BPH-only samples. Loss of the RB1 gene was detected in only one of 10 BPH samples, although the patient had an elevated PSA level of 20 ng/ml and a positive digital rectal examination (DRE) suspicious for prostate cancer.123 Another small study using SSCP demonstrated no alterations of the RB gene in four BPH samples examined.124 RB1 expression measured by reverse transcriptase PCR was noted as abnormal in only one of 13 BPH samples evaluated.125 While scarce, the available evidence fails to indicate any significant role for RB alteration in the pathogenesis of BPH. p27KIP1 In addition to these two well-established tumor suppressor genes, several new tumor suppressor genes have been discovered and play varying roles in human disease. One of these more recently discovered tumor suppressor genes is p27KIP1, a member of the cyclin-dependent kinase inhibitor family,126 which functions as a negative regulator of the cell cycle.127 Only a single published study has evaluated the expression of the p27KIP1 gene in BPH tissues.128 Using immunohistochemical staining for the p27 protein and in situ hybridization for p27KIP1 mRNA, CordonCardo et al. demonstrated reduced expression or absence of expression in 14 BPH samples and in BPH areas contiguous to PCa in an additional 46 samples, in contrast to strong expression observed in four normal prostates evaluated.128 In addition, mice with the p27KIP1 ‘knocked out’ develop enlarged prostate glands, with hyperplasia of epithelial cells and an increase in the fibromuscular stroma, further evidence that the p27KIP1 gene may play a role in the pathogenesis of BPH. Additional studies evaluating BPH specimens for expression or alteration of the p27KIP1 are needed before any firm conclusions can be reached. Other genes In addition to oncogenes and tumor suppressor genes that directly regulate cellular proliferation and file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_127.html[09.07.2009 11:52:19]

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Page 128 indirect mechanisms. Within this broad group, genes that impact pathways of androgen action have been studied extensively because of the importance of androgens in the development and pathophysiology of the prostate gland. Dihydrotestosterone (DHT), the critical androgen in the prostate gland, binds with the androgen receptor (AR) in the cell nucleus, creating a DHT-AR complex that interacts with the specific deoxyribonucleic acid (DNA) sequences, modulating transcription of target androgen-regulated genes. The AR gene contains a polymorphic CAG repeat region within exon 1 that varies in length among individuals, from approximately 15 to 40. Men with AR gene CAG repeat lengths greater than 40 have spinal and bulbar muscular atrophy and clinical androgen insensitivity.129,130 Shorter CAG repeat length in the AR gene has been shown to correlate with stronger transcriptional activation and function of the androgen receptor. Furthermore, shorter CAG repeat lengths have been shown to be associated with a higher risk of aggressive prostate cancer.131–133 In one study, Giovannucci et al. investigated whether shorter CAG repeat lengths in the AR gene correlated with the development of symptomatic BPH.134 Their study evaluated 51529 male health professionals aged 40 to 75 enrolled in the Health Professionals Follow-up Study (HPFS). At baseline in 1986 and every 2 years thereafter, enrollees provided information regarding a number of areas, including medical history. In this study, BPH was defined as an enlarged prostate identified by DRE, prior surgery for BPH, or a combination of both. In addition, men filled out an eight-item urinary symptom score similar to the American Urological Association symptom index (AUASI). From the 898 men selected for further study, 291 reported having an enlarged prostate, 158 reported having had surgery for BPH, and 449 men had neither. An inverse correlation between AR gene CAG repeat length and prevalence of surgery for BPH and enlarged prostate, determined either by DRE or a history of surgery for BPH, was found. Men with AR gene CAG repeat length of 19 or less had an odds ratio (OR) of BPH of 1.92 relative to men with a repeat length of 25 or more, and the OR increased linearly as CAG repeat length decreased ( ptrend =0.0002) (Figure 8.1). In men with BPH, but not treated with either medications or surgery ( n =291), a strong association (OR=3.62, p =0.004) was observed for men with severe obstructive symptoms (Table 8.4). While shorter CAG repeat length appears to be an important risk factor for both BPH and prostate cancer, mutation within the AR gene has not been found to play a significant role.135 Global expression profiling using DNA microarrays The recent introduction of DNA microarray technology, which allows for the simultaneous evaluation of the

Figure 8.1 Age-adjusted odds ratio and 95% confidence interval of BPH surgery or enlarged prostate gland in the Health Professionals Followup Study by androgen receptor gene CAG repeat length (ptrend=0.0002). (Reprinted from Giovannucci E, Platz E A, Stampfer M J et al. The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia. Urology Copyright 1999; 53:121–125, with permission from Elsevier Science.)

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Page 129 Table 8.4 Odds ratio and 95% confidence interval for a six-repeat decrement in CAG repeats in the androgen receptor gene in the Health Professionals Follow-up Study. (Reprinted from Giovannucci E, Platz E A, Stampfer M J et al. The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia. Urology Copyright 1999; 53:121– 125, with permission from Elsevier Science.)   Cases OR* 95% CI p Value BPH surgery or enlarged prostate gland 449 1.69 1.28–2.23 0.0002 BPH surgery 158 1.88 1.26–2.82 0.002 Enlarged prostate gland Total† 291 1.67 1.23–2.27 0.001 Obstructive symptoms 23 3.62 1.51–8.67 0.004 Irritative symptoms 25 1.49 0.65–3.41 0.34 *Based on modeling AR gene CAG repeats as a continuous variable in a logistic model and calculating the odds ratio for a decrement in six CAG repeats. †Total enlarged prostate gland excluding BPH surgery cases; obstructive and irritative symptoms represent those with enlarged gland who have high-moderate or severe obstructive or irritative symptoms based on a modified American Urological Association Symptom Index. relative mRNA level of thousands of genes, has revolutionized the way we evaluate disease-related alterations in gene expression. Two of the three DNA microarray technologies now in widespread use are based on the competitive binding of alternately labeled cDNA molecules to DNA molecules arrayed in a defined pattern on a solid surface. cDNA arrays rely on the ‘spotting’ of polymerase chain reaction (PCR) amplified cDNAs onto glass slides, while long oligonucleotide arrays (oligonucleotides of 50–70bp in length) are commonly synthesized in situ, or ‘printed’. A third DNA microarray platform is marketed by Affymetrix (Santa Clara, CA) and is based on the competitive binding of labeled cDNA to two short ‘printed’ oligonucleotide species for each microarray feature. Each feature contains an oligonucleotide species with sequence complementary to the target cDNA and a second oligonucleotide species with a single base mismatch. Because there is no competition between cDNAs from different sources for the features on an Affymetrix chip, measurement of the binding of labeled cDNA to the oligonucleotide species with divergent sequence is required in order to correct for nonspecific binding and background signal. Although the number of studies using microarray technology to evaluate the gene expression pattern of BPH is limited, the data generated by any one study are substantial. In a study using a cDNA microarray with 6500 genes 76 were identified as consistently up- or downregulated in BPH tissues. The upregulated genes included certain growth factors (e.g. bone morphogenic protein5, tumor growth factor-β3 (TGFβ3), and insulin-like growth factor-1 (IGF-1)), proteases and protease inhibitors (e.g. matrix metalloproteinase-2, neuropathy target esterase, and α2-macroglobulin), stress response enzymes (e.g. cyclooxygenase-2 and glutathione-S-transferase-M), and extracellular matrix molecules (e.g. laminin α-4 and lumican). Of the 76 genes with altered expression, ten were tested by PCR; six were confirmed to be over-represented in BPH tissue, and two were confirmed to be under-represented in BPH tissue.136 Although these genes were not randomly chosen, the results suggest that at least a majority of the cDNA-based observations made in this study may be validated. The main drawback of this study is that BPH transition zone tissue was compared to peripheral zone rather than normal transition zone tissue. Consequently, the gene expression differences found and validated here may represent inherent differences between peripheral and transition zone tissue and not necessarily differences that result in or are caused by BPH. Two published studies have compared BPH to prostate cancer. One used the Affymetrix technology while the other used cDNA microarrays.137,138 Although the gene expression changes found in these studies may represent changes induced by either BPH or prostate cancer, some of the findings do agree with other published studies that focus on BPH. For example, among the genes reported as being overrepresented in BPH compared to prostate cancer were TGF-β3, glutathione-S-transferase and insulinlike growth factor-2 (IGF-2).137 These genes have been found to be over-represented in BPH compared to normal prostate in various studies.136,139 Using cDNA technology, we have been able to corroborate prior studies demonstrating that c-fms-like

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Page 130 tyrosine kinase receptor-1 (FLT-1), latent TGF-β binding protein 1, and cyclooxygenase-1 are overexpressed in BPH.136,140,141 Our data are also in agreement with published studies indicating that constitutive nitric oxide synthase and estrogen receptor-α are essentially unchanged in BPH compared to the normal prostate transition zone.142,143 We are currently using long oligonucleotide DNA arrays to compare nodular BPH tissue to normal transition tissue zone and to matched normal peripheral zone tissue. We are also using this flexible platform to evaluate gene expression changes associated with medical therapy for BPH. Genetic mouse models of BPH While studies of BPH patients and human BPH tissues can identify associations between specific genetic alterations and the development of BPH, these studies are often inadequately designed to prove a direct causal link to the pathogenesis of BPH. Using either transgenic mouse models, in which specific genes are overexpressed in a general or tissue-specific pattern, or ‘knock-out’ mouse models in which specific genes are deleted, the causative role of specific genes in the development of prostatic disease can be directly tested. Furthermore, by crossing different transgenic and knock-out mice, and studying the prostatic phenotype of the offspring, investigators can study the combination of multiple genetic alterations on prostate morphogenesis. While dogs spontaneously develop BPH with aging,144,145 mice are naturally resistant to the development of BPH. Nevertheless, through the introduction of genetic alterations, it has been possible to develop lines of mice that develop prostatic phenotypes analogous to this disease. In an early attempt to test the role of fibroblast growth factors in the pathogenesis of BPH, transgenic mice were created146,147 that overexpressed the int-2 /FGF-3 oncogene, which is 55% homologous to basic fibroblast growth factor (bFGF), the dominant growth factor found in human BPH.148–151 In these mice, expression of the int-2 /FGF-3 gene was driven by a truncated mouse mammary tumor virus long terminal repeat (MMTV-LTR) promoter, that targeted expression of the int-2 transgene specifically to the mammary gland in female mice and to the prostate in males. In a startling result, male transgenic mice were initially thought to exhibit dramatic prostatic hyperplasia, involving the epithelium, but not the fibromuscular stroma, of the prostate gland. However, Donjacour et al. later demonstrated that the MMTV-LTR promoter directed transgene expression to the secondary sex organs of Wolffian duct origin (ampullary gland, seminal vesicle and ductus deferens), which exhibited hyperplastic enlargement, but not to those secondary sex organs of urogenital sinus origin (ventral prostate, coagulating gland, bulbourethral gland), which appeared normal in size and histology.152 Correlative studies quantifying the expression of int-2 /FGF-3 by semi-quantitative PCR in human BPH tissues have also failed to demonstrate an increase in int-2 /FGF-3 expression.92 The same promoter system was used to target keratinocyte growth factor (KGF, also known as FGF-7), another member of the FGF family that may play an important role in prostate morphogenesis, and transgenic mice were created that again demonstrated epithelial hyperplasia of the male sex accessory glands. However, the later findings by Donjacour et al. suggest that the phenotype most likely did not affect the prostate gland. Transgenic manipulation of the peptide growth factor transforming growth factor beta 1 (TGFβ1) or its receptor, important modulators of cellular differentiation and cell cycle progression,153 has also been shown to produce altered prostate phenotypes with features similar to BPH. When retroviruses were used to transduce and overexpress the TGFβ1 cDNA in prostate tissue in the mouse prostate reconstitution (MPR) model, the resultant MPRs demonstrated focal epithelial basal cell hyperplasia, stromal cell dysplasia, and an increase in the density of neuronal cells present compared to that in control MPRs.154 In a different approach, transgenic mice expressing a dominant negative TGFβ type II receptor, lacking the intracellular signaling domain, and targeted to the mouse prostate using the rat probasin promoter, were created. Overexpression of this defective TGFβ type II receptor within the prostatic epithelium leads to a failure of appropriate downstream signaling upon binding of the TGFβ growth factor. At 18 weeks of age, these transgenic mice exhibit a significantly greater mean prostatic weight than nontransgenic litter mates (50.5 mg vs 30 mg, p <0.05).155 Histological evaluation of the prostates of these transgenic mice revealed the presence of intraductal hyperplasia and proliferation of epithelial cells, as well as focal stromal dysplasia. Overexpression of TGFβ has also been demonstrated immunohistochemically in BPH tissue samples.156 These findings support a possible role for the TGFβ signaling pathway in prostate morphogenesis and suggest that disruption of this pathway may lead to abnormal prostate growth similar to BPH. Another study evaluated the phenotypic effect of ‘knocking out’ expression of the p27KIP1 gene on file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_130.html[09.07.2009 11:52:20]

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mouse prostate morphogenesis.128 While the difference in the mean prostate weight between p27-null mice and normal

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Page 131 littermates was not statistically significant, p27-null mice exhibited histologically hyperplastic glands, development of hypercellular acini of epithelial cells, and an increase in fibromuscular stromal cells. Moreover, the p27-null mice were found to have a significantly higher number of acini, which were associated with a greater increase in proliferative activity, as assessed by Ki-67 immunohistochemistry, than their p27 wild type counterparts. Since p27KIP1 mRNA levels and p27 expression were both reduced in human BPH tissue, and ablation from the p27KIP1 gene itself in the mouse caused BPH, loss of p27 expression is another potentially important genetic alteration that may be causally linked to BPH. Finally, using a different approach, Wennbo et al. reported that transgenic mice overexpressing the prolactin gene (PRL) in a nontissue-specific fashion developed prostate glands that were 20-fold larger than those of nontransgenic control mice.157 Histologic examination revealed that these mice, similar to those described by Cordon-Cardo et al., developed both epithelial and stromal hyperplasia. Transgenic animals had elevated circulating levels of prolactin, testosterone, and IGF-1. However, the level of testosterone did not correlate with prostate weight, and a separate line of transgenic mice overexpressing growth hormone, which demonstrated elevated serum levels of IGF-1 but normal serum prolactin levels, did not develop prostatic enlargement, making it unlikely that the hyperplastic phenotype in the PRL transgenic mice was due to either of these two hormones. As increasing numbers of transgenic and knock-out mice are produced by the manipulation of additional genes, and as these genetic alterations are combined through breeding, we will continue to gain insight into the specific genes that may cause BPH. Gene therapeutic approach to BPH All of the evidence accumulated to date suggests that BPH is most likely the result of a combination of direct and indirect genetic mechanisms, as well as epigenetic factors, that all play a role in the development and progression of pathologic BPH. The successful development of new gene therapeutic strategies for BPH will require a better identification of specific genes and understanding of the genetic mechanisms responsible for this disease. Meanwhile, the few early attempts at developing gene therapeutic approaches for the treatment of BPH have demonstrated encouraging results. Since the best evidence has linked a reduction in apoptosis within the prostate to the development of BPH, and since apoptotic regulatory genes, such as p53111,113 and bcl-2,85 have been shown to be abnormally expressed in BPH tissue, these approaches have focused on the manipulation of genes involved in the apoptotic pathway. Preliminary in vitro and in vivo studies using adenoviral vectors expressing p53158 and other apoptotic regulatory proteins, e.g. caspases,159 have shown early promise in increasing apoptosis and in reducing prostate volume in BPH model systems. As the field of human gene therapy progresses and matures, gene-based approaches may one day become the standard treatment of BPH. Acknowledgment The authors are extremely grateful to Ms Carolyn Schum for her excellent contribution in the preparation and editing of the manuscript. References 1. Berry S J, Coffey D S, Walsh P C, Ewing L L. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474 2. McNeal J. Pathology of benign prostatic hyperplasia: insights into etiology. Urol Clin N Am 1990; 17:477–486 3. Egawa S, Ohori M, Uchida T et al. Nodular hyperplasia in the peripheral zone of the prostate gland. Br J Urol 1994; 74:520–521 4. Schoenmakers E F, Wanschura S, Mols R et al. Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nat Genet 1995; 10:436–444 5. Kazmierczak B, Dal Cin P, Wanschura S et al. HMGIY is the target of 6p21.3 rearrangements in various benign mesenchymal tumors. Genes Chrom Cancer 1998; 23: 279–285 6. Ashar H R, Fejzo M S, Tkachenko A et al. Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell 1995; 82:57–65 7. Mandahl N, Heim S, Johansson B et al. Lipomas have characteristic structural chromosomal rearrangements of 12q13-q14. Int J Cancer 1987; 39:685–688 8. Sreekantaiah C, Leong S P, Karakousis C P et al. Cytogenetic profile of 109 lipomas. Cancer Res 1991; 51: 422–433 9. Williams A J, Powell W L, Collins T, Morton C C. HMGI(Y) expression in human uterine leiomyomata. Involvement of another high-mobility group architectural factor in a benign neoplasm. Am J Pathol file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_131.html[09.07.2009 11:52:21]

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1997; 150: 911–918

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Page 132 10. Ozisik Y Y, Meloni A M, Altungoz O et al. Translocation (6; 10) (p21; q22) in uterine leiomyomas. Cancer Genet Cytogenet 1995; 79:136–138 11. Nilbert M, Heim S, Mandahl N et al. Karyotypic rearrangements in 20 uterine leiomyomas. Cytogenet Cell Genet 1988; 49:300–304 12. Heim S, Nilbert M, Vanni R et al. A specific translocation, t(12; 14) (q14–15; q23–24), characterizes a subgroup of uterine leiomyomas. Cancer Genet Cytogenet 1988; 32: 13–17 13. Fletcher J A, Pinkus G S, Donovan K et al. Clonal rearrangement of chromosome band 6p21 in the mesenchymal component of pulmonary chondroid hamartoma. Cancer Res 1992; 52:6224–6228 14. Kazmierczak B, Rosigkeit J, Wanschura S et al. HMGI-C rearrangements as the molecular basis for the majority of pulmonary chondroid hamartomas: a survey of 30 tumors. Oncogene 1996; 12:515–521 15. Kazmierczak B, Wanschura S, Rosigkeit J et al. Molecular characterization of 12q14–15 rearrangements in three pulmonary chondroid hamartomas. Cancer Res 1995; 55: 2497–2499 16. Kazmierczak B, Wanschura S, Rommel B et al. Ten pulmonary chondroid hamartomas with chromosome 6p21 breakpoints within the HMG-I(Y) gene or its immediate surroundings. J Natl Cancer Inst 1996; 88:1234–1236 17. Bullerdiek J, Wobst G, Meyer-Bolte K et al. Cytogenetic subtyping of 220 salivary gland pleomorphic adenomas: correlation to occurrence, histological subtype, and in vitro cellular behavior. Cancer Genet Cytogenet 1993; 65: 27–31 18. Bullerdiek J, Bartnitzke S, Weinberg M et al. Rearrangements of chromosome region 12q13—q15 in pleomorphic adenomas of the human salivary gland (PSA). Cytogenet Cell Genet 1987; 45:187–190 19. Dal Cin P, De Wolf F, Klerckx P, Van Den Berghe H. The 6p21 chromosome region is nonrandomly involved in endometrial polyps. Gynecol Oncol 1992; 46:393–396 20. Fletcher J A, Pinkus J L, Lage J M et al. Clonal 6p21 rearrangement is restricted to the mesenchymal component of an endometrial polyp. Genes Chrom Cancer 1992; 5:260–263 21. Vanni R, Dal Cin P, Marras S et al. Endometrial polyp: another benign tumor characterized by 12q13q15 changes. Cancer Genet Cytogenet 1993; 68:32–33 22. Walter T A, Fan S X, Medchill M T et al. inv(12)(p11.2q13) in an endometrial polyp. Cancer Genet Cytogenet 1989; 41:99–103 23. Staats B, Bonk U, Wanschura S et al. A fibroadenoma with a t(4;12) (q27;q15) affecting the HMGI-C gene, a member of the high mobility group protein gene family. Breast Cancer Res Treat 1996; 38:299– 303 24. Bulun S E, Simpson E R, Word R A. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture. J Clin Endocrinol Metab 1994; 78:736–743 25. Andersen J, Barbieri R L. Abnormal gene expression in uterine leiomyomas. J Soc Gynecol Invest 1995; 2: 663–672 26. Tallini G, Dal Cin P, Rhoden K J et al. Expression of HMGI-C and HMGI(Y) in ordinary lipoma and atypical lipomatous tumors: immunohistochemical reactivity correlates with karyotypic alterations. Am J Pathol 1997; 151: 37–43 27. Ishwad C S, Ferrell R E, Hanley K et al. Two discrete regions of deletion at 7q in uterine leiomyomas. Genes Chrom Cancer 1997; 19:156–160 28. Boghosian L, Dal Cin P, Sandberg A A. An interstitial deletion of chromosome 7 may characterize a subgroup of uterine leiomyoma [letter]. Cancer Genet Cytogenet 1988; 34:207–208 29. Pandis N, Heim S, Bardi G et al. Chromosome analysis of 96 uterine leiomyomas. Cancer Genet Cytogenet 1991; 55:11–18 30. Dal Cin P, Moerman P, Deprest J et al. A new cytogenetic subgroup in uterine leiomyoma is characterized by a deletion of the long arm of chromosome 3. Genes Chromosomes Cancer 1995; 13:219–220 31. Morwessel N J. The genetic basis of diabetes mellitus. AACN Clin Issues 1998; 9:539–554 32. Kadowaki T, Bevins C L, Cama A et al. Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance. Science 1988; 240:787–790 33. Brunetti A, Goldfine I D. Insulin receptor gene expression and insulin resistance. J Endocrinol Invest 1995; 18: 398–405 34. Groop L C, Kankuri M, Schalin-Jantti C et al. Association between polymorphism of the glycogen synthase gene and non- insulin-dependent diabetes mellitus [published erratum appears in N Engl J Med 1993; 328:1136]. N Engl J Med 1993; 328:10–14 35. Groop L C, Eriksson J G. The etiology and pathogenesis of non-insulin-dependent diabetes. Ann Med file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_132.html[09.07.2009 11:52:21]

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Page 133 39. Girard J. Is leptin the link between obesity and insulin resistance? Diabetes Metab 1997; 23 Suppl 3:16–24 40. Oka Y. NIDDM—genetic marker; glucose transporter, glucokinase, and mitochondria gene. Diabetes Res Clin Pract 1994; 24 Suppl: S117–121 41. Mueckler M. Family of glucose-transporter genes. Implications for glucose homeostasis and diabetes. Diabetes 1990; 39:6–11 42. Powell S M, Petersen G M, Krush A J et al. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 1993; 329:1982–1987 43. Miyoshi Y, Ando H, Nagase H et al. Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci USA 1992; 89:4452–4456 44. Nagase H, Miyoshi Y, Horii A et al. Screening for germline mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients. Hum Mutat 1992; 1:467– 473 45. Nishisho I, Nakamura Y, Miyoshi Y et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991; 253:665–669 46. Groden J, Thliveris A, Samowitz W et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991; 66:589–600 47. Jen J, Powell S M, Papadopoulos N et al. Molecular determinants of dysplasia in colorectal lesions. Cancer Res 1994; 54:5523–5526 48. Smith K J, Johnson K A, Bryan T M et al. The APC gene product in normal and tumor cells. Proc Natl Acad Sci USA 1993; 90:2846–2850 49. Miyoshi Y, Nagase H, Ando H et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1992; 1: 229–233 50. Powell SM, Zilz N, Beazer-Barclay Y et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992; 359:235–237 51. Price H, McNeal J E, Stamey T A. Evolving patterns of tissue composition in benign prostatic hyperplasia as a function of specimen size. Hum Pathol 1990; 21:578–585 52. Walsh P C. Benign prostatic hyperplasia. In: Walsh P C, Retin A B, Stamey T A, Vaughan E D (eds). Campbell’s Urology. Philadelphia: WB Saunders 1992; 1:1009–1027 53. Sanda M G, Beaty T H, Stutzman R E et al. Genetic susceptibility of benign prostatic hyperplasia. J Urol 1994; 152:115–119 54. Doehring C B, Sanda M G, Partin A W et al. Histopathologic characterization of hereditary benign prostatic hyperplasia. Urology 1996; 48:650–653 55. Shapiro E, Becich M J, Hartanto V, Lepor H. The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostate hyperplasia. J Urol 1992; 147:1293–1297 56. Robert M, Costa P, Bressolle F et al. Percentage area density of epithelial and mesenchymal components in benign prostatic hyperplasia: comparison of results between single biopsy, multiple biopsies and multiple tissue specimens. Br J Urol 1995; 75:317–324 57. Schuster G A, Schuster T G. The relative amount of epithelium, muscle, connective tissue and lumen in prostatic hyperplasia as a function of the mass of tissue resected. J Urol 1999; 161:1168–1173 58. Sanda M G, Doehring C B, Binkowitz B et al. Clinical and biological characteristics of familial benign prostatic hyperplasia. J Urol 1997; 157:876–879 59. Gormley G J, Stoner E, Bruskewitz R C et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med 1992; 327: 1185–1191 60. Lepor H, Williford W O, Barry M J et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med 1996; 335:533–539 61. Roberts R O, Rhodes T, Panser L A et al. Association between family history of benign prostatic hyperplasia and urinary symptoms: results of a population-based study. Am J Epidemiol 1995; 142:965– 973 62. Nowell PC. Cytogenetic approaches to human cancer genes. FASEB J 1994; 8:408–413 63. Klein F A, Ratliff J E, White F K. DNA distribution patterns of prostatic tissue obtained at time of transurethral resection. Urology 1988; 31:260–265 64. Visakorpi T, Hyytinen E, Kallioniemi A et al. Sensitive detection of chromosome copy number aberrations in prostate cancer by fluorescence in situ hybridization. Am J Pathol 1994; 145:624–630 65. Micale M A, Sanford J S, Powell I J et al. Defining the extent and nature of cytogenetic events in file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_133.html[09.07.2009 11:52:22]

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prostatic adenocarcinoma: paraffin FISH vs. metaphase analysis. Cancer Genet Cytogenet 1993; 69:7–12 66. Konig J J, Teubel W, Romijn J C et al. Gain and loss of chromosomes 1, 7, 8, 10, 18, and Y in 46 prostate cancers. Hum Pathol 1996; 27:720–727 67. Deitch A D, Strand M A, de Vere White R W. Deoxyribonucleic acid flow cytometry of benign prostatic disease. J Urol 1989; 142:759–762 68. Berner A, Danielsen H E, Pettersen E O et al. DNA distribution in the prostate. Normal gland, benign and premalignant lesions, and subsequent adenocarcinomas. Anal Quant Cytol Histol 1993; 15:247–252

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Page 134 69. Brothman A R, Lesho L J, Somers K D et al. Cytogenetic analysis of four primary prostatic cultures. Cancer Genet Cytogenet 1989; 37:241–248 70. Aly M S, Cin P D, Van de Voorde W et al. Chromosome abnormalities in benign prostatic hyperplasia. Genes Chrom Cancer 1994; 9:227–233 71. Casalone R, Portentoso P, Granata P et al. Chromosome changes in benign prostatic hyperplasia and their significance in the origin of prostatic carcinoma. Cancer Genet Cytogenet 1993; 68:126–130 72. Pierre R V, Hoagland H C. 45, X cell lines in adult men: loss of Y chromosome, a normal aging phenomenon? Mayo Clin Proc 1971; 46:52–55 73. Miyauchi T, Nagayama T, Maruyama K. Chromosomal abnormalities in carcinoma and hyperplasia of the prostate. Nippon Hinyokika Gakkai Zasshi 1992; 83: 66–74 74. Crundwell M C, Chughtai S, Knowles M et al. Allelic loss on chromosomes 8p, 22q and 18q (DCC) in human prostate cancer. Int J Cancer 1996; 69:295–300 75. Werely C J, Heyns C F, Van Velden D J, Van Helden P D. DNA fingerprint detection of somatic mutations in benign prostatic hyperplasia and prostatic adenocarcinoma. Genes Chrom Cancer 1996; 17:31–36 76. White J J, Neuwirth H, Miller C D, Schneider E L. DNA alterations in prostatic adenocarcinoma and benign prostatic hyperplasia: detection by DNA fingerprint analyses. Mutat Res 1990; 237:37–43 77. Konishi N, Hiasa Y, Matsuda H et al. Genetic variations in human benign prostatic hyperplasia detected by restriction landmark genomic scanning. J Urol 1997; 157: 1499–1503 78. Anwar K, Nakakuki K, Shiraishi T et al. Presence of ras oncogene mutations and human papillomavirus DNA in human prostate carcinomas. Cancer Res 1992; 52: 5991–5996 79. Funa K, Nordgren H, Nilsson S. In situ expression of mRNA for proto-oncogenes in benign prostatic hyperplasia and in prostatic carcinoma. Scand J Urol Nephrol 1991; 25:95–100 80. Pisters L L, Troncoso P, Zhau H E et al. c-met proto-oncogene expression in benign and malignant human prostate tissues. J Urol 1995; 154:293–298 81. Tsuka H, Mori H, Li B et al. Expression of c-MET/HGF receptor mRNA and protein in human nonmalignant and malignant prostate tissues. Int J Oncol 1998; 13: 927–934 82. Claus S, Wrenger M, Senge T, Schulze H. Immunohistochemical determination of age related proliferation rates in normal and benign hyperplastic human prostates. Urol Res 1993; 21:305–308 83. Claus S, Berges R, Senge T, Schulze H. Cell kinetic in epithelium and stroma of benign prostatic hyperplasia. J Urol 1997; 158:217–221 84. Kyprianou N, Tu H, Jacobs S C. Apoptotic versus proliferative activities in human benign prostatic hyperplasia. Hum Pathol 1996; 27:668–675 85. Colombel M, Vacherot F, Diez S G et al. Zonal variation of apoptosis and proliferation in the normal prostate and in benign prostatic hyperplasia. Br J Urol 1998; 82: 380–385 86. Cardillo M, Berchem G, Tarkington M A et al. Resistance to apoptosis and up regulation of Bcl-2 in benign prostatic hyperplasia after androgen deprivation. J Urol 1997; 158:212–216 87. Yamamoto T, Ikawa S, Akiyama T et al. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature 1986; 319:230–234 88. Schechter A L, Hung M C, Vaidyanathan L et al. The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science 1985; 229:976–978 89. Ibrahim G K, MacDonald J A, Kerns B J et al. Differential immunoreactivity of her-2/neu oncoprotein in prostatic tissues. Surg Oncol 1992; 1:151–155 90. Giri D K, Wadhwa S N, Upadhaya S N, Talwar G P. Expression of NEU/HER-2 oncoprotein (p185neu) in prostate tumors: an immunohistochemical study. Prostate 1993; 23:329–336 91. Giri D K, Pal R, Wadhwa S N, Talwar G P. Immunohistochemical localization of transforming growth factor-alpha, epidermal growth factor receptor and c-erbB-2 protein in hyperplastic human prostates. Carcinogenesis 1995; 16:729–733 92. Schwartz S Jr, Caceres C, Morote J et al. Over-expression of epidermal growth factor receptor and cerbB2/neu but not of int-2 genes in benign prostatic hyperplasia by means of semi-quantitative PCR. Int J Cancer 1998; 76:464–467 93. Slamon D J, Clark G M, Wong S G et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177–182 94. Seshadri R, Firgaira F A, Horsfall D J et al. Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group. J Clin Oncol 1993; 11:1936– 1942 95. Slamon D J, Godolpbin W, Jones L A et al. Studies of the HER-2/neu proto-oncogene in human file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_134.html[09.07.2009 11:52:22]

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Page 135 97. Tsugawa K, Fushida S, Yonemura Y. Amplification of the c-erbB-2 gene in gastric carcinoma: correlation with survival. Oncology 1993; 50:418–425 98. Tal M, Wetzler M, Josefberg Z et al. Sporadic amplification of the HER2/neu protooncogene in adenocarcinomas of various tissues. Cancer Res 1988; 48:1517–1520 99. Weiner D B, Nordberg J, Robinson R et al. Expression of the neu gene-encoded protein (P185neu) in human nonsmall cell carcinomas of the lung. Cancer Res 1990; 50: 421–425 100. Schneider P M, Hung M C, Chiocca S M et al. Differential expression of the c-erbB-2 gene in human small cell and non-small cell lung cancer. Cancer Res 1989; 49:4968–4971 101. Yokota J, Yamamoto T, Toyoshima K et al. Amplification of c-erbB-2 oncogene in human adenocarcinomas in vivo. Lancet 1986; 1:765–767 102. Wright C, Mellon K, Neal D E et al. Expression of c-erbB-2 protein product in bladder cancer. Br J Cancer 1990; 62: 764–765 103. Hollstein M, Sidransky D, Vogelstein B, Harris C C. p53 mutations in human cancers. Science 1991; 253:49–53 104. Levine A J, Momand J, Finlay C A. The p53 tumour suppressor gene. Nature 1991; 351:453–456 105. Oren M, Maltzman W, Levine A J. Post-translational regulation of the 54K cellular tumor antigen in normal and transformed cells. Mol Cell Biol 1981; 1:101–110 106. Mellon K, Thompson S, Charlton RG et al. p53, c-erbB-2 and the epidermal growth factor receptor in the benign and malignant prostate. J Urol 1992; 147:496–499 107. Henke R P, Kruger E, Ayhan N et al. Immunohistochemical detection of p53 protein in human prostatic cancer. J Urol 1994; 152:1297–1301 108. Mottaz A E, Markwalder R, Fey M F et al. Abnormal p53 expression is rare in clinically localized human prostate cancer: comparison between immunohistochemical and molecular detection of p53 mutations. Prostate 1997; 31: 209–215 109. Fan K, Dao D D, Schutz M, Fink L M. Loss of heterozygosity and overexpression of p53 gene in human primary prostatic adenocarcinoma. Diagn Mol Pathol 1994; 3: 265–270 110. Zhang X H, Sakamoto H, Takenaka I. Accumulation of p53 and expression of CD44 in human prostatic cancer and benign prostatic hyperplasia: an immunohistochemical study. Br J Urol 1996; 77:441–444 111. Thompson T C, Truong L, Feeney D et al. Focal cytoplasmic accumulation of p53 protein in stromal cells of human BPH tissue: further evidence for an abnormal stroma Abstract 610. J Urol 1994; 151:380A 112. Wertz I E, Deitch A D, Gumerlock P H et al. Correlation of genetic and immunodetection of TP53 mutations in malignant and benign prostate tissues. Hum Pathol 1996; 27:573–580 113. Meyers F J, Chi S G, Fishman J R et al. p53 mutations in benign prostatic hyperplasia. J Natl Cancer Inst 1993; 85: 1856–1858 114. Schlechte H, Lenk S V, Loning T et al. p53 tumour suppressor gene mutations in benign prostatic hyperplasia and prostate cancer. Eur Urol 1998; 34:433–440 115. Fung Y K, Murphree A L, T’Ang A et al. Structural evidence for the authenticity of the human retinoblastoma gene. Science 1987; 236:1657–1661 116. Lee W H, Bookstein R, Hong F et al. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 1987; 235:1394–1399 117. Friend S H, Bernards R, Rogelj S et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986; 323: 643–646 118. Horowitz J M, Park S H, Bogenmann E et al. Frequent inactivation of the retinoblastoma antioncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci USA 1990; 87:2775–2779 119. Lee E Y, To H, Shew J Y et al. Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science 1988; 241:218–221 120. Yokota J, Akiyama T, Fung Y K et al. Altered expression of the retinoblastoma (RB) gene in smallcell carcinoma of the lung. Oncogene 1988; 3:471–475 121. Tricoli J V, Gumerlock P H, Yao J L et al. Alterations of the retinoblastoma gene in human prostate adenocarcinoma. Genes Chromosomes Cancer 1996; 15:108–114 122. Brooks J D, Bova G S, Isaacs W B. Allelic loss of the retinoblastoma gene in primary human prostatic adenocarcinomas. Prostate 1995; 26:35–39 123. Phillips S M, Barton C M, Lee S J et al. Loss of the retinoblastoma susceptibility gene (RB1) is a frequent and early event in prostatic tumorigenesis. Br J Cancer 1994; 70:1252–1257 124. Kubota Y, Fujinami K, Uemura H et al. Retinoblastoma gene mutations in primary human prostate file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_135.html[09.07.2009 11:52:23]

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cancer. Prostate 1995; 27:314–320 125. deVere White R, Anderson K R, Meyers F J et al. Molecular abnormalities in benign prostatic hypertrophy. Abstract 147. J Urol 1992; 4:250A 126. Polyak K, Lee M H, Erdjument-Bromage H et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 1994; 78:59–66 127. Kato J Y, Matsuoka M, Polyak K et al. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell 1994; 79:487–496

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Page 136 128. Cordon-Cardo C, Koff A, Drobnjak M et al. Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J Natl Cancer Inst 1998; 90:1284–1291 129. Igarashi S, Tanno Y, Onodera O et al. Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy. Neurology 1992; 42:2300–2302 130. La Spada A R, Wilson E M, Lubahn D B et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352:77–79 131. Giovannucci E, Stampfer M J, Krithivas K et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer [published erratum appears in Proc Natl Acad Sci USA 1997; 94:8272. Proc Natl Acad Sci USA 1997; 1:9 132. Stanford J L, Just J J, Gibbs M et al. Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 1997; 57:1194–1198 133. Ingles S A, Ross R K, Yu M C et al. Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 1997; 89:166–170 134. Giovannucci E, Platz E A, Stampfer M J et al. The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia. Urology 1999; 53:121–125 135. Evans B A, Harper M E, Daniells C E et al. Low incidence of androgen receptor gene mutations in human prostatic tumors using single strand conformation polymorphism analysis. Prostate 1996; 28:162–171 136. Luo J, Dunn T, Ewing C et al. Gene expression signature of benign prostatic hyperplasia revealed by cDNA microarray analysis. Prostate 2002; 51:189–200 137. Stamey T A, Warrington J A, Caldwell M C et al. Molecular genetic profiling of Gleason grade 4/5 prostate cancers compared to benign prostatic hyperplasia. J Urol 2001; 166:2171–2177 138. Luo J, Duggan D J, Chen Y et al. Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling. Cancer Res 2001; 61: 4683–4688 139. Monti S, Di Silverio F, Iraci R et al. Regional variations of insulin-like growth factor I (IGF-I), IGF-II, and receptor type I in benign prostatic hyperplasia tissue and their correlation with intraprostatic androgens. J Clin Endocrinol Metab 2001; 86:1700–1706 140. Kirschenbaum A, Klausner A P, Lee R et al. Expression of cyclooxygenase-1 and cyclooxygenase-2 in the human prostate. Urology 2000; 56:671–676 141. Hahn D, Simak R, Steiner G E et al. Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues. J Urol 2000; 164:506–510 142. Gradini R, Realacci M, Ginepri A et al. Nitric oxide synthases in normal and benign hyperplastic human prostate: immunohistochemistry and molecular biology. J Pathol 1999; 189:224–229 143. Royuela M, de Miguel M P, Bethencourt F R et al. Estrogen receptors alpha and beta in the normal, hyperplastic and carcinomatous human prostate. J Endocrinol 2001; 168:447–454 144 Huggins C. The etiology of benign prostatic hypertrophy. Bull NY Acad Med 1947; 23:696–704 145. Brendler C B, Berry S J, Ewing L L et al. Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate. J Clin Invest 1983; 71:1114–1123 146 Muller W J, Lee F S, Dickson C et al. The int-2 gene product acts as an epithelial growth factor in transgenic mice. EMBO J 1990; 9:907–913 147. Tutrone R F Jr, Ball R A, Ornitz D M et al. Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model. J Urol 1993; 149: 633–639 148. Story M T, Esch F, Shimasaki S et al. Amino-terminal sequence of a large form of basic fibroblast growth factor isolated from human benign prostatic hyperplastic tissue. Biochem Biophys Res Commun 1987; 142:702–709 149. Mori H, Maki M, Oishi K et al. Increased expression of genes for basic fibroblast growth factor and transforming growth factor type beta 2 in human benign prostatic hyperplasia. Prostate 1990; 16:71–80 150. Dickson C, Peters G. Potential oncogene product related to growth factors [letter]. Nature 1987; 326:833 151. Coffey D S, Walsh P C. Clinical and experimental studies of benign prostatic hyperplasia. Urol Clin North Am 1990; 17:461–475 152. Donjacour A A, Thomson A A, Cunha G R. Enlargement of the ampullary gland and seminal vesicle, but not the prostate in int-2/Fgf-3 transgenic mice. Differentiation 1998; 62:227–237 153. Roberts A, Sporn M. The transforming growth factors beta. In: Sporn M B, Roberts A B (eds). Handbook of experimental pharmacology. Peptide growth factors and their receptors. Berlin: Springerfile:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_136.html[09.07.2009 11:52:23]

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Verlag, 1990; 95:419–472 154. Timme T L, Yang G, Rogers E et al. Retroviral transduction of transforming growth factor-beta1 induces pleiotropic benign prostatic growth abnormalities in mouse prostate reconstitutions. Lab Invest 1996; 74: 747–760 155. Jiang A, Witte M, Kim I et al. A transgenic mouse model of impaired prostate growth control. Abstract 858. J Urol 1998; 161:223

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Page 137 156. Thompson T, Slawin K, Truong L et al. Focal accumulation of transforming growth factor ß1 in the stromal component of BPH tissue. Abstract 834. J Urol 1993; 149: 421A 157. Wennbo H, Kindblom J, Isaksson O G, Tornell J. Transgenic mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland. Endocrinology 1997; 138:4410–4415 158. Shirakawa T, Matsubara S, Gotoh A et al. Molecular therapy with recombinant WT-p53 adenovirus for the treatment of benign prostatic hyperplasia in human cells and rat experimental models. Abstract # 1391. J Urol 1999; 161:359 159. Slawin K, Spencer D, Song W. Adenoviral vector transfer of ‘conditional’ CID-regulated caspases: a novel ‘death switch’ gene therapeutic approach to BPH. Abstract 1390. J Urol 1999; 161:359 160. Partin A W, Page W F, Lee B R et al. Concordance rates for benign prostatic disease among twins suggest hereditary influence. Urology 1994; 44:646–650 161. Kyprianou N, Tu H, Jacobs S C. Apoptotic versus proliferative activities in human benign prostatic hyperplasia. Hum Pathol 1996; 27:668–675 162. Zhau H E, Wan D S, Zhou J et al. Expression of c-erb B-2/neu proto-oncogene in human prostatic cancer tissues and cell lines. Mol Carcinog 1992; 5:320–327 163. Gu K, Mes-Masson A M, Gauthier J, Saad F . Overexpression of her-2/neu in human prostate cancer and benign hyperplasia. Cancer Lett 1996; 99:185–189 164. Ware J L, Maygarden S J, Koontz W W Jr, Strom S C . Immunohistochemical detection of c-erbB-2 protein in human benign and neoplastic prostate. Hum Pathol 1991; 22:254–258 165. Kallakury B V, Jennings T A, Ross J S et al. Alteration of the p53 locus in benign hyperplastic prostatic epithelium associated with high-grade prostatic adenocarcinoma. Diagn Mol Pathol 1994; 3:227–232

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Page 139 II Epidemiology

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Page 141 9 Measuring and assessing BPH in population groups M J Barry Introduction Benign prostatic hyperplasia (BPH) is a common histologic condition among older men that exerts its morbidity through lower urinary tract symptoms (LUTS) and complications such as acute urinary retention, urinary tract infection, bladder stones, and rarely, renal failure due to obstructive uropathy. The frequency of BPH and its clinical manifestations, as well as risk factors for the development of BPH, in the general population are best defined in groups of men studied in geographically defined communities. Men selected for study because they see doctors, and particularly urologists, may not yield results that are truly reflective of BPH occurrence in the general population. This chapter reviews results of studies of the occurrence of BPH and its clinical manifestations, focusing on community-based studies with broad generalizability. Epidemiology of BPH To make a definitive diagnosis of histologic BPH, prostate tissue must be examined. Prostate biopsies are simply too invasive to be employed in epidemiologic studies, and even if they were practical, may be insensitive for BPH because of incomplete sampling. Therefore, knowledge about the prevalence of histologic BPH by age is derived from autopsy studies. Although these studies are not usually geographically based, assuming that the presence or absence of BPH does not influence the likelihood of obtaining an autopsy, estimates of BPH prevalence from these sources may well be reasonable estimates of BPH prevalence in the general population. In a classic paper, Berry et al.1 synthesized data from five autopsy studies from India, England (two studies), Norway, and Austria, presenting the prevalence of BPH by decade (Fig. 9.1). Point estimates of the prevalence of BPH ranged from 8%

Figure 9.1 Age-associated increase in the prevalence of histologic evidence of BPH at autopsy, synthesizing data from five studies. The results show mean±standard error of mean.1

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Page 142 for men in their 30s to 88% for men over 80; BPH is clearly a dramatically age-related condition. In another classic paper, Isaacs and Coffey2 compared the prevalence of BPH by age in autopsy studies from the USA, England, Denmark, Austria, India, and Japan. This study demonstrated relatively similar prevalences of histologic BPH by age across a spectrum of countries and ethnicities (Fig. 9.2). A contemporary autopsy series from China yielded very similar age-specific prevalence estimates.3 Epidemiology of prostatic enlargement Berry et al. also examined prostatic weight by age, again synthesizing data from five autopsy studies (Fig. 9.3).1In these series, the mean weight of a prostate without histologic evidence of BPH was about 20 g, while the mean prostatic weight of men with histologic BPH ranged from about 29 g for men in their 40s to about 40 g for men over 70. However, the distributions of prostatic weight in men with and without histologic BPH overlapped considerably, making it difficult to select a volume ‘cutpoint’ that separates men with and without BPH. For example, if prostates greater than 20 g are considered enlarged, over 90% of men with histologic BPH will have an enlarged prostate, but roughly half of men with histologically normal prostates will as well. On the other hand, while only about 10% of men with histologically normal prostates have weights greater than 30 g, a substantial minority of men with histologic BPH have prostatic weights below this cutpoint. Moving to community-based studies of the distribution of prostate volume in living men (with a density close to 1.0 g/ml, prostatic weight and volume can be considered roughly interchangeable), Bosch et al. studied prostate volumes as part of a trial of screening for prostate cancer among a sample of men aged 55–74 living in the city of Rotterdam.4 Table 9.1 displays the proportion of men by 5-year age group with prostatic volumes above various thresholds. In this study, the proportion of men with prostatic volumes greater than 20 ml was 95%; prostatic volumes were generally higher (by about 25%) at any given age than reported in the autopsy study by Berry et al. Whether the difference in the methods of determining prostate size in these two studies (autopsy versus ultrasound in living men) explains this discrepancy cannot be readily determined, but the authors of the more recent study proposed that desiccation or other post-mortem changes may have led to underestimations of prostatic weight in the earlier autopsy study. Masumori et al. compared the distributions of prostate volumes measured by transrectal ultrasound among Japanese men in the village of Shimamaki-mura and a sample of American men living in Olmsted County,

Figure 9.2 Age-specific prevalence of histologic BPH among men from six different countries.2

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Page 143 Minnesota.5 Table 9.2 presents predicted mean prostate volumes (adjusted for height and weight) for different age groups in the two populations. The proportion of men with prostate volumes greater than 20 ml (a sensitive but not specific cutpoint for identifying men with histologic evidence of BPH) in Japan ranged from 20% for men in their 40s to 37% for men in their 70s, and in America from 62% for men in their 40s to 93% for men in their 70s. Clearly, even after taking differences in body size into account, American men have larger prostates than Japanese men of the same age. However, the mean prostate volumes observed in the American men in this study were roughly similar to the mean volumes for similar-aged Dutch men in the study by Bosch et al. Epidemiology of peak uroflow Peak rates of urine flow are depressed in many men with bladder outlet obstruction due to BPH. However,

Figure 9.3 Age-associated increase in average prostatic weight at autopsy, synthesizing data from five studies. The results show mean± standard error of mean.1 Table 9.1 Percentage of Dutch men with total prostate volume more than 20, more than 30, more than 40, and more than 50 ml, respectively, per 5-year age group (n=502).4 Age Volume (%) >20 ml >30 ml >40 ml >50 ml 55–59 93 43 15 5 60–64 98 62 28 12 65–69 96 63 36 17 70–74 94 76 55 33 Overall 95 60 31 15 Table 9.2 Predicted mean prostatic weights (adjusted to average height and weight at the midpoint of the age interval) with 95% confidence intervals (95% CI) for men in Shimamaki-mura, Japan, and Olmsted County, Minnesota, USA.5 Age Predicted mean volume (ml) (95% CI) Japanese men American men ( n =271) ( n =467) 40–49 16.6 (15.4–17.9) 22.7 (21.7–23.7) 50–59 18.0 (17.1–18.8) 27.2 (26.4–28.0) 60–69 19.4 (18.6–20.2) 32.5 (31.2–33.9) 70–79 21.0 (19.7–22.4) 39.0 (36.5–41.5) file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_143.html[09.07.2009 11:52:26]

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Page 144 depressed peak uroflow may be seen in men without bladder outlet obstruction as determined by a ‘gold standard’ (simultaneous bladder pressure and urine flow measurements), and may also be ‘normal’ despite urodynamic evidence of outlet obstruction. Peak uroflow measurements are also confounded by voided volume. Nevertheless, because measuring peak uroflow is relatively easy and noninvasive, the distribution of this parameter has been examined in a number of community-based studies among older men. Girman et al. have reported mean peak uroflows and the proportion of men with peak flows less than 10 and 15 ml/s (two commonly used cutpoints for defining a ‘reduced’ peak flow) for 2113 men age 40–79 sampled from the population of Olmsted County, Minnesota (Figs. 9.4 and 9.5).6 Peak uroflow is clearly age-related, with a decrease in mean peak uroflow of about 2 ml/s per decade (ignoring voided volume). Interestingly, in the study comparing Japanese and American men (the same Olmsted County population) cited previously, despite the smaller prostates among Japanese men, their mean peak uroflow values decreased faster with age, and reached lower levels by the seventh and eighth decades than those of American men (Fig. 9.6).5 Epidemiology of postvoid residual volume In the past, postvoid residual volume has generally been considered to reflect the severity of bladder outlet obstruction. Measurements of postvoid residuals, however, are confounded by considerable within-patient variability,7 even more so than the parameters already discussed. Nevertheless, Kolman et al. have described the distribution of postvoid residual volumes by age among a randomly selected subset of men from the Olmsted County study who underwent bladder ultrasonography (Table 9.3).8 One striking feature of this table is the lack of relationship between the distribution of postvoid residual urine volume and age, in contrast to the situation for prostate volume and peak uroflow. Epidemiology of LUTS From the patient’s perspective, bothersome LUTS cause most of the morbidity of BPH. Many communitybased studies have now examined the prevalence of LUTS among older men across many countries, cultures, and ethnicities. Many of these studies have used translations of the International Prostate Symptom Score (I-PSS),9 originally developed and validated as the American Urological Association (AUA) Symptom Index,10 to quantify symptoms, which facilitates comparing results across studies. The seven-item self-administered symptom index produces a total symptom score ranging from 0 to 35, with higher scores indicating more symptoms. Based on correlations with patients’ ratings of the bother of any symptoms, this score range can be divided into scores of 0–7, reflecting none or mild symptoms, and scores of 8 or greater, reflecting moderate to severe symptoms. The I-PSS was included in the original 1994 Agency

Figure 9.4 Mean peak flow rate by age among men in Olmsted County, Minnesota.6

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Figure 9.5 Percentage of men in Olmsted County, Minnesota, with peak flow rates less than 10 and 15 ml/s, by age.6

Figure 9.6 Predicted mean peak urinary flow rates (Qmax) with 95% confidence intervals in Japanese and American men of average height and weight, and with average voided volume.5 for Health Care Policy and Research (AHCPR) guidelines for the diagnosis of BPH and recent revision of the guidelines by the AUA confirmed the ongoing validity of the diagnosis and treatment algorithm.11 Sagnier et al., as well as Badia et al., have described methods of translation and linguistic validation or ‘harmonization’ for the I-PSS in an attempt to assure scores are comparable across countries, ethnicities, and cultures.12,13 Versions of the I-PSS are now available in many languages for epidemiologic research.14 Table 9.4 presents estimates of the prevalence of an I-PSS of 8 or greater by age in a number of populationbased studies from different countries. This table extends a previous synthesis of a subset of these studies by Oishi et al.15 These studies are most remarkable for the consistency of their reported prevalences of these LUTS among

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Page 146 Table 9.3 Comparison of 25th centile, median and 75th centile postvoid residual volumes for men of different ages in Olmsted County, Minnesota.8 Age Postvoid residual volume (ml) 25th centile Median 75th centile 40–49 2.0 10.1 37.6 50–59 2.4 11.2 35.4 60–69 2.2 6.9 31.4 70–79 4.6 13.1 36.7 Table 9.4 Prevalence of moderate to severe lower urinary tract symptoms (LUTS) (I-PSS score of 8 or greater) among older men in community-based studies in different countries or regions.   Prevalence of moderate-severe symptoms by age (%) 50–59 60–69 70–79 Asia16 29 40 56 Australia16 36 33 37 China16 24 33 49 France12 8 14 27 The Netherlands17 26* 30 36† New Zealand18 24 34 33 Singapore19 8 18 27 Spain21 19 31 40 Spain21 21 29 45 USA22 31 36 44 *Age 54–59; †age 70–74. men of many ethnicities and cultures, as defined using many different translations of the I-PSS, although the studies from Singapore and France appear to be outliers suggesting somewhat lower estimates. In many different countries, almost half of men have moderate to severe LUTS by the time they are in their 70s. The implications of these relatively high prevalences of LUTS among older men around the world is debated. A number of community-based studies have documented that men with higher levels of these symptoms suffer quality-of-life impairment, decrements in functional status, and more bother and worry.23,24 Such studies imply that evaluation and treatment of these men (for BPH or other conditions that may be responsible for their symptoms), many who have not consulted physicians, might substantially improve their health status.25 Others are more dubious regarding the degree to which lack of consultation reflects embarrassment and worry about the sideeffects of treatment as opposed to the possibility that such symptoms are quite tolerable to many men, who therefore might not benefit much from treatment.26 Estimates of the prevalence of BPH with clinical manifestations BPH is no more than a histologic curiosity if it is not associated with LUTS or complications that affect the lives of the men who have it. Epidemiologic study of the prevalence of BPH with clinical manifestations has been hampered by the lack of a broadly accepted working definition of this condition. Men may have LUTS not due to BPH, and an impaired uroflow or prostatic enlargement is neither perfectly sensitive nor specific for BPH. In fact, even among men with LUTS and evidence of BPH histology (as might be obtained if they were biopsied), it is hard to be sure the symptoms are indeed due to the histologic process. One might think that the various parameters that have been thought to reflect the presence of BPH and its severity, such as prostate volume, peak uroflow, postvoid residual volume, and LUTS scores, might be closely related among older men. In fact, prostate volume, peak uroflow, and symptom scores are only weakly related, although the relationships are stronger in communitybased studies reflecting the full range of these parameters than clinic-based studies.27,28 Despite absent or weak relationships among these measures, many investigators have attempted to combine these parameters in working epidemiologic definitions of ‘BPH with clinical manifestations’ for population-based studies. One of the first of these efforts was presented by Garraway et al., based on data from a community-based study of men age 40–79 in central Scotland. These investigators reported the joint prevalence of either suggestive symptoms (above a specified cutpoint on a symptom score different from the I-PSS) or a reduced peak urinary flow rate (<15 ml/s) and a prostate weight greater than 20 g as measured by ultrasound (Table 9.5).28 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_146.html[09.07.2009 11:52:28]

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However, a number of subsequent studies have documented that estimates of the prevalence of BPH with clinical manifestations are quite dependent on the definition applied. For example, Bosch et al.29 collected data on LUTS, prostate volume, uroflow, and postvoid residual volume from 502 men aged 55– 74 living in four areas of the city of Rotterdam, after excluding men with prior

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Page 147 prostate surgery or a diagnosis of prostate cancer. Figure 9.7 displays the prevalence estimates for BPH with clinical manifestations using a spectrum of definitions. The prevalence estimates ranged from a high of about 30% when only an I-PSS>7 was required, to a low of about 5% when, in addition to an I-PSS>7, an enlarged prostate (>30 cm3), a low peak uroflow (<10 ml/s), and Table 9.5 Prevalence (with 95% confidence intervals) of BPH with clinical manifestations (as defined by the presence of symptoms or a depressed peak flow rate and a prostate weight greater than 20 g) among men in central Scotland, by age.28 Age Prevalence (%) 40–49 13.8 (9.7–17.8) 50–59 23.7 (17.3–28.8) 60–69 43.0 (35.0–50.9) 70–79 40.0 (28.5–51.5) a postvoid residual volume >50 ml were also required. For a moderately restrictive definition requiring symptoms (I-PSS>7), prostatic enlargement (>30 cm3), and a moderately low peak uroflow (<15 ml/s), the estimated prevalence of BPH with clinical manifestations was 9% for men aged 55–59, 20% for men aged 60–64, 19% for men aged 65–69, and 27% for men aged 70–74. Jacobsen et al. have taken a similar approach, applying different criteria for an epidemiologic definition of BPH to men in their Olmsted County, Minnesota cohort.30 Table 9.6 estimates the prevalences of BPH by age according to different epidemiologic definitions for this group of men. The absence of an acceptable ‘gold standard’ makes it difficult to decide which of these definitions of BPH with clinical manifestations, if any, is the most appropriate for epidemiologic research. An ideal ‘gold standard’ test would be able to determine when the clinical finding (particularly LUTS, the most important clinical manifestation from the patient’s perspective), is indeed caused through some mechanism by the histologic process of BPH. The

Figure 9.7 Prevalence of BPH with clinical manifestations among men aged 55–74 in Rotterdam, The Netherlands, using different criteria for a working epidemiologic definition.29

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Page 148 Table 9.6 Estimated prevalence of BPH by age for men in Olmsted County, Minnesota, with different epidemiologic definitions of BPH based on various symptom score (I-PSS), peak uroflow (Qmax in ml/s), and postvoid residual volume (PVR in ml) cutpoints.30   Estimated prevalence by age (%) 50–59 60–69 70–79 I-PSS>7 33 41 46 I-PSS>7, Q max<10 4 14 17 I-PSS>7, Q max<15 17 27 35 I-PSS>7, PVR>50 5 13 28 I-PSS>7, Q max<10 or PVR>50 7 24 37 I-PSS>7, Q max<15 or PVR>50 19 35 40 most logical gold standard, in some ways, would be the documented presence of histologic BPH, but its presence alone, along with symptoms, does not prove a causal relationship in individual cases (although its absence would presumably be a good indication that the symptoms had some other cause). The documentation of histologic BPH by biopsy, then, is a sensitive but not specific candidate gold standard. There are currently few or no published data correlating these various epidemiologic definitions with the presence or absence of histologic BPH, although the Medical Treatment of Prostatic Symptoms (MTOPS) trial should reveal this information, as a group of participants underwent prostate biopsies as part of a substudy.31 An alternative gold standard is the documentation of evidence of bladder outlet obstruction by simultaneous urodynamic measures of bladder pressure and uroflow.32 However, the poor correlation between symptom severity and degree of urodynamic obstruction (even among men with documented bladder outlet obstruction), and the fact that the great majority of men whom clinicians define as having symptoms due to BPH respond to treatment for BPH even in the absence of documented bladder outlet obstruction, at least suggest that this candidate gold standard, while specific, is not sensitive. It is reassuring that when clinicians make a diagnosis of symptomatic BPH, most of these men have urodynamic evidence of bladder outlet obstruction when studied, and even more respond to medical or surgical treatments aimed at BPH.33,34 Further definition of the mechanisms and pathways by which the histologic process of BPH leads to the development of LUTS will be necessary to arrive at a more optimal gold standard against which to judge more practical working epidemiologic definitions of this condition. Regarding the epidemiology of BPH, guidelines recently published by the AUA11 suggest that future research should focus on the following: • Establishment of an epidemiologic definition of BPH that is accepted worldwide. • Determination of outcome rates using established criteria in groups of BPH patients from different ethnic groups or environments stratified by age. • Identification of baseline parameters predictive of clinical outcome. • Study of the prevalence of concomitant conditions, both urologic (such as LUTS, erectile dysfunction and incontinence) and general (such as hypertension and vascular diseases) in the community. • Identification of familial and genetic aspects of BPH. • Means of preventing disease progression and/or development of BPH in high-risk patients and/or the population at large. Regarding the third point, the MTOPS trial has shown that prostate-specific antigen (PSA), Q max, PVR, and prostate volume at baseline correlate with disease progression and the need for BPH-related surgery.35 Community-based studies are needed to give further insight into this and the other aspects described above. Summary The histologic condition BPH is very common among older men around the developed world. Other manifestations of BPH, such as prostatic enlargement, depressed uroflow, and increased postvoid residual urine volume are likewise common, although in some cases these manifestations may be due to diseases other than BPH (even when histologic evidence of BPH is present). The clinical manifestations of BPH most important to patients, LUTS, are also extraordinarily common among older men, and their rising prevalence with aging is remarkably similar among men from many countries and of many ethnicities. Even if a substantial minority of these symptoms is caused

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Page 149 by other diseases, BPH as a cause of LUTS clearly is responsible for substantial morbidity worldwide. Acknowledgment The epidemiologic analyses supporting this chapter were funded by the Agency for Health Care Policy and Research (Grant No HS 08397). References 1. Berry S J, Coffey D S, Walsh P C, Ewing L L. The development of human benign prostatic hyperplasia by age. J Urol 1984; 132:474–479 2. Isaacs J T, Coffey D S. Etiology and disease process of benign prostatic hyperplasia. Prostate 1989; 2(Suppl): 33–50 3. Gu F -L, Xia T -L, Kong X -T. Preliminary study of the frequency of benign prostatic hyperplasia and prostatic cancer in China. Urology 1994; 44:688–691 4. Bosch J L H R, Hop W C J, Niemer A Q H J et al. Parameters of prostate volume and shape in a community based population of men 55 to 74 years old. J Urol 1994; 152:1501–1505 5. Masumori N, Tsukamoto T, Kumamoto Y et al. Japanese men have smaller prostates but comparable urinary flow rates relative to American men: results of community based studies in 2 countries. J Urol 1996; 155:1324–1327 6. Girman C J, Panser L A, Chute C G et al. Natural history of prostatism: urinary flow rates in a community-based study. J Urol 1993; 150:887–892 7. Bruskewitz R C, Iversen P, Madsen P O. Value of postvoid residual urine determination in evaluation of prostatism. Urology 1982; 20:602–604 8. Kolman C, Girman C J, Jacobsen S J, Lieber M M . Distribution of post-void residual volume in randomly selected men. J Urol 1999; 161:122–127 9. Mebust W, Kozio R, Shroeder F, Villers A. Correlations between pathology, clinical symptoms and the course of the disease. In: Cockett A T K, Aso S, Chatelain C et al. (eds). The international consultation on benign prostatic hyperplasia (BPH). Jersey, Channel Islands: Scientific Communication International Ltd, 1991:51–62 10. Barry M J, Fowler F J, O’Leary M P et al. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992; 148:1549–1557 11. AUA BPH Guideline Update Panel. The Management of BPH, 2003. https://shop.auanet.org/timssnet/products/guidelines/bph_management.cfm 12. Sagnier P -P, Macfarlane G, Richard F et al. Results of an epidemiologic survey using a modified American Urological Association symptom index for benign prostatic hyperplasia in France. J Urol 1994; 151:1266–1270 13. Badia X, Garcia-Losa M, Dal-Re R. Ten-language translation and harmonization of the International Prostate Symptom Score: developing a methodology for multinational clinical trials. Eur Urol 1997; 31:129–140 14. Barry M J, Adolfsson J, Batista J E et al. Measuring symptoms and health impact of benign prostatic hyperplasia and its treatments. In: Denis L, Griffiths K, Khoury S et al. (eds). Fourth international consultation on BPH. Plymouth: Plymbridge Distributors, 1998:265–321 15. Oishi K, Boyle P, Barry M J et al. Epidemiology and natural history of BPH. In: Denis L, Griffiths K, Khoury S et al. (eds). Fourth International Consultation on BPH. Plymouth: Plymbridge Distributors, 1998; 23–59 16. Homma Y, Kawabe K, Tsukamoto T et al. Epidemiologic survey of lower urinary tract symptoms in Asia and Australia using the International Prostate Symptom Score. Int Urol 1997; 4:40–46 17. Bosch J L H R, Hop W C J, Kirkels W J, Schroder F H . The International Prostate Symptom Score in a community-based sample of men between 55 and 74 years of age: prevalence and correlation of symptoms with age, prostate volume, flow rate and residual urine volume. Br J Urol 1995; 75:622–630 18. Nacey J N, Morum P, Delahunt B. Analysis of voiding symptoms in Maori, Pacific Island, and Caucasian New Zealand men. Urology 1995; 46:506–511 19. Tan H Y, Choo W C, Archibald C, Esuvaranathan K. A community-based study of prostatic symptoms in Singapore. J Urol 1997; 157:890–893 20. Hunter D J W, Berra-Unamuno A, Martin-Gordo A . Prevalence of urinary symptoms and other urological conditions in Spanish men 50 years old or older. J Urol 1996; 155:1965–1970 21. Chicharro-Molero J A, Burgos-Rodriquez R, SanchezCruz J J et al. Prevalence of benign prostatic hyperplasia in Spanish men 40 years old or older. J Urol 1998; 159: 878–882 22. Chute C G, Panser L A, Girman C J et al. The prevalence of prostatism: a population-based survey of urinary symptoms. J Urol 1993; 150:85–89 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_149.html[09.07.2009 11:52:29]

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23. Garraway W M, McKelvie G B, Russell E B A et al. Impact of previously unrecognized benign prostatic hyperplasia on the daily activities of middle-aged and elderly men. Br J Gen Pract 1993; 43:318–321 24. Girman C J, Jacobsen S J, Tsukamoto T et al. Health-related quality of life associated with lower urinary tract symptoms in four countries. Urology 1998; 51:428–436 25. McKelvie G B, Collins G N, Hehir M, Rogers C N. A study of benign prostatic hyperplasia—a challenge to British Urology. Br J Urol 1993; 71:38–42

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Page 150 26. Jolleys J V, Donovan J L, Nanchahal K et al. Urinary symptoms in the community: how bothersome are they? Br J Urol 1994; 74:551–555 27. Girman C J, Jacobsen S J, Guess H A et al. Natural history of prostatism: relationship among symptoms, prostate volume, and peak urinary flow rate. J Urol 1995; 153: 1510–1515 28. Garraway M, Collins R, Lee R. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991; 338:469–471 29. Bosch J L H R, Hop W C J, Kirkels W J, Schroeder F H . Natural history of benign prostatic hyperplasia: appropriate case definition and estimate of its prevalence in the community. Urology 1995; 46(Suppl 3A): 34–40 30. Jacobsen S J, Girman C J, Guess H A et al. New diagnostic and treatment guidelines for benign prostatic hyperplasia. Arch Intern Med 1995; 155:477–481 31. Bautista O M, Kusek J W, Nyberg L M et al for the MTOPS Research Group. Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial. Control Clin Trials 2003; 24:224–243 32. Abrams P. In support of pressure-flow studies for evaluating men with lower urinary tract symptoms. Urology 1994; 44:153–155 33. McConnell J D. Why pressure-flow studies should be optional and not mandatory studies for evaluating men with benign prostatic hyperplasia. Urology 1994; 44: 156–158 34. Jepsen J V, Bruskewitz R C. Comprehensive patient evaluation for benign prostatic hyperplasia. Urology 1998; 51(Suppl 4A): 13–18 35. McConnell J D, Roehrborn C G, Slawin K M et al. Baseline measures predict the risk of benign prostatic hyperplasia clinical progression in placebo-treated patients. J Urol 2003; 169 (Suppl 4): abstract 1287

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Page 151 10 Descriptive epidemiology of benign prostatic hyperplasia H A Guess C J Girman Introduction A thorough understanding of benign prostatic hyperplasia (BPH) requires a knowledge not only of its pathophysiology but also of its epidemiology. Until recently, most epidemiologic information about BPH had come from studies involving only men who had sought treatment for BPH. Such studies make it difficult to separate factors related to seeking treatment from factors related to other measures of disease progression. In addition, they do not provide information on the full spectrum of disease or of early findings, since they are limited to men in whom the clinical manifestations have progressed far enough to lead them to seek medical attention, To provide more complete information requires population-based studies, which involve representative sampling from a geographically defined population. Population-based studies of BPH can contribute to medical knowledge in at least three areas.1 First, there is the need to establish community-based normal ranges of symptom scores and commonly used diagnostic tests. A proper evaluation of any test requires that the study population include a sufficiently broad spectrum of diseased and nondiseased individuals.2 Studying only men seen in urology clinics can lead to optimistic estimates of sensitivity and specificity that are later proven to be incorrect when the test is applied to men with milder disease in a general practice setting.2,3 Studies to establish community-based normal ranges of tests also provide information on the community prevalence of symptoms and other measures of BPH. This information is useful in characterizing the amount of morbidity attributable to BPH. Second, it is important to determine how symptoms and other factors influence both the decision to seek treatment and the choice of treatment. Barry et al. have shown that differences in individual patient preferences are important in making rational choices of treatments.4 Such information is also useful in estimating how practice guidelines may affect utilization of medical services.5 A third potential contribution of long-term community-based studies is to provide information on outcomes from a representative sample of a defined population rather than only from patients treated at particular health-care facilities. What may appear to be intervention-related or hospital-related variation in outcomes may be variation in the magnitude and form of patient-selection bias. Selection bias in nonpopulation-based studies is often impossible to control by co-morbidity adjustments, because factors which bring patients to a particular facility or which lead to the choice of one type of treatment over another are often not adequately reflected in medical records or in any other readily available data source.6–9 It is the lower potential for selection bias which makes community-based studies of disease natural history preferable to natural history studies conducted in referral populations.10 Studies of BPH natural history are discussed in a subsequent chapter. In this chapter we will review a number of populationbased studies of urinary symptoms and health status related to BPH that have been conducted recently. Several of these studies are still ongoing and further publications of results will be forthcoming in the next few years. This chapter will acquaint readers with the designs of such studies and some of the cross-sectional and longitudinal results recently available from these studies. An overview of the sampling methods is given in the Appendix. Most of these studies were cross-sectional studies, with data collected at a single point in time. The earliest large community-based studies of BPH were conducted in the US and Scotland, and both of these studies were longitudinal in nature. Later studies involved a national survey of urinary symptoms and quality of life among French men, and community-based studies in Denmark, Japan, and The Netherlands. After introduction of a standard symptom assessment tool,11 a number of cross-sectional surveys were conducted in Europe, Asia, and worldwide.12–33 Several published community surveys have used instruments other than the American Urological Association Symptom Index or International Prostate Symptom Score (I-PSS),33–39 making it difficult to compare with studies using the more recent standard tools. A few of these studies assessed urological measurements in addition to frequency of urinary symptoms, including prostate volume and urinary flow rates. These include the studies conducted in the US, Scotland, Japan, Korea, The Netherlands, Norway, and Spain. For more comprehensive reviews of BPH epidemiology the reader is referred to a number of review articles.40–47

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Page 152 French national survey Sagnier et al. conducted a survey of urinary symptoms and quality of life in a nationally representative probability sample of 2011 French men 50–80 years old, using a French translation of the American Urological Association Symptom Index (AUASI).11,48–51 This French translation has been accepted as the French language version of the I-PSS.50 In the initial article describing prevalence of symptoms,18 the authors referred to their symptom score as the AUASI. In a subsequent article describing the impact of symptoms on quality of life,51 the same symptom score was referred to as the International Prostate Symptom Score. For the sake of consistency we will henceforth refer to their symptom score as the International Prostate Symptom Score. In the survey, information was collected by household interview, in which 12525 dwellings had to be contacted to obtain the above sample size. The authors noted that a calculation of the true response rate in this study is not possible, since the sampling unit (dwellings) and the reporting units (subjects) were different and the eligibility status of subjects who were not at home at the time of the initial contact is not known. However, one accepted definition of response rate is the ratio of the number of completed interviews divided by the number of known eligible units in the sample.52 By that definition the response rate was 53%. After exclusion of patients with prostate cancer, 7% of the subjects reported having undergone prostate surgery and an additional 8% reported having received a diagnosis of BPH. Among those with no history of surgery or prostate cancer, 19% had no symptoms, 67% had mild symptoms (I-PSS in the range 1– 7), 13% had moderate symptoms (I-PSS: 8–19), and 1% had severe symptoms (I-PSS: 20+). The proportion with moderate to severe symptoms approximately doubled with each decade of age. Nocturia and repeat voiding within 2 hours were the most prevalent symptoms. The index formed by the American Urological Association (AUA) questions on bother due to urinary symptoms (also known as the Symptom Problem Index,53 referred to here as the AUA Bother Score) was the best determinant of each subject’s level of worry about urinary conditions and the degree to which urinary symptoms interfered with daily life. Urgency was by far the most bothersome symptom among men who reported one or more urinary symptoms, followed by wet underclothes, revoiding within 10 minutes, and nocturia. Intermittency and weak stream appeared to be less bothersome. The AUA Bother Score was highly correlated to the I-PSS ( r=0.85, p <0.001). The authors estimated that in 1992 approximately 1.14 million French men had moderate to severe urinary symptoms. They noted that previous studies in other populations had yielded higher percentage prevalence estimates, probably due to differences in sampling design and diagnostic criteria. In particular, the prevalence of moderate to severe urinary symptoms (I-PSS of 8 or more) in France was somewhat similar to that in Scotland, but was considerably lower than that in Olmsted County, Minnesota.54–56 This large difference in age-specific symptom prevalence is in contrast to findings in two population-based studies that the age-specific incidence of initial prostatectomy for BPH in Olmsted County57 is nearly identical to that in Lyon, France, across all age groups.58 Other European Community-based studies Scandinavia Copenhagen, Denmark Jensen et al. conducted a survey of urological symptoms and urinary flow rates based on a randomly drawn sample of 200 men age 50 and older with an age distribution representative of the metropolitan population of Copenhagen, Denmark.59 The final sample consisted of 121 men, representing a 61% response rate. Seventeen per cent of the men were considered to have prostatism, which was defined as the presence of self-reported voiding problems unrelated to dysuria or hematuria. Only limited relationships between symptom scores and urinary flow rate were found and there was considerable overlap in urinary flow rates between those who did and did not meet the above definition of prostatism. The authors concluded that, no matter what flow rates are chosen as the cutoff limits of normal, urinary flow rate measurements are not an efficient means of confirming a clinical impression of prostatism. A similar conclusion as to the relative nonspecificity of urinary flow rate measurements was found by Girman et al.60 Sommer et al.38 conducted a questionnaire survey in men randomly selected from the Danish National Register, using an instrument similar to that used by Jensen.59 Of the 572 men who received questionnaires, 382 (67% response rate) were returned. Results were remarkedly similar to those found by Jensen et al.59 despite differences in administration (questionnaire vs oral interviews) between the two studies.

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Page 153 Norway As part of a larger population-based health study in Norway, all men aged 40 years and above in Trondheim, Norway, were invited to participate in a study of urinary symptoms and health status, and over 22000 completed a questionnaire containing the I-PSS. Overall, 16% of the men reported moderate to severe symptoms.19 The prevalence increased with increasing age, from 10% for men in their forties to over 30% for men in their seventies. The age-specific prevalences were similar to those found in studies in America, Spain, and The Netherlands.12,14,61 In addition, a random subsample of 636 men aged 55–70 years without prior prostate cancer or prostate surgery were invited for full urological examination, included transrectal ultrasonography, urinary flow rate measurement, and digital rectal examination. Between 20% (age 55–59 years) and 33% (age 65–70 years) of the men clinically evaluated reported moderate to severe symptoms.19 About 40–50% had a peak flow rate below 15 ml/s, and the percentage of men with prostate volume above 30 ml ranged from 36% for men aged 55– 59 to 54% for men aged 65–70 years. Finland Using a modified Danish prostatic symptom score system (DAN-PSS-1), questionnaires were mailed to all men ( n =3143) born in the years 1924, 1934, or 1944 in the city of Tampere or 11 rural and semirural municipalities of Finland.33 For those who returned the questionnaires (70%), about 89% reported at least one symptom, with post-micturition dribbling and nocturia as the most prevalent symptoms. The prevalence of bothersome symptoms increased from 48% for men 50 years of age to 58% for men 60 years of age and 62% for men 70 years of age, and the prevalence of individual symptoms was comparable to that found in other European studies.55 This study also documented the association between lower urinary tract symptoms (LUTS) and several non-urological diseases.62 The Netherlands The prevalence of symptoms in the Dutch community of Rotterdam was assessed as part of a randomized pilot study on the value of prostate cancer screening.12 The I-PSS was administered to 502 men (response rate 33–36%) aged 55–74 years, who had no history of prostatectomy or prostate cancer. Nocturia, frequency, and weak stream were the most prevalent symptoms. Overall, 30% of men reported moderate to severe symptoms, corresponding roughly to estimates from the US,61 Canada,37 and Spain,13,14 but higher than estimates from the populationbased survey in France.50 Other urological parameters were also measured in this study. Over 95% had a prostate volume greater than 20 ml based on transrectal ultrasonography, and prostate volume was greater than 30 ml in 60%, and greater than 40 ml in 30% of these Dutch community men.63 Mean prostate volume increased with increasing age, and was 20–30% higher than average weights measured at autopsy for men in the same age range.63,64 A survey of urinary symptoms and physician visits was conducted in all 2734 male patients 55 years of age and older registered in 10 general practices in Maastricht, The Netherlands.39 Responses were obtained from 1692 subjects (64% response rate). The authors noted that all Dutch inhabitants are registered with local general practices, so this survey was considered to represent a sample of the general male population of Maastricht. The symptom questionnaire used in this study was based on that of Boyarsky, but was different from that used in the Olmsted County study, the Forth Valley, Scotland, study, and other community studies. Hence direct comparisons are problematic, although the authors noted symptom prevalences in the same general range as in Scotland and lower than in Olmsted County. The percentage of men with physician visits for urinary conditions within the past 5 years (25%) appeared to be considerably higher than the percentage of men in Olmsted County or Scotland consulting a physician for urinary conditions within the past 1 year (approximately 6%). The authors concluded that more information is needed to identify determinants of health-care seeking behavior for urinary symptoms. In a more recent community-based study in The Netherlands the authors showed that the prevalence of BPH depends strongly on the definition and that response bias can also have an important influence on estimates of symptom prevalence.65 United Kingdom Forth Valley, Scotland Garraway et al. conducted a study of urinary symptoms in four villages in the Forth Valley of Scotland.66–70 As in the Olmsted County study discussed below, only men 40–79 years of age with no history at baseline of prostate cancer, prostate surgery, or other specified conditions that could interfere with normal voiding function were eligible to participate. This study used a definition of BPH based on a prostate size of more than 20 g plus (1) a maximum urinary flow rate less than 15 ml/s and/or (2) LUTS in excess of a specified level. 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Page 154 men in the community was higher than had previously been reported,66 increasing from 14% of men in their forties to 43% of men in their sixties. About half of men with BPH, as compared to one-fourth of men without BPH, reported some interference with one or more of the seven living activities on a scale developed and validated by Epstein et al. and discussed below.71 Among men of working age (40–64 years), 17% of those with BPH, as compared to 3% of those without BPH, reported interference most or all of the time.69 Men with BPH had more anxiety and depression, less vitality and self control, and more worry and embarrassment about urinary dysfunction than did men without BPH.70 In a 1-year follow-up of this cohort, the authors noted that a longer period of observation was needed to determine the extent to which a consistent pattern of urinary symptomatology exists in untreated BPH and whether interference with living activities continues to progress over time.68 These men (71% of original participants) were followed up at 5 years.72 Although the progression of LUTS in individual men was highly variable, results suggested an overall trend of deterioration in levels of LUTS as well as degree of bother and activity interference due to urinary symptoms in untreated men.72 Hunter et al.15 conducted a community-based study of British men aged 55 years and older in the North West Thames health region. From eight general practices, 1480 of the 2000 randomly selected men (78% response rate) completed questionnaires, which included the I-PSS. The overall percentage of men with moderate to severe symptoms was 20.4%. This increased from 16.2% for men 50–59 years of age to 20–25% for men aged 65–79 years. Of men with moderate or severe symptoms, 28% reported them to be a medium or big problem while 37% reported interference with activities at least some of the time and 43% reported that they would be unhappy at the prospect of a future with their symptoms as they are now.15 Trueman et al.16 found a somewhat higher prevalence of moderate to severe symptoms in a postal survey of an agestratified random sample of UK men 50 years of age and older. Spain A cross-sectional population survey of 2002 men 50 years or older in the community of Madrid was conducted by interview, and the I-PSS was used to assess prevalence of LUTS.14 About 30.4% of men reported moderate to severe symptoms, a comparable prevalence estimate to that found in the US.61 Like most other community-based studies, the proportion of men reporting moderate to severe symptoms increased with increasing age group. In this study, for men with moderate to severe symptoms, about 26.5% reported that their symptoms were a medium or great problem, while 5.4% reported that their symptoms interfered with their daily activities at least some of the time.14 A cross-sectional study of the prevalence of LUTS was also conducted in Spanish men aged 40 years or older residing in the Andalusia region of southern Spain. A probability sample of potential participants was selected using census data and a multistage, stratified sampling design. After exclusions, about 25% reported moderate to severe symptoms. The percentage of men with moderate to severe symptoms increased from 10.6% for men aged 40–49 to 45% for men aged 70 years or older.13 These rates are relatively comparable to estimates from studies in the US and Scotland, but higher than reported for French men.55 North America Canada A telephone survey was conducted in a probability sample of Canadian men aged 50 years and older, based on the Boyasky questionnaire.37 A total of 19359 telephone calls led to the completion of 508 interviews, although the direct refusal rate was only 23%. Approximately 23% of Canadian participants reported moderate to severe symptoms, ranging from 15% for men aged 50–59 years to 31% for those 70 years or older.37 For individual symptoms, the authors noted similarities to results found in populationbased studies in the UK and Denmark.38,59 Washtenaw County Urological Survey This study involved a probability sample of 802 community-dwelling men 60 years of age and older in Washtenaw County, Michigan (65% response rate). Approximately 20% of the men reported having had prior prostate surgery at baseline. Among those with no history of surgery at baseline, 35% reported at least one of six symptoms of voiding difficulty, while 15% reported two or more symptoms.35 The six symptoms were hesitancy, straining, weak stream, interrupted stream, need to void twice to completely empty the bladder, or use of a catheter in the past 6 months. Nonurological conditions related to the presence of moderate to severe symptoms of prostatism included use of sedatives or tranquilizers, arthritis, poor health status, and transient ischemic attacks. In follow-up surveys taken 1 year and 2 years later, substantial remissions and exacerbations were noted in the absence of any

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Page 155 treatment. In each of the two follow-up years, approximately 3% of men with no history of prostate surgery underwent prostatectomy. Flint Men’s Health Study Wei et al. published initial results from the Flint Men’s Health Study in African-American men living in Flint, Michigan.36 The study included 364 men who had determinations of serum prostate-specific antigen, uroflow, digital rectal examination, and prostate size by transrectal ultrasound. Nearly 40% had moderate to severe LUTS by the American Urological Association Symptom Scale, yet only about 8% reported an enlarged prostate and only 3% had received medical treatment for BPH. Olmsted County Study Study design The Olmsted County Study of Urinary Symptoms and Health Status Among Men (OCS) is a communitybased study of 2115 randomly selected Caucasian male residents of Olmsted County, Minnesota, between 40 and 79 years of age with no history of prostate surgery, prostate cancer, or any of a specified list of conditions known to affect voiding function.61 At the baseline evaluation, completed in 1991, all men had urinary flow rate measurements and completed the questionnaire previously validated by Epstein et al.71 This questionnaire covers frequency of urinary symptoms, bother due to urinary symptoms, worries and concerns about urinary problems and prostate cancer, interference in living activities due to urinary symptoms, sexual functioning, and general psychological well-being. The questionnaire predates the AUASI but includes questions on urinary symptoms that have nearly identical wording to the AUASI and permit computation of AUASI scores. The scale to measure BPH-Specific interference with daily activities is based on seven questions which ask about the extent to which urinary symptoms interfere with: (1) drinking fluids before traveling, (2) drinking fluids before going to bed, (3) driving for 2 hours without stopping, (4) getting enough sleep at night, (5) going to places that have no toilet, (6) playing outdoor sports such as golf, and (7) going to movies, shows, or church. Each question is scored from 0 (none of the time) to 4 (all of the time). Thus, a composite score describing the extent of interference with living activities can be calculated by adding the responses, with possible scores ranging from 0 to 28. Additional questions pertain to use of health care, fluid and alcohol intake, smoking history, personal and family medical history, and demographic information. This questionnaire has been used not only in the OCS, but also in the Forth Valley, Scotland, study66–70 and the Shimamakimura, Japan study,73,74 and a translated modified version was used in the French national survey.50,51 The OCS includes biennial mail-based follow-up questionnaires on the full cohort through 1996, with planned longer-term follow-up studies of medical care utilization and outcomes using the medical records database of the Rochester Epidemiology Project. A randomly chosen subset of approximately one-quarter of the OCS cohort (about 475 men) also had a baseline urological evaluation that included: digital rectal examination, prostate size determined by transrectal ultrasound, residual urine measurements by abdominal ultrasound, urinalysis, serum creatinine, prostate-specific antigen (PSA) determination, and serum storage. Participants have been followed for more than 10 years. Publications from the baseline phase of the study have included: BPH symptom prevalence,61 impact of urinary symptoms on quality of life,75 comparison of symptoms and their impact on living activities in Scottish and American men,56 relationships among symptoms, prostate volume, and peak urinary flow rate,76 community-based age-specific reference ranges for urinary flow rates,60 community-based ageSpecific reference ranges for PSA,77 health-care-seeking behavior for urinary symptoms,78 the relationship between health-care-seeking behavior and worry and embarrassment from urinary symptoms,79 cigarette smoking and prostatism,80 family history in association with prostatism,81 factors associated with discordance between the frequency and the extent of bother in urinary symptoms,82 the potential impact of BPH practice guidelines on health-care utilization,5 comparison of prevalence rates and health-care-seeking behavior of survey responders and nonresponders,83 effect of several different recruitment strategies on survey response rates,84 and the role of community-based studies in evaluating treatment effects in BPH.1 While some of these findings have been discussed earlier, it is worth summarizing some of the published findings here. Health-related quality of life and symptoms of BPH For men aged 50–79 years, 38% reported moderate to severe symptoms.55–61 Girman et al.75 found that men with moderate to severe voiding symptoms had about four to six times more bother and interference with daily activities and twice the level of worry experienced by men with mild symptoms. This study also confirmed original clinicbased studies11 in which an AUASI of 8 or more was found to differentiate men with and without some degree file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_155.html[09.07.2009 11:52:32]

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Page 156 of bother due to urinary symptoms. These results show that moderate to severe urinary symptoms have a significant impact on patients’ lives in terms of the degree of bother, worry, interference with living activities, and psychological well-being. The results also provide further support for the validity of an AUASI (or I-PSS) score of 8 as defining the lower limit of moderate symptoms. Results of the impact of urinary symptoms on men have been demonstrated using disease-specific, health-related quality-of-life instruments in studies conducted in four countries,85 as well as general measures of health status.86,87 In addition, men with prostatic enlargement have been shown to be 3 times more likely to have moderate to severe symptoms,76 and 2–2.5 times more likely to have bother and activity interference, relative to men with smaller prostates.88 Recent studies in this population have shown that ejaculation frequency is not related to LUTS, peak urinary flow rates, or prostate volume after adjusting for age. The apparent protective association when age is not taken into account in the analysis appears to be an artifact caused by the confounding effects of age.89 Health-care-seeking behavior and urinary symptoms Even though symptom severity is an important determinant of health-care-seeking behavior for treatment of urinary symptoms, it is neither sensitive nor specific as a predictor of health-care-seeking behavior.78 Worsening of symptoms over the past year was found to be a statistically significant independent predictor of health-care-Seeking behavior, even after controlling for symptom severity. Age was found to be the most highly predictive determinant of health-care-seeking behavior. This implies that there are unidentified age-related factors, other than symptoms or patient demographics, which influence health-care seeking for urinary symptoms. Identification of such factors may help account for at least some of the large variation which has been found in BPH treatment patterns both within the US and between European countries.78 Relationships among symptoms, prostate volume, and peak urinary flow rate Most previous studies of the relationships among symptoms, prostate volume, and peak flow rates have been conducted as clinic-based studies. To determine how these relationships would apply in a community-based study, an analysis of baseline data from the OCS was conducted based on data from 466 men.76 Age was found to explain only about 3% of the variability in symptom scores, while prostate volume and peak flow rate explained only an additional 10%. However, the odds of moderate to severe symptoms, adjusting for age, were 3.5 times higher for men who had prostate volumes above 50 ml than for those who did not. The correlation between prostate volume and AUASI was 0.185, which was similar in magnitude to the correlation of prostate volume and urinary flow rate of −0.214, but lower in magnitude than the correlation between symptoms and peak flow rate of −0.35. Because of the large number of patients involved, all of these correlations were statistically significant ( p <0.001). The correlations between physiologic measurements and symptoms, although relatively weak, are stronger than the correlations of 0.09–0.14 found in clinic-based studies and are roughly compatible with correlations between physiologic measures and symptoms in other chronic diseases.90,91 Post-void residual urine was not found to be related to age, urinary symptoms, or peak urinary flow rate, but tended to be lower in men with larger prostates ( r2=0.24, p <0.001).92 Urinary flow rate norms An example of the value of obtaining population-based age-specific normal ranges of parameters commonly used to evaluate treatment effects is given by studies of urinary flow rates. Normal ranges for urinary flow rates have often been based on selected groups of patients from clinics or referral practices. On the basis of such information urinary flow rates under 12 ml/s have been identified as indicative of obstruction.93 However, the median value of the maximum urinary flow rate among the 268 randomly selected history-negative men aged 70–79 in the OCS was found to be 12 ml/s.1–60 Clinical evaluation of the randomly chosen one-quarter sample of the OCS found none who were judged to require treatment. These results suggest that flow rates in the range of 12 ml/s may have poor specificity as indicators of obstruction, especially in older men. This result is consistent with earlier findings of Jensen et al. in a Danish population-based study discussed above.59 Longitudinal follow-up Few studies have conducted longitudinal follow-up over time in a defined community cohort of men. However, in the Olmsted County Study the measurable progression in symptom severity over time, despite high within-subject variability,94 is consistent with the longitudinal results from the Scotland study.72 Likewise, high within-subject variability has been found for prostate volume, but the average rate of growth has been estimated as 1.6% per year in community men95 and growth rates appear to be dependent on baseline prostate volume. More recent

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Page 157 results have assessed the incidence and risk for long-term outcomes such as acute urinary retention,97 and have documented consistent within-patient declines in urinary flow rates measured biennially over 6 years.96 Despite questions about whether prostate volume, symptoms, and urinary flow rates correlate cross-sectionally, all three measures as well as age were found to be predictive of acute urinary retention in community men.97 Longerterm follow-up is necessary to characterize the incidence and risk for more rare complications of BPH. Asia Shimamaki-mura, Japan A community-based cohort study of urological symptoms and health status was conducted in Shimamaki-mura, a small fishing village on the west coast of the island of Hokkaido in northern Japan, using a study design very close to that used in the Olmsted County Study. Symptoms, urinary flow rates, prostate size measurements, hormonal measurements, and serum PSA measurements have been obtained on 274 men between 40 and 79 years of age, as part of the baseline phase of this study.73 In this study the age-specific prevalence of moderate to severe symptoms was somewhat higher than in Olmsted County.55,61,73 Peak urinary flow rates were somewhat higher in Japanese men than in American men (21.3±0.6 ml/s and 17.2±0.4 ml/s, p <0.0001), although the estimated rate of decline with increasing age was greater for Japanese men than for American men (3 ml/s per decade of age for the Japanese men as compared to 1 ml/s for American).74 The American men had larger prostates than the Japanese men, even after adjusting for weight, height, and age. The increase in prostate size with increasing age was about 6 ml per decade of age in the American population as compared to about 3 ml per decade of age in the Japanese population.74 Korea A community-based study of Korean men (85% response rate) showed a high percentage of men with moderate to severe symptoms, ranging from 43.4% for men aged 40–49, to 74.2% for men aged 70– 79 years.17 These estimates are not markedly different from those reported in Japanese community men.73 Singapore A cross-sectional study in men 40 years or older in Queenstown, Singapore,20 suggested an overall prevalence of only 10%, about one-third of that found in studies conducted in Scotland, the US, and Japan.55 Within each age decade, large differences were seen between the Singapore study and results of studies in Japan and the US,55 with the prevalence in the US between 2 and 4 times greater and the prevalence in Scotland between 2 and 3 times greater than in Singapore. Even larger differences in prevalence were found between Japan and Singapore.73 The most prevalent symptoms were frequency and nocturia. Men in the Singapore study appeared to be less bothered by urinary symptoms than men in the US. In contrast to other studies,51,56,82 symptom frequency and bother scores correlated only moderately ( r=0.5). New Zealand A random sample of men 40 years and older was drawn from voter records in the Porirua area within the Wellington region of New Zealand, and a survey of urinary symptoms was conducted using the IPSS.98 The overall response rate was 64%, with predominantly Caucasian and Pacific Island Polynesian men participating. Mean symptom scores increased dramatically with increasing age decade, ranging from 2.9 for men aged 40–49 years, to 7.4 for men 70 years or older.98 The prevalence of moderate to severe symptoms was 13% for men aged 40–49 years, 22.3% for men aged 50–59, 33.7% for men aged 60–69 and 33.3% for men 70 years or older. These estimates are roughly equivalent to studies conducted in Scotland and other European countries. Summary Recent population-based studies in many different countries have confirmed that mild urinary symptoms are very common among men 50 years of age and older. While moderate to severe urinary symptoms are clearly less common than mild symptoms, their prevalence shows considerable variability among surveys. One consistent finding among studies is that symptoms classified as mild (I-PSS≤7) are associated with little bother, while those classified as moderate (I-PSS 8–19) and severe (I-PSS 20–35) are associated with increasingly higher levels of bother.51,56,75 Increasing symptoms are clearly associated with greater interference with living activities and with poorer scores on many indices of health-related quality of life.75,85–87 The relative nonspecificity of urinary flow rate measurements has been confirmed in several populationbased studies.59,60 While correlations among symptoms, prostate size, and urinary flow rates are relatively low, they are in the same general range as correlations between file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_157.html[09.07.2009 11:52:33]

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Page 158 measures of other chronic diseases.76,90 Symptom frequency and symptom bother together explain only a small proportion of the variation in health-care-seeking behavior for treatment of urinary symptoms.78 Ongoing populationbased studies of urinary symptoms have made substantial contributions to epidemiologic knowledge of BPH. Further research is needed to understand factors related to longer-term patient decision-making and health perceptions in this disease. Appendix: sampling methods used in BPH population studies One method of obtaining a representative sample from a geographically defined population is to attempt to enroll all eligible members of the population. This approach is only useful when the geographically defined population is a small community. One example where this technique was used was in the small fishing village of Shimamakimura, on the island of Hokkaido, Japan, and also in the Norwegian study. A closely related approach, which also only works for small communities, is to attempt to enroll all eligible patients in all primary-care practices serving a community. For this approach to yield a truly populationbased study, it is necessary that essentially all eligible residents of the community be registered with these practices and that all urological care be referred through the primary-care practices. This approach was used in studies in the Forth Valley, Scotland, and in a part of Maastricht, The Netherlands, as well as in the study conducted in British men in the North West Thames health region. When the population is too large to make it feasible to enroll all eligible residents, it is necessary to base the study on a sample from the defined population. A truly population-based study should be based on a probability sample, which is one in which every eligible resident of the population has a known, nonzero probability of being included in the sample.99 Statistics based on such samples can be extrapolated to provide unbiased estimates, of known precision, of quantities in the geographically defined population from which they were drawn. One example of such a study is the Olmsted County Study of Urinary Symptoms and Health Status Among Men (OCS). In this study the sample was an agestratified random sample, so that with-in each 5-year age stratum (e.g. 40–44, 45–49, and so on) every eligible resident had an equal probability of being sampled. The sampling was conducted from a list which included over 90% of all residents of the county in the age range of interest. This approach was also used in Spain, Canada, and New Zealand. When there is no complete listing of all residents of the defined population, the techniques for drawing a probability sample approach the problem in a series of stages. For national surveys the sampling first samples geographic regions, then localities within the regions, then blocks or land tracts within the localities, and then households within each block or tract. At each stage the sampling probability is known and so the results can be extrapolated back to produce national estimates of known precision. The response rate can also be calculated, according to accepted rules.52,99 This is the method of probability sampling used in the French national survey of urinary symptoms and quality of life.50 Acknowledgment Portions of this chapter were adapted from Guess43, with permission. References 1. Guess H A, Jacobsen S J, Girman C J et al. The role of community-based longitudinal studies in evaluating treatment effects—example: benign prostatic hyperplasia. Med Care 1995; 33: AS26–35 2. Ransohoff D F, Feinstein A R. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 1978; 299:926–930 3. Kulka R A, Schlenger W E, Fairbank J A. Validating questions against clinical evaluations: a recent example using diagnostic interview schedule-based and other measures of post-traumatic stress disorder. In: Fowler F J Jr (ed). Health survey research methods—conference proceedings. DHHS Publication No (PHS) 89–3447. National Center for Health Services Research and Health Care Technology Assessment. 1989:29–34 4. Barry M J, Mulley A G Jr, Fowler F J, Wennberg J W. Watchful waiting vs immediate transurethral resection for symptomatic prostatism. The importance of patients’ preferences. J Am Med Assoc 1988; 259:3010–3017 5. Jacobsen S J, Guess H A, Girman C J et al. New diagnostic and treatment guidelines for benign prostatic hyperplasia. Potential impact in the United States. Arch Intern Med 1995; 155:477–481 6. Melton III L J. Selection bias in the referral of patients and the natural history of surgical conditions. Mayo Clin Proc 1985; 60:880–889 7. Ballard D J, Duncan P W. Role of population-based epidemiologic surveillance in clinical practice guideline development. In: Clinical practice guideline development: methodologic perspectives. Washington, DC: US Department of Health and Human Services, Agency for Health Care Policy and file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_158.html[09.07.2009 11:52:34]

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Page 159 8. Ballard D J, Bryant S C, O’Brien P C et al. Referral selection bias in the Medicare hospital mortality prediction model: are centers of referral for Medicare beneficiaries necessarily centers of excellence? Health Serv Res 1994; 28:771–784 9. Anderson C. Measuring what works in health care [News and Comment]. Science 1994; 263:1080– 1082 10. Ellenberg J H, Nelson K B. Sample selection and the natural history of disease—studies of febrile seizures.J Am Med Assoc 1980; 243:1337–1340 11. Barry M J, Fowler F J, O’Leary M P. and the Measurement Committee of the American Urological Association. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992; 148:1549–1557 12. Bosch J L H R, Hop W C J, Kirkels W J, Schroder F H. The International Prostate Symptom Score in a community-based sample of men between fifty-five and seventyfour years of age. Prevalence and correlation of symptoms with age, prostate volume, flow rate and residual urine volume. Br J Urol 1995; 75:622–630 13. Chicharro-Molero J A, Burgos-Rodriguez R, SanchezCruz J J et al. Prevalence of benign prostatic hyperplasia in Spanish men 40 years old or older. J Urol 1998; 159: 878–882 14. Hunter D J W, Berra-Unamuno A, Martin-Gordo A. Prevalence of urinary symptoms and other urological conditions in Spanish men 50 years or older. J Urol 1996; 155; 1965–1970 15. Hunter D J W, McKee C M, Black N A, Sanderson C F. Urinary symptoms: prevalence and severity in British men aged 55 and over. J Epidemiol Comm Health 1994; 48: 569–575 16. Trueman P, Hood S C, Nayak U S, Mrazek M F. Prevalence of lower urinary tract symptoms and selfreported diagnosed ‘benign prostatic hyperplasia’, and their effect on quality of life in a communitybased survey of men in the UK. BJU Int 1999; 83:410–415 17. Moon H -J, Moon W -C, Seo K -K, Kim Y S. High prevalence of prostatism and benign prostatic hyperplasia in Korean men. J Urol 1995; 155(Suppl): 631A 18. Oishi K, Boyle P, Barry M J et al. Epidemiology and natural history of benign prostatic hyperplasia. In: Denis L, Griffiths K, Khoury S et al. (eds). Proceedings of the 4th International Consultation on Benign Prostatic Hyperplasia (BPH). Scientific Communication International Ltd, 1998 19. Overland G B, Vada K, Vatten L J. Prostate volume, peak urinary flow rate, residual urine, urinary symptoms and benign hyperplasia of the prostate in a population-based study in Norway. J Urol 1997; 157:373 20. Tan H Y, Choo W C, Archibald C, Esuvaranathan K. A community based study of prostatic symptoms in Singapore. J Urol 1997; 157:890–893 21. Tantiwong A, Nuanyong C, Vanprapar N et al. Benign prostatic hyperplasia in elderly Thai men in an urban community: the prevalence, natural history and health related behavior. J Med Assoc Thai 2002; 85:356–360 22. Hughes A M, Sladden M J, Hirst G H, Ward J E. Community study of uncomplicated lower urinary tract symptoms among male Italian immigrants in Sydney, Australia. Eur Urol 2000; 37:191–198 23. Klein B E, Klein R, Lee K E, Bruskewitz R C. Correlates of urinary symptom scores in men. Am J Public Health 1999; 89:1745–1748 24. Verhamme K M, Dieleman J P, Bleumink G S et al. Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care—the Triumph project. Eur Urol 2002; 42:323–328 25. Apolone G, Cattaneo A, Colombo P et al. Knowledge and opinion on prostate and prevalence of selfreported BPH and prostate-related events. A cross-sectional survey in Italy. Eur J Cancer Prev 2002; 11:473–479 26. Kay L, Stigsby B, Brasso K et al. Lower urinary tract symptoms—a population survey using the Danish Prostatic Symptom Score (DAN-PSS) questionnaire. Scand J Urol Nephrol 1999; 33:94–99 27. Chen T I, Hsu Y S, Wu T T. Lower urinary tract symptoms and uroflow in a community-based sample of Taiwanese men. J Chin Med Assoc 2003; 66:84–88 28. Madersbacher S, Haidinger G, Temml C, Schmidbauer C P. Prevalence of lower urinary tract symptoms in Austria as assessed by an open survey of 2096 men. Eur Urol 1998; 34:136–141 29. Lee E, Yoo K Y, Kim Y et al. Prevalence of lower urinary tract symptoms in Korean men in a community-based study. Eur Urol 1998; 33:17–21 30. Trueman P, Hood S C, Nayak U S, Mrazek M F. Prevalence of lower urinary tract symptoms and selfreported diagnosed ‘benign prostatic hyperplasia’, and their effect on quality of life in a communitybased survey of men in the UK. BJU Int 1999; 83:410–415 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_159.html[09.07.2009 11:52:34]

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31. Joseph M A, Harlow S D, Wei J T et al. Risk factors for lower urinary tract symptoms in a populationbased sample of African-American men. Am J Epidemiol 2003; 157: 906–914 32. Haidinger G, Madersbacher S, Waldhoer T et al. The prevalence of lower urinary tract symptoms in Austrian males and associations with sociodemographic variables. Eur J Epidemiol 1999; 15:717–722 33. Koskimaki J, Hakama M, Huhtala H, Tammela T I J. Prevalence of lower urinary tract symptoms in Finnish men: a population-based study. Br J Urol 1998; 81: 364–369 34. Britton J P, Dowell A C, Whelan P. Prevalence of urinary symptoms in men aged over 60. Br J Urol 1990; 66: 175–176

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Page 160 35. Diokno A C, Brown M B, Goldstein N, Herzog A R. Epidemiology of bladder emptying symptoms in elderly men. J Urol 1992; 148:1817–1821 36. Wei J T, Schottenfeld D, Cooper K et al. The natural history of lower urinary tract symptoms in black American men: relationships with aging, prostate size, flow rate and bothersomeness. J Urol 2001; 165:1521–1525 37. Norman R W, Nickel J C, Fish D, Pickett S N. ‘Prostaterelated symptoms’ in Canadian men 50 years of age or older: prevalence and relationships among symptoms. Br J Urol 1994; 74:542–550 38. Sommer P, Nielsen K K, Bauer T et al. Voiding patterns in men evaluated by a questionnaire survey. Br J Urol 1990; 65:155–160 39. Wolfs G G M C, Knottnerus J A, Janknegt R A. Prevalence and detection of micturition problems among 2734 elderly men. J Urol 1994; 152:1467–1470 40. Barry M J. Epidemiology and natural history of benign prostatic hyperplasia. Urol Clin North Am 1990; 17:495–507 41. Boyle P, McGinn R, Maisonneuve P et al. Epidemiology of benign prostatic hyperplasia: present knowledge and studies needed. Eur Urol 1991; 20(Suppl 2): 3–10 42. Guess H A. Benign prostatic hyperplasia: antecedents and natural history. Epidemiol Rev 1992; 14:131–153 43. Guess H A. Epidemiology and natural history of benign prostatic hyperplasia. Urol Clin N Am 1995; 22:247–261 44. Girman C J. Epidemiology of benign prostatic hyperplasia. Br J Urol 1998; 82(Suppl 1): 34–43 45. Jacobsen S J, Girman C J, Lieber M M. Natural history of benign prostatic hyperplasia. Urology 2001; 58:5–16 46. Guess H A. Benign prostatic hyperplasia and prostate cancer. Epidemiol Rev 2001; 23:152–158 47. Kirby R S. The natural history of benign prostatic hyperplasia: what have we learned in the last decade? Urology 2000; 56:3–6 48. Sagnier P P, Macfarlane G, Richard F et al. Adaptation et validation en langue française du score international des symptômes de l’hypertrophie bénigne de la prostate. [Adaptation and validation in the French language of the international score of symptoms of benign prostatic hypertrophy] Prog Urol 1994; 4:532–538; discussion 539–540 49. Sagnier P P, Macfarlane G, Richard F et al. Adaptation and cultural validation in French language of the International Prostate Symptom Score and Quality of Life Assessment. In: Cockett A T K, Khoury S, Aso Y et al. (eds). Proceedings of the 2nd international consultation on benign prostatic hyperplasia. Paris, June 27–30, 1993. Paris: Sci 1993:144–147 50. Sagnier P P, Macfarlane G, Richard F et al. Results of an epidemiological survey employing a modified American Urological Association Index for benign prostatic hyperplasia in France. J Urol 1994; 151:1266–1270 51. Sagnier P P, Macfarlane G, Teillac P et al. Impact of symptoms of prostatism on bothersomeness and quality of life of men in the French community. J Urol 1995; 153:669–673 52. Frankel L R. On the definition of response rates. A special report of the CASRO task force on completion rates. Council of American Survey Research Organizations. 1982 53. Barry M J, Fowler F J Jr, O’Leary M P and the Measurement Committee of the American Urological Association. Measuring disease-specific health status in men with benign prostatic hyperplasia. Med Care 1995; 33(Suppl):AS145-AS155 54. Guess H A. Prevalence of benign prostatic hyperplasia in community surveys. In: Garraway W M (ed). The epidemiology of prostate disease. Springer Verlag, 1995: 121–131 55. Sagnier P P, Girman C J, Garraway W M et al. International comparison of the community prevalence of symptoms of prostatism in four countries. Eur Urol 1996; 29:15–20 56. Guess H A, Chute C G, Garraway W M et al. Similar level of urologic symptoms have similar impact in Scottish and American men—though Scots report less symptoms. J Urol 1993; 150:1701–1705 57. Stephenson W P, Chute C G, Guess H A et al. Incidence and outcome of surgery for benign prostatic hyperplasia among residents of Rochester, Minnesota: 1980–87. A population-based study. Urology 1991; 38 (Suppl 1): 32–42 58. Teboul F, Ecochard R, Colin C et al. Descriptive analysis of a series of operations for prostatic adenomas in inhabitants of Lyon, France, in 1988. Eur Urol 1991; 20 (Suppl 2): 18–21 59. Jensen K M, Jorgensen J B, Mogensen P et al. Some clinical aspects of uroflowmetry in elderly males. A population survey. Scand J Urol Nephrol 1986; 20:93–99 60. Girman C J, Panser L A, Chute C G et al. Natural history of prostatism: urinary flow rates in a file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_160.html[09.07.2009 11:52:35]

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population-based study. J Urol 1993; 150:887–892 61. Chute C G, Panser L A, Girman, C J et al. The prevalence of prostatism: a population-based survey of urinary symptoms. J Urol 1996; 150:85–89 62. Koskimaki J, Hakama M, Huhtala H, Tammela T L. Association of non-urological diseases with lower urinary tract symptoms. Scand J Urol Nephrol 2001; 35:377–381 63. Bosch J L H R, Hop W C J, Niemer Q H J et al. Parameters of prostate volume and shape in a communitybased population of men 55 to 74 years old. J Urol 1994; 152:1501–1505 64. Berry S J, Coffey D S, Walsh P C et al. The development of human prostatic hyperplasia with age. J Urol 1984; 132:474–479

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Page 161 65. Blanker M H, Groeneveld F P, Prins A et al. Strong effects of definition and nonresponse bias on prevalence rates of clinical benign prostatic hyperplasia: the Krimpen study of male urogenital tract problems and general health status. BJU Int 2000; 85:665–671 66. Garraway W M, Collins G N, Lee R J. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991; 338:469–471 67. Garraway W, McKelvie G, Rogers A, Hehir M. Benign prostatic hypertrophy influences on daily living in middleaged and elderly men. Urology (Italy) 1992:161–164 68. Garraway W M, Armstrong C, Auld S et al. Follow-up of a cohort of men with untreated benign prostatic hyperplasia. Eur Urol 1993; 24:313–318 69. Garraway W M, Russell E B, Lee R J et al. Impact of previously unrecognized benign prostatic hyperplasia on the daily activities of middle-aged and elderly men. Br J Gen Pract 1993; 43:318–321 70. Tsang K K, Garraway W M. Impact of benign prostatic hyperplasia on general well-being of men. Prostate 1993; 23:1–7 71. Epstein R S, Deverka P A, Chute C G et al. Validation of a new quality of life questionnaire for benign prostatic hyperplasia. J Clin Epidemiol 1992; 45:1431–1445 72. Lee A J, Garraway W M, Simpson R J et al. The natural history of untreated lower urinary tract symptoms in middle-aged and elderly men over a period of five years. Eur Urol 1998; 34:325–332 73. Tsukamoto T, Kumamoto Y, Masumori N et al. Prevalence of prostatism in Japanese men in a population-based study with comparison to a similar American study. J Urol 1995; 154:391–395 74. Masumori N, Tsukamoto T, Kumamoto Y et al. Japanese men have smaller prostate volumes but comparable urinary flow rates relative to American men: results of a community-based study in two countries. J Urol 1996; 155: 1324–1327 75. Girman C J, Epstein R S, Jacobsen S J et al. Natural history of prostatism: impact of urinary symptoms on quality of life in 2115 randomly selected community men. Urology 1994; 44:825–831 76. Girman C J, Jacobsen S J, Guess H A et al. Natural history of prostatism: relationship among symptoms, prostate volume, and peak urinary flow. J Urol 1995; 153: 1510–1515 77. Oesterling J E, Jacobsen S J, Chute C G et al. Serum prostate-specific antigen in a community-based population of healthy men. Establishment of age-specific reference ranges. J Am Med Assoc 1993; 270:860–864 78. Jacobsen S J, Guess H A, Panser L A et al. A populationbased study of health-care-seeking behavior for treatment of urinary symptoms—The Olmsted County Study of Urinary Symptoms and Health Status Among Men. Arch Family Med 1993; 2:729–735 79. Roberts R O, Rhodes T, Panser L A et al. Natural history of prostatism: worry and embarrassment from urinary symptoms and health care-seeking behavior. Urology 1994; 43:621–628 80. Roberts R O, Jacobsen S J, Rhodes T et al. Cigarette smoking and prostatism: a biphasic association? Urology 1994; 43:797–801 81. Roberts R O, Rhodes T, Panser L A et al. Association between family history of benign prostatic hyperplasia and urinary symptoms: results of a population-based study. Am J Epidemiol 1995; 142:965– 973 82. Jacobsen S J, Girman C J, Guess H A et al. Natural history of prostatism: factors associated with discordance between frequency and bother of urinary symptoms. Urology 1993; 42:663–671 83. Panser L A, Chute C G, Larson-Keller J J et al. Comparison of prevalence rates and health careseeking behavior among survey responders and nonresponders: the Olmsted County study of urinary symptoms and health status among men. Am J Epidemiol 1993; 138:642 84. Panser L A, Chute C G, Girman C J et al. Effect of several recruitment strategies on response rates at baseline in a prospective cohort investigation. The Olmsted County study of urinary symptoms and health status among men. Ann Epidemiol 1994; 4:321–326 85. Girman C J, Jacobsen S J, Tsukamoto T et al. Health-related quality of life associated with lower urinary tract symptoms in four countries. Urology 1998; 51:428–436 86. Roberts R O, Jacobsen S J, Rhodes T et al. Natural history of prostatism: impaired health states in men with lower urinary tract symptoms. J Urol 1997; 157:1711–1717 87. Hunter D J W, McKee M, Black N A, Sanderson C F B. Health status and quality of life of British men with lower urinary tract symptoms: results from the SF-36. Urology 1995; 45:962–971 88. Girman C J, Jacobsen S J, Rhodes T et al. Association of health-related quality of life and benign prostatic enlargement. Eur Urol 1999; 35:277–284 89. Jacobsen S J, Jacobson D J, Rohe D E et al. Frequency of sexual activity and prostatic health: fact or fairy tale? Urology 2003; 61:348–353 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_161.html[09.07.2009 11:52:35]

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90. Wilson I B, Cleary P D. Linking clinical variables with health-related quality of life—a conceptual model of patient outcomes. J Am Med Assoc 1995; 273:59–65 91. Girman C J. Natural history and epidemiology of benign prostatic hyperplasia: relationship among urologic measures. Urology 1998; 51:8–12 92. Kolman C, Girman C J, Jacobsen S J, Lieber M M. Distribution of post-void residual urine volume in randomly selected men. J Urol 1999; 161:122–127

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Page 162 93. Cockett A T, Barry M J, Holtgrewe H L et al. Indications for treatment of benign prostatic hyperplasia. The American Urological Association Study. Cancer 1992; 70(Suppl): 280–283 94. Jacobsen S J, Girman C J, Guess H A et al. Natural history of prostatism: longitudinal changes in voiding symptoms in community-dwelling men. J Urol 1996; 155: 595–600 95. Rhodes T, Girman C J, Jacobsen S J et al. Longitudinal prostate growth rates during 5 years in randomly selected community men 40 to 79 years old. J Urol 1999; 161: 1174–1179 96. Roberts R O, Jacobsen S J, Jacobson D J et al. Longitudinal changes in peak urinary flow rates in a community based cohort. J Urol 2000; 163:107–113 97. Jacobsen S J, Jacobson D J, Girman C J et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997; 158:481–487 98. Nacey J M, Morum P, Delahunt B. Analysis of the prevalence of voiding symptoms in Maori, Pacific Island, and Caucasian New Zealand men. Urology 1995; 46:506–511 99. Levy P S, Lemeshow S. Sampling of populations: methods and applications. New York: John Wiley, 1991:17–18

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Page 163 11 Etiology of benign prostatic hyperplasia G S Sonke C A Mochtar L A L M Kiemeney Introduction Benign prostatic hyperplasia (BPH) is one of the most common benign conditions afflicting elderly men. The prevalence of histologic BPH increases with age, starting around the age of 30 and rising steadily to almost 90% in the ninth decade of life.1 Much effort has been put into studying the molecular and endocrine processes that may be implicated in the etiology of BPH and many epidemiologic studies have investigated putative risk factors. Unfortunately, this has not yet offered any prospect for prevention. In this chapter, we will review the risk factors that have been suggested for the development of BPH. A brief description of the growth regulation of the prostate gland is given as a basis for the review. Growth regulation Hormonal factors Advanced age and the presence of functioning testes are the two best-established factors required for the development of BPH. The role of the testes has been recognized for over a century. This phenomenon is related to the ability of the testes to secrete androgens and, to a lesser extent, estrogens. The prostate is highly androgen dependent for its growth and its structural and functional integrity.2 Although BPH was once reported in a phenotypic male with an XX karyotype and castrate levels of testosterone,3 the disease does not normally occur in males castrated before puberty or in males with disorders of androgen production or action.4 Furthermore, bilateral orchiectomy results in atrophy of the prostate. The agerelated risk of BPH is mainly ascribed to changes in endocrine environment and to an increasing imbalance between stimulatory and inhibitory growth factors.5 The principal androgen, testosterone, is mainly produced in the testes. Mediated by luteinizing hormone (LH), the hypothalamus-pituitary-testis axis strictly regulates blood levels of testosterone. This mechanism has been evaluated for its therapeutic value. Prolonged stimulation of the LH-releasing hormone (LHRH) receptor with LHRH analogs desensitizes the receptor, thereby inhibiting LH secretion and reducing the level of testosterone. Homozygosity for a common genetic variant of LH is associated with elevated levels of testosterone and possibly with early-onset prostate cancer.6 The frequency of occurrence of this variant ranges from 42% in Finnish Lapps to 7% in US Hispanics. The importance of this genetic polymorphism in the etiology of BPH awaits further clarification. Some testosterone also originates from the adrenal gland under control of adrenocorticotrophic hormone (ACTH) and possibly prolactin.7 Some evidence from an animal model suggests that prolactin acts synergistically with testosterone in causing prostatic enlargement.8 Testosterone and prolactin also regulate a citrate-related metabolic pathway in the secretory epithelial cells of the prostate, which produce and secrete citrate. Increased citrate production is a distinguishing characteristic of BPH compared with prostate cancer (PCa), where citrate production is decreased.9 Testosterone is metabolized to dihydrotestosterone (DHT) by 5α-reductase (5αR), located on the nuclear membrane of prostatic cells. Intranuclearly, DHT binds to the androgen receptor, and this complex associates with the genome. This results in modulation or initiation of transcription of genes concerned with cellular growth processes. A rare autosomal-recessive form of male pseudohermaphroditism is caused by mutations in the 5αR gene, despite normal levels of testosterone.10,11 Two isoenzymes of 5αR have been described, with type 2 being mainly involved in prostate development. Regression of prostate size in men with BPH can be produced by pharmacologic inhibition of 5αR-2 with finasteride.12 After 6 years of treatment with finasteride there seem to be durable improvements in symptom scores, flow rates, and prostate volume.13 Recently, the clinical relevance of type 1 5α-reductase (5αR-1) within the prostate has come to the surface.14 In a double-blinded randomized clinical trial, a dual inhibitor of 5αR-1 and -2, dutasteride, has also been considered safe and effective in reducing prostate volume, symptom scores, risk of acute urinary retention, and risk of BPHrelated surgery, after 24 months of follow-up.15 Whether this dual inhibitor is better than the single inhibitor needs to be further elucidated.

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Page 164 Next to testosterone and DHT, estradiol is the third steroid hormone involved in the pathogenesis of BPH, although its role is less clear.5 Estradiol, which is mainly produced by aromatase activity from adipose tissue, modulates the action of androgens by altering the sensitivity of the prostate to androgens. A small increase in estradiol concentrations results in an increase in prostatic androgen receptors and prostate size. Alternatively, a large increase in estradiol concentration can have the opposite effect. Presumably, some of the effects on androgen sensitivity are imprinted in utero by maternal estradiol levels and are sustained throughout adult life. Cell proliferation and apoptosis Prostate growth is under the immediate control of specific growth-stimulating and growth-inhibiting factors, such as transforming growth factor, basic fibroblast growth factor, keratinocyte growth factor, and epidermal growth factor. Insulin-like growth factors (IGFs) also have potent growth mitogenic and anti-apoptotic effects on prostate tissue, whereas IGF-binding proteins (IGFBPs) inhibit growth of prostatic tissue.16 In a population-based study in China, Chokkalingam et al.16 found that IGF-I and IGFBP-3, but not IGF-II and IGFBP-1, are associated with BPH risk. In a study exclusively among Black men in Michigan, Sarma et al.17 confirmed the result for IGFBP-3. Additionally, growth factors appear to be implicated in bladder hypertrophy secondary to bladder outlet obstruction.18 Any disturbance of the fine balance in growth factors may thus lead to the occurrence of BPH and lower urinary tract symptoms (LUTS). Within the prostate, there is a clear regional variation in the proportion of epithelial tissue to the surrounding stromal tissue, and the stroma surrounding the ducts manifests heterogeneity as far as the distribution of smooth muscles is concerned. It is now well accepted that an interaction between stromal tissue and epithelial tissue plays a role in the development of the prostate. Androgens mediate their effects primarily on the stroma and thereby produce inductive signals that influence epithelial growth and differentiation. It is furthermore hypothesized that stroma can re-attain embryonic properties, which might induce the epithelium to renew growth.19 Next to enhanced cell proliferation, the benign enlargement of the prostate observed at advanced age may also be due to the fact that cells lose their ability to die. This programmed cell death or apoptosis occurs by DNA fragmentation, which results from activation of Ca++/Mg++-dependent endonuclease. Androgendependent cells may be prevented from apoptosis by the presence of (dihydro)testosterone. Manipulation of the chemical reactions leading to programmed cell death is likely to influence the etiology of BPH. Adrenoreceptors Both adrenergic and cholinergic receptors are present in prostatic smooth muscle and bladder neck. The adrenergic nerves determine smooth muscle tone inside the prostate by stimulating postsynaptic α1receptors. Prostatic α1-adrenergic receptors have been subtyped into α1A-, α1B- and α1D-receptors, with α1A-receptors being mainly responsible for the contractile properties of human prostatic adenomas.20 Other subtypes, however, may also be important. Randomized clinical trials have shown that selective α1-adrenoceptor antagonists can reduce symptoms of BPH and improve urinary flow rates,21 demonstrating the importance of a dynamic component of BPH. Risk factors Introduction The increased understanding of the regulation of prostatic growth led to the idea that environmental and constitutional factors that can alter the concentration of steroid hormones or growth factors and mechanisms that can interfere with stromal-epithelial interaction or programmed cell death may also contribute to the etiology of BPH.22 Table 11.1 gives a summary of the most important studies for risk factors of BPH. Comparable to the study of the prevalence and incidence of BPH, epidemiological studies into these environmental influences have been hampered by the lack of a clear definition of BPH. Only about 50% of all microscopically identifiable BPH lesions ever give rise to a macroscopically enlarged prostate.52 An enlarged prostate may obstruct the urethra leading to LUTS, although many of the more bothersome symptoms are caused by the resulting bladder hypertrophy. Moreover, an enlarged prostate does not always cause LUTS, and LUTS is not always caused by bladder outlet obstruction; detrusor instability and detrusor underactivity may yield similar complaints. When interpreting the results of epidemiological studies on BPH, one must bear in mind that these various disease definitions, i.e. histological BPH, prostatic enlargement, bladder outlet obstruction, and LUTS, although undoubtedly interrelated, may well have a different etiology.

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Page 165 Racial differences In recent years, several authors have estimated incidence and prevalence of BPH in various countries. These reports are described extensively in the chapter on populationbased studies. An important observation from these studies is the difference in incidence of BPH between countries and races. African-American men are known to have a higher risk of clinical BPH than Caucasian and Asian men. The life-long probability for Western men to undergo prostatectomy is approximately 25–30%. This figure is much lower in many Asian countries. Next to differences in prostatic growth and regulation mechanisms between races, different health-care facilities and acceptance of aging are probably responsible for the observed differences. Smoking Cigarette smoking is the most extensively studied putative risk factor for BPH. Although conclusive evidence is still lacking, both androgen and estrogen levels seem to increase as an effect of smoking cigarettes due to their nicotine content. Thus, if smoking has any biologic effect on the etiology of BPH, it is probably inductive. Most epidemiologic studies of smoking-associated BPH, however, failed to show any relation or found an inverse relation instead (Fig. 11.1). Glynn et al.39 reported data on over 1700 men from the longitudinal VA Normative Aging Study in Boston, Massachusetts. They found a moderate protection for undergoing prostatectomy by smoking one pack of cigarettes per day compared to not smoking (relative risk (RR)=0.43; 95% confidence interval (CI): 0.17; 1.12). However, the probability of a clinical diagnosis, i.e. diffuse enlargement on manual rectal palpation, was comparable between both groups (RR=0.92; 95% CI: 0.71; 1.19). Sidney et al.41 followed a cohort of over 16000 members of the Kaiser Permanente Medical Care Program in California, although they had to exclude almost 50% of the subjects in multivariate analysis because of missing values. Smoking at initial evaluation carried a 25% (95% CI: −41%; −6%) decrease in risk for subsequent prostatectomy, while former smokers had a 16% decreased risk (95% CI: −32%; +3%). It seems implausible that an inverse association between smoking and BPH is hormonally mediated. An alternative explanation might be that smokers are less likely candidates for surgery because of smoking-associated co-morbidity, or that they are less likely to survive to the age of diagnosis. Seitter and Barrett-Connor40 found no association between smoking and surgically treated BPH in a 12year follow-up study of 895 White male residents from Rancho Bernardo, California. However, some evidence of effect modification by age and body mass index (BMI) was present, suggesting an increased risk by smoking only for moderate to severe obese and older men. However, the authors restricted the analyses to subjects who survived the first 10 years of follow-up and as a result they might have introduced differential loss-to-follow-up, if smokers died prematurely because of smoking-related diseases.

Figure 11.1 Association between smoking and BPH. (Due to the differences in design of the various studies, care should be taken when comparing the results of these studies.)

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Page 166 Table 11.1 Characteristics of selected, studies on risk factors for benign prostatic hyperplasia (BPH). Reference Study base Study type Study Years of Disease Risk factors assessed size enrollment definition Cetinkaya Patients with hepatic Case-control 80   LUTS and Hepatic cirrhosis et al.23 corrhosis and healthy prostate volunteers volume Daniell24 Patients scheduled for Case-control 432 1984–88 ProstatectomySmoking, obesity TURP and internal medicine office controls Morrison25 Rhode-Island hospitals Case-control 2913 1985–87 ProstatectomySmoking, alcohol, marital status, religion, coffee Sanda et Family of patients and Case-control 165 1985–92 ProstatectomyFamily history al.26 patients’ spouses in Johns Hopkins Küpeli et Patients acheduled for Case series 68   Clinical BPH Smoking al.27 TURP Matzkin et Patients with LUTS Case series 195   Prostate Smoking al.28 volume Pressler et Untreated patients with Case series 326   LUTS Hypertension al.29 LUTS Sanda et Finasteride trial Case series 414   Prostate Family history al.30 volume Koskimaki Community-dwelling Cross2128 1994 LUTS Smoking et al.31 Finnish man sectional Lee et al.32Yochon County, Korea Cross514 1995 LUTS Smoking, obesity, sectional alcohol Roberts et Olmsted County Cross2115 1989–91 Clinical BPH Smoking, family al.33,34 sectional Roberts et Shimamaki-mura, Japan Cross286 1990–92 Clinical BPH Smoking al.35 sectional Partin et WW II Military Twin Cross482 1985 Benign Family history al.36 Cohort sectional/twin prostatic study disease GiovannucciHealth Professionals Follow-up 25892 1986, LUTS and Obesity, physical et al.37 Follow-up Study follow-up prostatectomyactivity Platz et until 1992 al.38 Glynn et VA Normative Aging Follow-up 1747 1961–70, Clinical BPH Smoking, obesity, al.39 Study follow-up and alcohol, until 1982 prostatectomyhypertension, religion, socioeconomic status Seitter and Rancho Bernardo Follow-up 895 1972–74, ProstatectomySmoking, obesity Barrettfollow-up Connor.40 until 1987 Sidney et Kaiser Permanente Follow-up 16,219*1971–72, ProstatectomySmoking, obesity, al.41 Medical Care Program follow-up alcohol, vasectomy, until 1987 urine pH, tuberculosis, kidney radiography

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Study Years of Disease Risk factors assessed size enrollment definition Meigs et Massachusetts Follow-up 1019 1987–89 LUTS or PSA, cigarette smoking, heart al.42 Male Aging prostatectomydisease, beta-blocker usage, Study physical activity, and others Chokkalingam Shanghai, Case-control 512 1993–95 ProstatectomyInsulin-like growth factors et al.17 China (IGF-I, IGF-II, IGFBP-1, IGFBP-3) Sarma et The Flint Cross364 1996 Prostate Insulin-like growth factors al.16 Men’s Health sectional enlargement (IGF-I, IGFBP-3), body mass Study index Genesee County, Michigan, USA Prezioso et QUIBUS Cross1033 1998–99 LUTS or Alcohol and coffee al.43 Study, Italy sectional prostate consumption, smoking, enlargement physical activity, and body mass index Dahle et Shanghai, Case-control 502 1993–95 ProstatectomyInsulin and leptin levels, body al.44 China mass index, waist-to-hip ratio Gass45 Zurich, Cross882   LUTS or Alcohol intake, coffee Switzerland sectional prostatectomyconsumption, cigarette smoking, body mass index, professional education Pearson46 North Case-control 359   Clinical BPH Family history (segregation American analysis), age of onset Finasteride Trial Weisman et Ridley Park, Cross702   PSA level Coronary artery disease al.47 Pennsylvania, sectional (clinical BPH) USA (retrospective) Hammarsten Varberg, Cross307   LUTS Hyperinsulinemia and Sweden sectional Hogstedt48 Jacobsen et Olmsted Follow-up 2115 1989–90 LUTS Sexual activity al.49 County Study Lacey et Shanghai, Case-control 969 1993–95 ProstatectomyPhysical activity al.50 China Suzuki et Health Follow-up 279111986–94 LUTS or Intakes of energy and al.51 Professional’s prostatectomymacronutrients Follow-up Study, USA * 8292 for multivariate analyses. LUTS, lower urinary tract symptoms; TURP, transurethral resection of the prostate; PSA, prostate-specific antigen.

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Page 168 In a case-control study performed among 2913 Rhode Island inhabitants, Morrison found a weak negative association between smoking and prostatectomy.25 Smoking status 2 years prior to the interview was used as exposure of interest. Through this, the authors assured that exposure information represented the situation prior to prostatectomy. Nevertheless, it remains difficult to make any inference regarding the relevant time at which to measure smoking status as long as a causal pathway of smoking in the etiology of BPH is not clear. Daniell assessed the association between smoking status and frequency of prostatectomy in a casecontrol study.53 Cases were 432 patients who underwent TURP in Mercy Medical Center, California. Two separate control groups served as approximations of person time at risk: colon cancer patients and patients visiting the office practice of general internal medicine, both from the same hospital. Smokers are likely to be overrepresented in both control groups, which would make the RR estimations invalid. Furthermore, the applied definition of smoking status did not distinguish between former and current smokers, even though other studies have shown former smokers to be more similar to never smokers with respect to the probability of undergoing prostatectomy.25,53 With these limitations in mind, it is difficult to compare the results of this study (a small reduction in risk among current smokers) with the results found in other studies. Roberts et al.,33 cross-sectionally studying 2115 men from Olmsted County, Minnesota, did find an increase in moderate to severe urologic symptoms among heavy smokers compared to never smokers. Light smokers, however, appeared to have a decreased risk. According to the authors, this biphasic relation between cigarette smoking and BPH may be explained by the dual effect which nicotine has at postsynaptic parasympathetic receptors in and around the bladder, acting as an agonist at low doses and as an antagonist at high doses. Thus, low doses of nicotine could improve bladder function, while high doses could relatively impair micturition. All smokers combined were less likely to have peak flow rates below 15 ml/s and to have prostatic volumes greater than 40 ml. The study was hampered by its cross-sectional study design and the small percentage of current smokers (16%). This may imply an unrepresentative study population, or indicate misclassification of exposure leading to underestimated effect measures. Roberts et al.29 also conducted a similar study among 286 Japanese men, with comparable results as those found among Olmsted County men for all smokers combined and for ex-smokers. However, light smokers in Japan were at increased risk to have moderate to severe symptoms and to have an enlarged prostate, whereas comparable Olmsted County men were less likely to have moderate to severe symptoms and to have an enlarged prostate, compared to never smokers. Lee et al.32 studied 514 Korean men, selected by random cluster sampling from a general population of over 60000 residents of Yonchon County. Subjects with conditions that might interfere with normal voiding as well as those who had previously undergone prostatic surgery were excluded. This exploratory study related symptom scores assessed by the Korean version of the International Prostate Symptom Score (I-PSS) to several socio-demographic, physical and laboratory findings. Heavy smokers (≥1 pack per day) were at increased risk of having moderate to severe symptoms, although the relative risk of 1.56 compared to nonsmokers was not statistically significant in multivariate analyses (95% CI: 0.69; 2.51). Possibly, the group of patients that was excluded based on previous prostatic treatment contains a relatively large number of smokers, resulting in an underestimation of the effect of smoking on BPH. Using a cross-sectional study design, Küpeli et al.27 observed a weak inverse relation between smoking and prostate size, symptom score and urinary flow rate, among 68 men with obstructive uropathy scheduled for transurethral resection of the prostate (TURP). In this selected group of patients, smokers on average also had higher serum levels of estradiol, but free testosterone levels were comparable for smokers and nonsmokers. Koskimaki and colleagues studied the association between smoking and LUTS in community-dwelling Finnish men.31 Symptoms were assessed by a modified Danish Prostate Symptom Score, combining the presence of symptoms with their bothersomeness. Current and past smoking habits were gathered from self-administered mailed questionnaires. In this study, current smokers showed an increased risk of having LUTS compared to never smokers (RR=1.39; 95% CI: 1.02–1.93), after adjusting for a wide range of covariates. The results for former smokers were similar to those for current smokers, possibly indicating that direct effects of smoking on the dynamic component of LUTS are not involved. However, after the cessation of smoking a gradual decrease in symptoms was observed, suggesting that the process is reversible but recovery is a long-term process. In another cross-sectional study, Matzkin et al.28 observed no differences in prostate volume between file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_168.html[09.07.2009 11:52:38]

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195 current, ex- and never smokers with LUTS. Self-reported smoking history was combined with results from

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Page 169 transurethral ultrasonography of the prostate. The authors suggested that previously observed protective effects of cigarette smoking may be mediated through factors other than gland size, possibly the effect of smoke components on α-tonicity of the prostate and bladder neck. This would minimize the dynamic component of obstruction. Three recent studies again illustrate the inconsistent results on smoking and BPH. In the Massachusetts Male Aging Study (MMAS), current cigarette smoking decreased the risk (OR=0.5; 95% CI: 0.3–0.8) of clinical BPH (defined as surgery of BPH or frequent or difficulty urinating due to an enlarged prostate diagnosed by a health professional).42 In the QUIBUS study no major influence on symptoms was found in smokers.43 In the Health Professionals Follow-up Study current cigarette smoking was positively related to total BPH, although only among those who smoked 35 or more cigarettes per day.38 The OR compared with never smokers=1.45 (95% CI: 1.07–1.97). Epidemiologic studies reveal little evidence of a hormonally mediated response of smoking to a biologically expected increase in risk of (surgically treated) BPH, although some evidence suggests an elevated risk of experiencing bothersome symptoms. In contrast, other studies suggest an inverse association. Any effect of smoking related to BPH, however, is likely to be weak, if existing at all. Therefore, understanding the influence of smoking might add to our knowledge of disease mechanisms more than that it would have practical implications. Obesity Obese men produce more estradiol than nonobese men do, through transformation of adrenal androstenedione in adipose tissue. Underweight, on the other hand, has been related to increased testosterone levels.54 These mechanisms make an increased risk for both obese and lean people biologically plausible. Four longitudinal studies have looked at obesity as a potential risk indicator for BPH (Fig 11.2).24,25,40,41 Both Glynn et al.39 and Sidney et al.41 observed slightly reduced risks for more obese people in multivariate analysis. Seitter and Barrett-Connor40 did not observe substantial differences between strata of obesity. Prostatectomy was used as objective outcome measure in these studies, although Glynn et al. also assessed differences in occurrence of clinical diagnosis. Notably, they did not find an effect when using prostatectomy as outcome, but there was a small negative effect when considering clinical diagnosis as definition for BPH. The authors suggested the inherent difficulty in assessing prostatic size in obese men as an explanation for this difference. Giovannucci et al.37 followed a cohort of male US residents between 1986 and 1992 as a part of the Health Professionals Follow-up Study. Over 25000 subjects aged 40 years and over, without prior diagnosis of BPH or cancer, returned a mailed questionnaire with information on height, weight, and waist circumference at baseline. After 6 years, a second questionnaire assessed the presence of LUTS and BPH-related surgery since baseline. The results

Figure 11.2 Association between obesity and prostatic surgery. (Due to the differences in design of the various studies, care should be taken when comparing the results of these studies.)

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Page 170 of this study show waist circumference (adjusted for height) to be linearly related to both symptoms and surgery. Multivariate-adjusted RR for surgery of the most obese group versus the leanest group was 1.47 (95% CI: 1.06–2.04). The RR for the presence of symptoms was 1.43 (95% CI: 1.18–1.74). There was no evidence of a U-shaped relation. BMI, which is often used as a measure of obesity, was not independently related to BPH in this study. Due to an age-related decrease in stature and change in bone density, BMI is an increasingly invalid measure of obesity with advanced age. This could make any finding on BMI questionable. Daniell compared 379 patients, all of whom underwent TURP, with respect to the weight of the resected tissue.24 He concluded that obesity as quantified by deviation from a standardized weight for height distribution is a risk factor for prostatic enlargement. This relation was most apparent in men aged 60 years and older. No effect was seen for obesity in relation to uropathy requiring surgery. This was assessed by comparing the standardized weight for height distribution of the TURP patients to that of randomly selected internal medicine office controls with a similar age distribution. Some limitations of this study have been described in the paragraph on smoking. Lee et al. assessed abdominal obesity, quantified by the waist-to-hip ratio, in their cross-sectional study among 514 Korean men.32 A biphasic relation with LUTS was observed, with the highest prevalence of moderate or severe symptoms for lean and obese men, compared to men of average weight. The differences persisted in multivariate analyses, controlling for age, smoking habits, alco hol consumption, and serum high-density lipoprotein (HDL) level. Soygür et al. studied 68 men with bladder outlet obstruction and documented larger adenomas in men who were at least 40% over recommended weight.55 However, they did not observe an increase in symptoms. The authors concluded that obesity might be a risk factor for prostatic enlargement, but not for outlet obstruction. Dahle et al.44 observed that abdominal obesity (waist-to-hip ratio) and increasing serum insulin are associated with a higher risk of BPH (surgery) in Chinese men. The OR of the highest versus lowest quartile of waist-to-hip ratio is 2.42, and of insulin 2.47. BMI (as a measure of overall obesity) and serum leptin (a product of the obesity gene Ob) are not associated with a higher risk of BPH. Gass,45 in a population-based study of 882 men, also concluded that BMI was not associated with the risk of BPH. The same results were found in the MMAS, where neither BMI nor waist-to-hip ratio were associated with clinical BPH.42 In conclusion, obesity may be associated with prostatic enlargement, but firm evidence for a relation of obesity with either symptoms or obstruction requiring surgery is lacking. Further studies on the relation between obesity and BPH should pay more attention to other measures of obesity than BMI. The waistto-hip ratio to quantify fat distribution or waist circumference to estimate abdominal fat mass offer better but still suboptimal alternatives.55 Alcohol consumption and liver cirrhosis Alcohol consumption decreases testosterone production, and increases testosterone clearance. Therefore, alcohol consumption may reduce the risk of developing BPH. Indeed, Morrison25 reported a multivariate-adjusted RR of 0.49 (95% CI: 0.32; 0.77) for drinking three glasses of alcohol per day compared with less than one glass per day. The apparent protection by alcohol was strongest for consumption of beer (RR=0.30; 95% CI: 0.14; 0.63). Sidney et al.41 also found a lower risk for subjects who drank three or more glasses of alcohol per day compared to nondrinkers (age-adjusted RR=0.75; 95% CI: 0.60; 0.94). However, as both studies used BPH surgery as the outcome, the association could be due in part to the poorer surgical risk of heavier drinkers. The results found by Glynn et al.39 for both prostatectomy and clinical diagnosis of BPH are close to unity. Lee et al.32 again reported a trend towards lower risk of symptomatic BPH with increasing amount of daily intake of beer. This moderate inverse association between alcohol intake and men treated surgically for BPH or in ‘watchful waiting’ for surgery was also found by Gass45 and Platz et al.38 Contradictory results were seen in the QUIBUS study where alcohol consumption was associated with urgency and intermittency and with an overall higher IPSS.43 Some authors suggested that hepatic cirrhosis also reduces one’s risk of BPH. Cetinkaya et al.23 compared hormonal status, prostate volume, and symptom scores of 60 patients with hepatic cirrhosis with that of 20 healthy volunteers. Serum testosterone, gland size, and symptom scores were all significantly decreased in the case group, while serum estradiol level was comparable in both groups. Four previously published autopsy studies confirmed a somewhat lower prevalence of histologic BPH among men with cirrhosis compared to those without cirrhosis.57–60 One study found a positive crude association.61 Most cases of cirrhosis were alcohol related, which makes the separation of the effects of file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_170.html[09.07.2009 11:52:40]

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Page 171 cirrhosis on BPH were weak, with RRs in the range of 0.8 to 0.9. Family history Following the research on prostate cancer, studies have been conducted to show whether high penetrance genetic mechanisms and/or major genes exist in BPH (Fig. 11.3). Roberts et al.34 described data from the Olmsted County Study, regarding the association between family history of BPH and moderate to severe LUTS in the month prior to interview. Men with a first-degree male relative with prostatic enlargement had a 30% increase in risk compared to men without such family members, after controlling for age and worry (95% CI: +10%; +70%). The increase in risk was greatest among men with relatives diagnosed before the age of 60 (RR=2.5; 95% CI: 1.5; 4.3). Men with a positive family history were also 1.3 times more likely to have an impaired peak urinary flow rate (<15 ml/s). The information from a sample of the self-administered questionnaires was then compared to the corresponding medical records in order to assess the magnitude of misclassification of exposure. It was impossible to validate 8% of the affirmative answers, whereas 30% of the alleged negative answers were incorrect. Surprisingly, the information of men with moderate to severe symptoms seemed more reliable than that of men with mild or no symptoms. Thus, some recall bias may have diluted the results. Sanda et al.26 from Baltimore, tried to answer the question of whether having a first-degree male relative who underwent surgery for a greatly enlarged prostate at an early age increases the risk of having to undergo prostatectomy. The response with respect to prostatectomy among family members was not validated. For these reasons, misclassification of disease cannot be ruled out, and is likely to be differential. The 340% increase in risk for men with an affected family member, which was found in this study, should therefore be interpreted with some caution. A segregation analysis based on this dataset suggested Mendelian dominant inheritance of a gene associated with early age at onset of BPH. In another study, among patients enrolled in a 5αR inhibitor trial, Sanda et al.30 compared various clinical parameters according to whether or not the patient had two or more ‘BPH affected’ family members. The authors did not elaborate on the meaning of ‘BPH affected’. However, they did state that it was based on proband recall, allowing the possibility of recall bias. The main results from this study were a larger mean prostatic size and higher serum PSA level among patients with familial BPH, while differences in other parameters (symptom score, maximum urinary flow rate, age, and serum DHT) were small. Partin et al.36 looked for differences in concordance rates between monozygotic and dizygotic twin pairs, using the World War II Military Twin Cohort. Here, concordant means that both twins responded affirmative to a mailed

Figure 11.3 Association between family history and BPH. (Due to the differences in design of the various studies, care should be taken when comparing the results of these studies.)

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Page 172 questionnaire with reference to surgery or hospitalization for prostatic disease. This response was as vague as ‘prostate’ in over 50% of all reported cases and less than 2% specifically mentioned BPH. It is therefore likely that among cases there is a considerable proportion of men with prostate cancer, which most likely has a different etiology from BPH. It should also be acknowledged that twin studies assume environmental factors to be similar between monozygotic and dizygotic twins. Nevertheless, the 3.3-fold increased risk for monozygotic twins may reflect a difference in genetic predisposition to the disease. In an extension of the North American Finasteride Trial, Pearson et al.46 performed clustering and segregation analysis of bothersome BPH among 301 patients and 158 spousal controls. Although the lifetime risk of BPH was found to be the same among relatives of patients and relatives of their spouses, the age at onset was much lower among the relatives of the patients. The segregation analysis suggested an autosomal codominant inheritance of a rare allele (frequency 0.0004).46 Studies trying to demonstrate a genetic basis for BPH face several difficulties. The most prominent drawback lies in the fact that direct exposure measurement, that is genetic predisposition, is impossible until there is a specific gene to study. Therefore, investigators have few more options than to use proxy variables. The use of such variables will inevitably introduce misclassification of exposure. The single most often used proxy is (self-reported) family history of disease, but this may not completely capture all those with disease. The same problem that acts upon disease definition of BPH now also pertains to the definition of exposure. As mentioned earlier, there is a need for well-defined disease and exposure definitions and future studies must pay major attention to obtaining reliable information for both. Hypertension A study from the 1960s reported elevated blood pressure for patients admitted to surgery for prostatic disease compared to patients admitted for nongenitourinary elective surgery, suggesting that blood pressure influences the etiology of BPH.62 The authors of this study may well have reversed the actual time sequence, in that hypertension is a sequel to rather than a cause of prostatic obstruction. Yet another possible explanation is that both (diastolic) hypertension, resulting from an increased vascular wall stress, and a dynamic obstruction of the prostate have a common, α-receptor-related causal mechanism. Glynn et al. included systolic blood pressure in their analysis and found no association with either clinical diagnosis or prostatectomy.39 Likewise, the MMAS and the QUIBUS study found that hypertension and diastolic blood pressure are not related to clinical BPH.42,43 Pressler et al. correlated the incidence of hypertension (systolic pressure >140 mmHg or diastolic pressure >90 mmHg) with the I-PSS in 326 men with untreated BPH.29 Among men with mild (0–7), moderate (8–19), and severe (≥20) symptoms the prevalence of hypertension was found to be 15%, 18%, and 31%, respectively. Weisman et al.,47 studying 702 men with BPH in a urology practice setting, found a significant difference in the frequency of coronary artery disease between men with no BPH (PSA<1.0 pg/l) and with BPH (PSA>1.0 μ g/l) of 9% and 29%, respectively ( p <0.03). However, they found no significant differences between the two groups in other accepted risk factors for coronary artery disease including age, smoking, diabetes mellitus, or hypertension. Although there may be a relation between hypertension and BPH in theory (because of a common etiology), data do not clearly support this theory. Further research is needed to better elucidate the relationship between these two common conditions by follow-up studies. The metabolic syndrome A relatively new hypothesis on the etiology of BPH involves the so-called metabolic syndrome. Denominated syndrome X by Reaven in 1988,63 this condition is characterized by a defective insulinmediated glucose uptake and a compensatory hyperinsulinemia. It may predispose to the development of a large group of common metabolic disorders, including non-insulin-dependent diabetes mellitus (NIDDM), obesity, hypertension, hyperlipidemia, and atherosclerosis.64 Possibly, patients with BPH have the same primary metabolic disorder. Furthermore, induced hyperinsulinemia has been shown to increase sympathetic activity.65 Consequently, the metabolic syndrome may in part also be responsible for α-receptor-mediated changes in urethral obstruction. Moreover, as α-blocker medication is known to increase insulin sensitivity and decrease insulin levels,66 this therapy, in addition to having a beneficial effect on urethral obstruction, may also slow down the development of histologic BPH. A study by Hammarsten et al.67 showed that patients with LUTS having NIDDM, treated hypertension, obesity, or low HDL levels, had larger prostate volumes than patients with LUTS without such manifestations of the metabolic syndrome. A second study from the same department showed a high prevalence of the metabolic syndrome among patients with LUTS having a fast annual

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Page 173 prostate growth rate compared to those having a slow annual growth rate.68 A third study found that a higher level of fasting plasma insulin correlated significantly with annual BPH growth rates.48 The results of these three studies, albeit speculative, may link several suggested causative factors in the development of BPH, including hypertension, obesity, and hyperinsulinemia, to a common entity. Future studies are necessary to confirm the results from Hammarsten et al. However, the inherent difficulty in measuring the ill-defined metabolic syndrome and in defining BPH, prostatic enlargement, bladder outlet obstruction, and LUTS may pose enormous problems in the identification of any clear relation. Genetic polymorphisms A polymorphism in the number of cytosine-adenine-guanine (CAG) repeats in the androgen receptor (AR) gene has been associated with larger adenomas69,70 and increased risk of surgery for BPH,71 although other studies did not find a clear association.72,73 Shibata et al.70 examined the association of two single nucleotide polymorphisms (SNPs) A49T and V89L in the type II 5αR gene (SRD5A2) with the risk of prostate enlargement.70 Surgically removed prostates weighing ≥80 g from 68 men were compared with 197 controls with a prostate weighing less than 80 g. They found no consistent association with prostate enlargement for both polymorphisms. The same SNPs were investigated in a European setting by Schatzl et al.73 They found that individuals carrying the SRD5A2 A49T allele (53% of the total population of 190 men with LUTS) had larger prostates (54.1 vs 39.3 ml), higher PSA levels (12.2 vs 4.3 ng/ml), and a 35% reduction in prostatic stroma/epithelial cell ratio.73 Men with the SRD5A2 V89L allele had lower testosterone levels. Bousema et al.72 found no relationship between the risk of BPH (defined as treated for BPH-related complaints) with a TaqI restriction enzyme polymorphism in the vitamin D receptor (VDR) gene, although this receptor is sometimes said to interact with the same response elements on the genome as the androgen receptor complex does.72 The same result was achieved by the group of Schatzl et al.74 They did not find any association of the T1055C polymorphism in the VDR gene with prostate volume, clinical parameters (IPSS), or endocrine parameters.74 In contrast, in Japanese men, VDR genotype is said to play an important role in determining prostate enlargement.75,76 The group of Hamasaki et al.75 found that the absence of a TaqI restriction site (genotype TT) increased the risk of BPH (defined as prostate volume >50 ml). Surprisingly, also from Japan, the group of Habuchi et al.77 indicated that in fact the BsmI polymorphism, and not the TaqI and ApaI polymorphisms, in the VDR gene plays a significant role in protection against BPH. Homozygous or heterozygous alleles for the absence of the BsmI restriction site were associated with one-half the risk of BPH (OR 2.07).76 The three polymorphic sites are in linkage disequilibrium. Differences in the level of this equilibrium between populations may explain different study results. The CYP17 gene codes for the cytochrome P450c 17α enzyme, which mediates two key steps in the sex steroid synthesis. Habuchi et al.77 studied the association of a T-to-C polymorphism in the 5′untranslated region with the risk of BPH. They found that the A1 allele (the MspA1-undigested allele) of the CYP17 gene is associated with an increased risk of BPH, with a gene dosage effect. Azzouzi et al.78 acknowledged the role of CYP17. They suggested that the infrequent variant of allele 191 of the simple tandem repeat polymorphism (STRP) aromatase gene (CYP19) reduced the risk of BPH development.78 The group of Schatzl et al.74 did not find any association of a T-to-C substitution in the 5′ promoter region of the CYP17 gene with prostate volume, clinical parameters (IPSS), or endocrine parameters. The same group of Schatzl et al. did not find a relation between an A-to-G substitution polymorphism in the PSA gene and BPH.73 In Table 11.2 summarizes studies on gene polymorphisms and BPH. Miscellaneous In the pursuit of risk factors for BPH, several potential indicators have been examined in exploratory studies. For most of these relations, a convincing biologic mechanism is lacking and most factors have been analyzed in one single study. Hence, the results must be interpreted with caution. Morrison25 found elevated risks for men who never married, Jewish men, and for drinking coffee. Glynn et al.39 also found an increased risk among Jews. In addition, they identified lower socio-economic status as a possible risk indicator. Sidney,79 once more based on the Kaiser Permanente data set, reported a 1.2-fold increased risk of having a hospital diagnosis of BPH (95% CI: 0.7; 1.8) for men who had undergone vasectomy. However, in an update of this study, the RR leveled off at 0.97 (95% CI: 0.8; 1.3) and, likewise, the MMAS found no relation between vasectomy and clinical BPH.42 Until now, there has been no consistent evidence of an association of sexual activity in relation with BPH.80 Analyzing crosssectional data from the Olmsted County Study, Jacobsen

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Page 174 Table 11.2 Characteristics of selected studies on genetic polymorphism for the risk of benign prostatic hyperplasia (BPH). Reference Study Study Study Disease Genetic polymorphism Conclusion base/publication type size definition assessed year Mitsumori Kyoto, Japan Case- 176 Surgery for BPH AR gene: CAG repeat Shorter (≤22) et al.69 control BPH far BPH CAG repeats 41 may promote controls growth of BPH GiovannucciBoston, Case- 310 Surgery for BPH AR gene: CAG repeat Decreasing et al.71 USA/1999 control BPH (≤19) CAG 1041 repeat length controls increase the risk of BPH Bousema et Nijmegen, Case- 98 BPH Treated for VDR gene: TaqI RFLP No association al.72 The control 61 BPH-related (codon 352) with BPH Netherlands/2000 controlscomplaints AR gene: CAG repeats No association with BPH Habuchi et Akita, Case- 252 Treated for BPH CYP17 gene: T-to-C Increasing al.77 Japan/2000 control PCa substitution in 5′-UTR (at number of A1 202 34 bp upstream from the (MspA1BPH initiation of translation undigested) 131 and downstream from allele increased controls transcription start site) the risk of BPH. Habuchi et Akita, Case- 222 Treated for BPH VDR gene: BsmI, ApaI BsmI al.76 Japan/2000 control PCa and TaqI RFLP in 3′-UTR polymorphism 209 has a BPH significant role 128 in protection male against BPH controls ApaI and TaqI 198 have no female significant controls association with BPH Shibata et Stanford, Case- 68 BPH Prostate weight AR gene: CAG repeat The shorter al.70 USA/2001 control 197 ≥80g (enlarged) (≤20) CAG controlsand <80g repeats is (controls) related to prostate enlargement           SRD5A2 gene: A49T, V89LNo consistent association with prostate enlargement Schatzl et Vienna, Cross- 148 IPSS, prostate VDR gene: T1055C No association al.71 Austria/2001 sectionalmen volume, Q max, polymorphism with prostate with PSA, endocrine CYP17 gene: T-to-C volume, clinical LUTS parameters, substitution (in 5′ parameters and stroma/epithelialpromoter region) endocrine ratio parameters No association with prostate volume, clinical parameters and endocrine parameters file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_174.html[09.07.2009 11:52:42]

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Hamasaki et al.75

Fukuoka, Japan/2002

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Case- 110 Treated for BPH VDR gene: TaqI RFLP at Absence of the control PCa (sub: prostate codon 352 in exon 9 TaqI restriction 83 BPH volume >50 ml site increased 90 and <50 ml) the risk of BPH controls

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Genetic Conclusion polymorphism assessed Prostate SRD5A2 gene: A49T allele had larger volume, PSA A49T V89L prostates, higher PSA levels levels, and reduced stroma/epithelial stroma/epithelial ratio. V89L cell ratio allele had lower testosterone levels           AR gene: CAG No significant association repeats with BPH           PSA gene: A- No significant association to-G with BPH substitution (at position 158 in promoter region) Azzouzi Paris, Cross- 195 Prostate AR gene: CAG CAG repeat length showed et al.78 France/2002 sectionalFrench enlargement repeats low correlation with Caucasians increase prostate volume           SRD5A2 gene: All variants did not show TA repeats, association with prostate V89L and hyperplasia A49T mutations           CYP17 gene: Associated with increased T-to-C risk of prostate enlargement transition in 5′ Associated with reduced promoter risk of prostate enlargement region CYP 19 gene: STRP of allele 191 RFLP, restriction fragment length polymorphism; VDR, vitamin D receptor; AR, androgen receptor; IPSS, International Prostate Symptom Score; PSA, prostate-specific antigen; CYP17, cytochrome P450c17 alpha; 3′ or 5′-UTR, 3′ or 5′-untranslated region; SRD5A2, 5α-reductase; CYP19, aromatase; STRP, single tandem repeat polymorphism; Q max, maximum flow rate.

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Disease definition

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Page 176 et al.49 concluded that the frequency of ejaculation has no effect on LUTS, peak urinary flow rates, or prostate volume. The apparent protective association, which has been suggested historically, appears to be an artifact caused by the confounding effects of age. The results of the MMAS also suggest that sexual activity level is not related to clinical BPH. In a published update of the earlier described Health Professionals Follow-up Study, Platz et al.81 related increased physical activity to a lower frequency of LUTS. The multivariate-adjusted RR comparing the extreme quintiles of physical activity was 0.75 (95% CI: 0.64–0.87). The result for prostatic surgery was almost identical. The analyses were not corrected for obesity, although both factors are clearly interrelated. Thus, it is not evident that physical activity has an independent effect on BPH, apart from its effect on overweight. In a population-based case-control study in China, Lacey et al.50 also failed to find a consistent relationship between physical activity and BPH. But Meigs et al.42 found among subjects of the MMAS that high levels of physical activity decreased the odds (top vs bottom quartile kcal/day OR 0.5; 95% CI: 0.3–0.9) of BPH and this effect persisted in fully adjusted multivariable models. Sidney et al.41 found that urine pH>5 and a history of tuberculosis and kidney radiography raise the probability of having to undergo prostatectomy. Coffee constituents, which increase the serum concentration of lowdensity lipoprotein cholesterol, may be involved in the pathophysiology of BPH. Gass45 found a positive correlation between coffee consumption and men treated surgically for BPH. Again, by contrast, the QUIBUS study found that coffee consumption was not associated with prostate volume or LUTS.43 In the Health Professionals Follow-up Study, increasing total energy intake (stratified in quintiles), energyadjusted total protein intake, and the intake of specific long-chain polyunsaturated fatty acids were modestly associated with BPH (defined as surgery for BPH or moderately to severely symptomatic BPH).51 The association of highly unsaturated fatty acids with the risk of BPH supports a possible role of oxidative stress in the etiology of BPH. Only energy-adjusted total fat intake was not asso ciated with risk of BPH. Conflicting results were found in the MMAS, where total calorie intake and fat calorie intake were not related to clinical BPH.42 Perspectives Much effort has been put into the search for etiologic factors for BPH, yet no firm evidence for the presence of any of the examined factors has come forth. Consequently, a lot of work still has to be done in this area. Epidemiologic studies should focus on biologically plausible risk factors based on the increasing body of knowledge concerning the molecular and endocrine pathways regulating prostatic growth. Furthermore, several difficulties in the design and analysis stage of such studies must be considered. First, the likely differences in etiology of various disease definitions of BPH must be acknowledged in all future studies. For instance, the possible smaller risk of prostatectomy related to smoking cannot be distinguished from the higher cardiovascular and pulmonary co-morbidity, making smokers less likely candidates for surgery. Consequently, prostatectomy should not be used to study the effect of smoking on BPH. Likewise, hypertension may be associated with the dynamic component of bladder outlet obstruction (BOO), but not with the presence of histologic prostatic lesions. Second, the exposure of interest in each study must be clearly defined. When studying family history the same problem with disease definition holds for the definition of exposure. Furthermore, relevant levels of exposure must be compared. For instance, if a U-shaped relation is hypothesized to be present (both lean and obese men may be at increased risk for BPH) the extreme categories should not be compared directly, but the middle group should be used as a reference instead. Finally, it remains difficult to make any inference regarding the relevant time at which to measure exposure status as long as a causal pathway for putative risk factors in the etiology of BPH is not clear. This holds for all time varying, putative risk factors (e.g. smoking, alcohol consumption, and obesity). Most of the described follow-up studies use a single exposure measurement at baseline. Others measure exposure at consecutive medical check-ups and use most recent exposure. Now that the methodology of repeated measurement analysis in longitudinal studies has received more attention, time-varying exposure assessment should be used more often. Third, causal mechanisms are ideally investigated in follow-up studies among subjects at risk of getting the disease. If one wants to study the effect of, for instance, hypertension on BPH, it is necessary to use a follow-up design to assure a correct temporal sequence of cause and effect. Alternatively, a properly designed case-control study, with controls representing person time drawn from the population of people at risk, can be applied. However, self-reported history of exposure is subject to differential file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_176.html[09.07.2009 11:52:43]

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misclassification.

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Page 177 Fourth, a careful consideration of multivariate analyses is required. Correction for confounding only makes sense if the potential confounder is a well-established risk factor for the disease. As such factors are not known for BPH, apart from age and the presence of circulating androgens, correction for a wide range of covariates is not mechanism-based and may in fact adversely influence the power of the analyses. In addition, correction for age is not always called for. Age can be considered a proxy variable for changes in the endocrine environment and in the balance between inhibiting and stimulating growth factors. If these effects are controlled for, a truly present association with BPH may be masked. Correcting for changing smoking behavior or alcohol consumption with age or with aging cohorts, on the other hand, is without any doubt sensible. Due to these limitations facing etiologic research for BPH, all future plans to study risk factors should be considered critically. For all such studies, it must be assured that the expected outcome is high enough to justify the efforts and costs. References 1. Berry S J, Coffey D S, Walsh P C, Ewing L L. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474–479 2. Lee C, Kozlowski J M, Grayhack J T. Aetiology of benign prostatic hyperplasia. Urol Clin N Am 1995; 22:237–246 3. Marinello M J, Montes M, Farnsworth W E et al. Benign prostatic hyperplasia in an XX man. Urology 1979; 13: 640–645 4. Wilson J D. Role of dihydrotestosterone in androgen action. Prostate 1996; 6 (Suppl): 88–92 5. Griffiths K, Cockett A T, Coffey D et al. Regulation of prostate growth. In: Denis L, Griffiths K, Khoury S et al. (eds). The 4th international consultation on benign prostatic hyperplasia. Plymouth: Health Publications Ltd., 1998; 83–128 6. Pettersson K, Huhtaniemi I, Lilja H, Hugosson J. Frequency of a common genetic variant of luteinizing hormone (LH) in men aged 51–66 with elevated PSA levels: relationship to testosterone (abstract). J Urol 1998; 159 (Suppl): 124 7. Kadar T, Ben D M, Pontes J E et al. Prolactin and luteinizing hormone-releasing hormone receptors in human benign prostatic hyperplasia and prostate cancer. Prostate 1988; 12:299–307 8. Wennbo H, Kindblom J, Isaksson O G, Tornell J. Transgenic mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland. Endocrinology 1997; 138:4410–4415 9. Costello L C, Franklin R B. Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. Horm Metab Res 2002; 34: 417–24 10. Imperato-McGinley J, Guerrero L, Gautier T et al. Steroid 5α-reductase deficiency in man: an inherited form of pseudohermaphroditism. Science 1974; 186:1213–1215 11. Wilson J D, Harrod M J, Goldstein J L et al. Familial incomplete male pseudohermaphroditism type I: evidence for androgen resistance and variable clinical manifestations in a family with the Reifenstein syndrome. N Engl J Med 1974; 290:1097–1103 12. Boyle P, Gould L, Roehrborn C. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomised clinical trials. Urology 1996; 48:398–405 13. Lowe F C, McConnell J D, Hudson P B et al and Finasteride Study Group. Long-term 6-year experience with Finasteride in patients with benign prostatic hyperplasia. Urology 2003; 61:791–796 14. Bartsch G, Rittmaster R S, Klocker H. Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia. World J Urol 2002; 19:413–425 15. Roehrborn C G, Boyle P, Nickel J C, Hoefner K, Andriole G and ARIA3001, ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002; 60:434–441 16. Chokkalingam A P, Gao Y T, Deng J et al. Insulin-like growth factors and risk of benign prostatic hyperplasia. Prostate 2002; 52:98–105 17. Sarma A V, Jaffe C A, Schottenfeld D et al. Insulin-like growth factor-1, insulin-like growth factor binding pro-tein-3, and body mass index: clinical correlates of prostate volume among Black men. Urology 2002; 59:362–7 18. Lawson R K. Role of growth factors in benign prostatic hyperplasia. Eur Urol 1997; 32 (Suppl 1): 22– 27 19. Isaacs J T, Coffey D. Aetiology and disease process of benign prostatic hyperplasia. Prostate 1989; Suppl 2: 33–50 20. Forray C, Bard J A, Wetzel J M et al. The α1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human α1c subtype. Mol file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_177.html[09.07.2009 11:52:43]

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Pharmacol 1994; 45: 703–708 21. Lepor H, Williford W O, Barry M J et al. The efficacy of terazosin, finasteride or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med 1996; 335: 533–539 22. Oishi K, Boyle P, Barry M J et al. Epidemiology and natural history of benign prostatic hyperplasia. In: Denis L,

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Page 178 Griffiths K, Khoury S et al. (eds). The 4th international consultation on benign prostatic hyperplasia. Plymouth: Health Publications, 1998:23–59 23. Cetinkaya M, Cetinkaya H, Ulusoy E et al. Effect of postnecrotic and alcoholic hepatic cirrhosis on development of benign prostatic hyperplasia. Prostate 1998; 36:80–84 24. Daniell H W. Larger prostatic adenomas in obese men with no associated increase in obstructive uropathy. J Urol 1993; 149:315–317 25. Morrison A S. Risk factors for surgery for prostatic hypertrophy. Am J Epidemiol 1992; 135:974–980 26. Sanda M G, Beaty T H, Stutzman R E et al. Genetic susceptibility of benign prostatic hyperplasia. J Urol 1994; 152:115–119 27. Küpeli B, Soygür T, Aydos K et al. The role of cigarette smoking in prostatic enlargement. Br J Urol 1997; 80: 201–204 28. Matzkin H, Cytron S, Simon D. Is there an association between cigarette smoking and gland size in benign prostatic hyperplasia? Prostate 1996; 29:42–45 29. Pressler L B, Santarosa R P, Te A E et al. The incidence of hypertension (HTN) in a population of men with benign prostatic hyperplasia (BPH): analysis based on the AUA symptom score and race. J Urol 1997; 157 (Suppl): 371 30. Sanda M G, Doehring C B, Binkowitz B et al. Clinical and biological characteristics of familial benign prostatic hyperplasia.J Urol 1997; 157:876–879 31. Koskimaki J, Hakama M, Huhtala H, Tammela T L. Association of smoking with lower urinary tract symptoms. J Urol 1998; 159:1580–1582 32. Lee E, Park M S, Shin C et al. A high-risk group for prostatism: a population-based epidemiological study in Korea. Br J Urol 1997; 79:736–741 33. Roberts R O, Jacobsen S J, Rhodes T et al. Cigarette smoking and prostatism: a biphasic relation? Urology 1994; 43:797–801 34. Roberts R O, Rhodes T, Panser L A et al. Association between family history of benign prostatic hyperplasia and urinary symptoms: results of a population-based study. Am J Epidemiol 1995; 142:965– 973 35. Roberts R O, Tsukamoto T, Kumamoto Y et al. Association between cigarette smoking and prostatism in a Japanese community. Prostate 1997; 30:154–159 36. Partin A W, Page W F, Lee B R et al. Concordance rates for benign prostatic disease among twins suggested hereditary influence. Urology 1994; 44:646–650 37. Giovannucci E, Rimm E B, Chute C G et al. Obesity and benign prostatic hyperplasia. Am J Epidemiol 1994; 140: 989–1002 38. Platz E A, Rimm E B, Kawachi I et al. Alcohol consumption, cigarette smoking, and risk of benign prostatic hyperplasia. Am J Epidemiol 1999; 149:106–115 39. Glynn R J, Campion E W, Bouchard G R, Silbert J E. The development of benign prostatic hyperplasia among volunteers in the normative aging study. Am J Epidemiol 1985; 121:78–90 40. Seitter W R, Barrett-Connor E. Cigarette smoking, obesity and benign prostatic hypertrophy: a prospective population-based study. Am J Epidemiol 1992; 135:500–503 41. Sidney S, Quesenberry C P Sadler M C et al. Risk factors for surgically treated benign prostatic hyperplasia in a prepaid health care plan. Urology 1991; 38 (Suppl 1): 13–19 42. Meigs J B, Mohr B, Barry M J et al. Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men. J Clin Epidemiol 2001; 54:935–944 43. Prezioso D, Catuogno C, Galassi P et al. Life-style in patients with LUTS suggestive of BPH. Eur Urol 2001; 40 (Suppl 1): 9–12 44. Dahle S E, Chokkalingam A P, Gao Y T et al. Body size and serum levels of insulin and leptin in relation to the risk of benign prostatic hyperplasia. J Urol 2002; 168: 599–604 45. Gass R. Benign prostatic hyperplasia: the opposite effects of alcohol and coffee intake. BJU Int 2002; 90:649–654 46. Pearson J D, Lei H H, Beaty T H et al. Familial aggregation of bothersome benign prostatic hyperplasia symptoms. Urology 2003; 61:781–785 47. Weisman K M, Larijani G E, Goldstein M R, Goldberg M E. Relationship between benign prostatic hyperplasia and history of coronary artery disease in elderly men. Pharmacotherapy 2000; 20:383–386 48. Hammarsten J, Hogstedt B. Hyperinsulinaemia as a risk factor for developing benign prostatic hyperplasia. Eur Urol 2001;39:151–158 49. Jacobsen S J, Jacobson D J, Rohe D E et al. Frequency of sexual activity and prostatic health: fact or file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_178.html[09.07.2009 11:52:44]

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fairy tale? Urology 2003; 61:348–353 50. Lacey J V Jr, Deng J, Dosemeci M et al. Prostate cancer, benign prostatic hyperplasia and physical activity in Shanghai, China. Int J Epidemiol 2001; 30:341–349 51. Suzuki S, Platz E A, Kawachi I et al. Intakes of energy and macronutrients and the risk of benign prostatic hyperplasia. Am J Clin Nutr 2002; 75:689–697 52. Oesterling J E. Benign prostatic hyperplasia: a review of its histogenesis and natural history. Prostate 1996; 6 (Suppl): 67–73 53. Daniell H W. More stage A prostatic cancers, less surgery for benign prostatic hypertrophy in smokers. J Urol 1993; 149:68–72

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Page 179 54. Eldrup E, Lindholm J, Winkel P. Plasma sex hormones and ischemic heart disease. Clin Biochem 1987; 20:105–112 55. Soygür T, Küpeli B, Aydos K et al. Effect of obesity on prostatic hyperplasia: its relation to sex steroid levels. Int Urol Nephrol 1996; 28:55–59 56. Lean M E, Han T S, Deurenberg P. Predicting body composition by body density from simple anthropometric measurements. Am J Clin Nutr 1996; 63:4–14 57. Bennett H S, Baggenstoss A H, Butt H R. The testis, breast, and prostate of men who die of cirrhosis of the liver. Am J Clin Path 1950; 20:814–828 58. Frea B, Annoscia S, Stanta G et al. Correlation between liver cirrhosis and benign prostatic hyperplasia: a morphologic study. Urol Res 1987; 15:311–314 59. Robson M C. Cirrhosis and prostatic neoplasms. Geriatrics 1966; 21:150–154 60. Stumpf H H, Wilens S L. Inhibitory effects of portal cirrhosis of liver on prostatic enlargement. Arch Intern Med 1953; 91:304–309 61. Wu S D. Anatomic changes in the prostate of patients with cirrhosis of the liver. Arch Pathol 1942; 34:735–741 62. Bourke J B, Griffin J P. Hypertension, diabetes mellitus, and blood groups in benign prostatic hypertrophy. Br J Urol 1966; 38:18–23 63. Reaven G M. Banting lectures 1988. Role of insulin resistance in human disease. Diabetes 1988; 37:1595–1607 64. DeFronzo R A, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14:173–194 65. Berne C, Fagius J, Niklasson F. Sympathetic response to oral carbohydrate administration. Evidence from micro electrode nerve recordings. Clin Invest 1989; 84: 1403–1409 66. Shieh S M, Sheu W H, Shen D C et al. Glucose, insulin, and lipid metabolism in doxazosin-treated patients with hypertension. Am J Hypertens 1992; 5:827–831 67. Hammarsten J, Högstedt B, Holthuis N, Mellström D. Components of the metabolic syndrome—risk factors for the development of benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 1998; 1:157– 162 68. Hammarsten J, Högstedt B. Clinical, anthropometric, metabolic and insulin profile of men with fast annual growth rates of benign prostatic hyperplasia. Blood Press 1999; 8:29–36 69. Mitsumori K, Terai A, Oka H et al. Androgen receptor CAG repeat length polymorphism in benign prostatic hyperplasia (BPH): correlation with adenoma growth. Prostate 1999; 41:253–257 70. Shibata A, Stamey T A, McNeal J E et al. Genetic polymorphisms in the androgen receptor and type II 5-alphareductase genes in prostate enlargement. J Urol 2001; 166:1560–1564 71. Giovannucci E, Stampfer M J, Chan A et al. CAG within the androgen receptor gene and incidence of surgery for benign prostatic hyperplasia in US physicians. Prostate 1999; 39:130–134 72. Bousema J T, Bussemakers M J, van Houwelingen K P et al. Polymorphisms in the vitamin D receptor gene and the androgen receptor gene and the risk of benign prostatic hyperplasia. Eur Urol 2000; 37:234–238 73. Schatzl G, Madersbacher S, Gsur A et al. Association of polymorphisms within androgen receptor, 5alpha-reductase, and PSA genes with prostate volume, clinical parameters, and endocrine status in elderly men. Prostate 2002; 52:130–138 74. Schatzl G, Gsur A, Bernhofer G et al. Association of vitamin D receptor and 17 hydroxylase gene polymorphisms with benign prostatic hyperplasia and benign prostatic enlargement. Urology 2001; 57:567–572 75. Hamasaki T, Inatomi H, Katoh T et al. Significance of vitamin D receptor gene polymorphism for risk and disease severity of prostate cancer and benign prostatic hyperplasia in Japanese. Urol Int 2002; 68:226–31 76. Habuchi T, Suzuki T, Sasaki R et al. Association of vitamin D receptor gene polymorphism with prostate cancer and benign prostatic hyperplasia in a Japanese population. Cancer Res 2000; 60:305– 308 77. Habuchi T, Liqing Z, Suzuki T et al. Increased risk of prostate cancer and benign prostatic hyperplasia associated with a CYP17 gene polymorphism with a gene dosage effect. Cancer Res 2000; 60:5710–5713 78. Azzouzi A R, Cochand-Priollet B, Mangin P et al. Impact of constitutional genetic variation in androgen/oestrogenregulating genes on age-related changes in human prostate. Eur J Endocrinol 2002; file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_179.html[09.07.2009 11:52:44]

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147:479–484 79. Sidney S. Vasectomy and the risk of prostatic cancer and benign prostatic hypertrophy. J Urol 1987; 138:795–797 80. Guess H A. Benign prostatic hyperplasia: antecedents and natural history. Epidemiol Rev 1992; 14:131–153 81. Platz E A, Kawachi I, Rimm E B, et al. Physical activity and benign prostatic hyperplasia. Arch Intern Med 1998; 158:2349–2356

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Page 181 12 Epidemiology of acute urinary retention K Thomas P Boyle Introduction and definition Acute urinary retention (AUR) is a common urologic condition that often presents as an emergency with a sudden inability to pass urine associated with lower abdominal pain.1,2 The reported incidence varies between studies from a 4% to a 73% 10-year risk of AUR.3,4 One of the most common causes of AUR is benign prostatic hyperplasia (BPH), which with an aging population is likely to increase. It may be anticipated, therefore, that the incidence of AUR will also rise, unless preventative measures are taken for the treatment of BPH.5 Acute retention of urine is a relatively common indication for surgery in 25–30% of patients,6–8 however the immediate management of this condition usually involves placement of a urinary catheter either, suprapubic or urethral, medical therapy, and either immediate admission to hospital or discharge home with outpatient follow-up.9,10 In recent years the natural history and incidence of AUR have become better understood. However, further research is still needed into its etiology, methods of prevention and evaluation of the impact of an episode of AUR on the patient. Etiology The precise etiological factors responsible for the development of AUR are still unproven, but the main mechanisms postulated are (Table 12.1): • Increased resistance to flow of urine via mechanical or dynamic means;11 • Interruption of sensory innervation or motor supply to detrusor muscle;12 • Overdistension of the bladder.1,2,13 Increased resistance to the flow of urine can occur secondary to a mechanical obstruction such as stricture or prostatic enlargement or, less commonly, an increase in either the smooth or striated muscle tone. Interruption of the sensory or motor nerve supply to the detrusor muscle is caused by a variety of pathologies, e.g. spinal cord lesion (traumatic or neurologic), diabetic neuropathy, cerebrovascular accident. Overdistension of the bladder is seen after a general anesthetic or a large fluid challenge (often with alcohol). Postoperative AUR occurs during a prolonged procedure with the patient uncatheterized and in men who have had mild symptoms of BPH pre-operatively. It is also exacerbated by the use of opiates, concomitant anticholinergic administration, and the generalized increase in αadrenergic activity that exists after surgery.14 A scientific explanation for the clinically observed etiologies has been explored, with the following processes thought to be involved: • Prostatic infarction;15–17 • Neurotransmitter modulation;18,19 • Stromal epithelial tissue ratio.20,21 Prostatic infarction has been discussed as a potential cause for AUR by several authors15–17 (Figure 12.1). Spiro et al.15 evaluated the potential role of prostatic infarction as a cause of AUR by examining open prostatectomy specimens of 200 patients. The first 100 patients had large prostates and AUR while the second group of 100 patients had elective surgery for BPH. Of the AUR group, 85% had histologic evidence of prostatic infarction compared with 3% of the elective group. It has also been proposed that the elevated prostate-specific antigen (PSA) found in patients with AUR is secondary to prostatic infarction.17 Experimental work in animals has suggested that there may be multiple neuromodulators affecting the nerves that supply the bladder and urethra (Table 12.2).18,19 Reversible and irreversible changes are seen when AUR is induced experimentally in animals. In particular, changes in the nonadrenergic, noncholinergic neurotransmitters Table 12.1 Pathogenesis of acute urinary retention. Pathogenesis Example Increased resistance to flow Benign prostatic hyperplasia Urethral stricture Detrusor sphincter dysynergia Interruption of sensory or motor innervation to detrusor Spinal cord lesion Cerebrovascular lesion Diabetes mellitus Overdistension Postoperative file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_181.html[09.07.2009 11:52:45]

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Opiate analgesia High-volume alcohol consumption

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Figure 12.1 Prostatic infarction. have been reported in rats. It has been shown that if the episode of AUR is not relieved, cell death in ganglia in the bladder wall can occur within 24 hours and is well established by 48 hours. A retrospective study in a small number of patients ( n =10) found that the ratio of stromal to epithelial tissue was decreased in patients with AUR compared with age-matched controls.20 This finding was confirmed by another group who conducted a prospective study of the transurethral resection of the prostate (TURP) specimens of 70 patients (35 with AUR and 35 with symptomatic BPH). The AUR group had a significantly higher epithelial component: 71% compared with the BPH group of 60% ( p <0.01).21 The cause for this observation is uncertain, but it may explain why finasteride, which acts on the epithelial component, is effective in the prevention of AUR. Natural history Although the etiology of AUR may be unclear, a number of risk factors for AUR in men have been identified, mainly from population-based studies of men with BPH (Table 12.3). The most comprehensive of these is the Olmsted County trial, which identified a cohort of men in the general population aged between 40 and 79 years.22 Those with a previous history of prostatectomy, prostate cancer, or any other condition except BPH were excluded from the study. The 2115 men recruited underwent an interview, completed a questionnaire and had their flow rate measured. Of these, 537 (25%) were randomly selected for a clinical examination, PSA measurement and transrectal ultrasound (TRUS) of the prostate. The men were Table 12.2 Potential neuromodulators in the bladder. Acetylcholine (ACh) Noradrenaline (NAd) Vasoactive polypeptide (VIP) Neuropeptide Y (NYP) Substance P (SP) Enkephalin Somatostatin Nitric oxide (NO followed up for an average of 50 months. The risk of AUR was shown to be increased with age, from 1.6% risk at 5 years for men aged 40–49 to 10% for men aged 70–79 years. Symptom correlation was also found as men with moderate to severe symptoms had three times the risk of AUR compared with those with none to mild symptoms. In younger men, symptoms of double voiding and stopping and starting appeared most significant. A single peak flow rate measurement of <12 ml/s correlated with a 4-fold increase in risk of AUR and a prostate volume >30 ml was associated with a 3-fold increase in risk. Potential limitations of this study were the retrospective collection of follow-up data, and the ethnic and socio-economic status of the population studied who were mostly white, middleclass men. Also, the age range of the men was below that of most patients admitted with acute retention in the UK.25 These factors mean that caution should be taken in extrapolating the findings to hospital practice elsewhere in the world. The risk factors discussed have also been identified in other studies. In a population-based study of 6100 male health professionals aged between 45 and 82, there were 82 episodes of AUR.26 It was file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_182.html[09.07.2009 11:52:46]

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found that older age (>70 years), moderate or severe lower urinary tract symptoms, and the use of medications with adrenergic or anticholinergic side-effects significantly increased the risk of AUR. The incidence of AUR was 4.5/1000 person-years (95% confidence intervals 3.1 to 6.2). Men with moderate or severe lower urinary tract symptoms and a diagnosis of BPH had acute urinary retention rates nine times greater than those without symptoms or a BPH diagnosis. Of the seven lower urinary tract symptoms, three independently predicted AUR; a sensation of incomplete bladder emptying, having to void again after less than 2 hours, and a weak urinary stream all increased the risk of AUR by 20% or 2.4-fold.

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Page 183 Table 12.3 Risk factors for acute urinary retention. Risk factor Parameter Relative risk Confidence interval Age* >70 years 7.8 3.7–16.4 Symptoms* IPSS>7 3.2 1.9–5.4 Prostate volume* >30 ml 3.0 1.0–9.0 Flow rate* <12 ml/s 3.9 2.3–6.6 Risk factor Parameter Area under the curve   PSA† >2.5 0.70   Transition zone index‡ >0.65 0.924   *Jacobsen et al.22; †Roehrborn et al.23; ‡Kurita et al.24; IPSS, international prostate symptoms score; PSA, prostate-specific antigen. The placebo arms of trials of pharmaceutic treatments for BPH provide useful epidemiologic data and have demonstrated that PSA, prostate volume, and symptom severity significantly affect the risk of AUR.23,27–29 The largest study was a 4-year, double-blind randomized trial of 3040 men comparing the treatment of BPH with finasteride or placebo. Receiver operating characteristic (ROC) curve analyses showed that serum PSA and prostate volume were powerful predictors of the risk of AUR in placebotreated patients (area under the curve 0.70 and 0.81, respectively).23 The transition zone index (TZI=transition zone volume/total prostate volume) as measured with TRUS has been suggested as an accurate predictor for acute retention (area under the ROC curve 0.924).24 The authors concluded that patients with a TZI greater than 0.65 have a high risk of developing AUR. Quality of life As AUR usually involves an emergency admission to hospital and insertion of a catheter, it is perhaps not surprising that some patients may find the event traumatic. There have been a few studies which have looked at the impact of an episode of AUR on the patient, but this has remained a relatively neglected aspect of the management of this condition. A recent retrospective study of the management of patients with AUR in one surgeon’s practice over a 23-year period showed that 90% of patients were discharged home with a catheter to await surgery.30 While at home, 72% of patients experienced some complication, 69% found the catheter uncomfortable, and 65% found it inconvenient, particularly with respect to finding adequate toilet facilities. Another group prospectively evaluated the impact of discharging patients with AUR home with a catheter by means of a self-completion questionnaire (93% response rate).31 One hundred and one patients were seen with AUR and discharged home immediately with a catheter. Unlike the previous group, the majority of patients (87%) did not find that their activities were limited in any way although all of them had experienced at least one complication. The questionnaire used was not a validated measure, however it did show that despite having complications from the catheter most of the patients still found having a catheter at home acceptable. This study challenges the perception of most clinicians that patients do not like having a catheter. Treatment Catheterization The initial management of AUR is prompt relief of retention and pain by catheterization of the bladder. This can be achieved via the urethral or suprapubic route, each of which has its merits. Depending on the cause of the episode of AUR, local policy, the patient’s physical condition, and social circumstances, they may then be discharged with the catheter or admitted into hospital. Urethral catheterization is performed more commonly than suprapubic due to concern regarding the potential complications of inserting a suprapubic catheter and because the personnel (i.e. accident and emergency staff, family practitioners) who first see the patient are generally more familiar with the urethral route.32,33 A prospective study of 86 patients with AUR who were catheterized described a significantly lower incidence of urinary tract infection (18% vs 40%) and stricture formation (0 vs

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Page 184 16.7%) with suprapubic versus urethral catheters.34 It was also commented that trial without catheter was easier as it merely required clamping and unclamping of the suprapubic catheter. The relatively high stricture rate may be explained in part by the now outdated use of latex catheters by this group; however, the incidence is still likely to be higher than when the suprapubic route is used. The lower infection rate with suprapubic catheterization was also reported by a group who randomized patients to urethral versus suprapubic catheterization.35 In addition, they noted that patients found the suprapubic catheter was more comfortable and easier to manage. Despite these findings, the majority of patients with AUR are still managed with a urethral catheter, probably due to the continuing perception of suprapubic catheterization as a potentially hazardous procedure.36 A novel suggestion by one group is that patients with AUR can be managed by clean intermittent selfcatheterization (CISC),37 The authors found that the CISC group had a higher rate of spontaneous voiding (56% vs 25%) and lower infection rate (32% vs 75%) compared with the indwelling catheter group, They concluded that patients found CISC acceptable and manageable and experienced fewer complications than do those with an indwelling catheter. There is significant variation among studies in the timing of removal of a catheter (trial without catheter or TWOC). Some investigators have found no difference in success rates at 24 and 48 hours.38 Others have suggested a benefit to waiting longer, particularly in men with large residual volumes >1 liter.39 It has recently been suggested that prostate size >27.5 g, residual volume >1 liter and age >75 years may significantly reduce the chance of successfully voiding after a TWOC.40 It has also been suggested that the use of an α-blocker may improve the success rate of a TWOC.41 Pharmacotherapy There has been an increasing trend towards the use of drugs in both the prevention and treatment of AUR due to BPH. The two main classes of drugs used are α-block-ers and 5α-reductase inhibitors. α-Blockers act by relaxing the smooth muscle in the bladder neck and prostate, thereby decreasing the resist-ance to urinary flow. The potential role of α-blockers in the treatment and prevention of AUR was first described over 25 years ago.42 Since then, different types of α-block-ers have been produced and reported to have differing side-effect profiles.43 The impact of some of these in the prevention of AUR has been compared with placebo. A double-blind study of 2084 patients randomized to terazosin or placebo reported no difference in the incidence of AUR in each group during the 1-year follow-up period.44 In contrast, a study of 81 patients with AUR randomized to receive either alfuzosin or placebo for 48 hours prior to trial without catheter showed after 24 hours that those patients on alfuzosin had a significantly increased chance of passing a trial without catheter: 55% versus 28% ( p =0.03). This effect was sustained over 18 months of follow-up, although the study group was relatively small.45 Finasteride is at present the only 5α-reductase inhibitor available, although newer agents such as dutasteride are under evaluation.46 They act by selective inhibition of 5α-reductase responsible for the conversion of testosterone to dihydrotestosterone.47 In a large, doubleblind, randomized placebocontrolled trial 3040 men with moderate to severe lower urinary tract symptoms and enlarged prostates were recruited.48 Over a 4-year period they were treated daily with either 5 mg finasteride or placebo. Acute urinary retention developed in 99 (7%) of men in the placebo group versus 42 (3%) in the finasteride group. This represents over a 50% risk reduction for developing AUR. However, because of the relatively rarity of AUR, 15 men would have to be treated for 4 years to avoid one episode of AUR. Similar reductions in the risk of events such as heart attack or stroke occur with statins and antihypertensive medication.49 A pooled analysis of three randomized trials comprising 4222 men with moderately symptomatic BPH treated with either finasteride or placebo for 2 years reported 81 episodes of AUR (24/2113 finasteride group, 57/2109 placebo group).47 The hazard ratio for the occurrence of AUR was consistent amongst the studies, with a 57% decrease in the hazard rate for patients treated with finasteride compared with placebo ( p <0.001). Combination therapy Prevention of the progression of BPH and in particular AUR has been studied using the combination of an α-blocker and a 5α-reductase inhibitor by several investigators.48,50,51 Two four-arm, randomized placebo-controlled trials compared placebo with an α-blocker, finasteride, and combination therapy. Lepor et al50 used terazosin whereas Kirby’s group51 used doxazosin with similar results. Both groups found that the α-blocker was an effective treatment for BPH and that over the study period of 1 year, finasteride or combination therapy was no more effective than an α-blocker alone.

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Page 185 The medical therapy of prostatic symptoms (MTOPS) study, a 5-year, multicenter clinical trial evaluated whether treatment with doxazosin and finasteride was more effective than using either drug alone in preventing the clinical progression of BPH.48 One of the end-points for establishing the progression of BPH was AUR. Combination therapy and finasteride significantly reduced the long-term risk of AUR (crude rate per 100 patient years: placebo 0.6, doxazosin 0.4, finasteride 0.2, combination therapy 0.1). It was also noted that men in the placebo group with higher baseline serum PSA, prostate volumes and ages, and lower flow rate were significantly more likely to progress. Surgical intervention TURP has been the surgical treatment of BPH for many years.23 More recently, with greater insight into the potential morbidity and occasional mortality associated with this procedure, alternatives have been sought in the form of pharmacotherapy and minimally invasive techniques. Most of these new technologies are still based on the endoscopic removal or ablation of prostatic tissue: electrovaporization, laser resection (holmium, Nd-YAG, ELAP, interstitial), interstitial radiofrequency (TUNA), and microwave thermotherapy (TUMT). Each of these is discussed in more detail in other chapters. Temporary or permanent urethral stents are available to keep the prostatic urethra open, but only provide modest improvements in symptoms with a high incidence of complications such as migration, infection, encrustation, obstruction secondary to prostatic ‘ingrowth’, and calculus formation.52 These problems have limited their current use to elderly infirm patients unfit for surgery.53,54 At present, TURP remains the ‘gold standard’ surgical treatment for patients with AUR. It reduces the risk of developing AUR by a factor of 8.6 If, however, patients who have had an episode of AUR have a TURP they are at a higher risk of perioperative complications.55 The National Prostatectomy Audit found that men undergoing a TURP within 30 days of an episode of AUR had an excess risk of death independent of age, size of prostate, and co-morbidity (relative risk 26.6, 95% confidence interval 2.5– 204.5).23 Some patients may still be unable to void after a TURP.56 Urodynamic evaluation has not been shown to accurately predict this in patients under the age of 80 as detrusor failure may recover postoperatively.39 Therefore, urodynamics are not recommended for routine pre-operative evaluation in this age group. The presence of a residual volume >1500 ml, lack of detrusor instability, detrusor pressure at maximum fill of <9 cmH2O and maximal detrusor pressure <28 cmH2O were all found to predict treatment failure. Future research There are various aspects of the management of AUR that should be targeted in the future: • Catheters • Minimally invasive therapy • Medical therapy • Quality of life Catheters are crucial in the management of AUR. The ideal catheter material would be inert, malleable, biocompatible, and resistant to colonization with bacteria. In the future, technological developments should facilitate some of these improvements in catheter design and, therefore, reduce some of the complications associated with a catheter. Improvments in minimally invasive techniques will make daycase treatment of BPH feasible, which should reduce the time patients spend at home with a catheter following an episode of AUR. As discussed previously, the use of combination therapy for the treatment of BPH offers the opportunity to prevent the progression of BPH and, therefore, episodes of AUR. Newer agents are under development and may prove to be even more effective than the current formulations. An episode of AUR can have an adverse effect on a patient’s quality of life, which is further exacerbated by delay in treatment and a prolonged period of catheterization. Awareness of the impact of AUR on a patient and streamlining of the treatment of AUR so that prompt effective care is delivered would reduce the impact it has on the patient’s quality of life. Discussion Although AUR is an age-old condition, it remains a modern day management problem. As demonstrated by Modi et al.,30 treatment of patients with AUR may be considered to be regressing rather than progressing. New pharmacologic agents will emerge over the next few years and there will be advances in catheter design and minimally invasive techniques. When new therapies are introduced in the future, however, the effect of these on the patient’s quality of life must be evaluated in addition to their clinical effectiveness, if the management of AUR is to improve.

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Page 186 References 1. Emberton M, Anson K. Acute urinary retention in men: an age old problem. Br Med J 1999; 318:921– 925 2. Choong S, Emberton M. Acute urinary retention. BJU Int 2000; 85:186–201 3. Ball A, Feneley R, Abrahams P. The natural history of untreated ‘prostatism’. Br J Urol 1981; 53:613– 616 4. Birkhoff J, Wiederhorn A, Hamilton M, Zinsser H. Natural history of benign prostatic hypertrophy and acute urinary retention. Urology 1976; 7:48–52 5. McConnell J D. The long term effects of medical therapy on the progression of BPH. Results from the MTOPS trial. J Urol 2002; 167: abstract 1042 6. Wasson J H et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. N Engl J Med 1995; 332:75–79 7. Mebust W K, Holtgrewe H L, Cockett A T et al. Transurethral prostatectomy: immediate and postoperative complications: a comparative study of 13 participating institutions evaluating 3885 patients. J Urol 1989; 141:243 8. Graves E J. Detailed diagnoses and procedures. National Hospital Discharge Survey 1993. Vital Health Stat 1995; 13:122 9. Beard R, Hindley R, Borley N, Cox C. The management of acute urinary retention in the South Thames Region. South Thames Health Authorities Urology Audit 2001 10. Higgins P M, Karia S J, Mehta K. The management of acute retention of urine. Br J Urol 1981; 53:344–348 11. Powell P H, Smith P J B, Feneley R C L. The identification of patients at risk from acute retention. Br J Urol 1980; 52: 520–522 12. Murray K, Massey A, Feneley R C L. Acute urinary retention—a urodynamic assessment. Br J Urol 1984; 56: 468–473 13. Waterhouse N et al. Urinary retention after total hip replacement. A prospective study. J Bone Joint Surg Br 1987; 69:64–66 14. Raz S, Zeigler M, Caine M. Pharmacological receptors in the prostate. Br J Urol 1973; 45:663 15. Spiro L H, Labay G, Orkin LA. Prostatic infarction. Role in acute urinary retention. Urology 1974; 3:345–347 16. Strachan J R, Corbishley C M, Shearer R J. Post-operative retention associated with acute prostatic infarction. Br J Urol 1993; 72:311–313 17. McNeill S A et al. Serum PSA levels and histological changes associated with acute urinary retention. BJU Int 2000; 83: abstract P65 18. Zhou Y, Ling E A. Effects of acute complete outlet obstruction on the NADPH-diaphorase reactivity in the intra-mural ganglia of the guinea pig urinary bladder: light and electron microscopic studies. J Urol 1997; 158: 916–923 19. Crowe R, Haven A J, Burnstock G. Intramural neurons of the guinea pig urinary bladder: histochemical localisation of putative neurotransmitters in cultures and newborn animals. J Auton Nerv Syst 1986; 15:319 20. Abehouse B S. Infarct of the prostate. J Urol 1933; 3: 345–347 21. Saboorian M H et al. Morphometric analysis of pathological specimens in men undergoing prostate surgery for acute retention or symptoms of BPH only. J Urol 1998; 159: abstract 417 22. Jacobsen S J, Jacobson D J, Girman C J et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997; 158:481–487 23. Roehrborn C G, McConnell J D, Lieber M et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinically benign prostatic hyperplasia. Urology 1999; 53:473–479 24. Kurita Y, Masuda H, Terada H et al. Transition zone index as a risk factor for acute urinary retention in benign prostatic hyperplasia. Urology 1998; 51:595–600 25. Pickard R, Emberton M, Neal D E. The management of men with acute urinary retention. Br J Urol 1998; 81: 712–720 26. Meigs J B, Barry M J, Giovannucci E et al. Incidence rates and risk factors for acute urinary retention: the health professionals follow up study. J Urol 1999; 162:376–382 27. Lieber M et al. PSA is the strongest predictor of BPH related outcomes: results of a 4 year placebo controlled trial. J Urol 1998; 159:104 28. Marberger M J, Andersen J T, Nickel J C et al. Prostate volume and serum prostate specific antigen file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_186.html[09.07.2009 11:52:47]

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as predictors of acute urinary retention. Eur Urol 2000; 38:563–8 29. Rhodes T et al. Serum PSA levels predict acute urinary retention in 40–79 year old community men in Olmsted county. J Urol 2000; 161: abstract 1118 30. Modi P, Pleat J, Cheetham P et al. A 23 year review of the management of acute retention of urine: progressing or regressing? Ann R Coll Surg Engl 2000; 82:333–335 31. Khoubehi B, Watkin N A, Mee A D, Ogden C W. Morbidity and the impact on daily activities associated with catheter drainage-after acute urinary retention. BJU Int 2000; 85:1033–1036 32. Allardice J T, Standfield N J, Wyatt A P et al. Acute urinary retention: which catheter? Ann R Coll Surg Engl 1988; 70:366–368 33. Webb V J, Booth C M. Cutting the cost of catheterisation for acute retention—a hospital or domiciliary procedure? Br J Urol 1995; 76:443–445

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Page 187 34. Horgan A F, Prasad B, Waldron D J, O’Sullivan D C. Acute urinary retention. Comparison of suprapubic and urethral catheterisation. Br J Urol 1992; 70:149–151 35. Ischan J, Hunt D R. Supra-pubic catheters: a comparison of supra-pubic versus urethral catheters in the treatment of acute urinary retention. Aust NZ Surg 1987; 57:33–36 36. Abrams P H, Shan P J, Gaches C G et al. Role of suprapubic catheterisation in the retention of urine. J R Soc Med 1980; 73:845–848 37. Patel M I, Watts W, Grant A. The optimal form of urinary drainage after acute retention of urine. BJU Int 2001; 88: 26–29 38. Taube M, Gajraj H. Trial without catheter following acute retention of urine. Br J Urol 1989; 63:180– 182 39. Djavan B, Madersbacher S, Klinger C, Marberger M. Urodynamic assessment of patients with acute urinary retention: is treatment failure after prostatectomy predictable? J Urol 1997; 158:1829–1833 40. Kumar V, Marr C, Bhuvangiri A, Irwin P. A prospective study of conservatively managed acute urinary retention: prostate size matters. BJU Int 2000; 86:816–819 41. McNeill AS et al. Long term follow up following presentation with first episode of acute urinary retention. J Urol 2000; 163: abstract 1366 42. Caine M, Pfau A, Perlberg S. The use of alpha-adrenergic blockers in benign prostatic obstruction. Br J Urol 1976; 48:255–263 43. De Mey C. Alpha-blockers for BPH: are there differences? Eur Urol 1999; 36:52–63 44. Somers W J, Mora M J, Mason M F, Padley R J. The natural history of benign prostatic hypertrophy: incidence of urinary retention and significance of AUA symptom score. J Urol 1996; 155: abstract 1102 45. McNeill S A, Daruwala P D, Mitchell I D et al. Sustainedrelease alfuzosin and trial without catheter after acute urinary retention: a prospective, placebo-controlled trial. BJU Int 1999; 84:622–627 46. Clark R V et al. Effective suppression of dihydrotestosterone (DHT) by G1198745, a novel, dual 5 alpha-reductase inhibitor. J Urol 1999; 161: abstract 1037 47. Andersen J T, Nickel J C, Marshall V R et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology 1997; 49:839– 845 48. McConnell J D, Roehrborn C G, Bautista O M et al. Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349:2387–2398 49. Byington R P, Jukema J W, Salonen J T et al. Reduction in cardiovascular events during pravastatin therapy. Pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program. Circulation 1995; 92:2419–2425 50. Lepor H, Williford W O, Barry M J et al. The efficacy of terazosin, finasteride or both in benign prostatic hypertro phy. N Engl J Med 1996; 335:533–539 51. Kirby R S et al. Results of the PREDICT (prospective European doxazosin and combination therapy) trial. J Urol 1999; 161: abstract 266 52. Isotalo T, Talja M, Valimaa T et al. A pilot study of a bioabsorbable self-reinforced poly L-lactic acid urethral stent combined with finasteride in the treatment of acute urinary retention from benign prostatic enlargement. BJU Int 2000; 85:83–86 53. Perry M J, Roodhouse A J, Gidlow A B et al. Thermo expandable intraprostatic stent in bladder outlet obstruction: an 8 year study. BJU Int 2002; 90:216–223 54. Ogiste J S, Cooper K, Kaplan S A. Are stents still useful therapy for benign prostatic hyperplasia? Curr Opin Urol 2003; 13:51–57 55. Higgins P M, French M E, Chadalavada S R. Management of acute retention of urine: a reappraisal. Br J Urol 1990; 67:365–368 56. Reynard J M, Shearer R J. Failure to void after transurethral resection of the prostate and mode of presentation. Urology 1999; 53:336–339

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Page 189 13 Natural history of benign prostatic hyperplasia J Shah Introduction Benign prostatic hyperplasia (BPH) and the conditions associated with this disease process are extremely common among older men. Approximately 10% of men aged 25–30 years are affected by BPH compared to 90% by 85 years of age.1 Transurethral resection of the prostate (TURP) is the second most common operation performed in the United States (US) and the rates of this operation in a national sample of Medicare beneficiaries were approximately 25, 19, and 13 per 1000 men over the age of 75, 70–74, and 65–69, respectively.2 This represents a cost of between $2 and $5 billion in the US.1 In the United Kingdom, the parallel cost is between £62 and £91 million, representing 0.4% of the total National Health Service expenditure.3 More recently, a study investigating the prevalence of concomitant diseases in a group of 980 men presenting with erectile dysfunction suggested that BPH may be as prevalent as hypertension and diabetes4 (Fig. 13.1). Indeed, BPH is common. In light of this comment, it is surprising that rather little is known about the natural history of this condition. However, to understand the natural history of BPH we must know what we mean by ‘natural history’. Definition of natural history The natural history of a condition refers to its course over time. It is usually measured by noting changes in the parameters of interest and the incidence rates of outcome measures over a period of time. These changes may be either beneficial or harmful and in the case of BPH are direct (biologic) or indirect (proxy). Direct outcome measures are those that are immediately apparent to the patient, such as acute urinary retention (AUR), changes in other symptoms, or even death. By contrast, indirect measures do not manifest immediately and thus the patient may be unaware of changes in these. An example of an indirect measure is a change in flow rates.5 Other measures used to assess the natural history of BPH are listed in Table 13.1.6 Natural history allows clinicians to establish disease processes as a result of intervention and those that would have occurred in the absence of any intervention. Therefore, clinicians can appropriately counsel patients about the risks and benefits of any intervention against the risks and benefits of simply watching the progress of the disease (watchful waiting). Without an understanding of the natural history of any condition, it is difficult to assess the effectiveness of interventions or clinical trials.7

Figure 13.1 The prevalence of hypertension, diabetes, BPH, and prostate cancer in men with erectile dysfunction. (Data adapted from reference 4.)

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Page 190 It is possible that the lack of knowledge about the natural history of BPH is related to diagnostic methods. BPH is a pathologic process and is characterized by an increase in both epithelial and stromal elements of the prostate, and thus the diagnosis can really only be made after a biopsy, surgery, or at a postmortem. However, although much has been learnt from postmortem data, these do not Table 13.1 Measures used to assess progression of BPH. Measure Example Clinical Symptom scores: American Urological Association (AUA) symptom index   International Prostate Symptom Score (I-PSS)   Boyarsky score   Symptom problem index Physiologic Urinary fiow rates   Urodynamics Biochemical Prostate-specific antigen Anatomic Prostate volume necessarily translate into clinical information. After all, there is a mismatch between symptoms and signs in BPH.8 Hence the prevalence of BPH globally depends upon what surrogate measure has been used to define and therefore diagnose the condition (Fig. 13.2). Another source of error is acquiring information about the natural history of a condition from the placebo arm of a clinical trial. It is well recognized that patient behavior can change as a result of the individual knowing that they are being studied. This process, known as the Hawthorne effect, can itself produce a measurable change.10 Study designs to evaluate the natural history of BPH There are a variety of study designs that can be used to evaluate the natural history of BPH, each with its own problems: • Longitudinal studies of untreated men identified as having lower urinary tract symptoms (LUTS) and diagnosed with BPH using any of the available definitions. This group is called the watchful waiting group. There is likely to be a selection bias in this

Figure 13.2 Age-specific prevalence of BPH according to clinical features incorporated into the case definition. Bar 1 ( ): pathologically defined BPH from a compilation of five autopsy studies. Bar 2 ( ): clinically defined BPH based on both history and digital rectal examinationp (DRE) in the Baltimore Longitudinal Study of Aging (BLSA). Bar 3 ( ): BPH defined by DRE alone in the BLSA. Bar 4 ( ): BPH defined by DRE in a compilation of life insurance examinations. Bar 5 ( ): BPH defined by symptoms, DRE and urinary flow rates in a Scottish community. Bar 6 ( ): BPH defined by symptoms, DRE and urinary flow rates in Rochester, Minnesota. Bar 7 ( ): BPH defined by transrectal ultrasonography in a mass screening study in Japan. (Adapted from reference 9.)

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Page 191 type of study. There are two reasons for this: first there is no standard symptom threshold that brings patients to seek the advice of clinicians where BPH is concerned, and second there are no standard criteria available to clinicians regarding when to instigate treatment for BPH. Subjects are also susceptible to the Hawthorne effect in this type of study, and as they become more and more symptomatic, questions arise about the ethics of withholding treatment, even when the disease is not fatal. Additionally, as greater numbers of men become symptomatic and seek treatment, they will be with-drawn from the cohort. Hence fewer men will be available for final analysis. • Controlled studies examining the behavior of men with LUTS and BPH (the control group), and who are receiving: – no treatment (compared to the active intervention); – placebo treatment (compared with medical intervention); – sham treatment (compared with surgical treatment) Each of the subgroups in this study has frequent and regular contact with health-care professionals. They may therefore know which treatment arm they are in, and manifest behavior appropriate to that intervention (or lack thereof). They may also feel obliged to stay in that arm of the study until the trial is complete, and then seek alternative intervention at the end of the trial. • Longitudinal population-based studies of men in the community who have not been diagnosed with BPH and who are less likely to progress, and request or require treatment than men already diagnosed with BPH. This is the best type of study to understand the natural history of a condition, because the participants are not selected on the basis of any thresholds and no formal diagnosis of BPH has been made. However, in an attempt to monitor the individual, specific questions about BPH will have to be asked, thereby introducing bias.11 Early studies of BPH The first study of the natural history of BPH was a retrospective one and was reported in 1937.12 Ninety-three men with uncomplicated prostatic obstruction were followed for a mean period of 4.3 years and the study demonstrated spontaneous resolution of symptoms in a significant group of men.12 Craigen et al. reported the first prospective study in 1969.13 The only specified inclusion criterion was men with LUTS (they included 212 men in total, of whom 89 had presented with AUR), and the exclusion criterion was prostate cancer. After 4.7 years’ mean follow-up, only 10% of the symptomatic men progressed to urinary retention and almost half had become asymptomatic. This finding was similar for both the AUR and the symptomatic groups.13 The problem with this study is that LUTS are often the initial complaint of patients with BPH, but are not specific to BPH. LUTS can therefore by due to alternative causes. In another retrospective study involving 26 men with symptoms, elegant inclusion criteria were described for the first time.14 The researchers used a quantitative symptom questionnaire including urine flow (using flow rates), postvoid residual volume (calculated from the postvoid intravenous urogram film), renal function, and prostate volume (measured by digital rectal examination, DRE). The subjects were followed for 3 years, by which time almost half were either unchanged (15%) or had improved (27%).14 In 1981, Ball et al. reported the findings of a study that followed 107 men with symptoms of bladder outlet obstruction for 5 years.15 After initial clinical, radiographic and urodynamic evaluation, 53 subjects were found to be urodynamically obstructed. At follow-up, 10 patients (9%) had required prostatectomy. Of the nonsurgically treated group, only 16 patients reported that their overall symptoms had deteriorated, with the majority saying their symptoms were either unchanged (52%) or better (32%).15 Although these studies do not all have standard definitions of BPH, clear inclusion and exclusion criteria, or objective assessment methods, the findings suggest that up to 7 years after initial presentation, a significant proportion of men have improved or unchanged symptoms. In the Department of Veterans’ Affairs (VA) Cooperative Study, Wasson et al. randomized 556 men with BPH to undergo either a TURP ( n =280) or watchful waiting ( n =276).16 The definition of BPH in this study was men with moderate symptoms of BPH and men in whom urologists would consider a prostatectomy. Stringent exclusion criteria were employed (Table 13.2). Both symptoms and urodynamic parameters were used as outcome measures. In addition, the number of treatment failures and the number of men crossing over to the treatment group were evaluated.

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Page 192 Table 13.2 Exclusion criteria used in the Department of VA Cooperative Study. Exclusion criteria used in this study: Age <55 years Serious medical co-morbidity Bladder or prostate cancer Previous prostate surgery Previous radiotherapy Refractory urinary tract infections Postvoid residual volume >350 ml Low total score on BPH rating After an initial 3-year follow-up period, there were 47 treatment failures (17%) in the watchful waiting group compared to only 23 in the TURP arm. Reasons for treatment failures resulting in prostatectomy included high residual urine ( n =11), LUTS ( n =8), high symptom score ( n =8), and AUR ( n =5).16 A 5-year follow-up of the same study was subsequently published. Treatment failure rates were 10% for TURP versus 21% for the watchful waiting group. During this time, 76 men in the watchful waiting cohort crossed over to the surgery group. In a subanalysis, the group reported superior outcome measures (symptom score, peak flow rate, postvoid residual volume) in the patients who were initially randomized to the TURP group compared to those who had crossed over from the watchful waiting group. The most significant predictive factor for crossover was a higher symptom score at the time of entry to the study. This has led to the speculation that watchful waiting may cause irreversible damage that prevents as good an improvement after subsequent surgery compared to immediate surgery.17 However, this study only evaluated men with moderate symptoms of BPH, and whether the results can be extrapolated to men with mild or severe symptoms remains unclear at this stage. Placebo effects Placebo arms of clinical trials, if followed for a sufficient length of time, can provide information about the natural history of the condition. The Proscar Long-term Efficacy and Safety Study (PLESS) is an example of such a study. Over 3000 men with clinical BPH as diagnosed by enlarged prostate on DRE, reduced urinary flow rate, and moderate to severe symptoms of BPH were randomized to receive placebo ( n =1516) or finasteride 5 mg ( n =1324) for 4 years.18 The authors of this study found three emerging patterns for patients with prostate-specific antigen (PSA) levels 0–1.3, 1.4–3.2, and 3.3–10 ng/ml.19 The lowest PSA group maintained a placebo response over the 4-year follow-up period for symptom score and maximum flow rate. In the highest PSA group, the initial improvement in symptom score was negated by the end of the study. The flow rate in this group was also worse by the end of the study. In addition, prostate volume increased by a mean of 14% over the 4 years in 90% of the placebo group. Of interest, the growth rates of prostate volume in this study, where all the men were diagnosed with BPH, were higher than those reported in the Olmsted County Study based on men enrolled from a random sample of a community. This suggests that prostate growth may be greater in men already diagnosed with BPH than in the general population.20 Longitudinal studies Diokno et al. evaluated a random sample of over 800 men in a community in the US.21 The men were aged 60 years and over and the authors found a 35% prevalence of one or more symptoms of prostatism (hesitancy, straining, weak stream, intermittent flow, or use of catheter). The annual incidence rates of these symptoms at 1 and 2 years of follow-up were 16.4% and 16.1%, respectively. They also found that at 1-year follow-up, 22.9% of those with severe symptoms at baseline were asymptomatic. Another study in a random sample of 310 community-based Scottish men found that almost three-quarters of men aged over 40 years had enlarged prostates.22 They measured prostate size by transrectal ultrasound (TRUS) and defined an enlarged prostate as being over 20 g in weight (Table 13.3). Table 13.3 Age-stratified prevalence of enlarged prostates per 1000 men. Age (years) Prevalence per 1000 men 40–49 592 50–59 766 60–69 878 70–79 913

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Page 193 In a similar study, another group investigated the prevalence of BPH as defined by prostate volume >20 ml by TRUS and maximum flow rate <15 ml/s, and symptom severity in men 40–79 years old in Scotland. At baseline, they found a 14% prevalence of BPH in men in their 40s and 43% in men in their 60s.23 The results of their 3-year follow-up are summarized in Table 13.4. These studies provide evidence for the fluctuating nature of BPH over a period of time. The Olmsted County Study, a cross-sectional longitudinal community study, focused on urinary symptoms, flow rates, prostate volume, and age-dependent prevalence of BPH. The study included more than 2000 men from the Olmsted County area in Minnesota aged between 40 and 79 years.25 They reported a strong agestratified prevalence of moderate to severe symptoms (AUA symptom index ≥8) (Table 13.5). Of the men who reported none to mild symptoms at baseline (AUA symptom index 0–7), 13% reported moderate to severe symptoms at 18 months, and 22% at 42 months’ follow-up. The fluctuating nature of BPH symptoms was again evident from this study: 47 men with moderate to severe symptoms at 18 months had none to mild symptoms at 42 months’ follow-up.26 The age-related increase in symptom score was calculated at approximately 0.8 per year.27 Table 13.4 Three-year changes in various parameters.24 Parameter measured Change after 3 years Rise in men with moderate symptoms 34–45% Rise in AUA symptom index score 6.37–7.88 Men reporting interference with:   two or more activities 26–41% three or more activities 18–27% four or more activities 15–18% AUA, American Urological Association. Table 13.5 Prevalence of moderate to severe symptoms in each age category. Age (years) Prevalence (%) 40–49 26 50–59 33 60–69 41 70–79 44 The latest follow-up data at 92 months have shown an annual change of 0.34 points per year, with the greatest annual increase in men in their 60s, at 0.6 points per year.28 Mean peak flow rate measurements in this cohort of men showed a decrease from 20.3 ml/s in 40–44year-old men to 11.5 ml/s in men between 75 and 79 years of age.20 In this study, the authors used a cut-off point of 15 ml/s and found that 24% of men aged 40–44 years had impaired flow rates, compared to 69% of men older than 70 years of age.20 When the cut-off was reduced to 10 ml/s, 6% of men aged 40–44 years and 36% of men older than 70 years of age had impaired flow rates. The annual change was calculated at a 1.3% and 6.5% decrease per year for men in their 40s and 70s, respectively.21 The Olmsted County Study also investigated the presumed link between age and prostate volume, as determined by TRUS. The relationship was found to be statistically significant ( p <0.0001) and, with increasing age, they found a corresponding annual increase in prostate volume of 0.6 ml.29 Longitudinal studies of aging Studies in this category report age-dependent prevalence rates of BPH. The Veterans Administrative Normative Aging Study was conducted between 1967 and 1970. Over 2000 healthy male volunteers were enrolled and the diagnosis of BPH was based on a history of prostatism and DRE. The cumulative probability of a 40-year-old man developing clinical BPH based on the above diagnosis by 80 years of age was 0.777.30 The authors of the Baltimore Longitudinal Study of Aging reported similar results in a prospective longitudinal study.31 These studies reinforce the view that age is a factor for the development of BPH. However, neither of these studies has specific or standard criteria for diagnosing BPH. Complications of BPH Risk of surgery in men with BPH Of the various surgical therapies for BPH, TURP remains the most common procedure. However, there are few reports of the natural history of BPH leading to surgery. This is primarily because the majority of patients are initially seen because of symptoms, rather than because of the absolute indications for TURP (AUR, recurrent infections, recurrent hematuria, and azotemia). In 1968, the lifetime chance of a 40-year-old man having a prostatectomy was estimated at 10%.32 The file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_193.html[09.07.2009 11:52:51]

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Page 194 following year, Craigen et al. reported their estimates without specifying their indications for prostatectomy in their cohort of men: 35% incidence at 1 year and 45% incidence at 7 years. However, for men presenting with AUR these figures were 60% at 1 year and 80% at 7 years.13 Arrighi et al. conducted a more comprehensive study about the risk factors for prostate surgery.31,33 They evaluated 1057 men in the Baltimore Longitudinal Study of Aging (BLSA) with yearly symptom assessments, particularly size and force of stream and incomplete emptying, and a physical examination (DRE). Men who had previously undergone prostate surgery or had prostate cancer were excluded from this study. Age, sense of incomplete emptying, size and force of stream, and prostate enlargement were all independently associated with the risk of prostate surgery. In men who had no risk factors for surgery ( n =464) only 3% required prostate surgery. With increasing risk factors, the cumulative incidence increased such that in men with one risk factor ( n =303) the cumulative incidence was 9%; with two risk factors ( n =178), 16%; and with three risk factors ( n =112), 37%. In the Veterans’ Affairs Normative Aging Study (VANAS), 1868 men aged 49–68 years were evaluated over a period of 25 years.34 The authors excluded men with prostate cancer and found nocturia and hesitancy as the only independent predictors of surgery. Risk factors of BPH surgery were also evaluated in 16219 men older than 40 years of age at the Kaiser Permanent Health Plan in Northern California.35 After 12 years’ follow-up, 1027 (6.3%) men underwent prostatectomy. They reported age, dysuria, incontinence, hesitancy at initiating flow, nocturia, and slow stream as risk factors for surgery. Similar risk factors were reported by Diokno et al., who found the incidence of TURP to be 2.6% at 1 year and 3.3% at 2 years in their cohort.36 In the VA Cooperative study, a high bother symptom score at entry into the study was found to be a strong predictor of the need for surgery.16 In the Olmsted County study, there was a strong agerelated increase in the risk of any treatment for BPH. In addition, men with moderate to severe symptoms, flow rates <12 ml/s, or prostate volumes >30 ml were found to be four times more likely to receive treatment than those who did not have these criteria. Each of these factors was found to be an independent predictor of the need for treatment.37 Many of these studies use varying definitions of BPH, patient inclusion and exclusion criteria, and do not provide clear indications for surgery. However, they do suggest that age, prostate volume, and many urological symptoms are determinants of subsequent surgery. Acute urinary retention AUR is one of the most significant complications of BPH. For the clinician, AUR represents an indication to proceed to surgery in 25–30% of men in the US.38 For the patient, AUR means an inability to pass urine associated with increasing pain, catheterization, a subsequent trial without a catheter (TWOC), and finally either a spontaneous recovery or a TURP The natural history of AUR is also unknown and reported figures vary considerably. The Craigen series reported 0.015 episodes of retention per person-year,13 whereas the Birkoff series was considerably higher at 0.13 per person-year.14 In the Ball series, the incidence was lower at only 0.004 episodes per person-year.15 These figures translate to a wide range of 10-year cumulative incidence rates of AUR from 4% (data from the Ball series) to 73% (data from Birkoff). In the VA Cooperative Study, one man in the TURP arm had AUR compared to eight such cases in the watchful waiting arm ( n =276).16 The incidence rates of AUR from various studies are summarized in Table 13.6. The Physicians Health Study has reported increasing age and baseline symptom severity as risk factors for AUR.42 In men with mild symptoms, the incidence of AUR was 0.4/1000 person-years for men aged 45–49 years and increased to 7.9/1000 person-years for men aged Table 13.6 The incidence rates of acute urinary retention (AUR) per 1000 patient-years from various studies. (Adapted from reference 11.) Study Number of men Incidence rate of AUR per 1000 patient-years Craigen et al. 196913 — 15.0 Birkoff et al. 197614 26 130 Ball et al. 198115 107 3.7 Wasson et al. 199516 276 9.6 Andersen et al. 199739 2109 13.5 Olmsted County Study 199743 2115 6.8 Barry et al. 199740 500 25 Hunter et al. 199641 2002 50.9 McConnell et al. 199818 1376 18 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_194.html[09.07.2009 11:52:52]

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Page 195 70–83 years. They found that all seven LUTS included within the AUA symptom index independently predicted AUR, as did the use of adrenergic or anticholinergic medications. The authors of the Olmsted County Study found the relative risk (RR) of AUR increased for older men with moderate to severe symptoms (×3.2), for those men with a flow rate <12 ml/s (×3.9), and for men with a prostate volume >30 ml (×3).43 The PLESS study found symptom severity, prostate volume, and serum PSA to be predictors of episodes of AUR.18 Of interest to both clinicians and patients is what can be expected after an initial episode of AUR. When 59 Danish patients presenting to an emergency department with AUR were followed, 73% had a recurrent episode of retention within one week.44 There are two types of AUR: spontaneous and precipitated. Precipitated AUR usually occurs after a trigger such as anesthesia, catheterization, anticholinergic medication, or nonprostate-related surgery. Spontaneous AUR refers to all other episodes.45 After one episode of spontaneous retention, 15% of patients had another episode and 75% of these patients subsequently underwent prostate surgery. After an episode of precipitated AUR, 9% of men had another episode and 26% underwent prostate surgery.45 In contrast, another study reported that 55% of men underwent a prostatectomy within 3 months of an episode of AUR, although the authors of this study do not state whether the AUR was spontaneous or precipitated.13 After an episode of AUR, it is standard practice to give the patients a TWOC, although failure rates as high as 72% have been reported.46 The authors found bladder volume at the time of catheterization to be the strongest predictor of a successful TWOC. Of men with a volume of less than 900 ml, 44% had a successful TWOC, compared to only 8% with a bladder volume >900 ml. Urinary tract infections Recurrent urinary tract infection (UTI) is another indication for prostatectomy in the US and accounts for 12% of cases.38 In a large series of over 2000 men, 5.2% of patients self-reported episodes of UTI.41 Bladder stones Grosse evaluated the prevalence of bladder calculi in men with BPH at autopsy. He found bladder stones to be more common in men with a histologic diagnosis of BPH (3.4%) compared to controls (0.4%). He also found that kidney and ureteral stones were no more common in men with BPH (5.7%) compared to controls (6.0%).47 Another study found a 0.36% prevalence of bladder calculi in men with BPH on a watchful waiting policy after 3 years of follow-up.16 In the Hunter series of Spanish men, the reported prevalence was 0.7%.41 Bladder decompensation When evaluating men with BPH endoscopically, there is an impression that, with time, the normal mucosa becomes trabeculated and diverticulae start forming. This has been confirmed by biopsy samples of the chronically obstructed bladder, showing dense connective tissue deposition.48 However, Lepor et al. argue that bladder fibrosis, seen in men and women, is a consequence of aging and not just a result of BPH.49 The question of bladder decompensation affecting function is an unresolved one. It has been suggested that even men with severe bladder decompensation will improve after prostatectomy.50 Jones et al. followed 32 men with high-pressure chronic retention for a mean period of 43 months postprostatectomy. They reported an initial improvement in renal function in all but one man and the mean creatinine clearance rose from 53 ml/min to 83 ml/min. Twenty-five of 32 men had a residual volume <200 ml after surgery.51 It has subsequently been argued that delayed prostatectomy may result in some irreversible damage.17 Chronic renal failure Occult progressive renal damage was reported in 1.6% of men undergoing a prostatectomy.52 The AHCPR BPH guidelines reported a mean incidence of chronic renal failure (CRF) at 13.6% in men presenting for surgery.1 Of over 6000 men who underwent upper tract imaging prior to surgery, 7.6% had evidence of hydronephrosis. Of these, one-third had renal insufficiency.1 Hunter et al. found a 2.4% prevalence of self-reported renal failure in their Spanish study.41 Of concern, patients with renal failure have a greater risk of complication after TURP (25%) when compared to men with normal renal function (17%).53 Additionally, mortality rates after TURP are 6fold greater in men with impaired renal function.54 Hematuria Gross hematuria is a troublesome complication of BPH. When it occurs, hematuria causes a great deal of alarm to patients. In several studies, up to 20% of patients presenting with this complication were diagnosed with BPH.55 In a retrospective study of more than 3000 men, the authors

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Page 196 found that 12% of all TURPs were for hematuria.56 The Spanish study is one of the few studies to report the incidence of BPH-related hematuria at 2.5%.41 Recent interest in this complication arises from the response of hematuria to finasteride, a 5α-reductase inhibitor. Kearney et al. conducted a retrospective study investigating the time for resolution of hematuria. The degree of hematuria improved in 94% of the patients. The authors found prostate volume to correlate with the mean time for resolution of hematuria, which was 2.7 days for prostates <40 g; 10.3 days for those of 40–100 g; 19 days for those of 100–150 g and 45 days for those glands greater than 150 g.57 They also found that hematuria resolved more rapidly in patients who had previously undergone prostatectomy compared to those who had not undergone surgery (5.5 days and 18.6 days, respectively). This finding has previously been reported by Puchner and Miller in their personal experience of 18 patients with BPH treated with finasteride.58 References 1. McConnell J, Barry M, Bruskewitz R. Benign prostatic hyperplasia: diagnosis and treatment. Agency for Health Care Policy and Research (AHCPR). Clin Pract Guide Quick Ref Guide 1994; 8:1–17 2. Lu-Yao G, Barry M, Chang C et al. Transurethral resection of the prostate among medicare beneficiaries in the United States: time trends and outcomes. Prostate patient outcomes research team (PORT). Urology 1994; 44: 692–698 3. Drummond M, McGuire M, Black N et al. Economic burden of treated benign prostatic hyperplasia in the United Kingdom. Br J Urol 1993; 71:290–296 4. Curkendall S, Jones J, Dale G et al. Incidence of medically detected erectile dysfunction in and related diseases before and after Viagra (sildenafil citrate). Eur Urol 2000; 37(Suppl2):81 5. Eddy D. Clinical decision making from theory to practice. Comparing benefits and harms: the balance sheet. J Am Med Assoc 1990; 263:2493–2505 6. Jacobsen S, Girman C, Lieber M. Natural history of benign prostatic hyperplasia. Urology 2001; 58(Suppl 6A): 5–16 7. Guess H, Jacobsen S, Girman C et al. The role of community-based longitudinal studies in evaluating treatment effects: example—benign prostatic hyperplasia. Med Care 1995; 33(Suppl 4):AS26–35 8. Abrams P. Fortnightly review: managing lower urinary tract symptoms in older men. Br Med J 1995; 310: 1113–1117 9. Guess H. Epidemiology and natural history of benign prostatic hyperplasia. In: Chisholm G (ed). Handbook of benign prostatic hyperplasia. New York: Raven Press, 1994:1–18 10. Isaacs J. Importance of the natural history of benign prostatic hyperplasia in the evaluation of pharmacologic intervention. Prostate 1990; 3:1–7 11. Roehrborn C. The epidemiology of acute urinary retention in benign prostatic hyperplasia. Rev Urol 2001; 3: 187–192 12. Clarke R. The prostate and the endocrines: a control series. Br J Urol 1937; 9:254–271 13. Craigen A, Hickling J, Saunders C, Carpenter R. Natural history of prostatic obstruction. J R Coll Gen Pract 1969; 18:226–232 14. Birkoff J, Wiederhorn A, Hamilton M, Zinsser H. Natural history of benign prostatic hypertrophy and acute urinary retention. Urology 1976; 7:48–52 15. Ball A, Feneley R, Abrams P. The natural history of untreated ‘prostatism’. Br J Urol 1981; 53:613– 616 16. Wasson J, Reda D, Bruskewitz R et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans’ Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995; 332:75–79 17. Flanigan R, Reda D, Wasson J et al. 5-Year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign prostatic hyperplasia: a Department of Veterans’ Affairs Cooperative Study. J Urol 1998; 160:12–16 18. McConnell J, Bruskewitz R, Walsh P et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998; 338:557–563 19. Roehrborn C, Boyle P, Bergner D et al. Serum prostatespecific antigen and prostate volume predict long-term changes in symptoms and flow-rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS study group. Urology 1999; 54:662–669 20. Girman C, Panser L, Chute C et al. Natural history of prostatism: urinary flow rates in a communitybased study. J Urol 1993; 150:887–892 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_196.html[09.07.2009 11:52:53]

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21. Diokno A, Brown M, Goldstein N, Herzog A. Urinary flow rates and voiding pressures in elderly men living in a community. J Urol 1994; 151:1550–1553 22. Simpson R, Fisher W, Lee A et al. Benign prostatic hyperplasia in an unselected community-based population: a survey of urinary symptoms, bothersomeness and prostatic enlargement. Br J Urol 1996; 77:186–191 23. Garraway W, Collins G, Lee R. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991; 338:469–471

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Page 197 24. Lee A, Russell E, Garraway W, Prescott R. Three-year follow-up of a community-based cohort of men with untreated benign prostatic hyperplasia. Eur Urol 1996; 30:11–17 25. Chute C, Panser L, Girman C et al. The prevalence of prostatism: a population-based study of urinary symptoms. J Urol 1993; 150:85–89 26. Jacobsen S, Girman C, Guess H et al. Natural history of prostatism: four-year changes in urinary symptom frequency and bother. J Urol 1995; 153:300A 27. Jacobsen S, Oesterling J, Lieber M. Community-based population studies on the natural history of prostatism. Curr Opin Urol 1995; 5:13–17 28. Rhodes T, Girman C, Jacobsen D et al. Longitudinal prostate volume in a community-based sample: 7-year follow-up in the Olmsted County Study of Urinary Symptoms and Health Status among men. In: AUA Annual Meeting, Atlanta, May 2000, abstract 1105 29. Oesterling J, Jacobsen S, Chute C et al. Serum prostatespecific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. J Am Med Assoc 1993; 270:860–864 30. Glynn R, Campion E, Bouchard G, Silbert J. The development of benign prostatic hyperplasia among volunteers in the normative aging study. Am J Epidemiol 1985; 121: 78–90 31. Arrighi H, Guess H, Metter E, Fozard J. Symptoms and signs of prostatism as risk factors for prostatectomy. Prostate 1990; 16:253–261 32. Lytton B, Emery J, Havard BM. The incidence of benign prostatic obstruction. J Urol 1968; 99:639– 645 33. Arrighi H, Metter E, Guess H, Fozard J. Natural history of benign prostatic hyperplasia and risk of prostatectomy. Urology 1991; 38:4–8 34. Epstein R, Lydick E, DeLabry L, Volkonas P. Age related differences in risk factors for prostatectomy for bengin prostatic hyperplasia: the VA Normative Aging Study. Urology 1991; 38(Suppl 1): 9–12 35. Sidney S, Quesenberry J, Sadler M et al. Risk factors for surgically treated benign prostatic hyperplasia in a prepaid health care plan. Urology 1991; 38(Suppl 1): 13–19 36. Diokno A, Brown M, Goldstein N, Herzog A. Epidemiology of bladder emptying symptoms in elderly men. J Urol 1992; 148:1817–1821 37. Jacobsen S, Jacobsen D, Girman C et al. Treatment for benign prostatic hyperplasia among community-dwelling men: the Olmsted County Study of Urinary Symptoms and Health Care Status among Men. J Urol 1999; 162: 1301–1306 38. Holtgrewe H, Mebust W, Dowd J et al. Transurethral prostatectomy: practice aspects of the dominant operation in American urology. J Urol 1989; 141:248–253 39. Andersen J, Nickel J, Marshall V et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplais. Urology 1997; 49:839–845 40. Barry M, Fowler F, Bin L et al. The natural history of patients with benign prostatic hyperplasia as diagnosed by North American urologists. J Urol 1997; 157:10–15 41. Hunter D, Berra-Unamuno A, Martin-Gordo A. Prevalence of urinary symptoms and other urological conditions in Spanish men 50 years old or older. J Urol 1996; 155:1965–1970 42. Meigs J, Barry M, Giovannucci E et al. Incidence rates and risk factors for acute urinary retention: the health professionals follow-up study. J Urol 1999; 162:376–382 43. Jacobsen S, Jacobsen D, Girman C et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997; 158:481–487 44. Breum L, Klarskov P, Munck L et al. Significance of acute urinary retention due to intravesical obstruction. Scand J Urol Nephrol 1982; 16:21–24 45. Roehrborn C, Bruskewitz R, Nickel G et al. Urinary retention in patients with BPH treated with finasteride or placebo over 4 years. Characterization of patients and ultimate outcomes. The PLESS Study Group. Eur Urol 2000; 37:528–536 46. Taube M, Gajraj H. Trial without catheter following acute retention of urine. Br J Urol 1989; 63:180– 182 47. Grosse H. Frequency, localization and associated disorders in urinary calculi. Analysis of 1671 autopsies in urolithiasis. Z Urol Nephrol 1990; 83:469–474 48. Gosling J, Dixon J. The structure of the trabeculated detrusor smooth muscle in cases of prostatic hypertrophy. Urol Int 1980; 35:351–355 49. Lepor H, Sunaryadi I, Hartano V, Shapiro E. Quantitative morphometry of the adult human bladder. J Urol 1992; 148:414–417 50. Ghose R, Harinda V. Unrecognised high pressure chronic retention of urine presenting with systemic file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_197.html[09.07.2009 11:52:53]

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arterial hypertension. Br Med J 1989; 298:1626–1628 51. Jones D, Gilpin S, Holden D et al. Relationship between bladder morphology and long-term outcome of treatment in patients with high pressure chronic retention of urine. Br J Urol 1991; 67:280–285 52. Mukamel E, Nissenkorn I, Boner G, Servadino C. Occult progressive renal damage in the elderly male due to benign prostatic hypertrophy. J Am Geriatr Soc 1979; 27: 403–406 53. Mebust W, Holtgrewe H, Cockett A, Peters P. Transurethral prostatectomy: immediate and postoperative complications: a cooperative study of 13 institutions evaluating 3885 patients. J Urol 1989; 141:243–247

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Page 198 54. Melchior J, Valk W, Foret J, Mebest W. Transurethral prostatectomy in the azotemic patient. J Urol 1974; 112: 643–647 55. Hasan S, German K, Deny C. Same day diagnostic service for new cases of haematuria—a district general hospital experience. Br J Urol 1994; 73:151–153 56. Kashif K, Foley S, Basketter V, Holmes S. Haematuria associated with BPH—natural history and a new treatment option. Prostate Cancer Prostatic Dis 1998; 1: 154–156 57. Kearney M, Bingham J, Bergland R et al. Clinical predictors in the use of finasteride for control of gross hematuria due to benign prostatic hyperplasia. J Urol 2002; 167: 2489–2491 58. Puchner P, Miller M. The effects of finasteride on haematuria associated with benign prostatic hyperplasia: a preliminary report. J Urol 1995; 154:1779–1782

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Page 199 III Evaluation

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Page 201 14 Evaluating symptoms and functional status G S Adey M P O’Leary M J Barry Symptoms in BPH Benign prostatic hyperplasia (BPH) and its symptoms are extremely common among aging men; however, the effects of BPH vary greatly from patient to patient. In the United States, it is estimated that over 400000 men have surgical treatment of BPH annually, at a cost of more than 4 billion dollars.1 Data from the 2000 European Association of Urology meeting indicate that BPH may be as prevalent as hypertension and diabetes.2 The ideal treatment for each patient would involve relieving both the symptoms and the bladder outlet obstruction. Measuring patient symptoms has proved to be a challenging task for clinicians, and this has led to the development of several standardized instruments for symptom measurement. Ideally, these should be both reliable and valid. In diagnostic testing, these characteristics are called precision and accuracy, respectively. Reliability is measured as the consistency of a response to a particular question. The same question is asked within short time intervals and the responses are compared. When there is a high degree of agreement between the short-term responses, reliability of the question may be confirmed. This property of a set of questions is known as test-retest reliability. Validity is assessed by whether the question actually measures what it is intended to measure. Reliability does not guarantee validity. An analogy to archery is a fitting example: a tight grouping of arrows somewhere on the target demonstrates outstanding reliability, but if this group of arrows is located far from the bull’s eye, the validity is quite poor. Decisions regarding treatment of BPH involve both the severity of bladder outlet obstruction, as well as the severity of the patient’s symptoms. Clinicians are familiar with the devices to measure anatomic and physiologic phenomena associated with BPH. Uroflowmetry and pressure-volume studies provide the practicing urologist with concrete data. The development of instruments to measure symptoms has a similar goal. Urologists can now quantify the severity of their patients’ symptoms, track the progression of their disease, as well as track their improvement following therapy. These standardized instruments also allow direct comparison of different therapies for BPH. Principles for symptom measurement The methods used for the development of an instrument to measure a health index may differ according to the planned use of the measurement Kirshner and Guyatt have distinguished between discriminative, predictive, and evaluative measurement instruments.3 Discriminative instruments are created in the absence of a gold standard test, and they are used to differentiate groups based on a single characteristic. Predictive instruments have a gold standard test available, but it is too expensive or too risky to use this test routinely; therefore, these measurements are used to classify the individuals into groups. Evaluative instruments assess longitudinal change over time. Discriminative and predictive instruments relate to diagnosis and screening done in clinical practice, while evaluative instruments communicate the response to treatment. In order for an instrument to be clinically useful, its intended purpose must be clear. Responsiveness is a special type of validity and is another area of interest to those constructing measurement instruments. Responsiveness is the index’s ability to measure stability or change from baseline in either direction when administered repeatedly over time. For most measures of health status, this is a necessary component of a good instrument. When instruments are designed to measure qualitative items such as health status, multiple questions are used to formulate a detailed picture of the patient’s situation. It is important for this group of questions, called an index, to measure the same concept. One would not want to combine unrelated items, nor would one want to use items too closely related and possibly redundant. This property of an index of questions is called internal consistency, and it can be measured statistically using Cronbach’s α coefficient.4 A good index will have a high Cronbach’s a, showing that the questions within the index are measuring the same characteristic being studied. Parsimony must also be taken into account when dealing with internal consistency. An index that will be widely used in clinical practice must be one that is concise, as well as reliable and valid. A long questionnaire may burden patients and lower response rates. However, maximizing internal consistency and parsimony should not

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Page 202 allow valuable questions within the index to be discarded, particularly those items that allow further description of the patient’s experience. A broad set of response categories is one way to satisfy both demands. An ideal question is one that has an appropriate response for each subject (collectively exhaustive), but only one appropriate response for each subject (mutually exclusive). Investigators must carefully weigh these criteria against one another in order to create the best possible instrument. Measuring lower urinary tract symptom severity Multiple instruments have been developed in the past 15 years and used to measure urinary symptom severity in men with BPH. Three of the most recent and extensively used instruments are the International Prostate Symptom Score (I-PSS), the Danish Prostate Symptom Score (DAN-PSS-1), and the International Continence Society (ICS) male questionnaire. Prior instruments, such as the Boyarsky and Madsen-Iversen symptom indices and the Maine Medical Assessment Program (MMAP), have been replaced by the newer, easier to use instruments. The beginning of the development of these instruments was a long list of complaints from patients suffering from BPH. Frequency, urgency, nocturia, weak force of stream, intermittency, hesitancy, terminal dribbling, and a sense of incomplete emptying collectively comprise the entity known as ‘lower urinary tract symptoms’ (LUTS). The term LUTS is preferable to the traditional term ‘prostatism’, as other pathologic processes affecting the lower urinary tract may cause identical symptoms.5 There is considerable debate about which of these terms may actually best define the symptoms caused by BPH, and herein has led to the development of several different instruments. The first instruments developed to measure patient symptoms from BPH were landmark in the development of the instruments used today. The Boyarsky index was first published in 1977 in an effort to standardize comparison among pharmacologic agents being used in the treatment of BPH.6 It was the product of a group of urologists working with the United States Food and Drug Administration. The Boyarsky index listed a group of important symptoms to be assessed in study protocols, along with a set of recommended response categories. However, it contained only the list of symptoms, and did not specify how the questions were to be phrased and by whom. Some of the response categories were broad and not mutually exclusive, often combining two symptoms within one response choice. Clearly this instrument was developed for evaluative means, and not for predictive or discriminative purposes, yet it remained important in the development of all subsequent questionnaires. The Madsen-Iversen index was first reported in 1983 as part of a point system for selecting patients with BPH for prostatectomy.7 This instrument, similar to the Boyarsky index, contained a list of voiding symptoms with associated response choices. The responses were given point values, and the sum total of all responses was used to calculate a patient score. The total score was then used to determine the degree of obstruction and the potential need for surgical intervention. Like the Boyarsky paper, the Madsen-Iversen index did not specify how the questionnaire should be administered, nor how the questions should be worded. No attempt was made to formally study the validity or reliability of either the Boyarsky or Madsen-Iversen indices. Despite these findings, the theory behind the Madsen-Iversen scoring system has found its way into the questionnaires used today. The Maine Medical Assessment Program (MMAP) was the first instrument to emerge that was shown to be reliable and valid in the measurement of urinary symptoms in men with BPH.8 While the five-item MMAP was also shown to be responsive to clinical changes, it suffers from lack of content validity. Many clinicians were concerned that the MMAP includes questions concerning dysuria and postvoid dribbling, considered to be less specific for BPH, and ignores more closely related symptoms such as nocturia, weak force of stream, and the sensation of incomplete voiding. Given the lack of easy to use, validated instruments to measure LUTS in men, the American Urological Association (AUA) appointed a Measurement Committee to develop a new instrument.9 This was in part driven by the new development of multiple medical and surgical means by which to treat BPH, and the primary goal of such instruments was to be evaluative. However, a discriminative component to distinguish between the amount of patients’ bother was implicit as well. The end result was the creation of a validated, reliable instrument for measuring LUTS: the AUA symptom index. The AUA symptom index later became known as the International Prostate Symptom Score (I-PSS) after the addition of a quality of life question to the end of the index (Table 14.1). The Measurement Committee reviewed published and unpublished symptom questionnaires to develop an initial list of questions. A preliminary index containing 15

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Page 203 Table 14.1 The International Prostate Symptom Score (I-PSS).   Not Less Less than About More Almost at than 1 half the half the than half always all time in 5 time time the time 1. Over the past month or so, how often have you had a 0 □ 1 □ 2□ 3□ 4□ 5□ sensation of not emptying your bladder completely after you finished urinating? 2. Over the past month or so, how often have you had 0 □ 1 □ 2□ 3□ 4□ 5□ to urinate again less than 2 hours after you finished urinating? 3. Over the past month or so, how often have you found 0 □ 1 □ 2□ 3□ 4□ 5□ you stopped and started again several times when you urinated? 4. Over the past month or so, how often have you found 0 □ 1 □ 2□ 3□ 4□ 5□ it difficult to postpone urination? 5. Over the past month or so, how often have you had a 0 □ 1 □ 2□ 3□ 4□ 5□ weak urinary stream? 6. Over the past month or so, how often have you had 0 □ 1 □ 2□ 3□ 4□ 5□ to push or strain to begin urination? 7. Over the last month, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?   0 □ none   1 □ 1 time 2 □ 2 times 3 □ 3 times 4 □ 4 times 5 □ 5 or more times   I-PSS=sum of questions 1– 7=______________ Quality of life due to urinary symptoms: If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?   0 □ Delighted   1 □ Pleased 2 □ Mostly satisfied 3 □ Mixed (about equally satisfied and dissatisfied) 4 □ Mostly dissatisfied 5 □ Unhappy 6 □ Terrible Reference: Barry M J, Fowler F J, O’Leary M P et al. The American Urological Association Symptom Index for benign prostatic hyperplasia. J Urol 1992; 148:1549.

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Page 204 questions covering nine symptoms was created. This questionnaire was then evaluated within three different urological practices by men with LUTS who had not had prior surgery. These patients were then asked to complete an identical questionnaire 1 week later. It was on the basis of these data that the questionnaire was modified into its final form of seven items. The I-PSS addresses seven symptoms: (1) incomplete emptying, (2) frequency, (3) hesitancy, (4) urgency, (5) weak stream, (6) straining, and (7) nocturia, as well as the additional impact question regarding bother.10 Each response regarding symptoms is categorized within six gradations, from ‘not at all’ to ‘almost always’. Nocturia is scored according to the severity. The scores from the seven responses are summed for a possible maximum total of 35 points. The impact question asks how the patient would feel if he had to spend the rest of his life with his current urinary condition. It is rated from a score of 0 (delighted) to 6 (terrible). The score from the impact question is reported separately and it is not summed with the score from the seven symptom questions. The symptoms of dysuria and terminal dribbling were excluded from the final version of the I-PSS after the pilot study indicated responses to these questions were less strongly related to overall patients’ symptoms and to the other seven symptoms previously mentioned. The symptom scale of the I-PSS is a reliable instrument. The items within the I-PSS have a Cronbach’s α of 0.86, demonstrating high internal consistency and justification for summing the answers into a total point score.9 The 1-week test-retest reliability of the overall scores was excellent with a correlation coefficient of 0.92. The I-PSS is self-administered, avoiding the potential complication of observer bias and the need for a trained interviewer.11 When compared head-to-head, the I-PSS was found to better discriminate patients with BPH from control patients than the Maine Medical Assessment Program, and equivalently to the Boyarsky and Madsen-Iversen indices, thus demonstrating its construct validity.12 The responsiveness of the I-PSS has also been proven, as shown by a group of men whose score after undergoing prostatectomy dropped from a preoperative score of 17.6 points to 7.1 points 4 weeks postoperatively.9 These results have been corroborated in patients undergoing medical therapy for BPH, where decreases in I-PSS scores predicted global subjective improvement.13 Barry et al. found that a decrease in the I-PSS score of three points was the minimum change necessary to reveal noticeable improvement in symptoms.14 Symptom scores may be classified according to their severity. The designation is somewhat arbitrary, with the general classification as follows: ‘mild’ symptoms (1–7 points); ‘moderate’ symptoms (8–19 points); and ‘severe’ symptoms (20–35 points). Most men in the mild range are seldom bothered by their symptoms and rarely desire therapy. It should be re-emphasized that the I-PSS should not be used to diagnose LUTS secondary to BPH, as many different pathologies of the lower urinary tract will cause similar voiding symptoms. The I-PSS does not appear to be affected by other factors such as race or ethnicity.15 It has been linguistically and culturally validated in over 12 different languages, and is reported to require a sixthgrade reading level.16 I-PSS scores were shown to be reproducible when combined with other instruments used to measure health status,17 as well as when the order of the individual questions of the I-PSS was scrambled.18 There has not been a recent estimate of the prevalence of use of the I-PSS within clinical practice, but in 1993, 95% of surveyed urologists said they were familiar with the symptom index and 60% of those who were familiar were using it routinely.19 The Danish Prostate Symptom Score (DAN-PSS-1) is another instrument that has been developed to measure the frequency and severity of LUTS (Table 14.2). Published originally in 1991,20 the DAN-PSS1 covers 12 lower urinary tract symptoms. It includes areas not covered by the I-PSS, such as dysuria, terminal dribbling, and incontinence. Each of the 12 symptoms is given both a symptom severity score and a bother score. Each response frame has four sequential categories, scored from 0 to 3, and the authors recommend multiplying the symptom and bother scores for each question. The scores from the 12 questions are then added together to obtain a total score (maximum 108). The DAN-PSS-1 is subdivided into obstructive and irritative parts, and the authors originally proposed that this obstructive portion could be used to predict bladder outlet obstruction in men with BPH.21 This finding has been refuted by further study comparing the DAN-PSS-1 with pressure-flow studies.22,23 These same studies and others24 have not shown a correlation between the I-PSS and degree of bladder neck obstruction. The DAN-PSS-1 has been demonstrated to be a reliable and valid instrument for the purposes of evaluating and following patients with BPH, and its clinical use is more popular in Europe than the United States. In 1996, Donovan et al. proved the validity and reliability of the International Continence Society male (ICSmale ) questionnaire.25 The original goal in the construction of the ICS male was to create an instrument to predict bladder outlet obstruction. This goal was soon file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_204.html[09.07.2009 11:52:57]

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Page 205 Table 14.2 The Danish Prostatic Symptom Score (DAN-PSS-1). 1A Do you have to wait for urination to begin?   Answers; 0—No, never; 1—Rarely; 2—Often; 3—Always 1B If you have to wait for urination to begin, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 2A Do you consider your urinary stream as:   Answers: 0—Normal; 1—Weak; 2—Very weak; 3—Dribbling 2B If your urinary stream is weak, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 3A Do you feel that you empty your bladder completely when urinating?   Answers: 0—Yes, always; 1—Often; 2—Rarely; 3—Never 3B If you feel that you do not empty your bladder completely when urinating, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 4A Do you have to push or strain to begin urination and/or maintain urination?   Answers: 0—No, never; 1—Rarely; 2—Often; 3—Always 4B If you have to push or strain, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 5A What is the longest interval between each urination, from when you wake up in the morning until you go to bed?   Answers: 0—More than 3 hours; 1–2 to 3 hours; 2–1 to 2 hours; 3—Less than 1 hour 5B If you have to urinate often, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 6A How many times do you have to urinate during the night?   Answers: 0–0 times; 1–1 to 2 times; 2–3 to 4 times; 3–5 times or more 6B If you have to urinate during the night, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 7A Do you experience an urgent (strong) need to urinate?   Answers: 0—No, never; 1—Rarely; 2—Often; 3—Always 7B If you experience an urgent (strong) need to urinate, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 8A Is your need to urinate so urgent that you cannot hold it back until you reach the toilet?   Answers: 0—No, never; 1—Rarely; 2—Often; 3—Always 8B If you cannot hold back the urination until you reach the toilet, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 9A Does it hurt or burn when you urinate?   Answers: 0—No, never; 1—Rarely; 2—Often; 3—Always 9B If it hurts or burns when you urinate, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 10ADo you experience dribbling when you thought urination had finished (terminal dribbling) ?   Answers: 0—No, never; 1—In the toilet; 2—Small amount in the underpants; 3—Large amount in the underpants 10BIf you experience dribbling when you thought urination had finished, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 11ADo you urinate involuntarily during physical exertion (e.g. when coughing, sneezing, lifting objects)?   Answers: 0—No, never; 1—Rarely; 2—Often; 3—Always 11BIf you urinate involuatarily during physical exertion, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much 12ADo you urinate involuntarily without physically exerting yourself and without needing to urinate (seepage)?   Answers: 0—No, never; 1—Rarely; 2—Often; 3—Always 12BIf you urinate involuntarily without needing to and without physically exerting yourself, how bothersome is this for you?   Answers: 0—Not at all; 1—A little bit; 2—Moderately; 3—Very much From: Hansen B J, Flyger H, Brasso K et al. Validation of the self-administered Danish Prostatic Symptom Score (DAN-PSS-1) system for use in benign prostatic hyperplasia. Br J Urol 1995; 76:451. file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_205.html[09.07.2009 11:52:57]

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Page 206 proved not possible, as only the symptom of urge incontinence significantly correlated with bladder outlet obstruction.26 The long and detailed, 22-item instrument was later revised to a short form (11 items), the current ICS male SF (Table 14.3).26 The ICS male SF is subdivided into a six-item incontinence scale (ICSmale IS) and a five-item voiding scale (ICSmale VS). The ICS male IS and ICS male VS have both been shown to be valid and reliable, with Cronbach’s α of 0.78 and 0.76, respectively.26 Controlled studies across different treatment groups showed the ICS male SF to be highly responsive as well. Following the 11 items are three questions pertaining to frequency, nocturia, and quality of life. The low Cronbach’s α coefficient for frequency and nocturia supported their separate assessment, and they were not included in the subdivisions of the ICS male SF. Response frames to the 11 items have five sequential choices, scored from 0 to 4. A total point score is obtained from addition of answers from the 11 items. The ICS male SF is a hybrid of the two previously described instruments. The ICS male SF is similar to the I-PSS in that the scoring is done by simple addition. The ICS male SF has a question regarding quality of life, similar to the impact question that was added to the I-PSS. The ICS male SF is similar to the DAN-PSS-1 because both instruments contain questions regarding incontinence. However, the ICS male SF is different from both the I-PSS and the DAN-PSS-1 in that it does not consider frequency and nocturia in its total score. All three instruments, been shown to be valid evaluative tools for the measure- the I-PSS, the DAN-PSS-1, and the ICS male SF, have ment of LUTS. None of the three instruments has been shown to be predictive of bladder outlet obstruction. While the I-PSS remains the most popular in clinical use, it is important that clinicians are aware of these instruments and make use of them in the evaluation of the patients with LUTS. Correlation of symptoms with physiology Many investigators have tried unsuccessfully to correlate the severity of LUTS to the degree of physiologic bladder outlet obstruction. Studies of prostate size, uroflowmetry, and pressure-flow studies have long since exposed this weak relationship.27,28 The AUA completed the BPH Treatment Outcomes Pilot Study of 200 patients shortly after the creation of their symptom score.29 They found very weak but statistically significant relationships between answers to questions regarding incomplete emptying and postvoid residual volume, and between answers to questions regarding force of stream and average uroflow velocity. However, there was no statistically significant correlation between overall symptom severity and any of the anatomic or physiologic measures used in clinical practice. One limitation of this study is that pressure-flow studies were not used in the patient population. Other investigators have attempted to correlate office measurements with the results from physiologic studies in an effort to determine which patients need urodynamic studies. Ockrim et al. compared office I-PSS scores, uroflowmetry, and prostate size by transrectal ultrasonography to results from pressureflow studies in an attempt to create a mathematical formula to predict bladder outlet obstruction.30 They developed a complex formula, the bladder outlet obstruction index, where above the maximum designated cut-off yielded 92% probability of obstruction, and below the minimum threshold there was only 4% probability of obstruction. Reports on two large series of men with LUTS undergoing urodynamic studies show that detrusor instability may be present in as many as 45% of these patients, suggesting a role for urodynamics to help clarify competing etiologies of LUTS.31,32 It is impossible to predict the role innovative new formulae will have in the office diagnosis of men with BPH. Currently, pressure-flow studies during urodynamics remain the only objective physiologic or anatomic parameter by which to diagnose bladder outlet obstruction. Utility of symptom measurement in clinical practice and research The I-PSS, or another validated measure of voiding symptoms, should be administered upon initial office visit of patients with LUTS. The other tests that should be used at this time are continually debated and are the focus of another chapter in this text. The symptom score should help to give the clinician an idea of the symptom burden and the bother of the patient with this condition, and help inclusion of the I-PSS or the DAN-PSS-1 or ICS male SF in steer further discussion regarding future treatment. The research protocols of men with BPH will permit comparisons between studies. The known validity, reliability, and responsiveness of each of these indices will allow detection of clinically significant differences among treatment strategies. The I-PSS, DAN-PSS-1, and ICS male SF all allow tracking of patients’ progress once a treatment modality has begun. There will be some expected variability of score in individual patients on the basis of chance alone. In fact, when only two measurements of the I-PSS are available for a patient, changes in the score of up to five

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Page 207 Table 14.3 International Continence Society Male Questionnaire Short Form (ICSmaleSF). Please answer each question, thinking about the symptoms you have experienced in the last month. You will see that some of the questions ask how often you have a symptom: Occasionally=less than one-third of the time Sometimes=between one- and two-thirds of the time Most of the time=more than two-thirds of the time V1Is there a delay before you can start to 13 Does urine leak when you cough or sneeze? urinate? Never □0  Never □0 Occasionally □1  Occasionally □1 Sometimes □2  Sometimes □2 Most of the time □3  Most of the time □3 All of the time □4  All of the time □4 V2Do you have to strain to continue 14 Do you ever leak for no obvious reason and urinating? without feeling that you want to go? Never □0  Occasionally □1  Never □0 Sometimes □2  Occasionally □1 Most of the time □3  Sometimes □2 All of the time □4  Most of the time □3   All of the time □4 V3Would you say the strength of your 15 Do you leak urine when you are asleep? urinary stream is… Normal □0  Never □0 Occasionally reduced □1  Occasionally □1 Sometimes reduced □2  Sometimes □2 Reduced most of the time □3  Most of the time □3 Reduced all of the time □4  All of the time □4 V4Do you stop and start more than once 16 How often have you had a slight wetting of your while you urinate? pants a few minutes after you had finished Never □0  urinating and dressed yourself? Occasionally □1  Never □0 Sometimes □2  Occasionally □1 Most of the time □3  Sometimes □2 All of the time □4  Most of the time □3         All of the time □4 V5How often do you feel that your bladder FrequencyHow often do you pass urine during the day    has not emptied properly after you have urinated? Never □0 Hourly □3 Occasionally □1 Every 2 hours □2 Sometimes □2 Every 3 hours □1 Most of the time □3 Every 4 hours or more □0 All of the time □ 4 Nocturia During the night, how many times do you have to 11Do you have to rush to the toilet to get up to urinate, on average? urinate? Never □0  None □0 Occasionally □1  One □1 Sometimes □2  Two □2 Most of the time □3  Three □3 All of the time □4  Four or more □4 12Does urine leak before you can get to QoL Overall, how much do your urinary symptoms the toilet? interfere with your life? Never □0 Not at all □0 Occasionally □1 A little □1 Sometimes □2 Somewhat □2 Most of the time □3 A lot □3 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_207.html[09.07.2009 11:52:58]

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All of the time □4      From: Donovan J L, Peters T J, Abrams P, et al. Scoring the short form ICSmaleSF questionnaire. J Urol 2000; 164:1948.

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Page 208 points can be due to chance.33 Therefore, clinicians using I-PSS to follow their patients can reduce the effect of chance variation by averaging the results of multiple scores. The same point applies to other serial measurements in individual patients, such as measurements of peak uroflow or postvoid residual volume. Conclusions Valid, reliable instruments exist for the measurement of LUTS. The majority of the morbidity from BPH results from its symptoms. To date, no one has been able to correlate physiologic measurements with symptom severity, but this continues to be researched. Valid, reliable instruments exist for the measurement of LUTS. Clinicians need to make one of these questionnaires, such as the I-PSS, a part of routine patient care. References 1. Brawer M K, McConnell J D, Oesterling J E. What will replace TURP? Contemp Urol 1992; 4:30–40 2. Kirby R S. The natural history of benign prostatic hyperplasia: what have we learned in the last decade? Urology 2000; 56:3–6 3. Kirshner B, Guyatt G. A methodological framework for assessing health indices. J Chron Dis 1985; 38:27–36 4. Cronbach L J. Coefficient alpha and the internal structure of tests. Psychometrika 1951; 16:297 5. Abrams P. New words for old: lower urinary tract symptoms for prostatism. Br Med J 1994; 308:929– 930 6. Boyarsky S, Jones G, Paulson D F et al. A new look at bladder neck obstruction by the Food and Drug Administration regulators: guidelines for the investigation of benign prostatic hypertrophy. Trans Am Assoc Genitourin Surg 1977; 68:29–32 7. Madsen P O, Iversen P. A point system for selecting operative candidates. In: Hinman F Jr (ed). Benign prostatic hypertrophy. New York: Springer-Verlag, 1983:763–765 8. Fowler F J Jr, Weinberg J E, Timothy R P et al. Symptom status and quality of life following prostatectomy. J Am Med Assoc 1988; 259:3018–3022 9. Barry M J, Fowler F J, O’Leary M P et al. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992; 148:1549–1557 10. Cockett A T, Aso Y, Denis L et al. Recommendations of the International Consensus Committee concerning: 1. Prostate symptom score and quality of life assessment. In: Crockett A T K, Khoury S, Aso Y et al. (eds). Proceedings, the 2nd international consultation on benign prostatic hyperplasia (BPH), Paris, June 27–30, 1993. Jersey, Channel Islands: Scientific Communication International Ltd, 1994:553– 555 11. O’Leary M P Barry M J, Fowler F J. Hard measures of subjective outcomes: validating symptom indexes in urology. J Urol 1992; 148:1546–1548 12. Barry M J, Fowler F J, O’Leary M P et al. Correlation of the American Urological Association symptom index with self-administered versions of the Madsen-Iversen, Boyarsky, and Maine Medical Assessment Program symptom indices. J Urol 1992; 148:1558–1563 13. Lepor H, Williford W O, Barry M J et al. For the Veterans’ Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group: the efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996; 335: 533–539 14. Barry M J, Williford W O, Chang Y et al. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association Symptom Index and the Benign Prostatic Hyperplasia Impact Index is perceptible to patients. J Urol 1995; 154:1770–1774 15. Barry M J. Evaluation of symptoms and quality of life in men with benign prostatic hyperplasia. Urology 2001; 58: 25–32 16. MacDiarmid S A, Goodson T C, Holmes T M et al. An assessment of the comprehension of the American Urological Association Symptom Index. J Urol 1998; 159: 873–874 17. Barry M J, Walker-Corkery E, Chang Y et al. Measurement of overall and disease-specific health status: does the order of the questionnaires make a difference? J Health Serv Res Policy 1996; 1:20–27 18. Barnboym E, Ahrens A, Roehrborn C. Effect of scrambling on the short-term reliability of the American Urological Association Symptom Index. Urology 1999; 53:568–573 19. Gallup Poll Organization Inc. Practicing urologists survey. Baltimore: American Urological Association, 1993 20. Hald T, Nordling J, Andersen J T et al. A patient weighted symptom score system in the evaluation of uncomplicated benign prostatic hyperplasia. Scand J Urol Nephrol 1991; 138:59–62 21. Schou J, Poulsen A L, Nordling J. The value of a new symptom score (DAN-PSS-1) in diagnosing file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_208.html[09.07.2009 11:52:59]

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urodynamic infravesical obstruction in BPH. Scand J Urol Nephrol 1993; 27:489–492 22. Poulsen A L, Schou J, Puggard L, Torp-Petersen S. Prostatic enlargement, symptomatology, and pressure-flow evaluation: interrelations in patients with symptomatic BPH. Scand J Urol Nephrol 1994; 157:67–73 23. Pannek J, Berges R R, Haupt G, Senge T. Value of the Danish Prostate Symptom Score compared to the AUA Symptom Score and pressure/flow studies in the

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Page 209 preoperative evaluation of men with symptomatic benign prostatic hyperplasia. Neurourol Urodyn 1998; 17:9–18 24. Nitti V W, Kim Y, Coombs A J. Correlation of the AUA Symptom. Index with urodynamics in patients with suspected benign prostatic hyperplasia. Neurourol Urodyn 1994; 13:521–529 25. Donovan J L, Abrams P, Peters T J et al. The ICS-‘BPH’ study: the psychometric validity and reliability of the ICS male questionnaire. Br J Urol 1996; 77:554–562 26. Donovan J L, Peters T L, Abrams P et al. Scoring the short form ICS male SF questionnaire. J Urol 2000; 164: 1948–1955. 27. Frimodt-Moller P C, Jensen K M E, Iversen P et al. Analysis of presenting symptoms in prostatism. J Urol 1984; 132:272–276 28. Chapple C R. Correlation of symptomatology, urodynamics, morphology, and size of the prostate in benign prostatic hyperplasia. Curr Opin Urol 1993; 3:5 29. Barry M J, Cockett A T K, Holtgrewe H et al. Relationship of symptoms of prostatism to commonly used physio logical and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 1993; 150:351–358 30. Ockrim J L, Laniado M E, Patel A et al. A probability based system for combining simple office parameters as a predictor of bladder outflow obstruction. J Urol 2001; 166:2221–2225 31. Wadie B S, Ebrahim el-H E, Gomha M A. The relationship of detrusor instability and symptoms with objective parameters used for diagnosing bladder outlet obstruction: a prospective study. J Urol 2002; 168:132–134 32. Eckhardt M D, van Venrooij G E, Boon T A. Interactions between prostate volume, filling cystometric estimated parameters, and data from pressure-flow studies in 565 men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Neurourol Urodyn 2001; 20: 579–590 33. Barry M J, Girman C J, O’Leary M P et al. Using repeated measures of symptom score, uroflow, and prostate specific antigen in the clinical management of prostate disease. J Urol 1995; 153:99–103

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Page 211 15 Screening for prostate cancer in patients with benign prostatic hyperplasia D E Druchenberg M K Bruwer Introduction Prostate cancer has received considerable attention recently in both the medical literature and lay press, partly because it is the number one cancer in American adult males, the number two cause of cancer death, and also because of recent advances in screening for localized and, therefore, treatable disease. In 1999, an estimated 179300 cases of prostate cancer (CaP) were predicted to be diagnosed, resulting in an estimated 37000 deaths.1 By the end of the 20th century, a 37% increase in the rate of CaP deaths was predicted, with approximately 3% of these men dying from disseminated disease.2,3 Significant advancement in our knowledge of CaP in recent years with respect to genetics, molecular pathophysiology of disease, and epidemiology has occurred. Diagnostic technologic advancements such as transrectal ultrasound (TRUS), prostate needle biopsy (PNB), and prostate-specific antigen (PSA) have importantly contributed to the recognized ‘stage shift’ of CaP to that of early localized disease. Large-scale screening programs such as the American Cancer Society-National Prostate Cancer Detection Program (ACS-NPCDP), the Surveillance, Epidemiology, and End Results Program (SEER), and the European Randomized Study of Screening for Prostate Cancer (ERSPC) have demonstrated this definitively.4–6 However, despite the apparent success of these screening efforts, a clear decrease in cancerrelated mortality has yet to be definitively demonstrated. This has led to controversy in adapting screening programs for the detection of early localized disease and its subsequent treatment. Recommendations have been put forth by the American Cancer Society7 and both the American and Canadian Urological Associations for the use of annual PSA and digital rectal examination (DRE) in screening of CaP in men over the age of 50 years, and in men over 40 if they are of African-American descent or have a family history. However, equally auspicious agencies such as the US Preventative Health Task Force and the Canadian Task Force have concluded that, without proof that early detection reduces mortality, screening is unwarranted at this time. Arguments against screening include assertions that it will increase national medical expenditures and may lead to overdiagnosis and overtreatment, increased treatment morbidity, and unnecessary anxiety for patients and families. Despite the controversies, we now appreciate that screening for CaP has permitted the diagnosis of patients at an earlier stage, and because of the prolonged natural history of the disease, at an earlier age. A screened cancer is likely to be diagnosed in an individual with at least a 15-year life expectancy.8 We also can appreciate that the same patient population that is at risk for CaP is also the population in which we diagnose benign prostatic hyperplasia (BPH). In fact, in patients undergoing simple prostatectomy for BPH and bothersome obstructive symptoms, incidental carcinoma of the prostate is found in 10–20% of men.9 CaP has also been found in 10–20% of men with symptomatic BPH undergoing transurethral resection of the prostate (TURP) (T1a-b cancers).10 McNeal et al. examined a series of radical prostatectomy specimens and discovered that 95% of the cancers found by TURP occurred in the transition zone and that an overall 24% of all cancers arose in the transition zone.11 Although the biologic significance of transition zone cancers has been widely debated, Stamey et al. clearly demonstrated that a large proportion of these cancers are clinically significant by volumetric analysis and Gleason scores. Importantly, these transition zone cancers were frequently associated with a larger and higher-grade peripheral zone cancer.12 Given the well-recognized increasing use of nonsurgical or lesser surgical approaches to the treatment of BPH, such as α-adrenergic blockade, antiandrogens, laser prostatectomy, balloon dilation, endoprostatic stenting, high-intensity ultrasound, and hyperthermia, that do not permit us the advantage of surgical specimen for pathologic diagnosis, there is genuine need for noninvasive methods to discriminate those patients with potentially clinically significant carcinoma from those with BPH alone. Screening essentials In 1968 the World Health Organization Symposium defined screening as ‘presumptive identification of unrecognized disease by the application of tests, examinations, or other procedures which can be applied rapidly. Screening tests

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Page 212 sort out apparently well persons who probably do not have the disease from those who probably do. A screening test is not intended to be diagnostic.’ The accepted criteria for advocacy of screening state that: • The disease should have a high incidence in the screening population. • The biological behavior and natural history of the disease should be known. • The screening test should have a high sensitivity, specificity, and positive predictive value. • Screening should be rapid, inexpensive, noninvasive, and acceptable to patients. • Importantly, there must exist an acceptable and efficacious method of treatment for early diagnosed disease. For screening to make sense, the disease in question must have a high prevalence because of matters of cost efficiency and limitations in available test performance characteristics. Certainly, prostate carcinoma fulfills the requirement of high prevalence. The second requirement for a screening regimen is that the natural history of the disease be known. In general, CaP is associated with a prolonged natural history, again perhaps too prolonged. Preclinical forms of CaP are present in a substantial number of the male population. Autopsy studies have demonstrated that subclinical but invasive cancer is present in 27% of 30- to 40-year-old males and in over 60% of men over 80 years.13,14 As mentioned earlier, historically many of these cancers have been discovered incidentally at the time of treatment for BPH. Although it is believed that many of these tumors are indolent in nature and may not impart risk of mortality to the host, it is also known that a substantial number of younger patients diagnosed with CaP will eventually die of the disease if not treated with radical intent.15 The discrepancy between the autopsy prevalence of CaP and clinically manifest disease is the biggest problem facing any analysis of the merits of screening. Haas et al.16 demonstrated that very early carcinomas and their precursor lesion, prostatic intraepithelial neoplasia (PIN),17 are present in men aged 20–30. The term PIN was first introduced by Bostwick and Brawer,18 and has an incidence of between 7.6 and 31% in different studies reported depending on the population screened with PNB.19–23 PIN has been demonstrated to have the same glandular distribution as CaP, occurring in an apical location and the peripheral zone most commonly, however the central and transitional zones also have an incidence of PIN of 21% and 18–31%, respectively.24–26 The significant yield of carcinoma on repeat biopsy in men who have PIN is well established27,28 and repeat biopsy is mandated for patients with high-grade PIN who are young and healthy enough to be candidates for radical therapies should CaP be discovered on follow-up PNB. Digital rectal examination Until the PSA era, the most common presentation of potentially curable CaP was the presence of an abnormality on DRE.29,30 However, the limitations of this test in predicting localized disease are demonstrated by the fact that most men historically have presented with locally advanced or metastatic disease. Jewett,31 in his classic study, demonstrated that approximately one-half of the lesions believed on clinical examination to be suspicious for carcinoma actually revealed malignancy on biopsy, testimony to the lack of its specificity. A compilation of 15 series reviewed by Sika and Lindquist,32 plus 10 more recent needle biopsy series, revealed 1900 cases of prostatic carcinoma in 4939 patients (39%) with abnormal DREs.33 A great variability in the yield of cancer detected in men with an abnormality on DRE has been reported. Detection rates range from 0.1 to 25.2% and positive predictive values range from 17 to 31%.34–43 In our ultrasound-guided biopsy series44 we have noted carcinoma in 40 of 229 (17.5%) men with normalfeeling prostates undergoing biopsy because of elevated PSA levels, or being evaluated for alternative therapies to LUTS owing to presumed BPH. Twenty-four of 185 men (13.0%) with asymmetry as their only abnormality and 112 of 456 (24.6%) with prostatic induration revealed carcinoma. In contrast, 79 of 150 men (52.7%) with frank nodules or areas of marked induration strongly suggestive of carcinoma actually demonstrated malignancy. The continued recommendation for the use of DRE is based upon the presence of cancers characterized clinically by an abnormality on DRE and a normal PSA and the fact that it has demonstrated increased positive predictive value when combined with PSA screeening. Transrectal ultrasound TRUS is the most commonly utilized approach for imaging the prostate. TRUS is readily accepted by patients, is a simple and innocuous procedure affording excellent visualization of the gland, and may identify suspicious lesions in the prostate which are nonpalpable. Lee et al.45 were the first to report that the most common presentation for carcinoma was a hypoechoic peripheral zone lesion. Initial reports utilizing TRUS demonstrated file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_212.html[09.07.2009 11:53:01]

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Page 213 detection rates between 2.3 and 14.6%, with positive predictive values of 17 to 36%.34,41,42,45–51 Carter et al.52 have cast doubt on the sensitivity of TRUS for the detection of prostatic carcinoma. They demonstrated that nonpalpable carcinoma contralateral to the index cancer was noted in 25 of 59 patients (42%) upon examination of a series of prostatectomy specimens. Preoperative TRUS detected only 13 of these carcinomas (52%). In a review of systematic sector TRUS-guided biopsies in 1001 patients, we noted that 23 of the 253 patients in whom CaP was detected had carcinoma only in isoechoic regions.53 The lack of specificity of TRUS is also of concern. Whereas the most common sonographic appearance of carcinoma is a hypoechoic peripheral zone lesion, we have noted carcinoma in only 16% of such lesions.53 Entities such as acute and chronic inflammation, prostatic intraepithelial neoplasia, and prostatic infarct can give rise to hypoechoic peripheral zone areas.45,54 Transrectal-ultrasound-guided PNB is the best way of providing samples of the prostate for histologic analysis. However, the prohibitive cost and the relatively low sensitivity and specificity render TRUS ineffective for the diagnosis of CaP in the absence of other abnormalities. The widespread practice of performing TRUS only in men with either a palpable prostatic abnormality or an elevation in serum PSA, or both, is derived from these observations. Prostate-specific antigen PSA has revolutionized the screening for CaP and is the single best tumor marker for malignancy available today. First characterized by Wang et al. in 1979,55 this endogenous serine protease is a 33kilodalton protein that is produced primarily by the prostatic epithelium and periurethral gland epithelium.56 It functions to liquefy the seminal coagulum and is found in very high concentrations in seminal fluid (1×106 ng/ml) and low concentrations in serum of men without CaP (<4.0 ng/ml). The mechanism by which PSA gains access to the systemic circulation remains unknown. The serum PSA determination plays an important role in the evaluation of patients with lower urinary tract symptoms (LUTS) because these men also comprise the screening population for CaP and early cancer detection by PSA screening can be complicated by elevations secondary to BPH. In fact, early interest in PSA for diagnosis of carcinoma was thwarted by reports demonstrating that PSA was elevated in many men with BPH.57–60 Because of the certainty that men being evaluated for CaP would have at least histologic BPH, it was reasoned that the specificity of an elevated PSA would simply be too low. Stamey et al.,58 in an investigation of men undergoing simple prostatectomy, calculated that each gram of BPH tissue contributed approximately 0.30 ng/ml PSA to the serum. Weber et al.61 demonstrated that PSA was most strongly correlated with the epithelial component of BPH. Lepor et al. have confirmed these findings.62 To further elucidate the relationship of serum PSA to BPH, our group studied simple prostatectomy specimens from 81 men with bladder outlet obstruction thought to be secondary to BPH.63 In this study, preoperative serum PSA correlated with the histology of the specimen. We noted that 36 of the 81 men (44%) had a PSA >4.0 ng/ml. However, 35 had significant pathology which could allow leakage of PSA into the systemic circulation.62–66 PSA is normally secreted into the lumenal space of the acini and ductules, and the concentration of PSA in prostatic secretions is several logs greater than in the serum. To elevate serum levels, PSA must gain access to the systemic circulation, either directly or through the lymphatic system. The PSA must therefore penetrate the extracellular space. In the normal prostate the barriers to PSA leakage, including epithelial tight junctions, the basal cell layer, and the basement membrane, are intact. In our BPH series, examination of all excised BPH tissue disclosed adenocarcinoma in eleven (14%). Thirteen men (16%) had prostatic intraepithelial neoplasia and 11 (14%) had foci of acute inflammation.63 Only one of 26 men (4%) with BPH alone or associated with chronic inflammation had a PSA in the abnormal range (>4.0 ng/ml). Specific pathologic conditions, in addition to BPH, were felt to be the cause of elevation of PSA in the majority of patients. We have noted along with Lee et al. similar correlation of pathology with serum PSA levels in a TRUS-guided biopsy series.20,67 These observations suggested that BPH alone was infrequently a cause for elevation of serum PSA and thus offered some basis for investigating the role of this analyte in the diagnosis of prostate carcinoma. Catalona et al. have compared the yield of PSA and DRE in a multicenter early detection series of 6630 subjects.41 Abnormalities in either or both tests led to TRUS-guided biopsy in 1167 subjects. Of the 264 (22.6%) carcinomas detected, PSA was abnormal in significantly more men with CaP than DRE (216 vs 146). The positive predictive values were 34–4% for PSA >4.0 ng/ml and 21.4% for an abnormal DRE. The observed detection rates were 3.2%, 4.6%, and 5.8% for DRE, PSA, and the combination respectively, reiterating file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_213.html[09.07.2009 11:53:01]

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Page 214 the fact that these two tests are often complimentary. This monumental study clearly demonstrates the impressive ability of PSA to offer a risk assessment for the likelihood a man has CaP. As mentioned, PSA testing and DRE are recommended annually. Carter et al. recently evaluated the necessary PSA testing interval in men with a low PSA and normal DRE in an effort to reduce PSA testing while preserving the ability to detect cancer.68 Using the Baltimore Longitudinal Aging Cohort in a historical prospective study, the authors found that potentially curable prostate cancer (organ-confined or capsular penetration with Gleason score <7 and negative surgical margins) was identified in 95% of men with PSA levels ≤4 ng/ml, and the majority (69%) of tumors were small (Gleason grade ≤3 and tumor volume ≤0.5 cm3). With a pretreatment PSA between 4.0 and 5.0 ng/ml, 89% of detected cancers were potentially curable, with only 33% of these being small tumors. It was concluded that measuring PSA values every other year in men with a serum PSA <2.0 ng/ml and a normal DRE would be unlikely to miss a potentially curable cancer. Men with PSA levels >2.0 ng/ml should still be offered annual PSA testing as previously recommended. Smith et al. reported similar results with a low (4%) PSA conversion from a baseline PSA level of <2.5 ng/ml to PSA levels >4.0 ng/ml when followed semiannually over a 4-year period.69 In contrast, nearly 50% of men had PSA conversion to 4.0ng/ml with a baseline between the values of 2.6 and 4.0 ng/ml. Thus, with a normal DRE, it is reasonable to perform annual PSA levels on men with a PSA level >2.5 ng/ml and semiannually for those men with a serum PSA <2.5 ng/ml. Despite the impressive results attributed to the use of PSA, it is not an ideal tumor marker. Efforts are currently underway to enhance its performance and emphasis has been primarily directed at enhancing specificity by reduction of false-positive test results. In the presence of malignancy, if the PSA is below the threshold indicating the need for further evaluation, it is highly likely that repeat testing will occur and the cancer will be detected at a time when it is still curable. Therefore, a false negative may be of less importance when the patient population is following a routine screening protocol since routine use of screening will pick up the cancer before it becomes clinically manifest. In contrast, false-positive test results are expensive, the cost not only being economic (ultrasoundguided biopsy, pathology charges, etc.), but also psychologic and emotional since anxiety on the part of the patient and his family when he is told he has an abnormal PSA level can be of considerable detriment to well-being. Thus, the major efforts in PSA enhancement have been directed at the reduction of false positives (i.e. enhancing specificity). In general, whenever efforts are made to enhance the specificity of a diagnostic test, the sensitivity (the identification of patients with the disease in the population) is reduced. This inverse relationship of sensitivity and specificity derives from our large ultrasound-guided PNB experience in which the sensitivity and specificity for differing PSA levels were determined.70 Increasing the PSA threshold enhanced specificity, but only with a reduction in sensitivity. Therefore, the question now becomes, how many cancers are we willing to miss to avoid biopsy in men without malignancy? While there is no clear answer that is appropriate for all patients, and there is still considerable debate among CaP experts, most would recommend the 95% sensitivity goal. Table 15.1 lists a number of the modalities that have been utilized to enhance PSA performance as a screening tool to discriminate between CaP and BPH with PSA in the intermediate range between 4 and 10 ng/ml. PSA velocity The change of PSA concentration over time, or PSA velocity (PSAV), conceptually makes sense. It allows longitudinal measurements of PSA levels and therefore provides a more dynamic interpretation of PSA than does a single measurement. PSAV derives from the fact that, in the men who progress from benign disease to advanced prostate cancer, an elevation in the PSA level occurs, and almost always this exceeds the generally slow increase in PSA observed over time in men without evidence of CaP harboring only benign pathology.71 Carter et al. were the first to introduce this concept,72 and determined that PSAV changes were greater in men with CaP than in men without CaP 5 years prior to the Table 15.1 Methods of enhancing prostate-specific antigen (PSA) specificity. PSA velocity PSA density PSA transition zone density Age-specific PSA Free/total PSA ratio ACT complex PSA ACT, α1-anti-chymotrypsin file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_214.html[09.07.2009 11:53:02]

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Page 215 diagnosis of CaP and that significant velocity differences were noted up to 9 years prior to the diagnosis of CaP.73 It was recommended that to use PSAV, at least three measurements should be obtained over a 2-year period or spaced at least 12 to 18 months apart.73,74 Carter et al. found that a velocity of ≥0.75 ng/ml per year using the Hybritech Tandem-R assay was highly suggestive of cancer (72% sensitivity, 95% specificity).73 Both Smith and Catalona75 and Oesterling et al.76 independently verified a cut-off of ≥0.80 ng/ml per year and ≥0.75 ng/ml per year, respectively, to differentiate men with CaP from those with BPH. Based on the finding that almost 15% of their 265 study patients without CaP had a PSAV greater than 0.75 ng/ml per year over a 2-year period, Kadmon et al. suggested having at least a 2-year period of observation before using PSAV in the clinical decision-making process.77 Many clinicians have attempted to capitalize on these findings and have erroneously applied PSAV in patients followed at intervals as short as 1 year or even less. It is important to note that in the original study from Carter et al., a minimum of 7 years was available between PSA determinations. In our screening population, we were unable to reproduce the results of Carter with 1- and 2-year intervals between PSA determinations.78 In a further effort to elucidate the reason for this, we carried out an investigation on the biologic variation of PSA on a daily basis for 10 consecutive days.79,80 It was demonstrated that before a change in PSA could be ascribed to a real prostatic disease process, a 25% increase must be observed. This calculation includes biologic variation, as well as laboratory issues. For free PSA, an even greater, 36% change must be noted. PSA density PSA density is a derivative that involves the quotient of the total serum PSA by the transrectal ultrasound-determined volume of the prostate (in cc). This is an attempt at enhancing PSA specificity by correcting the PSA level for prostate volume (i.e. for that component of the serum PSA that may be elevated from BPH). Babaian et al. called attention to the relationship of prostate size and serum PSA level.81 Subsequently, Benson et al. introduced the notion of PSA density.82 Although conceptually and intuitively this also makes sense, our group was unable to recapitulate these findings. In our experience,83 PSA was shown to be as good a predictor of carcinoma as PSA density. A possible explanation for this discrepancy is as follows.84 If a man with an 80ml prostate has a serum PSA of 8 ng/ml his PSA density would be 0.1. A man with the same serum PSA level but a gland half as large would give a PSA density of 0.2. One might mistakenly assume that carcinoma was more prevalent in the later. If, indeed, both men have a 1 cm isoechoic nonpalpable (T1c) carcinoma, and we perform a standardized number of prostate biopsies in both glands, it is more likely that sampling constraints will allow us to miss the carcinoma in the larger gland and identify it in the smaller. A review of the major articles on PSA density clearly illustrates this point.82,83,85–90 The studies, which demonstrated the enhanced efficacy of PSA density compared with PSA alone, had the concomitant finding of the larger prostates showing benign histology. In contrast, the studies by our group and by Mettlin’s group showed no difference between glands with malignancy and those without. In the case of Mettlin, the cancer glands were actually slightly larger.86 More recent data from our group have demonstrated that the yield of PNB is reduced in larger glands.91 Since the majority of the prostatic enlargement of BPH occurs within the transition zone, adjusting for transition zone volume has been thought to be another way to enhance the specificity of PSA density. The transition zone density is defined as the serum PSA divided by the volume of the transition zone determined by transrectal ultrasound. Initial reports were promising.92–94 However, our group has been unable to reproduce these data in our series.91 No difference was noted in the ability of PSA, PSA density, or transition zone density to stratify men for the presence of cancer. The explanation of sampling bias may also be applicable in this situation. Age-adjusted PSA Age-adjusted PSA (APSA) derives from the concept that the use of a single cut-off for all ages is inappropriate, since it is recognized that PSA increases with age due to the development of BPH and that age-related changes in serum PSA are not taken into account with the standard PSA reference range of 0.0 to 4.0 ng/ml. Both Oesterling et al.95 and Dalkin and et al.96 suggested different cut-offs at different age groups. According to Oesterling, a man less than 50 should have a PSA below 2.5 ng/ml, whereas for a man in his 70 s, a PSA between 0 and 6.5 ng/ml may be considered normal. While this is a true observation based on men apparently free of prostatic disease, its utility in early detection and screening is unclear. Certainly it is recognized that the biopsy yield (positive predictive value) increases with increasing PSA level.71 What also is of course true, is that the detection of

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Page 216 carcinoma increases as men age. Thus, age-adjustment of PSA recapitulates the obvious, that PSA and CaP increase with age. By using the age-specific ranges in men, Partin et al.97 and Reissigl et al.98 have demonstrated an increase in detection of prostate cancer in men ≤59 years (18 and 8%, respectively) and a decrease in detection in men >60 years (22 and 4%, respectively). However, although the use of age-specific ranges affords greater sensitivity for cancer detection in younger men, the natural history of the missed tumors in the older age group is not known. Considerable disagreement over the benefit of agespecific PSA reference ranges exists. Catalona et al. determined that the standard cut-off of 4.0 ng/ml was optimal for all age groups in an early detection study encompassing over 6600 patients.41 In the ongoing study of the National Prostate Cancer Project, commissioned by the American Cancer Society to follow 3000 men for over 10 years, Littrup et al. reported that age-specific PSA ranges confer no additional benefit to the detection of CaP over the adopted cut-off value of 4.0 ng/ml.99,100 This adjustment in the PSA level only makes sense if the goal is to have the same yields for cancer in each age group. If the goal is to find the most cancer, we should preferentially test the older patients because they have a higher prevalence. It may be argued that finding cancer in younger men carries more weight since these men have the most to lose from a disease with such a prolonged natural history. Therefore, on the basis of our PSA screening cohort, we modeled the age-adjustment PSA cutoff versus 4.0 ng/ml.101 The number of men exceeding a threshold in a screening population derived from men older than 50, as well as the positive predictive value, is slightly enhanced with APSA. However, the detection rate (i.e. the number of cancer patients identified from the screening population) is significantly reduced with PSA cut-offs. Moreover, utilizing the US Life Table actuarial figures, it can be observed that there is a significant increase in the population longevity if 4.0 ng/ml is used for all men as opposed to age adjustment. By utilizing a more sophisticated statistical methodology we have found similar results.102 Molecular forms of PSA The most significant advance in the enhancement of PSA performance appears to be the recent recognition that PSA circulates in several molecular forms. In the ejaculate PSA exists in the free form (i.e. noncomplexed to other protein moieties). In the systemic circulation, PSA is complexed to a number of protease inhibitors. Alpha-1-aorta, and α2-macroglobulin are the most prevalent complexes present. When PSA is complexed with α1-antichymotrypsin (PSA-ACT), two epitopes remain unmasked and this complex can be detected with immunoassays. In contrast, when PSA is complexed with α2macroglobulin (PSA-A2M), all epitopes are sterically hindered, thus making this moiety undetectable by currently available assays. Free-PSA (fPSA) and PSA-ACT are thought to be enzymatically inactive, whereas some evidence suggests that PSA-A2M does not inactivate PSA’s protease activity.103,104 Scandinavian groups led by Ulf Stenman105 and Hans Lilja106 initially elucidated the nature of the circulating molecular forms of PSA. Stenman et al.105 demonstrated that the free form of PSA exists in a higher proportion in those men without CaP than in those with, although the majority of circulating PSA is complexed to the α1-antichymotrypsin. We and others have confirmed these findings. Christennson et al.107,108 found that they could significantly enhance the specificity by measuring the ratio of the free to total PSA as compared to total PSA alone. Numerous other investigators have echoed these findings.109–111 Several studies have suggested that perhaps the most useful application of percentage free PSA (%fPSA) is to detect CaP in men with intermediate PSA values between 4.0 and 10.0 ng/ml.109–112 Several retrospective studies report that sensitivity for CaP detection can be maintained at 90–95% while improving specificity ranging from 19 to 64% using %fPSA cut-offs ranging from 14 to 28%.109–121 The definitive investigation of the performance of the free to total PSA was recently reported by Catalona et al.122 In a multicenter prospective investigation using the Hybritech assay and a cut-off of < 25% fPSA, free and total PSA levels were evaluated in seven institutions in men undergoing systematic sector ultrasound-guided PNB, who had a total PSA between 4.0 and 10.0 ng/ml and negative DRE; 773 men were evaluated, including 379 (49%) who were ultimately demonstrated to have carcinoma. As expected, the total PSA was significantly higher in those men with carcinoma and the free to total PSA ratio was higher in those men with negative biopsies. Utilizing sensitivity analysis with cut-offs to provide 90% and 95% sensitivity, the specificity observed in these studies was 29% and 20%, respectively. In a man with a total PSA level between 4.0 and 10.0 ng/ml, the yield for cancer may vary drastically depending on the percentage of fPSA.122 Other studies have evaluated ‘optimal reflex ranges’ or the optimal range of total PSA for measuring file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_216.html[09.07.2009 11:53:03]

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Page 217 improve specificity for CaP detection.110,112,118,122 Several studies have demonstrated that 13–20% of men with serum PSA levels of 2.6–4.0 ng/ml will subsequently develop clinically detectable CaP within a 3–5 year period.124,125 Aus et al. reported on a Swedish screening study which performed DRE, TRUS, and sextant biopsy in men with a PSA >3.0 ng/ml.126 It was observed that among 243 men with a PSA between 3.0 and 4.0 ng/ml, 32 (13.2%) were shown to have carcinoma representing 23% of all cancers detected. Detecting these early nonpalpable cancers would likely lead to greater surgical cure rates as approximately 30–50% of men with serum PSA levels between 4 and 10 ng/ml have extraprostatic disease at time of surgery.41,127 Catalona et al. screened 914 consecutive men aged ≥50 years with a normal DRE and serum PSA levels between 2.6 and 4.0 ng/ml118 to assess the utility of %fPSA to detect cancer and decrease the number of prostate biopsies. In this population, cancer was identified in 22% of 332 men undergoing biopsy. A %fPSA cut-off of ≤27% was used to determine the need for biopsy, and the authors concluded that 18% of unnecessary biopsies could be avoided and 90% of cancers could be detected for a positive predictive value of 24% in men undergoing biopsy. Organ-confined tumors were demonstrated in 81% of 52 men undergoing surgery, with 83% of these cancers being clinically significant. Vashi et al. evaluated whether using %fPSA in men with total PSA levels between 3 and 4 ng/ml and between 4.1 and 10 ng/ml would improve the sensitivity for cancer detection.112 Using a %fPSA cut-off of 19% in men with a total PSA level between 3 and 4 ng/ml resulted in the detection of 90% of all cancers, with each cancer being detected per 1.7 biopsies performed. Although an improvement in CaP detection may be seen through reflex ranges defining the optimal use of fPSA in relation to total PSA values and normal DRE, more pragmatic would be a single cut-off value (e.g. 25% fPSA) for the entire total PSA range between 4.0 and 10.0 ng/ml to be clinically useful.121,122 More recent data from Carlson et al. looking at the appropriate lower limit for the reflex range in 479 men with no prior history of cancer and who underwent sextant needle biopsies at a single institution failed to demonstrate statistical significance below 4.0 ng/ml.128 Clinicians should be aware of the ex vivo stability of fPSA to correctly interpret corresponding laboratory data. Woodrum et al.129 and Paus et al.130 have demonstrated that storage at 4ºC causes a decrease in fPSA over time. Therefore, because fPSA is less stable in serum than total PSA, the recommendation is to process the specimen within 3 hours of collection and freeze at −70ºC if not assayed within 24 hours. Numerous issues remain with respect to elucidation of the true role of the measurement of the free to total PSA assay. These include defining the appropriate population in which to measure this analyte (i.e. all men, patients with a PSA in a ‘diagnostic gray zone’ for example, total PSA 4.0–10.0 ng/ml, patients with a negative biopsy, etc.). We have demonstrated that the total PSA has considerable variability when measuring a single serum sample with assays from different manufacturers.131–133 Manufacturer assay differences are compounded when two analytes are measured to obtain the ratio of the free to total PSA.134 We recently compared three different manufacturers free assays and their respective total PSA assays.135 This investigation also demonstrated the existence of considerable intra-assay and interassay variability. These data demonstrate the existence of potential problems when clinicians interpret the free to total PSA ratio and thus it behoves laboratories to provide information about which free and total assay they are utilizing, and provide meaningful risk assessment for malignancy at a given ratio. Although many published reports assessing the utility of fPSA in the detection of CAP exist, differences in study design, data analysis, and cut-off levels have made comparisons between studies virtually impossible. This, added to the newly appreciated findings of manufacturer differences in assays and stringent processing conditions, emphasize that physicians cannot apply published reports of cancer risk assessment for a given %fPSA cut-off to their own patients if different assays are employed. At present, the recommended use of %fPSA is to determine whether a patient with a normal DRE and a total serum PSA level between 4.0 and 10.0 ng/ml would benefit from an initial biopsy or a repeat biopsy having had at least one previous negative attempt. Further recommendations must be made on a case-by-case basis considering the patient’s age, race, prostate volume, and family history of CaP Stenman et al.105 observed that PSA complexed to α1-anti-chymotrypsin (PSA-ACT) occurs in a greater pro-portion of those with malignancy than with benign disease, and prompted a number of investigators to develop immunoassays that would recognize this form of PSA. Because of difficulty achieving this goal, the ratio of the free to total PSA was used as a surrogate since immunoassays were more readily generated against the free form of PSA. Nonspecific, high-affinity binding to cathepsin G and nonspecific attachment to plastic surfaces initially

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Page 218 hindered accurate PSA-ACT measurements, however, an assay that corrects for these initial difficulties, and which is specific for complexed, PSA, has been developed.136 We have carried out a preliminary investigation with this assay and compared it to the Hybritech total and Hybritech free to total assays.137 In this study total, complexed and free PSA levels were measured in 300 men, 75 with biopsy-proven carcinoma and 225 who had undergone systematic sector biopsy with benign histology. Generally there is a trend toward enhanced specificity with a complexed PSA relative to the total PSA at similar sensitivities. An upper limit of 3.75 ng/ml was demonstrated to have the same degree of sensitivity as a total PSA of 4.00 ng/ml with improved sensitivity. Moreover, this specificity enhancement seems to be greater than that afforded by the free to total PSA ratio. These findings have been confirmed by Sokoll et al.138 In an expanded multicenter investigation, we studied 385 men without CaP and 272 who had CaP detected on TRUS-guided biopsy.139 The specificities at 95% sensitivity for total PSA, complexed PSA, and the free/total ratio were 18%, 24%, and 23%, respectively. When considering only the abbreviated range of total PSA between 4 and 10 ng/ml, 439 men were evaluated including 202 with CaP At the 95% sensitivity cut-off, the specificities for total PSA, complexed PSA, and the free/total PSA ratio were 7%, 18%, and 17%, respectively. The implications of these findings are far reaching. It would appear that a single measurement of complexed PSA will perform with essentially the same sensitivity as total PSA, but will provide enhanced specificity. This obviously has economic advantages as well as offering methodologic simplicity relative to measuring both the free and total PSA analytes. Human kallikrein 2 Human kallikrein 2 (hK2) is another serine protease that has approximately 80% sequence homology with PSA. Human kallikrein 2 acts to cleave so-called pro-PSA into its active form,140 and monoclonal antibodies to hK2 immunohistochemically stain virtually all prostatic carcinoma.141 Unlike PSA, but similar to prostate-specific membrane antigen, the intensity of staining increases according to the progression between benign prostatic epithelium, high-grade prostatic intraepithelium neoplasia, and carcinoma. Kwiatkowski et al. recently used the ratio of hK2 to fPSA and demonstrated better specificity without loss of sensitivity for CaP compared to total PSA or %fPSA within the range of 4.0–10.0 ng/ml total PSA.142 More studies are needed to determine whether this novel marker will become important in CaP screening and diagnosis. Neural networks With the recent advances in computer technology it was inevitable that an application would be directed towards improving CaP detection in screening populations. Rather than relying on a single parameter like a single PSA value or the DRE result, the ProstAsure™ index involves weighting several variables and determines whether the result is ‘normal’ or ‘abnormal’. The variables included are the patient age, total PSA level, serum creatinine phosphokinase concentration, and the serum prostatic acid phosphatase and they are analyzed in an interdependent fashion using a sophisticated biostatistical-mathematical method of artificial neural network algorithms. The mathematical equation for this index is more than 12 pages in length. Stamey et al. first studied the index and its applicability to 457 patients with total PSA levels ≤4.0 ng/ml.143 They found that the use of the index could avoid 58% of biopsies compared to the 38% avoided by the use of %fPSA. Further studies144,145 have also demonstrated the superiority of the ProstAsure index in increasing specificity over %fPSA for men with total PSA values ≤4.0 ng/ml. Although these preliminary reports demonstrate that the ProstAsure index is a new and exciting approach to increasing the detection of early localized CaP in men with a high prevalence of BPH, the results must be interpreted with caution since PSA is the most useful variable used by the neural network and the other variables have limited utility in the diagnosis of CaP and its applicability is limited to patients with total PSA values ≤4.0 ng/ml. Further research including large prospective studies will be necessary to determine the widespread clinical utility of this neural network. Effects of finasteride on PSA Finasteride, a well known 5α-reductase inhibitor used to treat BPH and shown to reduce the risk of urinary retention and the need for surgical management of BPH, has been demonstrated to affect serum PSA levels.146 Studies have shown that on average, serum PSA levels are reduced by approximately 50% among men who have received finasteride for more than 6 months.147 The PLESS trial results from over 3000 men studied demonstrate that the usefulness of PSA in screening for CaP can be preserved by multiplying the obtained fPSA value by a factor of 2.148 Two further studies have shown that while total PSA levels are reduced by approximately 50% in

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Page 219 patients taking long-term finasteride, the PSA levels remain unaffected by concurrent finasteride usage.149,150 These studies suggest that the %fPSA measurements remain valid among men taking finasteride, but this needs confirmation by larger trials. Optimal biopsy strategies Hodge et al. were the first to propose the use of random sextant biopsies in the diagnosis of CaP.151 This has since become the gold standard for biopsy-driven diagnosis. The shortcomings of this biopsy strategy lie in the fact that at least 20% of cancers detected by PSA screening require more than one set of biopsies. Keetch et al. have demonstrated that sextant biopsies following radical prostatectomy for organ confined CaP were negative 45% of the time.152 By the use of mathematical modeling153 and computer simulation154 it has been shown that some men may require more than six core biopsies so as not to miss a significant cancer. Escew et al.155 and Levine et al.156 have demonstrated that, by adding an additional four laterally and three medially placed or 12 laterally directed cores, CaP detection was improved by 35% and 30%, respectively. In general, the larger the gland size the greater the improvement seen in cancer detection through the addition of increasing number of cores. As noted earlier, approximately 20% of clinically relevant CaP arise in the transition zone and a majority of them are associated with additional peripheral zone cancers. Standard sextant biopsy protocols do not sample the transition zone and several studies have demonstrated that routine transition zone biopsies are not beneficial.157–159 However, Fleschner et al.159 have demonstrated that the addition of transition-zone biopsies in the setting of persistently elevated PSA and negative peripheral zone biopsies improved cancer detection by 16% in 156 men with a mean PSA value of 11.4 ng/ml. This has been confirmed by Lui et al.160 Therefore, transition-zone biopsies are only of value for increasing detection of CaP in men who have undergone previous negative sextant biopsy protocols and have a persistently elevated PSA. Conclusions The widespread adoption of screening programs for CaP that began in the late 1980 s coincident with the utilization of serum PSA has resulted in a dramatic stage migration to diagnosis of early organconfined disease and for the first time an apparent improvement in cause-specific survival. Screening efforts have demonstrated a dramatic increase in CaP diagnosis since the start of the PSA era. These trends are characteristic of a successful and effective screening program. Furthermore, if a screening program detects insignificant disease then the increased incidence rates seen after the introduction of screening efforts will continue to be higher than before the start of the screening process, but if the test detects clinically relevant cases primarily, incidence rates eventually will return to levels similar to the prescreening era (the ‘Cull effect’).161 Since 1992, the detection of CaP has been steadily declining and is now approaching incidence rates preceding the initially seen precipitous rise in incidence.162–165 Screening efforts have further been criticized because of the potential for recognition of clinically indolent disease. In fact, overdetection is the greatest potential scientific problem in screening for CaP However, this does not appear to be the case since the detection of low-grade disease increased only modestly with the introduction of screening and has been steadily declining since then, whereas the proportion of cancers that are moderately differentiated at diagnosis has steadily increased.166 Pathologic examination of surgical specimens from men with treated PSA-detected cancers demonstrates that less than 10% of these cancers are thought to be clinically insignificant (low volume ≤0.5 ml, Gleason score ≤4) whereas more than 90% of ‘autopsy’ cancers have these characteristics.41,167–170 Given that young men with CaP and a life expectancy of 10–15 years have approximately a 60–80% probability of dying from their disease171,172 and that radical prostatectomy cures upwards of 80% of men with localized CaP, there is strong inferential evidence that screening will lead to improved diseasespecific survival rates. The recent modest increase in the 5-year survival rate of CaP173 supports this belief. However, the definitive answer to the most salient of questions with regards to screening: ‘Does treatment of early localized CaP impart increased diseasespecific survival?’ remains to be determined. Two studies are underway to address this important issue, one by the Scandinavian Prostatic Cancer Group started in 1989 involving more than 500 patients is nearing completion and the other, the Prostate Cancer Intervention Versus Observation Trial (PIVOT), which plans to recruit more than 1000 patients, is nearing the half way point of its enrolment in the United States.174 Both studies should have sufficient power to provide answers to whether treatment alters the natural history of CaP Until the contro versies surrounding screening for CaP are resolved, how should the individual clinician proceed today? An analysis of the patient’s overall health, intercurrent disease, socioeconomic considerations, and physiologic and

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Figure 15.1 Proposed prostate cancer (CaP) screening algorithm. Hx, history; DRE, digital rectal examination; PSA, prostate-specific antigen; f, free; t, total; V, velocity. chronologic age should be made. If it is determined that it is in the best interest of the patient to be evaluated for CaP, a carefully performed DRE and serum PSA determination should be accomplished. In the presence of an abnormal DRE, standard TRUS-guided biopsy should be performed regardless of PSA value. If there is no DRE abnormality, then Fig. 15.1 illustrates a suggested algorithm that can be followed. This derives from an assessment of the current literature and it should be noted that many of the studies this is based upon are small and preliminary and need confirmation by large, randomized, controlled clinical trials. Finally, the risks and benefits of intervention must be addressed should CaP be discovered and comprehensive patient education of potential therapeutic options and patient-directed decision making remains the best approach to the treatment of prostate cancer. References 1. Landis S H, Murray T, Bolden S, Wingo P A. Cancer statistics 1998. CA Can J Clin 1998; 48:6–29 2. Seidman H, Mushinski M H, Geib S K et al. Probabilities of eventually dying of cancer—United States, 1985. Cancer 1985; 35:36–56 3. Carter H B, Coffey D. The prostate: an increasing medical problem. Prostate 1990; 16:39–48 4. Mettlin C, Murphy G P, Babaian R J et al. Observations on the early detection of prostate cancer from the American Cancer Society National Prostate Cancer Detection Project. Cancer 1997; 80:1814–1817 5. Smart C R. The results of prostate carcinoma screening in the US as reflected in the Surveillance, Epidemiology, and End Results Program. Cancer 1997; 80:1835–1844

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Page 221 6. Standaer B, Denis L. The European Randomized Study of Screening for Prostate Cancer: an update. Cancer 1997; 80:1830–1834 7. Mettlin C, Jones G, Averette H et al. Defining and updating the ACS guidelines for the cancer related checkup: prostate and endometrial cancer. CA Can J Clin 1993; 43:42–46 8. Hall R R. Screening and early detection of prostate cancer will decrease morbidity and mortality from prostate cancer: the argument against. Eur Urol 1996; 29 (Suppl 2): 24–26 9. Matzkin H, Altwein J E, Patel J P, Soloway M S. Stage T1A carcinoma of prostate. Urology 1994; 43:11–21 10. Bostwick D G, Cooner W H, Denis L et al. The association of benign prostatic hyperplasia and cancer of the prostate. Cancer 1992; 70 (Suppl 1): 291 11. McNeal J E, Redwine E A, Freiha F S et al. Zonal distribution of prostatic adenocarcinoma, correlation with histological pattern and direction of spread. Am J Surg Pathol 1988; 12:897 12. Greene D R, Wheeler T M, Egawa S et al. A comparison of the morphological features of cancer arising in the transition zone and in the peripheral zone of the prostate. J Urol 1991; 146:1069 13. Breslow N, Chan C W, Dhom G et al. Latent carcinoma of the prostate of autopsy in seven areas. Int J Cancer 1977; 20:680 14. Sakr W A, Haas G P, Cassin B F et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993; 150:379 15. Aus G, Hugosson J, Norlen L. Long-term survival and mortality in prostate cancer treated with noncurative intent. J Urol 1995; 154:460 16. Haas G P, Sakr W, Cassin B et al. The prevalence of prostate cancer in young black and white males. J Urol 1992; 147:290A 17. Brawer M K. PIN: a premalignant lesion. Hum Pathol 1992; 23:242–248 18. Bostwick D G, Brawer M K. Prostatic intraepithelial neo plasia and early invasion in prostate cancer. Cancer 1987; 59:788 19. Brawer M K. Prostatic intraepithelial neoplasia and prostate specific antigen. Urology 1989; 34 (Suppl 6): 62 20. Lee F, Torp-Pedersen S T, Carroll J T et al. Use of transrectal ultrasound and prostate specific antigen in diagno sis of prostatic intraepithelial neoplasia. Urology 1989; 34 (Suppl 6):4 21. Keetch D W, Humphrey P, Stahl D et al. Morphometric analysis and clinical followup of isolated prostatic intraepithelial neoplasia in needle biopsy of the prostate. J Urol 1995; 154:347 22. Brawer M K, Rennels M A, Nagle R B et al. Serum prostate specific antigen and prostate pathology in men having simple prostatectomy. Am J Clin Path 1989; 92: 760 23. Bostwick D G, Qian J, Frankel K. The incidence of high grade prostatic intraepithelial neoplasia in needle biopsies. J Urol 1995; 154:1791 24. De la Torre M, Haggman M, Brandstedt S et al. Prostatic intraepithelial neoplasia (PIN) and invasive carcinoma in total prostatectomy specimens: distribution, volumes, and DNA ploidy. Br J Urol 1993; 72:207 25. Troncoso P, Babaian R J, Ro J Y et al. Prostatic intraepithelial neoplasia and invasive prostatic adenocarcinoma in cystoprostatectomy specimens. Urology 1989; 34 (Suppl): 52 26. Porter J R, Brawer M K. Prostatic intraepithelial neoplasia and prostate specific antigen. World J Urol 1993; 11:196 27. Brawer M K, Nagle R B, Bigler S A et al. Significance of PIN on prostate needle biopsy. Urology 1991; 38:103–107 28. Humphrey P, Keetch D W, Stahl D et al. Isolated PIN in prostatic biopsies as a marker for detection of adenocarcinoma on repeat biopsy. J Urol 1994; 151 (Suppl): 293A 29. Van Buskirk K E, Kimborough J C. Carcinoma of the prostate. J Urol 1954; 71:742 30. Thompson I M, Rounder J B, Teaque J L et al. Impact of routine screening for adenocarcinoma of the prostate on stage distribution. J Urol 1987; 137:424–426 31. Jewett J J. Significance of the palpable prostatic nodule. J Am Med Assoc 1956; 160:838 32. Sika J V, Lindquist H D. Relationship of needle biopsy diagnosis of prostate to clinical signs of prostatic cancer: an evaluation of 300 cases. J Urol 1963; 89:737 33. Brawer M K. The diagnosis of prostatic carcinoma. Cancer 1993; 71:899–905 34. Chodak G W, Schoenberg H W. Progress and problems in screening for carcinoma of the prostate. World J Surg 1989; 13:60–64 35. Gilbertsen V A. Cancer of the prostate gland: results of early diagnosis and therapy undertaken for cure of the disease. J Am Med Assoc 1976; 215:81–84 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_221.html[09.07.2009 11:53:06]

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36. Jenson C B, Shahon D B, Wangensteen O H. Evaluation of annual examinations in the detection of cancer: special reference to cancer of the gastrointestinal tract, prostate, breast, and female reproductive tract. J Am Med Assoc 1960; 174:1783–1788 37. McWhorter W P, Hernandez A D, Meikle A W et al. A screening study prostate cancer in high risk families. J Urol 1992; 148:826–828 38. Mueller E J, Crain T W, Thompson I M et al. An evaluation of serial digital rectal examinations in screening for prostate cancer. J Urol 1988; 140:1445–1447

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Page 222 39. Vihko P, Kontturi M, Lukkarinen O et al. Screening for carcinoma of the prostate: rectal examination, and enzymatic and radioimmunologic measurements of serum acid phosphatase compared. Cancer 1985; 56:173–177 40. Waaler G, Ludvigsen T C, Runden T O et al. Digital rectal examination to screen for prostatic cancer. Eur Urol 1988; 15:34–36 41. Catalona W J, Richie J P, Ahmann F R et al. Comparison of DRE and serum PSA in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994; 151:1283– 1290 42. Cooner W H, Mosley R B, Rutherford C L Jr et al. Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol 1990; 143:1146–1152 43. Lee F, Littrup P J, Torp-Pederson S T et al. Prostate cancer: comparison of transrectal US and DRE for screening. Radiology 1988; 168:389–394 44. Ellis W J, Chetner M, Preston S, Brawer M K. Diagnosis of prostatic carcinoma: the yield of serum PSA, DRE and TRUS. J Urol 1994; 152:1520–1525 45. Lee F R, Gray J M, McLeary R D et al. Prostatic evaluation by transrectal sonography: criteria for diagnosis of early carcinoma. Radiology 1986; 158:91–95 46. Devonec M, Chapeleon J Y, Cathignol D. Comparison of the diagnostic value of sonography and rectal examination in cancer of the prostate. Eur Urol 1988; 14:189–195 47. Fritzsche P J, Axford P O, Ching V C et al. Correlation of transrectal sonographic findings in patients with suspected and unsuspected prostatic disease. J Urol 1983; 30: 272–274 48. Hunter P T, Butler S A, Hodge G B et al. Detection of prostatic cancer using transrectal ultrasound and sono graphically guided biopsy in 1410 symptomatic. J Endourol 1989; 3:167 49. Perrin P, Mouriquand P, Monsallier M et al. Irradiation of carcinoma of the prostate localized to the pelvis: analysis of tumor response and prognosis. Int J Radiat Oncol Biol Phys 1980; 6:555 50. Ragde H, Bagley C M, Aldpae H C. Screening for prostatic cancer with high-resolution ultrasound. J Endourol 1989; 3:115 51. Rifkin M D, Friedland G W, Shortliffe L. Prostatic evaluation by transrectal ultrasonography: detection of carcinoma. Radiology 1986; 158:85–90 52. Carter H B, Hamper U M, Sheth S et al. Evaluation of transrectal ultrasound in the early detection of prostate cancer. J Urol 1989; 142:1008–1010 53. Amblin R J. A retrospective and prospective overview of prostate specific antigen. J Cancer Res Clin Oncol 1997; 123:583–594 54. Brawer M K. Clinical management of prostatic tumors. In: Bostwick D G (eds). Contemporary issues in surgical pathology: pathology of the prostate. New York: Churchill Livingstone, 1990 55. Wang M C, Valezuela L A, Murphy G P et al. Purification of a human prostate specific antigen. Invest Urol 1979; 17:159 56. Pollen J J, Dreilinger A. Immunohistochemical identification of prostatic specific acid phosphatase and prostate specific antigen in female periurethral glands. Urol 1984; 23:303 57. Stamey T A, Kabalin J N. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. J Urol 1989; 141:1070–1075 58. Stamey T A, Yang N, Hay A R et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987; 317:909–916 59. Ferro M A, Barnes I, Roberts J B M, Smith P J B. Tumor markers in prostatic carcinoma. A comparison of prostate-specific antigen with acid phosphatase. Br J Urol 1987; 60:69–73 60. Hudson M A, Bahnson R B, Catalona W J. Clinical use of prostate specific antigen in patients with prostate cancer. J Urol 1989; 142:1011–1017 61. Weber J P, Oesterling K E, Peters C A et al. The influence of reversible androgen deprivation on serum prostate specific antigen levels in men with benign prostatic hyperplasia. J Urol 1989; 141:987– 992 62. Lepor H, Wang B, Shapiro E. The relationship between prostatic intraepithelial volume and serum PSA levels. J Urol 1994; 151 (Suppl): 294A 63. Brawer M K, Rennels M A, Nagle R B et al. Serum PSA and prostate pathology in men having simple prostatectomy. Am J Clin Pathol 1989; 92:760–764 64. Bostwick D M, Brawer M K. PIN and early invasion in prostatic cancer. Cancer 1987; 59:788–794 65. Bigler S A, Brawer M K, Deering R E, Brown M. Microcirculation in PIN and typical benign hyperplasia of the prostate. J US Can Acad Path 1993; file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_222.html[09.07.2009 11:53:06]

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66. Fuchs M E, Brawer M K, Rennels M A, Nagle R B. The relationship of basement membrane to histologic grade of human prostatic carcinoma. Mod Pathol 1989; 2: 105–111 67. Brawer M K, Nagle R B. Transrectal ultrasound guided prostate needle biopsy following negative digitally guided biopsy. J Urol 1989; 141:278A 68. Carter H B, Epstein J L, Chan D W et al. Recommended prostate-specific antigen testing interval for the detection of curable prostate cancer. J Am Med Assoc 1997; 277: 1456–1460

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Page 223 69. Smith D S, Catalona W J, Herschman J D. Longitudinal screening for prostate cancer with prostatespecific antigen. J Am Med Assoc 1996; 276:1309–1315 70. Brawer M K. How to use PSA in the early detection or screening for prostatic carcinoma. CA Canc J Clin 1995; 45:148–164 71. Williford W O, Lepor H, Dixon C M et al. The serum levels of PSA in terazosin, finasteride, or both combination, and placebo: results of the VA Cooperative study #359. J Urol 1996; 155 (Suppl): 235A 72. Carter H B, Morrell C H, Pearson J D et al. Estimation of prostatic growth using serial PSA measurements in men with and without prostate disease. Cancer Res 1992; 52: 3323–3328 73. Carter H B, Pearson J D, Metter E J et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. J Am Med Assoc 1992; 267: 2215–2220 74. Carter H B, Pearson J D, Waclawiw Z et al. Prostate-specific antigen variability in men without prostate cancer: effect of sampling interval on prostate-specific antigen velocity. Urology 1995; 45:591– 596 75. Smith D S, Catalona W J. Rate of change in serum prostate specific antigen levels as a method for prostate cancer detection. J Urol 1994; 152:1163–1167 76. Oesterling J E, Chute C G, Jacobsen S J. Longitudinal changes in serum PSA (PSA velocity) in a communitybased cohort of men. J Urol 1993; 149:412A 77. Kadmon D, Weinberg A D, Williams R H et al. Pitfalls in interpreting prostate specific antigen velocity. J Urol 1996; 155:1655–1657 78. Porter J R, Hayward R, Brawer M K. The significance of short-term PSA change in men undergoing ultrasound guided prostate biopsy. J Urol 1994; 151:293A 79. Nixon R G, Wener M H, Smith K M et al. Day to day changes in free and total PSA: significance of biological variation. Pros Cancer Pros Dis 1997; 3:90–96 80. Nixon R G, Wener M H, Smith K M et al. Biological variation of prostate-specific antigen levels in serum: an evaluation of day-to-day physiological fluctuations in a welldefined cohort of 24 patients. J Urol 1997; 157: 2183–2190 81. Babaian R J, Fritsche H A, Evans R B. PSA and prostate gland volume: correlation and clinical application. J Clin Lab 1990; 4:135–137 82. Benson M C, Whang I S, Olsson C A et al. The use of PSA density to enhance the predictive value of intermediate levels of serum PSA. J Urol 1992; 147:817–821 83. Brawer M K, Aramburu E A G, Chen G L et al. The inability of PSA index to enhance the predictive value of PSA in the diagnosis of prostatic carcinoma. J Urol 1993; 150:369–373 84. Brawer M K. How to use PSA in the early detection or screening for prostatic carcinoma. CA Canc J Clin 1995; 45:148–164 85. Bazinet M, Meshref A W, Trudel C et al. Prospective evaluation of prostate-specific antigen density and systematic biopsies for early detection of prostatic carcinoma. Urology: 1994; 43:44–51 86. Mettlin C, Littrup P J, Kane R A et al. Relative sensitivity and specificity of serum PSA level compared with agereferenced PSA, PSA density and PSA change. Cancer 1994; 74:1615–1620 87. Rommel F M, Augusta V E, Breslin J A et al. The use of PSA and PSAD in the diagnosis of prostate cancer in a community based urology practice. J Urol 1994; 151: 88–93 88. Benson M C, Whang I S, Olsson C A et al. The use of prostate-specific antigen density to enhance the predictive value of intermediate levels of serum prostate-specific antigen. J Urol 1992; 147:817–821 89. Seaman E, Whang M, Olsson C A et al. PSA density (PSAD): role in patient evaluation and management. Urol Clin North Am 1993; 20:653 90. Ohori M, Dunn J K, Scardino P T. Is prostate-specific antigen density more useful than prostatespecific antigen levels in the diagnosis of prostate cancer. Urology 1995; 46:666–671 91. Lin D W, Gold M H, Ransom S et al. Transition zone PSA density: lack of utility in prediction of prostatic carcinoma. J Urol 1998; 160:77–82 92. Kalish J, Cooner W H, Graham S D. Serum PSA adjusted for volume of transition zone (PSAT) is more accurate than PSA adjusted for total gland volume (PSAD) in detecting adenocarcinoma of the prostate. Urology 1994; 43:601–606 93. Maeda H, Ishitoya S, Maekawa S et al. Prostate specific antigen density of the transition zone in the detection of prostate cancer. J Urol 1997:157:58A 94. Zlotta A R, Djavan B, Marberger M, Schulman C C. Prostate specific antigen density of the transition zone: a new effective parameter for prostate cancer prediction. J Urol 1997; 157:1315–1321 95. Oesterling J E, Jacobsen S J, Chute C G et al. Serum PSA in a community-based population of healthy men: establishment of age-specific reference ranges. J Am Med Assoc 1993; 270:860–864 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_223.html[09.07.2009 11:53:07]

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96. Dalkin B L, Ahmann F R, Kopp J B. PSA levels in men older than 50 years without clinical evidence of prostatic carcinoma. J Urol 1993; 150:1837–1839 97. Partin A W, Criley S R, Subong E N et al. Standard versus age-specific prostate specific antigen reference ranges among men with clinically localized prostate cancer: a pathological analysis. J Urol 1996; 155:1336–1339

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Page 224 98. Reissigl A, Pointner J, Horninger W et al. Comparison of different prostate-specific antigen cutpoints for early detection of prostate cancer: results of a large screening study. Urology 1995; 46:662–665 99. Littrup P J, Kane R A, Mettlin C J. Cost-effective prostate cancer detection. Cancer 1994; 74:3146 100. Murphy G P. Editorial. Oncology 1997; 11:1279 101. Brawer M K, Kirby R S. Fast Facts. PSA London: Health Press, 1998 102. Etzioni R, Shen Y, Petteway J C, Brawer M K. Age-specific PSA: a reassessment. Prostate 1996; 7:70–77 103. Huber P R, Mattarelli G, Strittmatter B et al. In vivo and in vitro complex formation of prostate specific antigen with alpha 1-anti-chymotrypsin. Prostate 1995; 27: 166–175 104. Vessella R L, Lange P H. Issues in the assessment of prostate-specific antigen immunoassays. Urol Clin North Am 1997; 24:261 105. Stenman U, Leinonen J, Alfthan H et al. A complex between PSA and a 1-antichymotrypsin is the major form of PSA in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. Can Res 1991; 51:222 106. Lilja H, Christensson A, Dahlen U et al. PSA in human serum occurs predominantly in complex with alpha-1 antichymotrypsin. Clin Chem 1991; 37:1618–1625 107. Christensson A, Bjork T, Nilsson O et al. Serum prostatespecific antigen complexed to alpha 1antichymotrypsin as an indicator of prostate cancer. J Urol 1993; 150:100–105 108. Luderer A A, Chen Y, Thiel R et al. Measurement of the proportion of free to total PSA improves diagnostic performance of PSA in the diagnostic gray zone of total PSA. Urology 1995; 46:187–194 109. Catalona W J, Smith D S, Wolfert R L et al. Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. J Am Med Assoc 1995; 274:1214–1220 110. Partin A W, Catalona W J, Southwick P C et al. Analysis of percent free prostate-specific antigen (PSA) for prostate cancer detection: influence of total PSA, prostate volume, and age. Urology 1996; 48 (Suppl 6A): 55–61 111. Luderer A A, Chen Y T, Soriano T F et al. Measurement of the proportion of free to total prostatespecific antigen improves diagnostic performance of prostate-specific antigen in the diagnostic gray zone of total prostate-specific antigen. Urology 1995; 46:187–194 112. Vashi A R, Wojno K J, Henricks W et al. Determination of the ‘reflex range’ and appropriate cutpoints for percent free prostate-specific antigen in 413 men referred for prostatic evaluation using the AxSYM system. Urology 1997; 49:19–27 113. Christensson A, Bjork T, Nilsson O et al. Serum prostate specific antigen complexed to alpha 1antichymotrypsin as an indicator of prostate cancer. J Urol 1993; 150:100–105 114. Bangma C H, Kranse R, Blijenberg B G, Schroder F H. The value of screening tests in the detection of prostate cancer. Part I: results of a retrospective evaluation of 1726 men. Urology 1995; 46:773–778 115. Chen Y T, Luderer A A, Thiel R P et al. Using proportions of free to total prostate-specific antigen, age, and total prostate-specific antigen to predict the probability of prostate cancer. Urology 1996; 47:518–524 116. Prestigiacomo A F, Lilja H, Pettersson K et al. A comparison of the free fraction of serum prostate specific antigen in men with benign and cancerous prostates: the best case scenario. J Urol 1996; 156:350–354 117. Van Cangh P J, De Nayer P, De Vischer L et al. Free to total prostate-specific antigen (PSA) ratio improves the discrimination between prostate cancer and benign prostatic hyperplasia (BPH) in the diagnostic gray zone of 1.8 to 10 ng/ml total PSA. Urology 1996; 48 (Suppl 6A): 67–70 118. Catalona W J, Smith D S, Ornstein D K. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/ml and benign prostate examination. Enhancement of specificity with free PSA measurements. J Am Med Assoc 1997; 277:1452–1455 119. Thiel R P Oesterling J E, Wojno K J et al. Multicenter comparison of the diagnostic performance of free prostatespecific antigen. Urology 1996; 48 (Suppl 6A): 45–50 120. Marley G M, Miller M C, Kattan M W et al. Free and complexed prostate-specific antigen serum ratios to predict probability of primary prostate cancer and benign prostatic hyperplasia. Urology 1996; 48 (Suppl 6A): 16–22 121. Reissigl A, Klocker H, Pointner J et al. Usefulness of the ratio free/total prostate-specific antigen in addition to total PSA levels in prostate cancer screening. Urology 1996; 48 (Suppl 6A): 62–66 122. Catalona W J, Partin A W, Slawin K M et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. J Am Med Assoc 1998; 279:1542–1547 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_224.html[09.07.2009 11:53:07]

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123. Partin A W, Brawer M K, Subong E N P et al. Multi-institutional prospective evaluation of free-PSA and complexed-PSA for the early detection of prostate cancer. Prostate Cancer Prostatic Dis 1998; in press 124. Gann P H, Hennekens C H, Stampfer M J. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. J Am Med Assoc 1995; 273: 289–294 125. Stenman U H, Hakama M, Knekt P et al. Serum concentrations of prostate specific antigen and its complex with

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Page 225 alpha 1-antichymotrypsin before diagnosis of prostate cancer. Lancet 1994; 344:1594–1598 126. Aus G. (Eighth International Prostate Cancer Update). Screening for Prostate Cancer in Sweden. February 1998 127. Partin A W, Kattan M W, Subong E N et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. J Am Med Assoc 1997; 277:1445–1451 128. Carlson G D, Calvanese C B, Childs S J. The appropriate lower limit for the percent free prostatespecific antigen reflex range. Urology 1998; 52:450–454 129. Woodrum D, French C, Shamel L B. Stability of free prostate-specific antigen in serum samples under a variety of sample collection and sample storage conditions. Urology 1996; 48 (Suppl 6A): 33–39 130. Paus E, Nilsson O, Bormer O P et al. Stability of free and total prostate specific antigen in serum from patients with prostate carcinoma and benign hyperplasia. J Urol 1998; 159:1599–1605 131. Brawer M K, Daum P, Petteway J C, Wener M H. Assay variability in serum PSA determination. Prostate 1995; 26:1–6 132. Brawer M K, Daum P, Tagle W S et al. Variability in serum PSA level owing to different manufacturers’ assay: results of a prospective study. J Urol 1995; 153:464A 133. Brawer M K, Bankson D D, Haver V M, Petteway J C. Comparison of three commercial PSA assays: results of restandardization of the Ciba Corning method. Prostate 1997; 30:269–273 134. Nixon R G, Gold M H, Blase A B et al. Comparison of three investigative assays for the free form of prostate-specific antigen. J Urol 1998; 160:420–425 135. Roth H J, Christensen-Stewart S, Brawer M K. A comparison of three free and total PSA assays. Prostate Cancer Prostatic Dis 1998; 1:326–331 136. Allard W J, Zhou Z, Yeung K K. Novel immunoassay for the measurement of complexed prostatespecific antigen in serum. Clin Chem 1998; 44:1216–1223 137. Brawer M K, Meyer G E, Letran J L et al. Measurement of complexed PSA improves specificity for early detection of prostate cancer. Urology 1998; 52:372–378 138. Sokoll L J, Bruzek D J, Cox J L et al. Is complexed PSA alone clinically useful? J Urol 1998; 159:234A 139. Brawer M K, Baukson D O, Partin A W et al. Complexed PSA: results of a multicenter biopsy experience. J Urol 1999; 161 (Suppl): 208 140. Saedi M S, Hill T M, Kuus-Reichel K et al. The precursor form of the human kallikrein 2, a kallikrein homologous to prostate-specific antigen, is present in human sera and is increased in prostate cancer and benign prostatic hyperplasia. Clin Chem 1998; 44:2115–2119 141. Darson M F, Pacelli A, Roche P et al. Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology 1997; 49:857– 862 142. Kwiatkowski M K, Recker F, Piironen T et al. In prostatism patients the ratio of human glandular kallikrein to free PSA improves the discrimination between prostate cancer and benign hyperplasia within the diagnostic ‘gray zone’ of total PSA 4 to 10 ng/ml. Urology 1998; 52: 360–365 143. Stamey T A, Barnhill S D, Zhang Z et al. A neural network (ProstAsure™) with a sensitivity and specificity of 75% for detecting prostate cancer in men with a PSA < 4.0 ng/ml. J Urol 1997; 157 (Suppl 4): 364 144. Babaian R J, Fritsche H A, Zhang Z et al. Evaluation of ProstAsure index in the detection of prostate cancer. A preliminary report. Urology 1998; 51:132–136 145. Zhang Z, Stamey T A, Oesterling J E et al. A comparison of percent free PSA and prostAsure index in separating prostate cancer from BPH and normal in men with PSA between 2.5 and 4.0 ng/ml. J Urol 1998; 159:109 146. McConnell JD, Bruskewitz R, Walsh P et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998; 338:557–563 147. Guess H A, Gormley G J, Stoner E et al. The effect of finasteride on PSA. Review of available data. J Urol 1996; 155:3–9 148. Andriole G L, Walsh P C, Epstein J L et al. Treatment with finasteride preserves usefulness of PSA in prostate cancer detection. J Urol 1998; 159:73 149. Pannek J, Marks L S, Pearson J D et al. Influence of finasteride on free and total serum PSA levels in men with benign prostatic hyperplasia. J Urol 1998; 159:449–453 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_225.html[09.07.2009 11:53:08]

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150. Keetch D W, Andriole G L, Ratliff T L et al. Comparison of percent free PSA levels in men with benign prostatic hyperplasia treated with finasteride, terazosin, or watchful waiting. Urology 1997; 50:901 151. Hodge K K, McNeal J E, Terris M K et al. Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 1989; 142:71–75 152. Keetch D W, Catalona W J, Smith D S. Serial prostatic biopsies in men with persistently elevated serum PSA values. J Urol 1994; 151:1571–1574 153. Vashi A R, Wojno K J, Gillespie B et al. A model for the number of cores per prostate biopsy based on the patient age and prostate gland volume. J Urol 1998; 159:920 154. Daneshgari F, Taylor G D, Miller G J et al. Computer simulation of the probability of detecting low volume carcinoma of the prostate with 6 random systematic core biopsies. Urol 1995; 45:604–609

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Page 226 155. Escew L A, Bare R L, McCullough D L. Systematic 5 region prostate biosy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 1997; 157: 199–203 156. Levine M A, Ittman M, Melamed J et al. 2 consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 1998; 159:471–476 157. Keetch D W, Catalona W J. Prostatic transition zone biopsies in men with previous negative biopsies and persistently elevated serum PSA values. J Urol 1995; 154: 1795–1797 158. Bazinet M, Karakiewicz P I, Aprikan A G et al. Value of systematic transition zone biopsies in the early detection of prostate cancer. J Urol 1996; 155:605–606 159. Fleschner N E, Fair W R. Indications for transition zone biopsies in the detection of prostate cancer. J Urol 1997; 158:556–558 160. Lui P D, Terris M K, McNeal J E et al. Indications for ultrasound guided transition zone biopsies in the detection of prostate cancer. J Urol 1995; 153:1000–1003 161. Gann P H. Interpreting recent trends in prostate cancer incidence and mortality. Epidemiology 1997; 8:117–120 162. Merrill R M, Potosky A L, Feuer E J. Changing trends in US prostate cancer incidence rates. J Natl Cancer Inst 1996; 88:1683–1685 163. Stevenson R A, Smart C R, Mineau G P et al. The fall in incidence of prostate carcinoma; on the downside of a prostate specific antigen induced peak in incidence—data from the Utah cancer registry. Cancer 1995; 77: 1342–1348 164. Labrie F, Candas B, Cusan L et al. Diagnosis of advanced or noncurable prostate cancer can be practically eliminated by prostate specific antigen. Urology 1996; 47: 212–217 165. Smith D S, Catalona W J, Hershman J D. Longitudinal screening for prostate cancer with prostate specific antigen. J Am Med Assoc 1996; 276:1309–1315 166. Stevenson R A. Population based prostate cancer trends in the PSA era. Data from the Surveillance, epidemiology, and end-results (SEER) program. Monogr Urol 1998; 19: 3–19 167. Smith D S, Catalona W J. The nature of prostate cancer detected through PSA screening. J Urol 1994; 152: 1732–1736 168. Mettlin C, Murphy G P, Lee F et al. Characteristics of prostate cancers detected in a multimodality early detection program. Cancer 1993; 72:1701–1708 169. Scaletscky R, Koch M O, Eckstein C W et al. Tumor volume and stage in carcinoma of the prostate detected by elevations in PSA. J Urol 1994; 152:129–131 170. Ohori M, Wheeler T M, Dunn J K et al. The pathological features and prognosis of prostate cancer detcted with current diagnostic tests. J Urol 1994; 152:1714–1720 171. Aus G, Hugosson J. 15 year survival with prostate cancer in Sweden. J Am Med Assoc 1997; 278:205 172. Johansson J, Holmberg L, Johansson S et al. 15 year survival in prostate cancer. J Am Med Assoc 1997; 277: 467–471 173. Mettlin C J, Murphy G P, Rosenthal D S et al. The National Cancer Data Base report on prostate carcinoma after the peak in incidence rates in the U.S. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998; 83: 1679–1684 174. Wilt T J, Brawer M K. The prostate cancer intervention versus observation trial (PIVOT): a randomized trial comparing radical prostatectomy versus expectant management for the treatment of clinically localized prostate cancer. J Urol 1994; 152:1910–1914

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Page 227 16 Flow rate and postvoid residual issues E P Arnold Introduction There are an increasing number of men in the over 60 year age group, and they are becoming increasingly aware of men’s health issues, in particular of lower urinary tract symptoms and of prostate cancer. The symptoms do not always give an accurate idea of the cause. Further investigations are indicated in order to be able to give proper and informed advice to the patient. In men with BPH, symptoms can arise due to mechanical obstruction by the size of the gland, or to functional obstruction arising from changes produced by contraction of the abundant smooth muscle at the bladder neck and within the prostate. The bulk of the prostate might produce sensory changes at the bladder base and contribute to sensory urgency or to a feeling of incomplete evacuation. It could be that, in certain cases, there might be no close correlation between the symptoms produced by the enlarging prostate and the degree of obstruction.1,2 Symptoms are heterogeneous and although often grouped as ‘obstructive’ or ‘irritative’, these symptoms overlap and do not always correlate with obstruction as measured objectively. The terms ‘obstructive’ and ‘irritative’ would be best abandoned in favor of ‘impaired voiding’ or ‘impaired storage’, without assuming that we understand the cause. Overactive detrusor dysfunction is common in patients with bladder outlet obstruction; its incidence rises with age even in the absence of obstruction, and indeed this rise with age also occurs in women. It is often associated with symptoms of frequency, nocturia, urgency, and urge incontinence. Relief of outlet obstruction does reduce the incidence of overactive detrusor dysfunction by approximately 30%,3 but it persists in the remainder. Overactive detrusor dysfunction represents an increased excitability of the micturition reflex and its rising incidence in age might indicate an occult, or overt, neuropathy. In patients with known neurologic disorders, like multiple sclerosis or Parkinson’s disease, detrusor overactivity is common and can give symptoms which are difficult to distinguish from those of bladder outlet obstruction. Of course it is the same age group in which prostate enlargement is so common, and both problems can occur together. In this group of elderly men with neurologic disorders, it is essential to document obstruction before contemplating interventional treatment. Postobstructive overactive detrusor dysfunction may also have a myogenic basis with spontaneous rhythmic contractions seen in organ bath studies increased in number and amplitude.4 Symptoms and symptom scores have been developed to grade and quantify the severity of symptoms. Their impact on the quality of life, and the degree of bother caused, are perhaps the most important considerations in planning management strategies. Good management demands accurate diagnosis for the following reasons: • To identify obstruction and to determine the site. • To assess the efficacy of any particular treatment strategy by tests done before and after the treatment. • To exclude prostate cancer. This has been addressed in the previous chapter. The most widely accepted objective definition of obstruction is the demonstration of a low flow rate and a high pressure. Postvoid residual (PVR) urine is considered to be the result of poor detrusor activity and its significance will be addressed in the latter part of this chapter. To undertake pressure/flow studies in all those with urinary symptoms before offering treatment would be too time consuming and costly for the resources available. However, the costs of the studies can be more than offset against savings made by avoiding surgery for the 30% of men who are not obstructed, despite the same symptoms and flow rate records as those who are. This chapter attempts to assess the value of flow rate and PVR measurements in making the diagnosis of obstruction. Flow rate Self-assessment The ‘cast distance’ popularized by school boys is grossly inaccurate because it depends on the exit velocity at the external urethral meatus. A urethral stricture can cause a fine jet and a long cast distance without the flow rate changing, until the stricture has progressed to become almost completely occlusive. However, if a man has noticed his stream is less forceful, he is usually right when this is measured. More commonly, the man might not

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Page 228 have noticed any change in the stream because the slowing of the flow has come on so gradually. In any case, according to Rosier et al.,2 the symptom scores do not correlate with the flow rate measurements. Andersen et al.5 and Simonsen et al.6 showed no relation between severity of symptoms and obstruction and maximum flow rate. A high flow rate greater than 15 ml per second does not preclude obstruction, and the patient with bothersome symptoms should be further investigated with pressure/flow studies.7 Similarly, in the ICS BPH study of 1271 men with lower urinary tract symptoms, obstruction was diagnosed in 60% according to the Schafer criteria. The symptom of a poor flow was significantly but weakly associated with a low Q max (correlation coefficient of −0.19, which is in agreement with −0.22 in the study reported by Barry et al.8 and Reynard et al.).9 Technical aspects It has often been said that, to evaluate voiding disorders, any self-respecting urology unit should have a flow meter. There are many different types of flow meters available. The majority are load cells or weight transducers which weigh the urine and then differentiate the rate of change of volume against time. Another popular type of flow meter directs the voiding volume onto a disk with a slightly raised ribbed perimeter rotating at constant speed. The urine increases the impedance to the constant speed motor and this is detected electronically and converted to a flow rate. The voided volume is subsequently calculated by integration of the flow curve. Electronic dipstick methods measure capacitance changes in a bimetallic strip as the volume of electrolyte-containing urine rises in a cylindrical container. Most machines provide a printout and also some software to calculate and print the maximum flow rate, average flow rate, voided volume, and time, etc. They are accurate within 1–5%, but artifacts occur due to ‘splashing’ and it is always necessary to correct these spikes and artifacts visually before accepting the machine’s readout.10 The machines should be calibrated regularly.11 Variability of flow rate Learning effect Anxiety can be aroused by the fear of not being able to hold on until the flow is done, from voiding in an unusual environment, and from being anxious to do the best. Such anxiety can cause a slower flow, presumably due to overactivity of the urethral striated muscle and its failure to relax, and perhaps the adrenergic effects of increasing smooth muscle tone in the bladder neck and prostatic urethra. A learning effect through repeated studies was noted by George and Slade;12 however, Haylen et al.13 showed no difference for maximum or average flow rates between first and second voids, in a large number of men and women. Individual variation The patient should always be asked if he considers that his flow rate test was representative of his usual voiding. If there is any doubt, that test should be discarded and another arranged. Siroky et al.14 found that the variation in flow in a single asymptomatic individual voiding on multiple occasions was minimal and the probability that a flow rate will occur below −1 standard deviation (SD) is 0.159. They calculated that a change of 1.2 SD has a probability of only 2.5%. In the normal individual the flow rate varied by >1.2 SD in only three of the 32 voids (9%). However, variation of flow in patients with bladder outlet symptoms is often a feature of their history. Home uroflowmetry with multiple voids in more normal surroundings may give a better indication.15 Golomb et al.16 studied flow rate variations by home uroflowmetry in 32 men with symptoms of obstruction who did a mean of 14.9 tests, and 16 controls without symptoms, by a mean of 6.25 tests. They found that the men with obstruction varied their flow rates by >1 SD in 87.5% and by >2 SD in 47%. The normal men had flows showing less variation but which still varied by >1 SD in 50% and by >2 SD in 12.5%. In an elderly population of incontinent men and women who underwent two urodynamic studies 2–4 weeks apart, the between-session variability of the flow rate was ±4.7 ml/s and the correlation coefficient was 0.44.17 Similarly, the URA, which is a measure of obstruction, varied by ±11.7 with a correlation coefficient of 0.61.18 The results suggest there is substantial long-term variability in voiding function, including urethral resistance. Diurnal variation Many patients say their flow is worse at night, and this was borne out in the study done by Golomb et al.16 In their study the adjusted flow rate was lower in the home flowmetry studies done between midnight and noon than in the subsequent half-day. This variation was not seen in younger men.19

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Page 229 Bladder volume The flow rate depends on volume voided and is slower than representative with volumes less than 150– 200 ml.20 Older men often have greater difficulty holding on to do this volume and hence volumes of 100 ml are not uncommon. When they do hold on deliberately, it does not always result in a representative voiding rate, and after going home they often have marked frequency. In the ICS BPH study,9 the voided volume was less than 150 ml and therefore bladder outlet obstruction was diagnosed in 72% of cases, compared to 56% in men in whom the voided volume was greater than 150 ml. Because of this, some centers have developed ‘flow clinics’, at which patients are asked to drink plenty and to do three or four tests. In this way, the proportion of men voiding less than 150 ml fell from 59% to 21%.21 Several workers studying flow patterns have developed nomograms and volume-independent variables. First, Drake22 developed the idea of a ‘corrected’ peak flow rate derived by dividing maximum flow rate by the square root of bladder volume itself measured as a sum of the volume voided and the residual urine volume. Second, the importance of using the initial bladder volume, rather than the voided volume alone, which would disregard the PVR, was emphasized by Siroky et al.14 Use of voided volume would result in an overestimate of voiding ability. Despite this, the measurement of PVR is considered unnecessary in the majority of cases unless the flow rate is normal or borderline. Siroky et al.14 constructed a nomogram of flow rate against volume in a small group of young men, and expressed the variance in terms of a mean and standard deviation which paralleled the mean. None of the normals had values below −2 SD, whereas in a group of 53 men considered obstructed on clinical grounds, 52 had values below −2 SD.23 The clinical diagnosis of obstruction was not validated by urodynamic studies, however. Lim et al.24 compared the reliability of the Bristol and Siroky nomograms against the objective criteria of obstruction using a URA of >29. They showed that the Siroky nomogram had poor specificity (30%) but good sensitivity in diagnosing obstruction (91%). The Bristol nomogram had a specificity of 70% and a sensitivity of 53%. They concluded that if a precise diagnosis of obstruction is required, then pressure/flow studies must be performed. Schafer et al.25 reported that only 75% of men considered obstructed in the Siroky nomogram were proven to be obstructed on pressure/flow studies. Flow rates were slower with higher volumes in several studies.11,20 Haylen et al.13 constructed a Liverpool nomogram based on a large number of men and women. They found a strong correlation with voided volume of both maximum and average flow rate, but did not see any deterioration of flow rate in either sex with higher voided volumes. Pooling the results from 12 studies in 817 men aged 25–60 years showed the relation between flow rate and voided volume displayed in Fig. 16.1.26 For voided volumes of <150 ml, Marshall et al.27 used the slope of the curve of the flow rate versus volume voided, always including the point (0, 0) (Fig. 16.2). They found that

Figure 16.1 Pooled results of studies on the relation between maximum flow rate and voided volume: , mean value; , +1 SD; , −1 SD; , minimum value; , maximum value. (Reproduced from ref. 25 with permission.) file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_229.html[09.07.2009 11:53:10]

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Figure 16.2 Slope of the curve of flow rate versus volume voided extrapolated back to the origin. (Reproduced from reference 27 with permission.)

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Page 230 measurement of this slope was useful to determine normal and impaired voiding irrespective of the volume voided. Age Several studies have indicated that flow rate deteriorates with age.13,20,27–30 The slower flows might well indicate increased incidence of obstruction in older men, but could also reflect lower voided volumes, probably due to overactive detrusor dysfunction, when flow rates have been shown to be slower. Impaired detrusor contractility due to aging is another possible cause. Jorgensen et al.31 followed 61 men and repeated studies 5 years later. They showed a significant fall in maximum flow rate and a drop in voided volume from 280 to 100 ml. It is of interest that few men with obstruction, when observed longitudinally on a long surgical waiting list, actually go into acute retention. Ball et al.28 showed that of the 107 patients seen initially and reviewed 5 years later, only two had gone into acute retention and in the majority the symptoms had not worsened significantly with age. Flow rate and the diagnosis of bladder outlet obstruction Neither the maximum flow rate ( Q max) nor any of the derivatives of the flow curve could predict the low pressure/low flow syndrome.32,33 In the ICS BPH study,9 pressure/flow studies were available in 933. Of these, obstruction was confirmed in 563 (60.2%) and absent or minor in 17.5% and 22.5%, respectively. For each of three voids, the flow rate was lower in those with obstruction than in those without ( p <0.001); Schafer obstruction grade correlated with Q max ( p <0.001) an this held when re-analyzed controling for age. In the above study, the sensitivity of a flow rate less than 10 ml/s in making a diagnosis of obstruction was 47% and the specificity was 70%. Where a flow rate was less than 15 ml/s, the sensitivity in diagnosing obstruction rose to 82%, but the specificity fell to 38%. The positive predictive value (PPV) of a flow rate less than 10 ml/s in diagnosing obstruction was 70%, but where a flow rate of less than 15 ml/s was used the PPV was 67%. Does the flow rate pattern help in the diagnosis of obstruction? A reduced flow rate can be due to obstruction or to reduced bladder contractility. There is no way to distinguish these apart from a pressure/flow study. Several variables have been developed from the flow rate curve and pattern in an attempt to discriminate between them. Because the elderly with bladder outflow symptoms only rarely void volumes more than 100–150 ml each time, this poses a difficulty in interpreting flow rates. To overcome this, various manipulations of the flow parameters have been used. Apart from the corrected flow rate, MUDI (male uroflow diagnostic interpretation) variables developed by the Dantec Elektronik Company include: Q max maximum flow rate Q m the mean flow rate for the middle 90% of the voided volume, but this does not account for 90 residual urine 40 the velocity of detrusor contraction at 40 ml volume calculated from flow rates at that point Tdesc the time from Q max to when 95% of the volume has been voided Rollema et al.34 performed these measurements on men considered obstructed on the basis of the Abrams—Griffiths nomogram,35 and the CLIM program, and applied it to small volumes less than 100 ml, with the results shown in Table 16.1. Even with this method, 22% were considered obstructed using maximum flow rate values but were not in fact obstructed, and 18–30% were considered obstructed using the three derived factors. Patients with a flow rate of more than 15 ml/s are less likely to have an obstruction proven by urodynamic studies than those with a flow rate of less than 5 ml/s. However, this does not deny that there are some obstructed patients who have a high flow/high pressure syndrome.36 Can the flow rate predict the outcome of subsequent prostatectomy? Abrams37 showed that patients who underwent a prostatectomy had an overall success rate of 72% where the indications for prostatectomy were based on symptoms Table 16.1 Male uroflow diagnostic interpretation (MUDI) variables measured on men considered to be obstructed on the basis of the Abrams-Griffiths nomogram and the CLIM program (volumes <100 ml).   Q max Q m90 40 Tdesc Sensitivity (%) 78 82 85 70 Specificity (%) 88 88 88 96

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Page 231 and flow rate. He reported a less satisfactory outcome in those with normal preoperative flow rates than in those with low flow rates. Neal et al.38 achieved a success rate of 75%, A proportion of those having an unsatisfactory result are not obstruction but have similar symptoms of frequency, nocturia, poor stream, urgency, and the occasional urge incontinence. These symptoms could relate to overactive detrusor dysfunction.39,40 Another cause is the low pressure/low flow syndrome. Where the preoperative flow rate was >15 ml/s, Jorgensen et al.41 found a higher incidence of detrusor instability, a lower incidence of obstruction, and a lower success rate from surgery. These authors found that 17 of 134 men with lower urinary tract symptoms had a flow rate greater than 15 ml/s. There was a higher incidence of detrusor instability, a lower incidence of obstruction, and a lower postoperative success rate in this group. Van Mastrigt42 performed 109 pressure/flow studies and, on the basis of URA being less than 29,18,43 defined a group of 70 obstructed and 39 nonobstructed patients. In relating this to the preoperative flow rates, where the flow was less than 4.8 ml/s, 91% were obstructed. Per contra, those with a flow rate over 12 ml/s were usually not obstructed. The group between were impossible to discriminate and the author recommended that they would need pressure/flow studies. However, this would mean that the numbers needing such studies could be rationalized to 53% of those with symptoms. Jensen et al.44,45 looked at the results of prostatectomy and the preoperative flow rate. If the flow rate exceeded 15 ml/s, success was achieved in 70%, whereas the success was around 91% for those with flow rates less than 15 ml/s. The opposite conclusion was reached by Neal et al.,40 where preoperative flow rates were not associated with the outcome of the operation. Those with higher flow rates did as well as those with lower flow rates. Some patients with the low flow/low pressure syndrome considered to be due to an underactive detrusor do obtain symptom relief after prostatectomy. Neal et al.40 found a subjective success rate postoperatively in the high pressure group of 38/43 (88%), compared to 13/34 (38%) in the low pressure group. In a group of 253 men undergoing urodynamic studies before prostatectomy, they found no clinical parameters that could identify men with voiding pressures in the high or low end of the range. However, several studies showed a reasonable outcome in patients with flow rates above 15 ml/s and high voiding pressures.1,36 In an analysis of the results of transurethral resection (TUR), Nordling46 summarized three series, as shown in Table 16.2. While there is a wide variation between these three studies, within each one the results of prostatectomy are worse in the unobstructed group compared to the obstructed, but it was not possible to distinguish these groups by preoperative flow rate. Summary Variations in individual flow rate support the suggestion that more than one flow rate test should be done and then corrected for bladder volume, either by use of various formulae or by nomograms. Symptoms correlate poorly with flow rate. From the flow rate it appears possible to separate those with impaired voiding from those who are normal. The flow rate does not discriminate those whose impaired voiding is due to obstruction from those where the cause is impaired detrusor contractility. Neither does it distinguish those with symptoms and a high flow rate who also have high voiding pressures and are obstructed. Pressure/flow studies are indicated to avoid surgery in those patients with neurologic disorders who do not have obstruction, to allow comparison of outcomes of various medical and surgical interventions in relation to bladder function, and to define the role of obstruction and instability in both the cause of symptoms and the results of intervention. Table 16.2 Results of TUR in three series of men with or without preoperative obstruction.   No of No unobstructed Percentage with symptomatic failure patients preoperatively postoperatively Obstructed Nonobstructed Jensen et al.44 123 29 7 21 Neal et al.40 217 14 24 43 Rollema and van 29 34 10 70 Mastrigt43

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Page 232 Postvoid residual urine Normal bladder emptying The normal bladder is able to empty itself completely or to a negligible few ml, through a normal urethra. This is achieved by a bladder which continues to contract and a urethra that remains relaxed, until emptying is completed (Fig. 16.3). Di Mare et al.47 noted that 78% of 46 normal males had residual urine of less than 5 ml and all had residual urine of less than 12 ml.

Figure 16.3 Normal voiding and table filling. Detrusor contraction is sustained until the bladder is emptied.

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Page 233 Self-assessment Subjectively, the symptom of a feeling of incomplete emptying did correlate with the presence of PVR in one study.5 However, other studies have shown no correlation between the sensation of incomplete emptying and the PVR.9,48 Many men with chronic retention are quite unaware that they do not empty their bladders completely. Techniques of measurement Abdominal examination can reveal a large non-painful bladder in chronic retention, but the PVR needs to be quite large before this can be palpated or percussed, depending on bodily habitus. Lesser volumes cannot be felt. Catheterization might be considered the gold standard for measuring PVR. However, Stoller and Millard49 demonstrated its inaccuracies, although these can be largely reduced by attention to detail in the technique of catheterization. Indirect assessment of PVR can be performed by measurements taken from the postvoid film of the intravenous urogram (IVU) or from abdominal ultrasound using a variety of formulae based on assumptions of a symmetric shape of the bladder, rectangular or box shaped, or a pyramid. These methods have inherent inaccuracies, but because the clinical significance of small changes in bladder residual volume is unimportant, it seems that most of the methods for measuring ultrasound volumes are satisfactory. Variability of PVR Intra-individual variation Anxiety affects the emptying ability, which is a wellknown phenomenon in studies done in radiography departments using the after-micturition film of the IVU. Similarly, patients in hospital, particularly women, have difficulty voiding when bedridden, and a residual is left which seems to predispose to infection in some of these patients. In a study by Birch et al.,50 30 men due for a TUR had three ultrasound examinations of PVR the day before surgery. Five different formulae were used. Wide variations from one void to the next were noted and two-thirds of the patients had significant variations in residual urine volume as measured by the different methods. Bruskewitz et al.48 also showed wide variations in 49 individual men and a lack of correlation with urodynamic parameters or symptoms. This wide intra-individual variation in PVR prior to TUR must render questionable its value as a means of diagnosing obstruction. Age PVR appears to be a function of age in both sexes. Abrams and Griffiths35 reported that 50% of men with lower urinary tract symptoms and in whom obstruction had been excluded by urodynamic testing had a PVR of greater than 50 ml. Pathogenesis of PVR ‘Compensation’ and ‘decompensation’ The response of the bladder to obstruction of its outlet is to raise its pressure. This has been called ‘compensation’, implying increased strength of the detrusor to overcome the obstruction. This is now understood to be a misinterpretation. The detrusor pressure rises in obstruction because of the slower flow rate and the movement along the hyperbolic pressure/flow plot in accordance with the Hill equation. The bladder may continue to contract until it is empty (Fig. 16.4). There is no evidence that the obstructed bladder compensates by contracting with greater force. Although the voiding pressure is high in obstruction, the bladder contracts at a slower contraction speed and the force is often unchanged or even slightly reduced.51,52 Detrusor muscle strips from obstructed patients showed a normal or nearnormal force but a reduced velocity in the obstructed patients compared to the controls.53 The slower velocity is possibly caused by structural and ultrastructural changes due to obstruction, with an increase in noncontractile elements, smooth muscle atrophy, and axonal degeneration as discussed by Elbadawi.54

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Figure 16.4 Pressure/flow relation.

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Page 234 Decompensation after a period of ‘compensation’ has been suggested to explain PVR and correlate it with left ventricular heart failure where the postejection volume fraction is a marker of the severity of heart failure. Schafer55,56 has suggested that PVR is caused by the limited amount of work the bladder is able to perform during any voiding cycle. Smooth muscle is capable of maintaining tension for a long period of time. Even those with high pressure chronic retention are capable of strong detrusor contractions during voiding, even though the bladder volume may be distended to 1000 ml or more. After an initial strong burst of high pressure, the detrusor fades away before the bladder empties (Fig. 16.5). Progress of obstruction leading to increasingly large residual urines, or to acute retention, happens relatively infrequently. Ball et al.28 followed 107 patients with symptoms of obstruction, untreated for 5 years, and found no increase in residual urine in that time, and only two went into acute retention. Inactivation of micturition reflex Another concept of why residual urine accumulates is that it may be the micturition reflex is switched off by afferents within the urethra, perhaps due to the high pressure within it.57 Sphincter-active voiding could do this

Figure 16.5 High pressure/low flow prostatic obstruction.

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Page 235 too. However, Griffiths examined P/Q plots in patients with PVR and found that almost invariably the urethral opening pressure was lower towards the end of voiding than at the beginning, indicating relaxation of the urethra.58 PVR and neuropathy Patients with spinal cord injuries and lesions above the spinal micturition reflex center have a varying degree of detrusor-sphincter dyssynergia, which will result in PVR, partly because of sphincter activity and partly because such sphincter activity can switch off the detrusor contraction reflex. Those with cauda equine or sacral root damage have a flaccid bladder and inability to excite a contraction voluntarily or reflexly. This will result in some voiding by straining, but rarely does this empty the bladder completely. Some patients with diabetes and autonomic neuropathy have large capacity bladders which empty incompletely too. Impaired detrusor contractility This can coexist with an initially high voiding pressure and an overactive detrusor in the elderly.59,60 Elbadawi54 has documented the ultrastructural basis for this altered function to occur. He showed evidence of smooth muscle hyperplasia and some areas of muscle atrophy, neural disintegration, and increased deposition of collagen and elastin in the bladder wall, all of which could contribute to reduced contractility and detrusor instability. Some of these changes have been seen in the aging process. Because of these structural changes, the muscle may not be able to shorten to the extent it could formerly, with resulting inability to empty completely. In summary, residual urine appears to be an abnormality of bladder function rather than a direct result of mechanical obstruction. Chronic retention This has been arbitrarily defined as a PVR of greater than 300 ml. Bladder compliance The normal end filling pressure is equal to or less than 15 cmH2O. In low pressure chronic retention (LPCR) the end filling pressure is less than 25 cmH2O. Such patients often have minimal ‘obstructive’ symptoms. They have a large floppy bladder and do less well after prostatectomy. The high pressure chronic retention (HPCR) group, in whom the end filling pressure is greater than 25 cmH2O, is at risk of dilatation of the upper tracts and postobstructive renal failure. They do have a better success postoperatively and the upper tract dilatation often resolves after prostatectomy unless permanent damage has ensued.61 Is LPCR due to detrusor contractility impaired for many years, and is it the end result of the low pressure/low flow syndrome? Long-term studies have not yet been done to address this question, but Neal et al. provided little support for the concept.38 A sensory problem? Diabetics often have large bladders and significant PVR and this has been ascribed to autonomic neuropathy.62 Parys et al.63 found an increased sensory threshold in those with chronic retention when using electrical stimulation via the dorsal nerve of the penis and at the bladder neck using a catheter-mounted electrode. They found normal somatic reflex latencies, however. Clinical significance of PVR PVR and outlet obstruction PVR does not indicate obstruction, nor does its absence rule it out. No correlation has been demonstrated between flow rate and PVR.1,64,65 Although some urologists still rely on PVR as an indication of obstruction and hence an indication for TUR, the PVR does not correlate with symptoms, prostatic size, or urethral resistence.66 This has also been shown by Cetinel et al.,67 who showed that 70% of those with urodynamically proven bladder outlet obstruction had a PVR of less than 50 ml. In another study PVR did not correlate with the symptom of incomplete emptying, nor with the peak flow rate, the presence or absence of detrusor instability, or the size of the gland.48 Shoukry et al.64 also showed no correlation between PVR and urodynamic criteria of obstruction. The absence of residual urine does not rule out obstruction. This was demonstrated by Turner-Warwick et al.39 As can be seen in Fig. 16.6, there are a large number of patients who have no or insignificant volumes of residual urine and yet who have high pressure and the lowest of flows. Neal et al.38 showed that weak voiding pressures (less than 55 cmH2O) were found infrequently (9.1%) and were not associated with a large PVR. Their data provide no support for the concept of PVR being a consequence of a weak detrusor, or detrusor decompensation. Bruskewitz et al.48 showed no correlation of PVR with uninhibited bladder contractions, although others have shown that there is a possible combination of detrusor overactivity of this type and poor detrusor contractility.59 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_235.html[09.07.2009 11:53:13]

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Figure 16.6 Residual urine ( , 0–30 ml; , 30–200 ml; , >200 ml) in relation to severity of obstruction. (Adapted from ref. 39 with permission.) PVR and urinary tract infection It has been a precept of urologic thought that residual urine predisposes to urinary tract infection (UTI). In patients who have bladder outlet obstruction, the incidence of infection is relatively uncommon. Hasner68 showed no correlation between PVR and the incidence of UTI, nor did Bruskewitz et al.48 or Hampson et al.69 The incidence would appear to be around 5–10%. However, no studies have compared the risk of urinary infection in those with and without residual urine. PVR and results of surgery The presence or absence of residual urine per se should not bear directly on the indications for prostatectomy.39 Although the association of residual urine with high voiding pressures is weak,39 there is evidence that the residual urine does fall significantly by about 70% following successful prostatectomy from a mean of about 100 ml to 30 ml.40 In looking at the success rate of surgery, Abrams et al.70 showed an unsatisfactory outcome in the low pressure chronic retention in eight of 12 cases, whereas in those with high pressures the unsatisfactory result was one in nine. Neal et al.40 showed an unsatisfactory outcome in approximately 29% of cases which was associated with preoperative urge incontinence, a small prostatic size, and a low voiding pressure. There was, however, no correlation of an unsatisfactory outcome with either maximum preoperative flow rate or PVR. George et al.61 looked at 25 men with prostatism and a residual urine greater than 100 ml; 21 had preserved normal upper tracts. High voiding pressures predicted a good result following TUR, but where the pressures were below 70 cmH2O during voiding, this produced a poor symptomatic response and also poor postoperative urodynamic findings. Prostatectomy for patients in chronic retention led to a significant reduction in PVR from a mean of 1141 ml (±789) to a mean of 206 ml (±268) postoperatively.71 Acute retention There is no single theory of the cause of acute retention. Some factors associated with the risk of retention were identified in a longitudinal study by the Department of Health Sciences Research at the Mayo Clinic. Increased risk of retention was noted in those with symptom scores greater than 7, with increasing age, with a prostate larger than 30 g, and with a flow rate greater than 12 ml/s.72 Overdistension due to increased diuretics or alcohol is a precipitating event in a patient developing acute retention on top of obstructive symptoms. Other factors include cold, pain, stress of many types, and surgery. Alpha-adrenergic receptors in the urethra may be responsible in part. Caine and Perlberg73 used α-adrenergic blockers with some success. This presumably works by reducing urethral and prostatic smooth muscle contractility. Detrusor instability, by causing urgency and frequency, may file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_236.html[09.07.2009 11:53:13]

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protect against acute retention by avoiding overdistension. Where there are pre-existing symptoms of impaired voiding, the development of acute retention of urine is an indication for prostatectomy. If a catheter is passed to evacuate the retention and then removed there is a high risk of the patient returning in retention. This is most likely within the first week, when 50% will again develop acute retention, and this incidence increases to around 60% at the end of 4 weeks and 68% by the end of 12 months. For patients able to void after an in-out catheter, if the flow rate is <5 ml/s, there is a 90% risk of repeat retention.74 The histology shows an increased incidence of infarction in prostates removed after acute retention when compared to elective prostatectomy specimens, and it may be that the edema associated with this event suddenly increases the urethral resistance.

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Page 237 Practical issues The justification for doing any test should depend on its ability to identify obstruction and to determine its site. This will then allow informed choice of any treatment strategy which can be retested posttreatment. There are two aspects to a successful outcome of any procedure. One is the symptomatic improvement and the other is an objective improvement in parameters of obstruction for which the surgeon has done the procedure. Subjective success can occur without any measurable improvement in flow rate or pressure! The reverse is also true. Definition of obstruction and use of flow rate The only objective way of making a diagnosis of obstruc tion is to demonstrate: • Slow flow rate; • Elevated detrusor pressure during voiding; • Narrow area on video-cystourethrography; • Ablation of the narrow area that reverses the first three. To undertake urodynamic studies in all those with symptoms of impaired storage/voiding would be timeconsuming and costly, well beyond the resources of most urology departments throughout the world. Cost-benefit analysis does indicate that if resources of time, equipment, and staff are available, savings can be made by operating on only the 70% of men with symptoms who have demonstrable obstruction.75 However, for most units these resources are not available and it would therefore appear reasonable to adopt the following practical guidelines for patients with moderate to severe symptoms: • It is reasonable to measure the flow rate in all men before considering treatment options. Because of variation in flow rates, some have argued that two or three tests should be done. • If the flow rate is greater than 15 ml/s, obstruction is unlikely. Symptoms might be due to overactive detrusor dysfunction. Urodynamic studies should be performed if the patient is bothered by the symptoms. • If the flow rate is less than 5 ml/s, the likelihood of obstruction is high, and pressure/flow studies are probably not necessary. • Where the flow rate lies between 5 and 15 ml/s, pressure/flow studies are advisable in order to identify which are obstructed and which have the low flow/low pressure syndrome. Guidelines for evaluation Because flow rate measurements are readily available and have some predictive value in the diagnosis, the flow rate is recommended by the WHO Sponsored International Consultation on Benign Prostatic Hyperplasia (BPH), for the evaluation of patients with impaired voiding or storage functions of the bladder. It is considered only as an optional test in the clinical practice guidelines for the diagnosis and treatment of BPH developed for the US Agency for Health Care Policy and Research (AHCPR) edited by McConnell et al.26 Guidelines as such, while aiming to improve the overall standard of care, are the lowest common denominator of acceptable care and not of ideal care. Thoughts about optimum pathways for diagnosis and treatment do change, indeed quite rapidly, so guidelines will need frequent revision. Another concern about guidelines is that there would be a risk that those funding healthcare might restrict their funding to users of their accepted guidelines and refuse to fund or support any additional tests or any tests considered ‘optional’ or for clinical research purposes. Measurement of the PVR is considered recommended by the International Consultation on BPH, although it would appear less easily justified for the reasons discussed above. More information is needed on the risk of upper tract dilatation in those who have small or insignificant residual urine volumes. If delays in treatment are a fact of life because of long waiting lists, it would seem prudent to assess upper urinary tracts by ultrasound, which is more sensitive in detecting upper tract dilatation than is measuring serum creatinine, a test recommended by both groups. For those with chronic retention and a palpably enlarged bladder which remains after voiding, the upper tracts should be checked by ultrasound before discussing treatment options aimed at improving bladder emptying. Secondly, if other treatment options are considered in managing the outlet obstruction, measurement of the PVR should be included in the protocols. It is not enough to rely on symptoms alone; flow rates and urodynamic studies should be included to measure what has been achieved. Who then should be treated? Most urologists would agree that those who develop the complications of obstruction, such as acute or chronic retention, and postobstructive renal failure, bladder stones, and recurrent urinary infections, file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_237.html[09.07.2009 11:53:14]

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should be treated. However, the majority present with symptoms. Priorities for selecting patients with bladder outlet

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Page 238 obstruction for treatment could be developed if we knew the risk factors for developing these complications; currently we do not. In particular, it appears no information can be gained from the symptoms, from the flow rate and its pattern, or from the PVR. If obstruction remains untreated, is there any evidence of progressive detrusor failure or progressive overactive detrusor dysfunction? Overactive detrusor dysfunction does become more frequent with aging irrespective of obstruction, and may become more bothersome in producing urgency and urge incontinence. The observation that postprostatectomy the detrusor instability improves in 30% of cases indicates that the micturition reflex is less excitable after obstruction is treated, but obstruction is only one factor predisposing to reflex excitability. Detrusor failure might develop or become progressive. Elbadawi54 suggests that this is so and that chronic fibrosis and elastosis causes separation of smooth muscle cells, which develop increased sarcolemmal dense bodies, and that there is degeneration of intrinsic nerves. All of this could cause reduced contractility due to obstruction. However, similar changes have been seen due to aging, Untreated, very few patients go into acute retention.28 It is likely that the pathophysiology is different in acute and chronic retention, rather than that chronic retention is the end stage of decompensation. The concern remains as to which patients with high pressure obstruction are those who will develop poorly compliant bladders and high end-filling pressures, and hence be at risk of upper tract dilatation and obstructive renal failure. Because the PVR varies within the same individual as well as according to the technique of assessing it, it remains impossible to predict who will go into chronic retention. There is no ‘grand unifying theory’, as Ball76 points out, that would indicate progression from symptoms which are so variable on to acute or chronic retention. If PVR is large and there is upper tract dilatation, then this should lead to prompt treatment. From symptoms and flow rate alone, it remains impossible to establish which patients are most in need of treatment. References 1. Dorflinger T, Bruskewitz R C, Jensen K M E et al. Predictive value of low maximum flow rate in benign prostatic hyperplasia. Urology 1986; 27; 569–573 2. Rosier P F W M, Rollema H J, van der Beek C, Janknegt R A. Diagnosis of ‘prostatism’ relation between symptoms and urodynamic evaluation of obstruction and bladder function. Neurourol Urodyn 1992; 11:399–400 3. Arnold E P. Bladder outlet obstruction in the male: a urodynamic analysis of the detrusor responses. PhD thesis, University of London, 1980 4. Brading A F. A myogenic basis for the overactive bladder. Urology 1997; 50:57–67 5. Andersen J T, Nordling J, Walter S. Prostatism. 1. The correlation between symptoms, cystometric and urodynamic findings. Scand J Urol Nephrol 1979; 13:229–236 6. Simonsen O, Moller-Madsen B, Dorflinger T et al. The significance of age on symptoms—urodynamic and cystoscopic findings in BPH. Urol Res 1987; 15:355–358 7. Iversen P. Bruskewitz R C, Jensen K M E, Madsen P O. Transurethral prostatic resection in the treatment of prostatism with high urinary flow. J Urol 1983; 129:995–997 8. Barry M J, Cockett A T K, Holtgrewe H L et al. Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 1993; 150:351–358 9. Reynard J M, Yang Q, Donovan J L et al. The ICS-BPH study: uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. Br J Urol 1998; 82:619–623 10. Grino P B, Bruskewitz R, Blaivas J G et al. Maximum urinary flow rate of uroflowmetry: automatic or visual interpretation. J Urol 1993; 149:339–341 11. Ryall R L, Marshall V R. Normal peak urinary flow rates obtained from small voided volumes can provide a reliable assessment of bladder function. J Urol 1982; 127:484–488 12. George N J R, Slade N. Hesitancy and poor stream in younger men without outflow tract obstruction —the anxious bladder. Br J Urol 1979; 51:506–510 13. Haylen B T, Ashby D, Sutherst J R et al. Maximum and average urine flow rates in normal male and female populations—the Liverpool nomograms. Br J Urol 1989; 64: 30–38 14. Siroky M B, Olsson C A, Krane R J. The flow rate nomogram: I development. J Urol 1979; 122:665– 668 15. Hansen M V, Zdamowski A. The value of a patientadministered home flow test compared to office uroflowmetry in the evaluation of prostatism patients. Neurourol Urodyn 1994; 13:452–453 16. Golomb J, Lindner A, Siegel Y, Koczak D. Variability and Circadian changes in home uroflowmetry in patients with BPH compared to normal controls. J Urol 1992; 147: 1044–1047 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_238.html[09.07.2009 11:53:14]

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17. Griffiths D J. Effects of bladder outlet obstruction. Prospective 1992; 2:1–8 18. Griffiths D J, van Mastrigt R, Bosch R. Quantification of urethral resistance during voiding, with special reference to the effects of prostatic size reduction or urethral obstruction due to BPH. Neurourol Urodyn 1989; 8: 17–27

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Page 239 19. Underberg Poulsen E, Kirkeby H J. Home monitoring of uroflow in normal male adolescents: relation between flow curve, voided volume and time of day. Scand J Urol Nephrol 1988; 114 (Suppl): 58–61 20. von Garrelts B. Micturition in the normal male. Acta Chir Scand 1957; 114:197 21. Abrams P H. The urine flow clinics. In: Fitzpatrick J N (ed). Conservative treatment of BPH. Edinburgh: Churchill Livingstone, 1991:33–43 22. Drake W M. The uroflowmeter: an aid to the study of the lower urinary tract. J Urol 1948; 59:650– 658 23. Siroky M B, Olsson C A, Krane R J. The flow rate nomogram: II clinical correlation. J Urol 1980; 123:208–210 24. Lim C S, Reynard J, Abrams P. Flow rate nomograms. Their reliability in diagnosing bladder outflow obstruction. Proc ICS 1994; 74–75 25. Schafer W, Noppency R, Rubben H, Lutzmeyer W. The value of free flow rate and pressure/flow studies in the routine investigation of BPH patients. Neurourol Urodyn 1988; 7:219–221 26. McConnell J D, Barry M J, Bruskewitz R C et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical practise guidelines. AHCPR Publication No. 94–0582. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service. US Department of Health and Human Services, February 1994 27. Marshall V R, Ryall R L, Austin M L, Sinclair G R. The use of urinary flow rates obtained from voided volumes less than 150 mls in the assessment of voiding ability. Br J Urol 1983; 55:28–33 28. Ball A J, Feneley R C L, Abrams P H. The natural history of untreated prostatism. Br J Urol 1981; 53:613–616 29. Drach G W, Layton T, Bottaccini M R. A method of adjustment of male peak urinary flow rate for varying age and volume voided. J Urol 1982; 128:960–962 30. Jorgensen J B, Jensen K M E, Bille-Brake N E, Mogensen P. Uroflowmetry in asymptomatic elderly males. Br J Urol 1986; 58:390–395 31. Jorgensen J B, Jensen K M E, Mogensen P. Age-related variation in urinary flow variables and flow curve patterns in elderly males. Br J Urol 1992; 69:265–271 32. Gleason D M, Bottaccini M R, Drach G W, Layton T N. Urinary velocity as an index of male voiding function. J Urol 1982; 128:1363–1367 33. Chancellor M B, Blaivas J G, Kaplan S A, Axelrod S. Bladder outlet obstruction versus impaired detrusor contractility: the role of uroflow. J Urol 1991; 145:810–812 34. Rollema H J, Ambergen A W, van den Ouden D. On-line uroflowmetry in males: clinical application to small (<100 mls) voided volumes. Neurourol Urodyn 1989; 8: 407–408 35. Abrams P H, Griffiths D J. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 1979; 51:129–134 36. Gerstenberg T C, Andersen J T, Klarskov P et al. High flow infravesical obstruction in men: symptomatology, urodynamics and the results of surgery. J Urol 1982; 127: 943–945 37. Abrams P. Prostatism and prostatectomy: the value of urine flow rate measurement in the preoperation assessment for operation. J Urol 1977; 117:71–74 38. Neal D E, Styles R A, Powell P H, Ramsden P D. Relationship between detrusor function and residual urine, in men undergoing prostatectomy. Br J Urol 1987; 60:560–566 39. Turner-Warwick R T, Whiteside C G, Arnold E P et al. A urodynamic view of prostatic obstruction and the results of prostatectomy. Br J Urol 1973; 45:631–645 40. Neal D E, Ramsden P D, Sharples L et al. Outcome of elective prostatectomy. Br Med J 1989; 299:762–767 41. Jorgensen J B, Jensen K M E, Mogensen P. Predictive value of uroflowmetry in prostatism. Neurourol Urodyn 1987; 6: 221–223 42. van Mastrigt R. Is it really necessary to do a pressure-flow study in each patient? Neurourol Urodyn 1993; 12: 419–420 43. Rollema H J, van Mastrigt R. Improved indication and follow-up in transurethral resection of the prostate using the computer program CLIM: a prospective study. J Urol 1992; 148:111–116 44. Jensen K M E, Jorgensen J B, Mogensen P. Urodynamics in prostatism: 1. Prognostic value of uroflowmetry. Scand J Urol Nephrol 1988; 22:109–117 45. Jensen K M E. Clinical evaluation of routine urodynamic investigations in prostatism. Neurourol Urodyn 1989; 8: 545–578 46. Nordling J. Definition of prostatic urethral obstruction. Urol Res 1994; 22:267–271 47. Di Mare, Fish S R, Harper J M, Politano V A. Residual urine in normal male subjects. J Urol 1966; file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_239.html[09.07.2009 11:53:15]

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96:180–181 48. Bruskewitz R C, Iversen P, Madsen P O. Value of post void residual urine determinations in evaluation of prostatism. Urology 1982; 20:602–604 49. Stoller M, Millard R J M. The accuracy of a catheterized residual urine. J Urol 1989; 141:15–16 50. Birch N C, Hirst G, Doyle P T. Serial residual urine volumes in men with prostatic hypertrophy. Br J Urol 1988; 62:571–575 51. Griffiths D J. The mechanics of the urethra and of micturition. Br J Urol 1973; 45:497–507

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Page 240 52. Williams J H, Turner W H, Sainsbury G M, Brading A F. Experimental model of bladder outflow tract obstruction in the guinea pig. Br J Urol 1993; 71:543–554 53. Gilling P J, Arnold E P. Contractility of detrusor muscle from patients undergoing elective transurethral resection of the prostate. Proceedings of the Urological Society of Australasia AGM 1990. Br J Urol 1991:400 54. Elbadawi A. BPH-associated voiding dysfunction: detrusor is pivotal. Contemp Urol 1994; 6:21–38 55. Schafer W. Urethral resistance? Urodynamic concepts of physiological and pathological bladder outlet function during voiding. Neurourol Urodyn 1985; 4:161–201 56. Schafer W. Analysis of active detrusor function during voiding with the bladder working function. Neurourol Urodyn 1991; 10:19–35 57. Griffiths D J, Constantinou C, van Mastrigt R. Urinary bladder function and its control in healthy females. Am J Physiol 1986; 251: R225-R230 58. Griffiths D J. Residual urine, underactive detrusor function, and the nature of detrusor/sphincter dyssynergia. Neurourol Urodyn 1983; 2:289–294 59. Resnick N M, Yalla S V. Detrusor hyperactivity with impaired contractile function. An unrecognized but common cause of incontinence in elderly patients. J Am Med Assoc 1987; 257:3076–3081 60. Ghoneim G M, Susset J G. Impaired bladder contractility in association with detrusor instability: underestimated occurrence in benign prostatic hyperplasia. Neurourol Urodyn 1988; 7:230–231 61. George N J R, Feneley R C L, Roberts J B M. Identification of the poor risk patient with ‘prostatism’ and detrusor failure. Br J Urol 1986; 58:290–295 62. Frimodt-Moller C. Diabetic cystopathy: epidemiology and related disorders. Ann Intern Med 1980; 92:318–321 63. Parys B T, Machen D G, Woolfenden K A, Parsons K F. Chronic urinary retention—a sensory problem? Br J Urol 1988; 62:546–549 64. Shoukry I, Susset J G, Elhillali M M, Dutartre D. Role of uroflowmetry in the assessment of lower urinary tract obstruction in adult males. Br J Urol 1975; 47:559–566 65. Andersen J T. Prostatism III. Detrusor hyperreflexia and residual urine. Clinical and urodynamic aspects, and the influence of surgery on the prostate. Scand J Urol Nephrol 1982; 16:25–30 66. Griffiths H J. An evaluation of the importance of residual urine. Br J Radiol 1970; 43:409–413 67. Cetinel B, Turan T, Talat Z et al. Update evaluation of benign prostatic hyperplasia: when should we offer prostatectomy? Br J Urol 1994; 74:566–571 68. Hasner E. Prostatic urinary infection. Acta Chir Scand 1962; 285 (Suppl): 1 69 Hampson S J, Noble J G, Richards D, Milroy E J G. Does residual urine predispose to urinary tract infection? Br J Urol 1992; 70:506–508 70 Abrams P H, Dunn M, George N. Urodynamic findings in chronic retention of urine and their relevance to the results of surgery. Br Med J 1978; 2:1258–1260 71. Styles R A, Ransden P D, Neal D E. The outcome of prostatectomy on chronic retention of urine. J Urol 1991; 146:1029–1033 72. Jacobsen S J, Jacobson D J, Girman C et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997; 158:481–487 73. Caine M, Perlberg S. Dynamics of acute retention in prostatic patients and role of adrenergic receptors. Urology 1977; 9:399–403 74. Klarskov P, Andersen J T, Asmussen C F et al. Symptoms and signs predictive of the voiding patterns after acute urinary retention in men. Scand J Urol Nephrol 1987; 21: 23–28 75. Nordling J. Views from international experts. Prospectives, Kirby R (ed). July 1994:7 76. Ball A J. Natural history of benign prostatic hyperplasia. Prospectives 1992; 3:1–5

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Page 241 17 Urodynamics and benign prostatic hyperplasia A E Te E F Ikeguchi S A Kaplan Introduction Despite the many medical and technological advances available to us in the new millennium, there is still no definitive answer addressing the role of urodynamics in the evaluation of men with symptoms of prostatism. In part, this is due to clinical differences between the symptoms commonly attributed to benign prostatic hyperplasia (BPH) and the presence or absence of mechanical bladder outflow obstruction as defined by urodynamics.1–3 Because pressure-flow urodynamic studies remain the most definitive method of documenting outflow obstruction, they serve as the best instrument to differentiate men whose symptoms are due to prostatic obstruction versus inherent bladder dysfunction.1 However, within the realm of obtaining a diagnosis of BPH, do we need to diagnose obstruction? Is management of patients with symptoms of prostatism significantly altered by the knowledge that the patient has urodynamic evidence of outflow obstruction? Consequently, do patients with documented urodynamic outflow obstruction fare better after procedures designed to alleviate obstruction, i.e. prostatectomy, than those who do not? Finally, in the face of all the newer minimally invasive technologies for the treatment of symptomatic BPH, how does urodynamic evaluation have an expanding role, or can clinicians truly tailor their therapeutic recommendations based upon history and physical exam alone? Until recently, there have been few objective studies of the natural history of untreated prostatism.3,4 This remains the case with regard to untreated ‘urodynamic obstruction’. In addition, past studies of the natural progression of BPH have been hard to evaluate because of the poor correlation of symptoms with age of the patient, size of the prostate gland, and urodynamic parameters such as uroflow, postvoid residual, and detrusor pressure.3,5–12 However, in 1997, Jacobsen et al. reported their findings on the natural history of BPH in a cohort of over 2000 randomly selected men aged 40 to 79 in Olmsted County, Minnesota.13 They found that in men with urinary symptoms and physical findings consistent with BPH, the incidence of urinary retention was dramatically increased with age and symptoms. The incidence of acute urinary retention amongst men in the general population in the studied age range was 7/1000 person-years of follow-up. This was in contrast to men in their seventies who had a 1 in 10 chance of acute urinary retention within 5 years’ follow-up, and even greater risk if they had urinary symptoms. Jacobsen et al. identified several risk factors for acute urinary retention as being age greater than 70 years, American Urological Association (AUA) symptom index of 8 or greater, and a prostatic size determined by digital rectal examination of greater than 30 g. In addition, they identified one of the ‘urodynamic parameters’ as clearly having a predictive value in patient outcome. Patients in their study with a peak urinary flow rate ( Q max) of <12 were found to have a 3.9-fold unadjusted or 2.1-fold adjusted relative risk of urinary retention. As more medical and surgical therapies evolve, the treatment of BPH is becoming more of an artform than a science. Nonetheless, there still is a need for some objectivity to support a clinician’s decision to offer one therapy over another in any given instance. In another study of the natural behavior of BPH, Wasson et al. addressed the issue of the ultimate outcome of people with moderate lower urinary tract symptoms (LUTS) due to BPH randomized to either watchful waiting or transurethral resection of the prostate (TURP) in a prospective multicenter trial.14 Over an average follow-up period of 2.8 years, immediate TURP was found to be superior to watchful waiting in regard to treatment failure and in eradicating moderate to severe LUTS. Of course the question in today’s era becomes: what kind of TURP? As in the cancer analogy, are we as clinicians capable of identifying which patients with BPH will do ‘worse’? All these issues are reflective of the controversy involved in applying urodynamics to the diagnosis of BPH. However, it is valid to conclude that urodynamic studies continue to be a valuable tool in elucidating pathophysiologic and therapeutic aspects of BPH. This chapter reviews various technical and clinical urodynamic issues, including their clinical diagnostic impact, indications for usage, and clinical utility in the management of men with ‘prostatism.’ Background The relationship of voiding symptoms to bladder function and outlet obstruction is not simple. Although voiding

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Page 242 symptoms often represent the clinical manifestations of inherent detrusor dysfunction and/or outlet obstruction, this relationship is not universal. ‘Silent’ obstructive uropathy secondary to BPH, for example, may occur without the patient experiencing significant voiding symptoms. Clinically, these symptoms are not ‘prostate specific’ and can often represent other ‘nonprostatic’ etiologies such as impaired bladder contractility, detrusor instability, sensory urgency, and vesical neck obstruction.15–19 In fact, about 25–50% of men undergoing urodynamic investigation for prostatism symptoms do not have urodynamic evidence of obstruction.18,20,21 In the authors’ review of the records of over 2500 consecutive men with symptoms of prostatism undergoing synchronous video pressure-flow urodynamic studies between February 1982 and July 1994, among the 787 evaluable patients, the most common diagnosis was prostatic obstruction and detrusor instability (39%), followed by isolated prostatic obstruction (23%). Only 504 patients (64%) had demonstrable urodynamic evidence of prostatic urethral obstruction, of which 318 (63%) had concomitant detrusor instability. For the group, 425 (54%) had detrusor instability; 181 (23%) had it as their sole diagnosis. Impaired detrusor contractility was noted in 134 (17%) patients; 49 (6%) of these had it as their only diagnosis. Finally, three (0.4%) patients had sensory urgency as the urodynamic etiology of their symptoms. To clarify the poor correlation between what a patient feels and what is occurring physiologically, uroflowmetry and multichannel urodynamics have been applied to provide a rational diagnostic approach to BPH. However, the suitability of urodynamics in assessing BPH has been confounded by controversy, as study findings have been difficult to reproduce.1–3 Furthermore, there is debate among leading urodynamic experts about which parameters to assess. Some inconsistencies can be attributed to differences in technique, equipment, operator interpretation, patient population, and patient cooperation.22,23 Within the modern realm of urodynamics there are few, if any, true controls or normal standards. Currently, urodynamic studies provide a meaningful understanding of bladder function and its potential relationship to outlet obstruction. More importantly, they are clinically useful in diagnosing subtle differential etiologies of irritative and obstructive voiding symptoms, incontinence, urinary retention, and the development of bladder outlet obstruction.1–3,17 Their greatest clinical impact has been in elucidating voiding dysfunctional processes in patients with an underlying associated neurologic process such as spina bifida, multiple sclerosis, diabetes, and others in the face of BPH.3,17,24–28 In addition, they have provided a more objective measurement of success in outcomes of BPH treatments whose previous yardsticks of success were based on subjective criteria.28–32 Cystometry A simple but invasive urodynamic study is the cystometrogram (CMG). Technically, there are two types, the filling CMG and the voiding CMG. The term CMG generally refers to a filling CMG and can be performed with either a gas or liquid medium. The study is generally performed with a two-lumen catheter, one lumen to fill the bladder and the other to measure intravesical pressure. The filling CMG provides information regarding bladder capacity, presence of involuntary detrusor contractions (IDC), bladder compliance, and contraction pressures. However, the major limitation of simple cystometry is that the urodynamic diagnosis of bladder outlet obstruction cannot be made.17,33 Data provided by several studies, including the authors’ own, indicate that approximately 60% of men with symptoms of prostatism have IDC; postoperatively the incidence is 25–30%.15,17,18,20,33–35 Although the presence of IDC may be associated with higher treatment failure after prostatectomy, there is currently no a priori method to predict which patients will have persistent IDC after therapy.36,37 In addition, although a CMG may provide valuable information in patients with concomitant neurologic conditions such as Parkinson’s disease or diabetes, it is not as valuable as video multichannel pressureflow studies.2,27 Currently, simple cystometry is not recommended by the AUA BPH guidelines.28 Multichannel urodynamics and video multichannel urodynamics Multichannel urodynamics are synchronous pressure—flow studies ‘and are best suited to define bladder outlet obstruction. Simultaneous fluoroscopic video allows for visualization of the precise anatomic location of obstruction (prostatic obstruction versus vesical neck obstruction) in men with symptomatic prostatism (Fig. 17.1).38 In addition, it can better define issues of impaired contractility, detrusor instability, and sensory urgency.17,25,39–41 It is particularly valuable in assisting in the differential diagnosis of patients with an associated underlying neurologic or postoperative surgical condition. Essentially, it fills the diagnostic void left by simple uroflowmetry and cystometry. However, one caveat of pressure-flow studies is that

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Figure 17.1 Simultaneous video multichannel urodynamics (voiding cystourethrogram views): (a) patient with prostatic obstruction; (b) patient with impaired contractility; (c) file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_243.html[09.07.2009 11:53:17]

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patient with classic vesical neck obstruction. Note that (a) and (b) are indistinguishable radiographically but that (a) demonstrates a detrusor contraction (high detrusor pressure) whereas (b) does not. there are significant combinations of detrusor pressures and flows that are diagnostically equivocal. The principal role of multichannel urodynamics is to analyze the act of micturition. In other words, what is the detrusor function as measured by its generation of pressure in relation to its outlet resistance as defined by its flow? The association of an elevated voiding pressure with low peak urinary flow is the sine qua non of bladder outlet obstruction.17,24 Reduced bladder pressure function or contractility is defined as low voiding pressure in the presence of diminished flow (‘low pressure, low flow’). One main advantage of the multichannel urodynamic study is its ability as a pressure-flow study to distinguish whether low urinary flow is secondary to obstruction and to impaired contractility. It also facilitates the identification of normal urinary flow and high detrusor contraction pressure due to obstruction. It also allows measurement of capacity, filling pressure, various parameters of a contraction, and the presence of uninhibited contractions; observation of detrusor sphincter synergy and anatomic function; clarification of bladder function in the neurologic patient; and a pretherapeutic assessment of bladder function that improves outcome prediction. Thus, it has become an objective physiologic tool with which to study patients with BPH.6,17,21,42–46 Methods and techniques The standard multichannel urodynamic study consists of simultaneous synchronous real-time measurements of abdominal pressure, total intravesical pressure, a calculated detrusor pressure, (total intravesical pressure minus abdominal pressure), and a urinary flow rate. In addition, other simultaneous measurements can be performed to provide additional information—electromyography (EMG) of the striated sphincter, video cystourethroradiographic imaging during voiding, and urethral pressure profilometry.17,47–50 A standard multichannel urodynamic flow recording is demonstrated in Figure 17.2. EMG, in the authors’ practice, has little role as a diagnostic modality in patients with lower urinary tract symptoms; it has been reserved for those patients suspected of having external urethral contractions (‘pseudodyssynergia’) during voiding.25 Urethral pressure profilometry (UPP) involves synchronous measurement of urethral and bladder pressure. Normally, the bladder and prostatic urethra are isobaric during voiding. The occurrence of a ‘pressure drop’ in the urethra suggests obstruction. Teleologically, UPP should be the optimal method of assessing outlet obstruction. However, because of difficulty in standardizing

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Figure 17.2 A multichannel urodynamic study. Component simultaneous measurements include the following: (1) uroflowmetry; (2) P1/Pves=total intravesical pressure; (3) P2/Pabd=abdominal pressure; (4) P1−P2/Pdet=detrusor pressure; (5) volume infused; (6) electromyelography. significant ‘pressure drops’, UPP has not been used routinely in men with BPH.17 Urodynamic quantitative analytic investigation of prostatic obstruction As with all objective scientific instruments of measurement, standards of reference are important.24 In considering the various techniques proposed to analyze prostatism, one must take into account the variability of urodynamic philosophies and operator preference utilized in each set of analytic studies. Specifically, issues as simple as catheter size (8–14 Fr), employment of suprapubic access, techniques of zeroing, and type of EMG probe may cause differences in standards of reference of various individual laboratories and thus in interpretation of data. However, the basic concepts of diagnosis are the same. In urodynamics, much attention has been given to both biomechanical engineering and mathematical modeling using theoretical dynamic states of voiding. Early efforts emphasized theories based on rigidtube physics.50,51 These efforts evolved into complex equations analyzing resistance coefficients/factors. These factors were then developed into elegant models to describe the complex relationships between detrusor pressure and flow, utilizing sophisticated computer analysis to simplify the process. Given the lack of fixed parameters to compare, a series of correlated parameters has been developed and studied.50,52–56 Whereas the subjective definition of obstruction is easy to understand and identify, quantifiable standards for comparison have been difficult. Detrusor pressure has been the subject of various cutoff criteria for obstruction in the low-flow state. This value has varied from 45 to 100 cmH2O at the peak of urinary flow.17,24,57 Because pressure is flow (force) against a resistance produced by an obstruction, one can theoretically calculate a resistance factor to define the cut-off for significant obstruction. Early endeavors tried to derive and describe this outlet or urethral resistance factor based on the rigid tube hydrodynamic theory described by Griffiths in 1975.51 If the calculated factor exceeded a certain value, obstruction would be diagnosed. Applying a predefined resistance factor of 0.6, Bruskewitz et al. examined 46 patients treated for prostatism and found no significant changes in subjective or objective criteria in

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Page 245 patients above or below the defined cut-off criteria.58 This is not surprising, as the urethra is not a rigid tube. Because the concept of simplifying urethral function to its cross-sectional area was attractive, it was the subject of many attempts to characterize outlet obstruction. However, as stated previously, these attempts were based on a hydrodynamic basis of voiding; that is, the bladder outlet is similar to a rigid pipe with the urinary stream compared to laminar or turbulent flow. However, these models are limited by the following: • In a strict physical and mathematical sense, flow is neither turbulent nor laminar. • All resistance factors are calculated for a single point in the voiding cycle and thus do not reflect timedependent flow changes. In addition, the urethra is elastic and distensible, and the flow-controlling zone is situated in the membranous urethra, as described by rigid-tube hydrodynamic theory.52,59,60 Although many have reported application of these resistance factors, some of which are still in use, it should be emphasized that the pathophysiologic meanings of calculated values remain vague and hard to compare.52,54,60 In obvious cases of high pressure/low flow states or low pressure/high flow states, the equation works well. However, in borderline cases, especially in preoperative evaluations, it has proved inadequate. Thus, the concept of these resistance factors based on rigid-tube hydrodynamic theory was abandoned by the International Continent Society Standardization Committee in 1979.60,61 Additional attempts have been made to describe and interpret the voiding phase of the bladder through the characterization of the outlet alone and are achieved by quantifying ‘resistance’ or energy loss in the bladder outlet by factors based on advanced theoretical hydrodynamic understanding of micturition.52 These efforts have involved developing conclusive biophysical models and have thereby derived advanced analytic procedures to assess characteristic features of voiding dynamics from pressure-flow recordings.40,56,60,62 These natural analytic extrapolations of the hydrodynamic concepts have encouraged many investigators to apply elegant mathematical models to characterize the complex interrelationship between detrusor pressure and uroflow.56,59,60 To determine the adequacy of the detrusor contraction with respect to flow rate, several investigators have devised mathematical definitions of bladder outlet obstruction by calculating ‘resistance coefficients’.51–54,59,60 Because flow is dependent not only on outlet resistance but also on the power or pressure behind the resistance, this required investigators to first focus on techniques to assess the power of the bladder muscle or detrusor contractility. The work of Griffiths describes a method to assess quantitatively the strength of detrusor contractions during any voiding where flow rate, detrusor pressure, and residual urine are measured.25,51,59,62 This is done by mathematically extrapolating a single point from the Hill curves, i.e. force versus contraction velocity. The parameters assessed include power (the product of detrusor pressure (Pdet) and flow rate) and work (power integrated over time). Within a physiologic range, maximum power increases with initial volume in the bladder as a function of the stretch created. This leads to an increase in peak flow with large volumes voided. However, when comparing power developed by the detrusor in bladders before and after prostatectomy, Schafer reported no differences.52 He suggested that the overall contractile capability of the bladder is limited and well determined before surgery. However, Gleason looked at power at one point in time, either at maximal flow or maximal detrusor pressure, and reported a 20% increase after prostatectomy.48 This suggests that, rather than a series of points, ‘maximal’ power may be a more important parameter. This is particularly true because power is volume dependent and is not constant for a constant contraction strength, failing to zero if the contraction is isovolumetric. Detrusor contractility has also been defined by measurement of the ‘bladder output relation’, which is a mathematical relationship between pressure and flow based on the Hill model (an equation describing the relation between force and contraction velocity of a muscle). More recently, Griffiths has used the term WF, a factor depend’ ent on detrusor pressure, uroflow, speed of detrusor contraction, and bladder volume.62–64 The advantage of such a model is that its two adjustable parameters—isovolumetric pressure and detrusor shortening velocity—are volume independent. In the authors’ laboratory, using a rabbit whole bladder in vitro model, changes in urethral resistance resulted in significant changes in both maximal power and WF.65,66 It is noteworthy that detrusor pressure did not show variation with alteration of outlet resistance. Of interest, in a review of the urodynamic literature, Nielsen et al. reported considerable overlap in maximal intravesical detrusor pressure and intravesical detrusor opening pressure in men with and without obstruction.60 It may be possible, therefore, to extrapolate that therapies that alter and reduce outlet resistance may result in file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_245.html[09.07.2009 11:53:18]

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Page 246 By utilizing the complex relationship between pressure, flow and outlet resistance during the dynamic function of voiding, biophysical models and advanced quantitative analytic techniques have been developed to study this complex relationship. These elegant models have sought to characterize and simplify this complex relationship to a quantitative value of comparison. In the 1970 s, Griffiths et al. introduced their urethral resistance relation, a graphic concept that analyzed the relationship between detrusor pressure and flow during voiding to define the lowest resistance when the bladder outlet was passive or relaxed.67–69 This graphic relationship later evolved to a pressure-flow nomogram in 1979, due to Abrams and Griffiths.16 With this nomogram (Fig. 17.3), patients could be classified as obstructed, equivocal, or unobstructed. In 1988, Jensen et al. classified a group of patients undergoing prostatectomy for ‘prostatism’ according to the nomogram.19 Those classified as obstructed preoperatively became unobstructed postoperatively, on the basis of the nomogram and various other urodynamic parameters. Those unobstructed preoperatively remained unobstructed postoperatively without significant changes in other urodynamic parameters. These results validating the Abrams-Griffiths (AG) nomogram were similarly confirmed by Rollema and van Mastrigt in 1992.70 To advance further the concepts involved in the AG nomogram to a quantitative value of comparison, the analysis of the relationship between pressure, flow, and outlet resistance evolved into a complex graphical quadratic equation that simplified this relationship into a variety of quantitative values for comparison. In some models, computer analysis was employed. The following is a brief description of various published models and quantitative parameters. Schafer’s model describes the urethra as a distensible tube with a flow-controlling zone in its proximal urethra.11,50,52,64,71 A relationship between detrusor pressure and flow rate is described by the tube’s distensibility and the size of the flow-controlling zone. It has been simplified to an estimated graphical relationship called PURR, the passive urethral resistance relationship. From this graphical description, an index quantifying obstruction is derived, termed the LPURR, the linear passive urethral resistance relation. This is derived by looking up the position of a line segment that connects the point Q max, p ( Q max) with the point of lowest pressure during flow in a nomogram (Fig. 17.4). As an extrapolation of this theory from the AG nomo gram, Griffiths et al. proposed the group-specific factor URA to characterize obstruction.62 This parameter is estimated from the intersection of the quadratric urethral

Figure 17.3 Plot of detrusor pressure versus flow rate with the Abrams-Griffiths (AG) nomogram demonstrating pressure-flow regions of obstructed/equivocal/unobstructed relationships based on maximum pressure-flow recordings. Dotted line indicates extrapolation of an AG number: if Pdet=80 and Qmax=10, AG no=60.

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Page 247 resistance relation with the pressure axis of the pressure-flow rate plot, basically connecting point Q max, p ( Q max) to the lowest pressure point during flow. A groupspecific URA nomogram was then created (Fig. 17.4). From the nomogram, a simpler AG number can be extrapolated.72 To obtain the AG number from the pressure-flow plot, a line is drawn through the PdetQ max/ Q max point, parallel to the upper line of the AG nomogram, to intersect with the pressure axis where an AG number is derived (Fig. 17.3). In 85 patients, Lim et al. compared AG number, URA, and LPURR.72 They found that the agreement between AG number and URA was 94%, the agreement between AG number and LPURR was 98.2%, and the agreement between URA and LPURR was 94.7%. Thus the three parameters appear to substantiate each other. In an application utilizing computer analysis, van Mastrigt and Rollema developed a computer program, CLIM, to analyze detrusor pressure, flow rate signals during voiding, and isometric detrusor pressure increase just before flow starts.70,73,74 From this analysis, U/L, the maximum extrapolated rate of increase of isometric pressure, as well as URA, can be calculated. In addition, OBI, another quantification of urethral resistance, can be calculated. Briefly, OBI is the parameter that fits the lowest part of a pressure-flow rate relation with an orthogonal polynomial.75 Kranse and van Mastrigt critically compared URA, LPURR, OBI, Q max, and pQ max for quantification of bladder outlet obstruction.76 Utilizing various alternative methods of comparing and classifying obstruction preoperatively and postoperatively, they critically analyzed the

Figure 17.4 Pressure-flow plot of a void and a demonstration of a graphical estimate of PURR ( ) LPURR ( ) and URA of this void. The group-specific URA nomogram curves (—) are for values of 10 and are calculated on the basis of the formula: URA=puo (urethral opening pressure)=[(1+4dQ2Pdet) 1/2−1]/(2dQ2), where d=0.00038. The pressure-flow curve is shown as .

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Page 248 sensitivity and specificity of each factor. They concluded that different classifications lead to different conclusions and that these parameters have a dependence on contractility that is not analyzed, and which affects their ability to measure obstruction. In addition, Spangberg et al. described a model based on computer analysis of pressure-flow data.77,78 Briefly, the model describes the flow-controlling zone I in the urethra as it distends with increasing urethral pressure and calculates a urethral pressure/area relationship quantity. Its clinical usefulness still remains to be examined. In 1988, Sarky and Blaivas described a series of computer-generated parameters that added a time factor to the pressure-flow curve.79,80 This was translated into a bladder outlet conductance curve and a conductance factor was generated. Although this factor seems to be decreased in patients with outlet obstruction, its clinical validity remains to be determined. Another interesting urodynamic parameter is detrusor contraction duration, which is the length of time during which the detrusor is contracting. It is measured from the first upward contraction pressure deflection until its return to baseline. The parameter is reminiscent of Griffiths’ work on assessing the strength of bladder contraction. In his equation, Griffiths incorporated detrusor work which factors in the variable of time into its definition. In 1996, detrusor contraction duration was studied to ascertain whether or not any particular urodynamic parameter would correlate with AUA symptom score. The authors found that there was no correlation between uro dynamic parameters and symptoms in women. However, it was determined that the two urodynamic parameters which most accurately correlated with worsening LUTS in males was the presence of involuntary detrusor contractions and the presence of prolonged detrusor contraction duration.81 As this brief description of these various models and parameters demonstrates, the state of quantitative urodynamic analysis and comparison of urodynamic data is still evolving and being assessed. Although the concepts are basic and useful in daily qualitative clinical application towards a urodynamic diagnosis, the quantitative techniques and parameters are at present all theoretical estimates of obstruction, as well as being too complicated and cumbersome for daily urodynamic patient examinations. Despite these analytic limitations, the pressure-flow relationship may serve as the most widely clinically applicable measurable urodynamic parameter. In the study by Spangberg et al.,54 23 men were studied both pre- and postoperatively with sophisticated pressure-flow studies. A host of ‘contractility’ and ‘resistance’ factors were measured, including the more standard detrusor pressure at maximum flow and maximal detrusor pressure. In this small population, conventional curve fitting of the pressure-flow plot allowed urodynamic estimation for quantifying obstruction, to determine whether detrusor pressure was adequate and to ascertain bladder function. Similarly, Jensen and Andersen noted that utilization of obstructive parameters (catheterized flow of less than 12 ml/s and a peak detrusor pressure of more than 45 cmH2O) lowered the failure rate after surgery from as high as 20% to 8% and increased the exclusion from surgery from 5% to 9%.35 However, to date there have been no long-term follow-up pressure-flow analyses in symptomatic patients with prostatism who are left untreated, or those who are treated either surgically or pharmacologically. Clinical application of urodynamic studies and BPH treatments One important question that remains to be elucidated fully is the predictive value of urodynamic studies —specifically, their value in predicting which patient will benefit most from intervention and which will not improve after intervention. In particular, are urodynamic studies instrumental in providing information to obtain the best outcome, both symptomatically and objectively? Studies utilizing urodynamics to predict outcome look at several urodynamic parameters and associated outcome success based on two general criteria—an objective measure such as flow rate and a subjective criterion such as patient satisfaction or improved symptomatology. In 1979, Abrams et al. examined 152 men who underwent prostatectomy for BPH based on urodynamic testing.15 Although the study did not specify the operative criteria or the process of operative decisionmaking, Abrams et al. reported 86% of patients improved, on the basis of Q max and a decrease in voiding pressure. Subjectively, 88% of patients had improvement in their symptoms. In an earlier study, Abrams reported that the inclusion of urodynamic testing in the operative criteria lowered their postoperative failure from 28% to 12%.29 However, 28% is a higher surgical failure rate than that reported by others.28 The application of urodynamic pressure-flow studies to operative criteria is also advocated by Abrams and Griffiths, who reported that 50% of patients could be correctly classified as obstructed and unobstructed, on the basis of Q max alone.16 In addition, with detrusor pressure at Q max, the diagnostic accuracy increased to 66%. The remaining one-third were assessed with pressure-flow file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_248.html[09.07.2009 11:53:19]

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Page 249 plots and many of these demonstrated impaired contractility as a factor for their low-flow state. If the addition of multichannel urodynamic testing appears to have improved diagnostic accuracy, is it possible to identify a population of patients who would most benefit from these studies without having to perform them on every patient to increase diagnostic accuracy? In 1988, Kuo and Tsai examined 50 patients urodynamically and by a general symptom analysis, before and after prostatectomy.82 Subjective outcome analysis was divided into good, fair, and worse. They looked at the subjective outcome analysis of the prostatectomy based on selected preoperative urodynamic parameters such as different levels of Q max, and those with high-pressure obstruction, low-pressure obstruction and lowpressure/no obstruction (LPNOB). While they concluded that prostatectomy might be best for those with a Q max less than 15 ml/s and for those with high-pressure obstruction, the more interesting observation is the poor outcome in patients with a Q max greater than 15 ml/s and those classified as LPNOB. Since the failure rate is this high, does this identify a population with flows greater than 15 ml/s who would benefit from multichannel urodynamic testing to identify them as LPNOB? Do these patients with poor subjective outcome fail after prostatectomy because their symptoms are due to involuntary contractions? Recently, the application of sophisticated computer analysis of pressure-flow data has been used by many to analyze BPH and treatment efficacy.83 Schafer et al. applied these complex analyses better to define passive and dynamic urethral resistance measurement.11,50,71 Using this model, they identified patients with low Q max who were not obstructed; objective improvement rates were 100% in the severely obstructed and less in the mildly obstructed. The application of this model, as well as the CLIM model by Rollema and van Mastrigt, improves the definition of obstruction and the efficacy of BPH treatment through better urodynamic assessment.73,74 However, in recent reports by Schafer et al. in which manual urodynamic analysis was studied in order to examine issues of quality control and analysis as well as reproducibility, the application of automated computer analysis did not appear to be superior or acceptable because of lack of standards and issues of operator and patient variability.22,23 Involuntary detrusor contraction (or detrusor instability) is a urodynamic entity that has become more important, especially with the recent trend to treat and monitor BPH with symptom scores. The prognostic significance of its presence preoperatively and its risk for persistence postoperatively has an impact, especially if the goal of treatment is to improve symptom score. Currently, the presence of instability on a urodynamic assessment does not have good predictive value for its presence postoperatively. Furthermore, pressure—flow studies have shown very little difference between patients with and without detrusor instability in bladder outflow obstruction parameters, although its incidence has been reported in between 40 and 60% of cases.84 We have recently reported our findings regarding 129 consecutive men, after prostatectomy (mean age 72 years), with voiding symptoms after transurethral resection of the prostate, whose urodynamic findings were retrospectively analyzed with respect to symptoms, uroflow, and synchronous video pressure-flow cystometry.37 Obstruction was found in 38% of patients, impaired contractility in 25%, and intrinsic sphincter deficiency in 8%. In 80 patients without neurologic disorders, involuntary bladder contractions were detected in 50%; however, in 49 patients with neurologic disorders, involuntary bladder contractions were detected in 76%. This difference was statistically significant. This study revealed the significance of involuntary contractions as a potential cause of treatment failure after prostatectomy. In spite of the complexity of modern-day management of bladder outlet obstruction and BPH, there are few data to elucidate the questions: What is the optimum yardstick to gauge treatment efficacy? What is the ultimate outcome of patients treated for only symptoms without a pressure-flow diagnosis of bladder outlet obstruction versus patients who are treated with a definitive diagnosis? Although there are recent data to suggest that patients with LUTS fare better when given TURP versus watchful waiting, can these ‘watchful-waiting failures’ be identified with the help of urodynamics?14 As more men are subject to watchful waiting, there will be a greater need to identify the natural history of prostatism as men grow older. From a urodynamic standpoint, Madersbacher et al. investigated the age-related urodynamic changes of patients with untreated symptomatic BPH.85 They found that the age correlation to falling maximum flow rate and voided volumes among patients with prostatism did not correspond to urodynamic findings of worsening bladder outflow obstruction or detrusor contractility. Particularly in men over the age of 80 years, they found that urodynamic evidence of obstruction was absent in as many as 60% of patients, despite decreasing maximum flow rates to the 10–15 ml/s range. This led the authors to the conclusion that the mere criteria of LUTS and diminished maximal

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Page 250 flow rates might not be adequate for surgical intervention, and that pressure-flow studies would be useful. With newer, minimally invasive prostate procedures such as microwave therapy and interstitial prostate operations, urodynamics appears to be playing more of a prognostic role. In addressing clinical variables helpful in predicting outcome after transurethral microwave thermotherapy, Walden et al. reported their results on 38 men with LUTS and BPH undergoing therapy after urodynamic assessment.86 They found that urodynamic parameters of bladder outlet obstruction were predictive of favorable outcome in the setting of low to moderate obstruction as graded according to the Schafer nomogram and the detrusoradjusted mean passive urethral resistance factor classification (DAMPF). The authors concluded that patients with high-grade obstructions were poorly suited for transurethral microwave thermotherapy.86 In addition, few people will dispute the use of urodynamic studies as an invaluable research tool for assessing the efficacy of various treatments. This continues to hold true for all the newer modalities of BPH therapy. Symptomatic, pathologic, urodynamic, and molecular expression of BPH The ideal study of BPH would entail analyzing the complex interrelationship of symptomatology, pathology, physiology, and molecular biology of the progression of BPH and its response to therapy. Currently, it is a widely held belief that the development and persistence of symptoms in the untreated population are related to increasing severity of obstruction. It is believed that a proportion of symptoms, such as poor urinary stream and incomplete voiding, are directly related to an obstructive process itself, however, detrusor instability makes a significant contribution. One current approach to examining the development of instability focuses on the innervation of the bladder and prostate. One study suggests that the constantly increased pressure produced by mild chronic obstruction causes an autonomic denervation injury that produces a state of supersensitivity in the target organ, resulting in new or persistent instability.34 This concept of an autonomic denervation injury in the target organ is also consistent with the urodynamic finding of neuropathic changes in the diabetic bladder. Thus, numerous studies have combined analysis of the molecular expression of numerous biological factors with urodynamically documented findings in the animal model. These approaches have yielded a host of new questions to investigate. Does relief of obstruction allow for reinnervation to a normal state and thus for instability to resolve? Is there a point where reinnervation is not possible and instability remains persistent? These issues of urodynamics and molecular biology are speculative and warrant investigation. It is noteworthy that over 50% of those diabetic patients with voiding symptoms who undergo urodynamic testing have detrusor instability.27 These patients are typical suspects for autonomic denervation injury in the bladder. From the standpoint of histologic correlation between prostatic composition and urodynamic findings, Ichiyanagi and Nakada reported on 18 patients undergo ing transurethral resection in Japan, in whom pathologic analysis was conducted.87 They found that while stroma comprised the majority of the prostate (73%) and fibrous tissue was the largest histologic element (48%), very little correlation could be drawn between tissue composition and urodynamic outcome. This held true even in subsets of patients with histologically ‘smooth muscle-rich’ prostates or prostates of various sizes. The authors concluded that the degree of infravesical obstruction caused by the prostate could not be determined by histologic factors alone. Conclusions It is clear that, given our current understanding of BPH and its relationship to symptoms of prostatism and obstructive uropathy, the role of urodynamics as both a diagnostic tool and an instrument to assist in therapeutic management remains to be defined. Currently, urodynamic studies have provided an understanding of these three processes and their complex interaction. They are, at present, a tool best utilized in diagnosing obstruction. How prostatic obstruction interrelates to symptoms and progression toward obstructive uropathy and the concurrent development of BPH is still not well understood. It is through our increasing elucidation of molecular and neurologic events occurring at the cellular level that we may understand further how prostatic growth leads to symptoms and bladder dysfunction. Urodynamics remains, indisputably, an excellent research tool, with which detrusor and bladder outlet physiology may be elucidated. In the case of BPH, further investigation is necessary to determine how bladder outlet and detrusor interactions impact upon patient symptoms, response to therapy, and ultimate progression to complications. Nonetheless, urodynamics is still the best way to lend objectivity to the treatment of BPH. In an era where there are so many different therapeutic options available for BPH, it becomes easy for all patients to fall into the category of ‘nail’ if the only therapy within the clinician’s file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_250.html[09.07.2009 11:53:20]

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Page 251 grasp is a ‘hammer’. For well-rounded urologists to offer patients various forms of therapy, each of the newer therapies needs to find their appropriate indication. Ultimately, it may be urodynamic parameters that distinguish patient characteristics enough to allow for recommendations based on fact rather than the subjective needs of both patient and urologist. References 1. Abrams P. In support of pressure-flow studies for evaluating men with lower urinary tract symptoms. Urology 1994; 44:153–155 2. McConnell J D. Why pressure-flow studies should be optional and not mandatory studies for evaluating men with benign prostatic hyperplasia. Urology 1994; 44: 156–158 3. McGuire E J. The role of urodynamic investigation in the assessment of benign prostatic hypertrophy. J Urol 1992; 148:1133–1136 4. Ball A J, Feneley R C L, Abrams P H. The natural history of untreated prostatism. Br J Urol 1981; 53:613–616 5. Andersen J T, Nordling J. Prostatism II. The correlation between cysto-urethroscopic, cystometric and urodynamic findings. Scand J Urol Nephrol 1980; 14:23–27 6. Barry M J, Cockett A T, Holtgrewe H L et al. Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 1993; 150:351–358 7. Barry M J, Fowler F J Jr, O’Leary M P et al. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992; 148:1549–1557 8. Barry M J, Fowler F J Jr, O’Leary M P et al. Correlation of the American Urological Association symptom index with self-administered versions of the Madsen-Iverson, Boyarsky and Maine Medical Assessment Program Symptom Indexes. J Urol 1992; 148:1558–1563 9. Boyarsky S, Jones G, Paulson DF, Prout G R Jr. A new look at bladder neck obstruction by the Food and Drug Administration regulators; guide lines for the investigation of benign prostatic hypertrophy. Trans Am Assoc Genito Urin Surg 1977; 68:29 10. Bruskewitz R C, Larsen E H, Madsen P O, Dorflinger T. 3-year followup of urinary symptoms after transurethral resection of the prostate. J Urol 1986; 136:613–615 11. Schafer W, Rubben H, Noppeney R, Deutz F J. Obstructed and unobstructed prostatic obstruction. A plea for urodynamic objectivation of bladder outflow obstruction in benign prostatic hyperplasia. World J Urol 1989; 6: 198–203 12. Simonsen O, Moller-Madsen B, Dorflinger T et al. The significance of age on symptoms and urodynamic and cystoscopic findings in benign prostatic hypertrophy. Urol Res 1987; 15:355–358 13. Jacobsen S J, Jacobson D J, Girman C J et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997; 158:481–487 14. Wasson J H, Reda D J, Bruskewitz R C et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans’ Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995; 332:75–79 15. Abrams P H, Farrar D J, Turner-Warwick R T et al. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol 1979; 121:640–642 16. Abrams P H, Griffiths D J. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 1979; 51:129–134 17. Blaivas J G. Multichannel urodynamic studies in men with benign prostatic hyperplasia: indications and interpretation. Urol Clin North Am 1990; 17:543–552 18. Coolsaet B R L A, Blok C. Detrusor properties related to prostatism. Neurourol Urodyn 1986; 5:435 19. Jensen K M E, Jorgensen J B, Mogensen P. Urodynamics in prostatism II. Prognostic value of pressure-flow study combined with stop-flow test. Scand J Urol Nephrol 1988; 114 (Suppl): 72–77 20. Dean G E, Kaplan S A, Blaivas J G. The differential diagnosis of prostatism: a urodynamic survey. J Urol 1991; 145: 79A 21. Hellstrom P, Lukkarinen O, Kontturi M. Bladder neck incision or transurethral eletroresection for the treatment of urinary obstruction caused by a small benign prostate? A randomized urodynamic study. Scand J Urol Nephrol 1986; 20:187–192 22. Donovan J L, Abrams P, Schafter W. The International Continence Society study on BPH: urodynamic quality control and data analysis. J Urol 1994; 151:294A 23. Kirchner-Hermanns R, Thorner M, Schafer W et al. Reproducibility of urodynamic data in BPH: influence of patient and investigator on data quality and analysis. J Urol 1994; 151:295A 24. Abrams P, Blaivas J G, Stanton S L, Andersen J T. Standardization of terminology of lower urinary file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_251.html[09.07.2009 11:53:21]

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tract function. Neurourol Urodyn 1988; 7:403–427 25. Griffiths D J, Scholtmeirer R J. Detrusor/sphincter dysynergia in neurologically normal children. Neurourol Urodyn 1983; 2:27 26. Kaplan M H, Feinstein A R. The importance of classifying initial co-morbidity in evaluating the outcome of diabetes mellitus. J Chron Dis 1974; 27:387–404 27. Kaplan S A, Te A E. Bladder dysfunction in diabetes. Probl Urol 1992; 6:659–668

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Page 252 28. McConnell J D, Barry M J, Bruskewitz R C et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical Practice Guideline No 8. AHCPR Publication 94–0582. Rockville: AHCPR, PHS, US Department of Health and Human Services, 1994 29. Abrams P H. Prostatism and prostatectomy: the value of urine flow rate measurement in the preoperative assessment for operation. J Urol 1977; 117:70–71 30. Ball A J, Smith P J B. The long-term effects of prostatectomy: a uroflowmetric analysis. J Urol 1982; 128:538–540 31. Kelly M J, Roskamp D, Leach G E. Transurethral incision of the prostate: a preoperative and postoperative analysis of symptoms and urodynamic findings. J Urol 1989; 142: 1507–1509 32. Scott F B, Cardus D, Quesada E M, Riles T. Uroflowmetry before and after prostatectomy. South Med J 1967; 60: 948–952 33. Jensen K M E, Jorgensen JB, Mogensen P. Urodynamics in prostatism III. Prognostic value of medium-fill water cystometry. Scand J Urol Nephrol 1988; 114 (Suppl): 78–83 34. Cucchi A. The development of detrusor instability in prostatic obstruction in relation to sequential changes in voiding dynamics. J Urol 1994; 51:1342–1344 35. Jensen K M E, Andersen J T. Urodynamic implications of benign prostatic hyperplasia. Urologe [A] 1990; 29:1–4 36. McLoughlin J, Gill K P, Abel P D, Williams G. Symptoms versus flow rates versus urodynamics in the selection of patients for prostatectomy. Br J Urol 1990; 66:303–305 37. Olsson C A, Goluboff E T, Chang D T, Kaplan S A. Urodynamics and the etiology of postprostatectomy urinary incontinence (PPI). J Urol 1994; 151:326A 38. Kaplan S A, Te A E, Jacobs B Z. Urodynamic evidence of vesical neck obstruction in men with misdiagnosed chronic nonbacterial prostatitis and therapeutic role of endoscopic incision of bladder neck. J Urol 1994; 152: 2063–2065 39. George N J R, Feneley R C L, Roberts J B M. Identification of the poor risk patient with prostatism and detrusor failure. Br J Urol 1986; 58:290–295 40. Glemain P Buzelin J M, Cordonnier J P. New urodynamic model to explain micturition disorders in benign prostatic hyperplasia patients. Pressure-flow relationships in collapsable tubes, hydraulic analysis of the urethra and evaluation of urethral resistance. Eur Urol 1993:24:12–17 41. Neal D E, Styles R A, Powell P H, Ramsden P D. Relationships between detrusor function and residual urine in men undergoing prostectomy. Br J Urol 1987; 60: 560–566 42. Andersen J T. Prostatism III. Detrusor hyperreflexia and residual urine. Clinical and urodynamic aspects and the influence of surgery on the prostate. Scand J Urol Nephrol 1982; 16:25–30 43. Hald T. Urodynamics in benign prostatic hyperplasia: a survey. Prostate 1989; 2 (Suppl): 69–77 44. Haylen B T, Ashby D, Sutherst J R et al. Maximum and average urine flow rates in normal male and female populations: the Liverpool nomograms. Br J Urol 1989; 64: 30–38 45. Jensen KME. Clinical evaluation of routine urodynamic investigations in prostatism. Neurourol Urodyn 1989; 8: 545 46. Grino P B, Bruskewitz R, Blaivas J G et al. Maximum urinary flow rate by uroflowmetry: automatic or visual interpretation. J Urol 1993; 149:339–341 47. Frimodt-Moller C, Hald T. Clinical urodynamics: methods and results. Scand J Urol Nephrol 1972; 6:143 48. Gleason D M, Lattimer J K. The pressure flow study: a method for measuring bladder neck resistance. J Urol 1962; 87:844 49. Jensen K M E, Bruskewitz R C, Iversen P, Madsen P O. Predictive value of voiding pressures in benign prostatic hyperplasia. Neurourol Urodyn 1983; 2:117 50. Schafer W. Principles and clinical application of advance urodynamic analysis of voiding function. Urol Clin North Am 1990; 17:553–566 51. Griffiths D J. Urethral resistance to flow: the urethral resistance relation. Abbreviated report. Urol Int 1975; 30: 28 52. Schafer W. Urethral resistance? Urodynamic concepts of physiological and pathological bladder outlet function during voiding. Neurourol Urodyn 1985; 4:161 53. Spangberg A, Terio H, Ask P, Engberg A. Quantification of urethral function based on Griffiths’ model of flow through elastic tubes. Neurourol Urodyn 1989; 8:29 54. Spangberg A, Terio H, Ask P, Engberg A. Pressure/flow studies preoperatively and postoperatively in patients with benign prostatic hypertrophy: estimation of the urethral pressure/flow relation and urethral elasticity. Neurourol Urodyn 1991; 10:139–167 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_252.html[09.07.2009 11:53:21]

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55. Susset J G. Resistance to flow in the lower urinary tract: clinical application. In: Hinman F Jr (ed). Hydrodynamics of micturition. Springfield: Thomas C C, 1981 56. Van Mastrigt R, Rollema J H. Urethral resistance and urinary bladder contractility before and after transurethral resection as determined by the computer program CLIM. Neurourol Urodyn 1988; 7:226 57. Smith J C. Urethral resistance to micturition. Br J Urol 1968;40:125–156 58. Bruskewitz R C, Jensen K M E, Iversen P, Madsen P O. The relevance of minimum urethral resistance in prostatism. J Urol 1983; 129:769–771

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Page 253 59. Griffiths D J. Urodynamics: the mechanics and the hydrodynamics of the lower urinary tract. Medical Physics Handbook 4. Bristol: Adam Hilger, 1980 60. Nielsen K K, Nordling J, Hald T. Critical review of the diagnosis of prostatic obstruction. Neurourol Urodyn 1994; 13:201–217 61. Bates P, Bradley W E, Glen E et al. The standardization of terminology of lower urinary tract function.J Urol 1979; 121:551–554 62. Griffiths D J, van Mastrigt R, Bosch R. Quantification of urethral resistance and bladder function during voiding, with special reference to effects of prostate size reduction on urethral obstruction due to benign prostatic hyperplasia. Neurourol Urodyn 1989; 8:17 63. Griffiths D J, Constantinou C E, van Mastrigt R. Urinary bladder function and its control in healthy females. Am J Physiol 1986; 2: R251 64. Schafer W. Detrusor as the energy source of micturition. In: Hinman F Jr (ed). Benign prostatic hypertrophy. New York: Springer-Verlag, 1983:450 65. Kaplan S A, Blaivas J G, Brown W C, Schuessler G. Parameters of detrusor contractility I. The effect of outlet resistance on Q max, power and work in an in-vitro whole rabbit model. Neurourol Urodyn 1989; 8:375–376 66. Kaplan S A, Brown W C, Chancellor M B et al. Parameters of detrusor contractility II. The effect of outlet resistance on the mechanical indices: power, work and WF. J Urol 1990; 143:354 67. Griffiths D J. Hydrodynamics of male micturition I. Therapy of steady state flow through elastic walled tubes. Med Biol Eng 1971; 7:201–215 68. Griffiths D J. Hydrodynamics of male micturition II. Measurement of stream parameters and urethral elasticity. Med Biol Eng 1971; 9:589–596 69. Griffiths D J. The mechanics of the urethra and of micturition. Br J Urol 1973; 45:497–507 70. Rollema H J, van Mastrigt R. Improved indication and followup in transurethral resection of the prostate using the computer program CLIM: a prospective study. J Urol 1992; 148:111–116 71. Schafer W, Noppeney R, Rubben H, Lutzeyer W. The value of free flow rate and pressure/flow studies in the routine investigation of BPH patients. Neurourol Urodyn 1988; 7:219–221 72. Lim C S, Reynard J, Cannon A, Abrams P. The Abrams-Griffith number: a simple way to quantify bladder outflow obstruction. Neurourol Urodyn 1994; 13: 475–476 73. Rollema H J, van Mastrigt R. Objective analysis of prostatism: a clinical application of the computer program CLIM. Neurourol Urodyn 1991; 10:71–76 74. Rollema H J, van Mastrigt R, Janknegt R A. Urodynamic assessment and quantification of prostatic obstruction before and after transurethral resection of the prostate: standardization with the aid of the computer program CLIM. Urol Int 1991; 1 (Suppl): 52–54 75. Kranse M, van Mastrigt R. The derivation of an obstruction index from a three parameter model fitted to the lowest part of the pressure flow plot. J Urol 1991; 145:261A 76. Kranse M, van Mastrigt R. A critical comparison of methods proposed for quantification of bladder outlet obstruction. Neurourol Urodyn 1993; 12:267–272 77. Spangberg A, Terio H, Ask P. Pressure-flow studies in elderly without voiding problems: estimation of the urethral pressure-flow relation and urethral elasticity. Neurourol Urodyn 1990; 9:123–138 78. Terio H, Spangberg A, Engberg A, Ask P. Estimation of elastic properties in the urethral flow controlling zone by signal analysis of urodynamic pressure-flow data. Med Biol Eng Comput 1989; 27:314–321 79. Sarky M S, Blaivas J G. Functional types of prostatic obstruction. Neurourol Urodyn 1988; 7:221–222 80. Sarky M S, Blaivas J G, Schussler G. Bladder outlet conductance: evolution, normal and obstructive patterns. Neurourol Urodyn 1988; 7:223 81. Kaplan S A, Reis R B. Significant correlation of the American Urological Association symptom score and a novel urodynamic parameter: detrusor contraction duration. J Urol 1996; 156:1668–1672 82. Kuo H C, Tsai T C. The predictive value of urine flow rate and voiding pressure in the operative outcome of benign prostatic hypertrophy. Taiwan I Hsueh Hui Tsa Chih 1988; 87:323–330 83. Van Mastrigt R, Kranse M. Automated evaluation of urethral obstruction. Urology 1993; 42:216 84. Rosier P F W M, de la Rosette J J M C H, Wijkstra H et al. Is detrusor instability in elderly males related to the grade of obstruction? Neurourol Urodyn 1995; 14: 625–633 85. Madersbacher S, Klingler H C, Schatzl G et al. Age related urodynamic changes in patients with benign prostatic hyperplasia. J Urol 1996; 156:1662–1667 86. Walden M, Dahlstrand C, Schafer W, Pettersson S. How to select patients suitable for transurethral microwave thermotherapy: a systematic evaluation of potentially predictive variables. Br J Urol 1998; file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_253.html[09.07.2009 11:53:22]

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81:817–822 87. Ichiyanagi O, Nakada T. Correlations between parameters in pressure-flow analysis and histological compositions in prostate in patients with benign prostatic hyperplasia. Urol Int 1997; 59:154–160

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Page 255 18 Imaging and benign prostatic hyperplasia D Rickards Introduction All imaging modalities have a role to play in both imaging the prostate gland and the effect that prostate pathology has upon the rest of the urinary tract. Imaging is directed towards determining intraprostatic anatomy and measuring lower urinary tract function. Departments of radiology involved in such studies need the use of a flow rate machine. To image postmicturition bladders/volumes without a flow rate is meaningless. Excretory urography and benign prostatic hyperplasia Initial plain kidneys, ureters, and bladders (KUB) films of the abdomen and pelvis (kidneys, ureters, and bladder) may indicate that there is prostatomegaly (Table 18.1). A prostate soft tissue mass will only be seen with very large prostates. Corpora amylacea occurs between the peripheral and central/transitional zones of the prostate and appears as a curvilinear calcific line arching above the symphysis pubis or as block-like calcification, usually bilateral (Fig. 18.1), but occasionally unilateral. Such calcification is characteristic and if seen above the symphysis indicates that there is prostatomegaly. Sclerotic metastases due to prostate carcinoma may be seen in conjunction with benign prostatic hyperplasia (BPH). A large bladder shadow suggests chronic retention, possibly on the basis of BPH. Following contrast, upper tract dilatation down to the vesico-ureteric junction is unusual except in highpressure chronic retention of urine, characterized by late onset enuresis, hypertension, and renal failure. Elevation of the bladder base by a soft tissue mass suggests prostatomegaly (Fig. 18.2), which is further evidenced by Table 18.1 Findings on kidneys, ureters, and bladder films in BPH. 1. Suprapubic soft tissue mass 2. Corpora amylacea the symphysis pubis 3. Large bladder 4. Sclerotic bony metastases fish-hooking of the distal ureters, which can be slightly dilated (Fig. 18.3). The bladder outline may be crenated, suggesting hypertrophy. This occurs in detrusor instability as well as in high-pressure voiding. The enlarged prostate can be seen as a vesical-filling defect, more

Figure 18.1 Plain film of the pelvis. There is calcification projected above the symphysis pubis (arrow) characteristic of corpora amylacea associated with BPH.

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Figure 18.2 Coned film of the pelvis following IV contrast. There is considerable elevation of the bladder base due to prostatomegaly.

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Page 256 commonly seen with so-called ‘median lobes’, which in effect are superior extensions of the central and transitional zones of the prostate. Small filling defects seen on the surface of the prostate represent prominent blood vessels seen on cystoscopy to lie just beneath the bladder mucosa. Outflow obstruction due to BPH can be complicated by bladder stones which can be large, often laminated, usually single and radio-opaque (Fig. 18.4). Small and multiple acquired diverticula are further evidence of highpressure voiding due to outflow obstruction and BPH. A large diverticulum that distends with micturition and appears larger on the postmicturition film is another finding. The walls of such diverticula do not contain muscle and the bladder can decompress into these low-pressure sacs. Stones complicate diverticula because of stasis. Small stones are best seen on ultrasound.

Figure 18.3 BPH on an excretory urogram. The distal ureters are elevated and there is slight dilatation of the left distal ureter.

Figure 18.4 There is a large bladder stone (curved arrow). In addition, there is gross dilatation of both distal ureters (arrows). This patient had high-pressure chronic retention due to BPH. Excretory urography for outflow obstruction should include a flow rate after the 20-minute full-length film followed by an immediate postmicturition film. Assessment of the volume of postmicturition urine on such films is very inaccurate and is best described as large, moderate, minimal, or none. Urethrography and BPH Ascending urethrography shows a normal anterior urethra. The posterior urethra in BPH will be attenuated and posteriorly displaced (Fig. 18.5) with elevation of the bladder base (Fig. 18.6). Clearly, the larger the BPH, the more pronounced such findings. Splitting of contrast is a feature. Descending studies confirm these findings (Fig. 18.7), but provide additional information about the state of the bladder wall, bladder capacity, postmicturition residual, and vesico-ureteric reflux. Surgery for BPH may be complicated by an anterior urethral (Fig. 18.8) or distal sphincter stricture. Computed tomography and BPH Computed tomography (CT) is unable to differentiate the different zones of the prostate, which appears as a homogeneous structure, well defined and with an attenuation file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_256.html[09.07.2009 11:53:24]

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Figure 18.5 Ascending urethrogram showing slight posterior displacement of the posterior urethra due to early BPH (arrow).

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Page 257

Figure 18.6 Ascending urethrogram. There is a large soft tissue mass lesion invaginating the bladder base to a large BPH.

Figure 18.7 Descending urethrogram showing gross attenuation of the posterior urethra and posterior displacement of it due to BPH. value of 25–30 Hounsfield units (HU). Glands involved in BPH appear larger, but still well defined and with a similar attenuation value (Fig. 18.9). Coexistent pathology in the bladder and distal ureters should be sought. There is no role for CT in the diagnosis of BPH. Magnetic resonance and BPH Magnetic resonance imaging (MRI) has been advocated as the imaging modality of choice for the prostate gland1.

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Figure 18.8 Descending urethrogram showing an anterior urethral stricture (arrow) following TURP for BPH (curved arrow).

Figure 18.9 CT scan of the pelvis showing an enlarged, homogeneous and well-defined prostate due to BPH. There is no differentiation of the zonal anatomy of the prostate. MRI can differentiate the zonal anatomy of the prostate. The appearances depend upon the distribution and size of glandular tissue as well as on the composition of the surrounding stroma2. Nonstromal hyperplasia was diagnosed when (1) the nodules in the central/transitional zone of the gland were characterized as having heterogeneous high-signal intensity (Fig. 18.10) on T2-weighted images and peripheral enhancement on gadolinium enhanced T1-weighted images, (2) a surgical capsule was present, or (3) the central/transitional zone volume to total volume

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Page 258 was greater than 0.75. When none of these findings was present, stromal BPH was diagnosed. The usefulness of this differentiation is relevant for predicting the response of BPH to pharmacotherapy. Stromal hyperplasia has a large smooth muscle component and is more likely to respond to α-blockers. Published reports suggest four different appearances on T1-weighted sequences. The appearance of the prostate on MRI differs depending upon the predominate cellular pathology. Glandular type hyperplasia has a nodular appearance with high signal intensity within the nodules. Fibromuscular hyperplasia has a rather low signal intensity and a homogeneous appearance. BPH associated with collagen has a lower signal intensity still, while BPH made up of stroma and glandular tissue has a heterogeneous appearance.3 Albeit more expensive, MRI has been shown to be more accurate in the determination of prostate volume.4 Ultrasound and BPH Transabdominal ultrasound and lower urinary tract dysfunction due to benign prostatic hypertrophy As an initial investigation in any patient with symptoms due to BPH, an ultrasound cystodynamogram (USCD) should be performed.4 Bladder volumes are measured before and after micturition using the standard technique described by Poston,5 i.e. the bladder volume in milliliters is 0.7 HDW (where D is depth in the sagittal plane, H is maximum diameter in the sagittal plane, and W is maximum transverse diameter in the transverse plane, all measurements are in centimeters). Voided volumes of less than 200 ml are of little clinical relevance. Overfull bladders are to be avoided as such a state will inhibit micturition. Once the full bladder has been scanned and its volume measured, the patient voids into a standard flow rate machine, having been asked to void as normally as possible and not try to impress with superimposed abdominal straining. Immediately after voiding, the bladder is rescanned and any residual measured. If there is a large residual (100 ml or more), the bladder should be rescanned after a second void and that residual assessed. The USCD provides both anatomic and physiologic information (Tables 18.2 and 18.3). Prostate dimensions can be measured on suprapubic scanning, but are not accurate. The following combinations can be identified: • Normal flow rate; complete bladder emptying; normal bladder wall. A normal USCD does not exclude abnormalities of bladder function. Early prostate

Figure 18.10 Endorectal T2-weighted MRI of BPH. There are well-defined nodules (arrow)

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in the central part of the gland suggesting nonstromal BPH. There is marked compression of the peripheral zone (curved arrow). Table 18.2 Information gained from an ultrasound cystodynamogram: anatomic. 1. Full bladder volume 2. Thickness of bladder wall 3. Distal ureteric anatomy 4. Intravesical filling defects, e.g. stone, ureterocele, tumor 5. Bladder diverticula 6. Residual bladder volume 7. Relationship of the prostate to the base of the bladder 8. Perivesical anatomy outflow obstruction is compensated for by the bladder generating higher voiding pressures to establish complete bladder emptying at normal flow rates. It will be in the later stages of bladder decompensation that flow rates will deteriorate and residual urine volumes will be seen. Instability (involuntary bladder contraction) will not be excluded.

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Page 259 • Low flow rate; complete bladder emptying. This combination will be commonly seen in the following conditions: – With hypertrophied bladder wall—outflow obstruction (vide supra). The bladder wall may be thickened with elevation of the bladder base due to prostatomegaly (Fig. 18.11). Other causes of outflow obstruction, e.g. urethral stricture and bladder neck dyssynergia, cannot be excluded. – With normal bladder wall—poor detrusor—partial detrusor failure. Poorly functioning bladder without outflow obstruction. This is seen in women who are infrequent voiders (socalled cameloid bladders). It is also seen in males who have low-pressure chronic retention of urine and whose detrusor function has deteriorated. The bladder becomes chronically overdistended and the bladder muscle Table 18.3 Information gained from an ultrasound cystodynamogram: physiologic. 1. Voided volume 2. Maximum flow rate 3. Average flow rate 4. Time to peak flow 5. Voiding time 6. Flow time

Figure 18.11 Longitudinal scan of the bladder showing marked invagination of the bladder base (arrow) due to prostatomegaly. (detrusor) subsequently damaged. There will probably be elevation of the bladder base, but the bladder wall will be of normal thickness. • High flow rate; complete bladder emptying; normal or hypertrophied bladder wall; no prostatomegaly. This can be seen in normals who augment micturition with abdominal straining. It is also seen in detrusor instability without obstruction. Such patients void with high pressures against a normal outflow tract that generates no increased resistance. Such bladders are referred to as ‘super bladders’. • Low flow rate; incomplete emptying; normal or hypertrophied bladder wall; prostatomegaly. This is characteristic of decompensated outflow obstruction. The detrusor can only manage to generate sufficient pressure to overcome the outflow resistance for so long; it decompensates and a residual is left. These patients characteristically feel the need to void a few minutes after the initial void as the detrusor recovers. The bladder wall is likely to be hypertrophied. This pattern is also seen in patients with poor detrusors and no outflow obstruction. These patients will have normal bladder walls. • Intermittent flow rate; variable emptying; normal bladder wall. Such flow patterns are characteristic of patients in whom voiding is predominantly by abdominal pressure, the detrusor having all but failed. The effectiveness of abdominal straining will determine how much of a residual is left. • No flow rate; no emptying; hypertrophied bladder wall. This combination is seen in patients with neuro pathic bladders and detrusor sphincter dyssynergia in whom voluntary voiding is usually not possible. • Normal flow rate; large residual urine; hypertrophied bladder wall; dilated distal ureters. This classic set of findings occurs in high-pressure chronic retention of urine. This condition accounts for 10% of patients who present with chronic urinary retention and is important because renal function is file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_259.html[09.07.2009 11:53:26]

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likely to be impaired and chronic renal failure will ensue if treatment is not undertaken. The prostate in these patients is often not enlarged and the condition probably represents the end stages of bladder neck obstruction.6 The distal ureters will be seen to be symmetrically dilated. The USCD is most useful in the follow-up of patients treated by transurethral resection of the prostate (TURP) for outflow obstruction due to BPH. As a diagnostic test it is limited, being unable to differentiate between an overactive detrusor in the presence of obstruction and a

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Page 260 normal patient. More invasive, but definitive urodynamic studies will have to be performed. In our unit, USCD is used as an initial test of lower tract function in all symptomatic patients. This gives some idea as to which patients need to go on to formal urodynamic studies. It is extensively used to monitor the effect of treatment of any kind of lower tract obstruction, whether it be prostate mediated or due to urethral stricture. USCD also affords the advantage of defining other pelvic pathology which may be significant in determining the cause of lower tract function and pelvic pain. Other pathology due to BPH that might be seen on the USCD Bladder diverticula are congenital or acquired.7 Acquired diverticula are thin walled, contain very little muscle, are virtually always associated with outflow tract obstruction, and 85% arise just lateral and superior to the ureteric orifice. They can achieve enormous sizes, calculi commonly form in them because of stasis and there is a 5% association between diverticula and transitional cell tumor.8 Ultrasonography (US) can rapidly confirm the presence of a diverticulum (Fig. 18.12) and to what extent it empties following micturition. In some, the diverticulum might transiently increase in size as a functioning detrusor voids into it rather than through an obstructed lower tract. The position and size of the orifice can help in preoperative planning. The most important use of US is to detect complications, i.e. stone or tumor. It is not always possible to assess a diverticulum endoscopically. Bladder stones appear as echogenic masses within the bladder that move with altered posture (Fig. 18.13).

Figure 18.12 Longitudinal scan of the bladder showing invagination of the bladder base and a thickened bladder wall with diverticula (arrow). Bladder tumors can calcify, but do not move. Stones can be multiple and are always associated with outflow obstruction. If stones are seen, a USDC should be performed immediately as well as assessment of the prostate. Stones complicating diverticula are common. Transrectal ultrasound and lower urinary tract dysfunction due to BPH Technique Accurate assessment of prostate volume requires scanning in two planes.9 There is no linear correlation between prostate size and the degree of outflow obstruction. BPH can occur in the absence of any prostatomegaly with compression of the peripheral zones at the expense of the enlarging central part of the gland. Volume measurements are useful in deciding how patients might be treated, so are worth measuring. Huge prostates (in excess of 75 ml) might be considered for open prostatectomy and are unlikely to be considered for brachytherapy. Posterior urethral imaging requires the prostate to be scanned in the sagittal plane using a 7-MHz linear array probe.10,11 Such a configuration is available with biplane probes or dedicated linear array probes, but such technology is increasingly difficult to source. The present trend is for tight curved-array transducers that can be used for both transrectal and transvaginal work, providing images of the prostate in an elongated, forward-looking sagittal section, ideal for biopsy but not for posterior urethral imaging. Prostate imaging is an integral part of assessing lower urinary tract function at rest before, or during urodynamics.

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Figure 18.13 Transverse scan of the bladder showing an echogenic focus (arrow) associated with acoustic shadowing due to a small bladder stone.

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Page 261 Transrectal ultrasound (TRUS) can be performed as an investigative procedure of lower urinary tract abnormalities in the following ways: • In combination with renal US and a USCD. These studies will provide all the functional information gained by the USCD plus: – Prostate pathology; – Prostate volume; – Bladder neck configuration; – Urethral position; – Periurethral pathology. • During micturition. Patients find it difficult to micturate in either the left lateral decubitus position or when standing with a transrectal probe in their rectums. This is hardly surprising! The temptation is to overfill the patient’s bladder by natural means by overhydrating the patient or through the administration of a diuretic, but overfilling the bladder inhibits micturition and causes pain, bladder wall damage, and is to be avoided. It is not surprising that most papers on TRUS and urodynamics are on patients with neuropathic bladders who void spontaneously, irrespective of what is within their rectums.12,13 Additional information gained will be: – Bladder neck function; – Caliber of the posterior urethra – Posterior urethral pathology; – Distal sphincter function; – Posterior urethral emptying on interruption of micturition, the ‘stop test’.14 • TRUS and bladder US prior to a full urodynamic study. This has the potential of reducing the requirement for fluoroscopy to nothing, thus ridding the potential harm caused by radiation to the gonads, especially in young males. The only information that will not be seen is vesico-ureteric reflux and anterior urethral pathology, although US is being promoted as the first line of investigation for that. Normal TRUS appearance of the posterior urethra At rest, the posterior urethra can usually be identified as two echogenic interfaces opposed to each other at the bladder neck with an echo-poor area anterior to it, the anterior fibromuscular stroma (Fig. 18.14). The urethra as it courses through the prostate assumes a very gentle curve until the apex of the gland is surrounded by the echo-poor distal sphincter mechanism, where the subprostatic urethra takes a sharp turn anteriorly.

Figure 18.14 Normal sagittal TRUS showing the urethra (arrows), ejaculatory duct (curved arrow), and anterior fibromuscular stroma (open arrow). If the patient can initiate micturition while under continuous TRUS control, it is wise to record the event on video. As detrusor pressure increases, the prostate is displaced slightly inferiorly. Then the bladder neck starts to open, the posterior urethra fills with urine, and the distal sphincter opens and micturition ensues. The posterior urethra is a thin-walled structure with a caliber between 5 and 10mm, depending on what rate the patient manages to micturate, and runs in almost a straight line through the prostate. The verumontanum can be identified towards the apex of the gland and marks the proximal aspect of the distal sphincter mechanism. When the patient is asked to stop micturition in mid-flow, the distal sphincter closes under voluntary control, the urine within the posterior urethra is milked back into the

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bladder through the bladder neck, and then the bladder neck closes, leaving the urethra totally empty. TRUS and BPH Early degrees of BPH produce an increase in the anteroposterior dimension of the prostate, normally less that 2.5 cm. This is due to enlargement of the transitional zones of the prostate (Fig. 18.15). The peripheral zones should be normal. As the prostate increases in size, the bladder base is elevated and, in very large glands, it may not be possible to insert the probe far enough into the rectum to image the base of the prostate. The peripheral zones become markedly compressed by the enlarging central part of the gland, and become more echogenic than normal (Fig. 18.16). The enlarged central part of the gland assumes varying echogenicities. Echogenic discrete adenomas can be mixed with predominantly heterogeneous

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Figure 18.15 Transverse axial TRUS of early BPH (between arrows). The peripheral zones are homogeneous.

Figure 18.16 Transverse axial TRUS of BPH. There is compression of the peripheral zones and corpora amylacea (arrow). tissue and cystic degeneration is a feature (Fig. 18.17). Enlarged median lobes can be associated with apparently normal glands and are best seen on sagittal imaging. Color Doppler scanning often reveals markedly increased blood flow in the central and transitional zones of the gland (Fig 18.18). Such a finding can alert the surgeon to a possible increase in hemorrhage and the possibility that thermotherapy will be less successful. The capsule of the gland should be intact. In the early phases of BPH, the prostate may appear to be of normal size, both clinically and on TRUS measurement, because the enlarging adenoma compresses the peripheral zones preferentially. This is more likely to happen when BPH occurs in the presence of bladder neck obstruction, where the prostate becomes trapped. The following patterns will be seen: • At rest: – Normal TRUS; normal USCD. This combination excludes any significant degree of outflow obstruction due to BPH, but will not diagnose detrusor instability.

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Figure 18.17 Sagittal TRUS of a huge BPH. There is cystic degeneration (arrow).

Figure 18.18 Transverse axial color. Doppler scan of the prostate in BPH. There is considerable increased blood flow within the central part of the gland. – Normal TRUS; low flow rate; variable bladder emptying. This will be seen in those patients with poor detrusor function, detrusor failure where voiding is through abdominal straining, or where the obstruction is distal to the distal sphincter mechanism, e.g. urethral stricture. – BPH on TRUS; normal USCD. This is seen in the early stages of BPH where the increased resistance afforded by the outflow tract is overcome by increased voiding pressure maintaining normal flow rates. – BPH on TRUS; low flow rates; complete emptying; hypertrophied bladder wall. This combination is classic of outflow obstruction. The

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Page 263 detrusor is able to generate sufficiently high pressures for long enough to ensure complete emptying. – BPH on TRUS; low flow rates; incomplete emptying; hypertrophied bladder wall. When seen, this combination is that of decompensated outflow obstruction where the bladder wall cannot generate sufficiently high pressures for long enough to ensure bladder emptying. The detrusor pressure falls and residual urine is left. As the detrusor recovers after a few minutes, the patient becomes aware of incomplete emptying and returns to empty his bladder. This is the classical symptom of ‘pis-endeux’. – BPH on TRUS; low or intermittent flow rates; incomplete emptying; normal bladder wall. This can occur in the late stages of outflow obstruction where larger and larger residuals are being formed; the detrusor muscle decompensates and becomes thin-walled. It will also be seen in those patients who, in the presence of increasing obstruction, do not compensate for it by generating higher bladder pressures and therefore bladder wall hypertrophy. • During micturition. The cardinal features seen on TRUS in patients with BPH during micturition are: –Attenuation of all or part of the posterior urethra. – Posterior displacement of the posterior urethra. – Lateral displacement of the posterior urethra. – Some trapping of contrast within the posterior urethra on interruption of micturition. All of the above features depend upon the extent of BPH and bladder function. In practice, little is to be learned from these appearances except in early degrees of BPH where the prostate is near normal size and minor degrees of posterior displacement can be identified (Figs. 18.19 and 18.20). Trapping of urine is classically seen in bladder-neck disorders, but may be seen in BPH. It can be distinguished from bladder-neck pathology because there will be no distension of the posterior urethra. As the prostate increases in size, the urethra becomes more posteriorly displaced and more attenuated. • Prior to urodynamics. TRUS assessment before formal lower urinary tract urodynamics allows for interpretation of the urodynamics without the use of ionizing radiation to image the posterior urethra. In cases where cystometry suggests obstruction, TRUS

Figure 18.19 Sagittal TRUS of the prostate at rest. The posterior urethra is posteriorly displaced due to BPH (arrow).

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Figure 18.20 Sagittal TRUS during micturition. There is posterior displacement and attenuation of the posterior urethra (arrow) due to BPH. will be able to determine whether the obstruction is at the level of the bladder neck, prostate, or distal sphincter. Anterior urethral causes of obstruction will not be imaged, but significant strictures or other anterior urethral pathology will make catheterization prior to urodynamic studies difficult, if not impossible. Such pathology is best demonstrated by urethrography of prior urethral ultrasound.15–18 TRUS appearance of the prostate following treatment The traditional surgical treatment by TURP for BPH is being challenged by less invasive treatments and ones that preserve the bladder neck and sexual function. Surgery is the only effective method of treatment available for bladder neck dyssynergia.

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Page 264 TRUS appearances following TURP At TURP, the bladder neck and varying amounts of the central and transitional zones of the prostate are removed down towards the apex of the prostate gland, but not involving the distal sphincter mechanism (Fig. 18.21). TRUS following TURP will show the cavity produced by surgery, but failure to see a cavity does not necessarily imply that there isn’t one. To accurately assess the size of the cavity, the patient should have a full bladder and be asked to pass urine or strain in the attempt to do so while continuously scanning the prostate. Suprapubic compression of the full bladder will also extend what appear to be small or nonexistent TURP cavities. Postoperative strictures of the bladder neck will appear as a mid-prostate cavity and a closed bladder neck (Fig. 18.22). Recurrent adenomas encroaching upon the operative cavity have similar appearances to preoperative benign tumors and for carcinoma to obstruct a cavity, it would have to be very extensive and would be obvious clinically. Obstruction to the ejaculatory ducts is commonly seen following TURP and can cause perineal pain due to seminal vesiculitis. Dilatation of the ducts will be seen on TRUS. Postoperative hematuria is often caused by prominent vessels lining the TURP cavity. These will be identified on color Doppler imaging. Incontinence following TURP is due either to distal sphincter damage or to underlying detrusor instability. Sphincter damage can be assessed with TRUS by compressing the full bladder and seeing the distal sphincter open up.

Figure 18.21 Sagittal TRUS following TURP showing a good cavity (arrow). TRUS appearances following stent insertion for the treatment of BPH Temporary stents have a closely woven mesh that attenuates the ultrasound beam to such an extent that it is not possible to image the intrastent lumen or the relationship of the stent to the bladder neck, not that it is important to do so as the stents extend into the bladder by design. Assessment is best done by urethrography. The position of permanent stents is clearly defined by TRUS. For accurate scanning, the bladder needs to be partially full. This will allow for very accurate depiction of the relationship of the stent to the bladder neck. The position of the distal end of the stent and its relationship to the distal sphincter and apical prostatic tissue is then assessed. Postoperative incontinence may be due to pre-existing instability, instability as a result of instrumentation, or compromise of distal sphincter function because the stent is partly or wholly covering it. TRUS will help to differentiate between poor positioning and a functional abnormality.19,20 In the first few months following insertion, permanent stents evoke a hyperplastic reaction, but this settles within 6 months to leave a smooth urothelial covering of the stent (Figs. 18.22 and 18.23). The extent and uniformity of urothelium can be assessed by TRUS. Usually, the stent is covered by a uniform thickness (1–2 mm) of urothelium, leaving an adequate intrastent lumen. Occasionally focal areas of overgrowth are seen. Color Doppler imaging (CDI) in the transverse axial or forward-looking sagittal planes allows for definition of the vascularity of the neourothelium.21

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Figure 18.22 Recurrent obstruction following TURP. There is a mid-prostatic cavity (arrow), but a bladder-neck stenosis.

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Figure 18.23 Sagittal TRUS following insertion of a permanent metal stent in the treatment of BPH. The stent is placed exactly at the bladder neck and there is good urothelial coating of the stent (arrows). Misplacement of the stent at the bladder neck with free wires not in contact with urothelium is likely to lead the wires becoming encrusted. TRUS will demonstrate such free wires and show whether small stones are forming on them. Perineal pain following stent insertion may be due to the development of prostatic inflammatory disease, prostate abscess, or blockage to the prostatic and ejaculatory ducts. TRUS will differentiate between these entities and point the clinician to the appropriate therapeutic course. Prolonged hematuria following stent insertion may be caused by prominent vessels supplying the urothelial covering. TRUS combined with CDI will demonstrate such vessels. References 1. Lovett K J, Rifkin M D, McCue P A, Choi H. MR imaging characteristics of non-cancerous lesions of the prostate. J Magn Reson Imaging 1992; 2:35–39 2. Ishida J, Sugimura K, Okizuka H et al. Benign prostatic hyperplasia: value of MR imaging for detection of histological type. Radiology 1994; 190:329–331 3. Ramchandani P, Schnall M D. Magnetic resonance imaging of the prostate. Semin Roentgenol 1993; 28:74–82 4. Boothroyd A E, Dixon P J, Christmas T J et al. The ultrasound cystodynamogram—a new technique. Br J Radiol 1989; 63:331–332 5. Poston G L, Joseph A E A, Riddle P R. The accuracy of ultrasound in the measurement of changes in bladder volume. Br J Urol 1983; 55:361–363 6. Holden D, George N, Rickards D et al. Renal pelvic pressures in human chronic obstructive uropathy. Br J Urol 1984; 56:565–567 7. Millar A. The aetiology and treatment of diverticulum of the bladder. Br J Urol 1958; 85:145–148 8. Fox M, Power R F, Bruce A W. Diverticulum of the bladder presentation and evaluation in 115 cases. Br J Urol 1962; 34:286–289 9. Jones D R, Roberts E E, Griffiths J G et al. Assessment of volume measurement of the prostate using per-rectal ultrasound. Br J Urol 1989; 64:493–495 10. Shabsigh R, Fishman I J, Krebs M. The use of transrectal longitudinal real-time ultrasonography in urodynamics. J Urol 1987; 138:1416–1419 11. Brown M C, Sutherst J R, Myrray A, Richmond D H. Potential use of ultrasound in place of X-ray fluoroscopy in urodynamics. Br J Urol 1985; 57:88–90 12. Petritsch P, Colombo T H, Rauchenwald M et al. Ultrasonography of the urinary tract as an alternative to radiologic investigation in spinal cord injured patients. Eur Urol 1991; 20:97–102 13. Shapeero L G, Friedland G W, Perkash I. Transrectal sonographic voiding cystourethrography: studies of neuromuscular bladder dysfunction. Am J Roentgenol 1983; 141:83–90 14. Abrams P H, Torrens M. Clinical urodynamics. Urol Clin North Am 1979; 6:1–79 15. Heidenreich A, Derschum W, Bonfig R, Wilbert D M. Ultrasound in the evaluation of urethral stricture disease: a prospective study of 175 patients. Br J Urol 1994; 74: 93–98 16. Perkash I, Friedland G W. Real time grey scale transrectal linear ultrasonography in urodynamic file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_265.html[09.07.2009 11:53:30]

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evaluation. Semin Urol 1985; 3:49–59 17. Shabsigh R, Fishman I L, Krebs M. Combined transrectal ultrasonography and urodynamics in the evaluation of detrusor sphincter dyssynergia. Br J Urol 1988; 62: 326–330 18. Bidair M, Tiechman J M H, Brodak P P, Juma S. Transrectal ultrasound urodynamics. Urology 1993; 42: 640–645 19. Chapple C R, Milroy E M, Rickards D. Permanently implanted urethral stent for prostatic outflow obstruction in the unfit patient: preliminary report. Br J Urol 1990; 66:58–65 20. Milroy E M, Chapple C R, Cooper J E. A new treatment for urethral stricture. Lancet 1988; 15:1424– 1427 21. Rickards D. Advances in ultrasound. In: Kirby R S, Henry W F (eds). Recent advances in urology. London: Churchill Livingstone, 1993:2–15

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Page 267 19 Prostatic needle biopsy in men with BPH: histopathologic interpretation and clinical significance M R Feneley S R J Bott Introduction Prostatic needle biopsy may be necessary in men with benign prostatic hyperplasia (BPH), not for the diagnosis of benign disease, but to exclude cancer. BPH and prostate cancer frequently coexist in men presenting with lower urinary tract symptoms, since both are androgen dependent and both become more common with advancing age. As both also cause elevated serum prostate-specific antigen (PSA) levels, and PSA testing is undertaken for prostate cancer detection, the management of BPH has become linked to considerations of PSA testing and diagnosis of concomitant malignancy. These issues also have to be considered in longer-term monitoring of men with benign disease, particularly those with ongoing symptoms and those receiving medical therapies. In men with BPH, there is an overlap in the range of PSA levels found in those with and without early stage prostate cancer. This diagnostic overlap is not uncommon in men over 50 years of age and becomes an increasing concern in older men. It relates particularly to those patients with benign digital rectal examination (DRE) and PSA levels in the intermediate range, between 4.0 and 10.0 ng/ml. Most data relating DRE findings and serum PSA to cancer detection are derived from screening or opportunistic testing, rather than investigation of men with BPH. Thus, the role of biopsies for cancer detection in men otherwise considered to have BPH is frequently based on selected observations and extrapolations from studies examining cancer detection in various settings. It has long been recognized that biologically and clinically significant prostate cancers may be undetectable by DRE in men with clinical BPH. The so-called ‘incidental’ presentation of such tumors in those treated by transurethral resection (TURP) (stages T1a and T1b) has substantially reduced since the advent of PSA testing.1 As the prevalence of prostate cancer, like BPH, increases with age, changes in PSA performance in cancer detection are frequently presented in relation to prostate volume and age. Prostate volume and age have both been evaluated extensively in the performance of PSA in cancer detection and attempts have been made to improve its diagnostic accuracy. Neither approach, however, has become widely accepted as a reliable and convenient adjustment in routine clinical practice. For men in their seventh or eighth decade, age-specific reference ranges would increase the acceptable range of PSA and reduce the indication for biopsy in men without cancer. However, some men with a PSA in the normal age-specific range will, with advancing years, subsequently be diagnosed with prostate cancer, with the potentially adverse consequences of a delayed diagnosis.2 Adjustment of PSA for total prostate volume or transition zone volume requires transrectal ultrasound, and similar concerns arise from the possibility of missing malignancy, particularly in larger glands. PSA testing in men with BPH PSA testing, driven by concerns and the uncertain implications of otherwise unsuspected cancer, has been responsible for the growing number of men having prostatic needle biopsies. In practice, the need for biopsy may be increased by the presence of BPH or greater age, and for the majority without cancer, the benefit relates to the relief of PSA-induced concern. For those with cancer, the anxiety must be justified by the potential benefit of treatment. For men with BPH and biopsies negative for cancer, these needle cores have a very limited role in the management of benign disease.3,4 The PSA level itself, besides its diagnostic value for cancer, is acquiring increasing clinical importance as an indicator of the likelihood of BPH progression. Serum PSA, derived from prostatic luminal epithelial cells in response to androgen stimulation, correlates with both total prostate volume5 and volume of the transition zone, the region of prostate specifically involved in the pathogenesis of BPH.6 Changes in serum PSA with time appear to relate specifically to the epithelial compo nent of BPH,7 and elevated PSA may also indicate a greater likelihood of future surgical intervention.8 An elevated PSA in men with BPH also predicts prostate growth rate and likelihood of developing acute urinary retention.8,9 In men with elevated PSA, DRE findings consistent with BPH, and no evidence of cancer on biopsy, concern may relate to the risk of ‘missed’ malignancy. Where men

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Page 268 are selected by prostate cancer screening and those with abnormal DRE and/or elevated PSA undergo biopsy, the classical sextant protocol may miss around 15–30% of men with cancer identified by more extensive sampling. The presence of morphologic abnormalities that may be premalignant or associated with ‘missed’ neoplasia, such as high-grade prostatic intraepithelial neoplasia, would further indicate the need for additional biopsy and careful follow-up. The risk of missing cancer clearly relates to sampling technique and factors that include prostate size, biopsy sites, and the number of cores, as well as tumorrelated factors such as multifocality, distribution, and size. Urologists and pathologists need to be aware of the pitfalls in diagnosing or excluding carcinoma on biopsy, and the importance of identifying morphological changes that may relate to malignancy, particularly in the presence of elevated serum PSA or other risk factors for cancer. Clinicians may also be concerned that biopsies may detect microscopic cancers that will not influence the future health of the individual.10 Evaluation of BPH BPH develops in the transition zone of the prostate. It is associated with variable hyperplasia of prostatic epithelial and stromal (fibrous and muscle) components, and an increase in ratio of stromal to epithelial elements.11 Although these histologic changes have been shown not to correlate with urodynamic obstruction, prostatic biopsies have been used to relate particular morphologic patterns to the presence of symptoms and outcome from various therapies.12 As BPH is not a homogeneous change, a single biopsy is unlikely to be representative of all components.3 Some studies have suggested that needle biopsies may be representative of the stromal content of BPH when compared with large tissue samples (as from open prostatectomy).13–16 A significantly higher stromal to epithelial ratio has been found in symptomatic hyperplasia than in asymptomatic hyperplastic glands.17 In men undergoing surgery for BPH there appears to be an increase in epithelial content as the surgical specimen increases in size.18,19 Furthermore, patients undergoing TURP in whom BPH is predominantly stromal may respond less well to surgery when evaluated urodynamically than do those patients in whom the major component is glandular.20 The facility of 5α-reductase inhibitors such as finasteride and dutasteride to improve outcomes in BPH may relate to progressive epithelial regression throughout the prostate,21 although some studies have observed preferential reduction of the transition zone volume in responding patients.22 The type II isoenzyme is predominant within the prostate, expressed by stromal and basal epithelial cells where it functions by converting testosterone to dihydrotestosterone (DHT). DHT is the more active androgen and, mostly derived from prostatic stroma, it supports the secretory functions of adjacent epithelium by paracrine activity. Smooth muscle hyperplasia in BPH may contribute specific qualities relevant to treatment of BPH. In a study of men undergoing TURP for symptomatic BPH, bladder outflow obstruction was significantly correlated with a lower proportion of smooth muscle.23 Correlation has also been observed between the success of α1-adrenergic blockers and muscle density in BPH.24 Additional therapeutic benefits of such α-blockers may be achieved through inducing stromal regression by apoptosis as well as loss of prostatic smooth muscle cells.25 It is interesting to speculate that the analysis of tissue content of transition zone biopsies may become more frequent. Detection of malignant disease in men with clinically benign prostatic enlargement Discrepancies between the clinical presentation of prostate cancer, its mortality rate, and prevalence at postmortem have given rise to concern that prostatic biopsy may detect clinically unimportant malignancy that would never adversely affect the health of the patient. This risk will be determined by the biologic potential of such lesions, and the life expectancy of the individual. Variability in the reported prevalence of prostate cancer is determined by differences in the presentation and age range of the populations, and the method of pathologic examination. Adenocarcinoma may be diagnosed in around 10% of men undergoing TURP for apparently benign disease. The age for this presentation is set by the need for surgery and the range of cancer prevalence is related to sampling extent.26 Undiagnosed peripheral zone malignancy may account for the unpredictable disease course as well as the disparity between the cancer detection rate and its prevalence at postmortem. In postmortem surveys, the prevalence of prostatic carcinoma asymptomatic during life and not the cause of death varies 2–3-fold according to whether random or systematic whole-mount sections are examined.27,28 When the entire gland is examined using whole-mount step sections at 4–5-mm intervals, foci of cancer are commonly found and their prevalence increases with age.29

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Page 269 Cancer detection rates with needle biopsy are influenced by the population selected, the clinical indications for biopsy, and the biopsy technique. Cooner et al. used transrectal ultrasound abnormalities as an indication for biopsy in men with symptoms or concern about prostate cancer.30 In the 69% with a palpably benign gland, cancer was diagnosed in 5%. Most of these tumors arose in the peripheral zone where the detection rate compares with prevalence.30 In contrast, among men responding to invitation for screening using DRE and PSA, Catalona et al. found 12% of the study population had a raised PSA between 4.0 and 9.9 ng/ml and a clinically benign gland, and in this group cancer was diagnosed in 21%.31 In men undergoing biopsy, it is important to remember that advancing age will increase cancer detection rates. The relationship between age and prevalence remained significant within PSA increments from 4.1 and 10.0 ng/ml in a series of 5006 prostate biopsies from men with benign DRE reported by Orozco et al.32 In men with BPH and no evidence of prostate cancer, prostate volume contributes to elevated serum PSA levels: age correlates with volume, but there are additional effects on PSA levels from the variable proportion of epithelium33 and in some studies from an effect of age independent of volume.34,35 The sensitivity of needle biopsy for detecting prostate cancer relates to the number of cores and sites sampled.36 The sextant technique, originally described by Hodge et al.,37 takes six biopsies from the parasagittal plane midway between the sulcus and the lateral border of the prostate and is reported to miss 15–31% of prostate cancers.38,39 Stamey subsequently modified this technique, shifting the middle biopsy laterally to adequately sample the anterior horns of the peripheral zone.40 Levine et al., using the Stamey protocol, increased cancer detection by 30% when taking two sets of sextant biopsies at the same visit.41 Taking 8–12 cores, including the lateral horns, may substantially reduce the need for repeat biopsy, and the superior reliability of this strategy compared with the standard sextant is now generally recognized.42 A number of protocols incorporating transition zone and anterior prostate biopsies have also been suggested, and should be considered particularly worthwhile if these sites were not initially sampled.43–45 Tumor size, multifocality, spatial distribution within the prostate, tumor stage, and prostate volume may also influence the performance of any given biopsy strategy, but somewhat surprisingly the detection of insignificant tumors has not been found to relate to biopsy strategy.46–52 Generally, tumors larger than 1 ml can be reliably detected by multiple systematic biopsies. As tumor volume is one of several potentially important indicators of metastatic capability and tumors less than 1 ml are rarely associated with extraprostatic disease,53 smaller cancers have often been assumed (not necessarily correctly) to be clinically insignificant, particularly if low grade.54 Various models have been explored relating tumor volume to preoperative findings, including serum PSA, ultrasound findings, extent and grade of cancer in biopsy specimens, and various combinations of these,55 but their prospective accuracy for the individual patient and reproducibility between centers remains unproven. Needle biopsies can provide additional prognostic information when tumor is seen infiltrating adipose tissue, large diameter nerves, striated muscle, and seminal vesicle. The most reliable prognostic indicators remain pathologic stage and whole tumor grade. Prior to definitive treatment, pathologic stage is most reliably predicted by the combination of DRE, serum PSA, and needle biopsy grade.56 Tumors arising from the transition zone comprise nearly a quarter of prostate cancers,57 and some have recommended routine transition zone biopsy in the presence of a raised PSA and normal DRE.43 Although transition zone tumors tend to be associated with more favorable prognosis than pathologic equivalents in the peripheral zone, many coexist with more significant tumors in the peripheral zone.58 Thus, most authors report an increased detection rate of just 1.8–10% when transition zone biopsies are included at the first biopsy session. Transition zone biopsies are therefore usually reserved for patients with a high suspicion of cancer, but in whom initial biopsies are negative. Cancers anterior to the urethra may also be missed without anteriorly directed biopsies.44 This region includes the anterior transition zone, the anterior horns of the peripheral zone, and the fibromuscular stroma. Thus, in men with a high index of suspicion for cancer, more than one set of appropriately directed biopsies may be necessary for cancer diagnosis. Undertaking biopsies for elevated PSA levels in men with nonsuspicious DRE may bias detection of prostate cancer towards men with BPH. A study from The Johns Hopkins Hospital has shown that prostate size in men with PSA-detected organ-confined prostate cancer (stage T1c) is significantly greater than in men with organconfined stage T2 cancer. This raises the possibility of serendipitous detection of cancer in men with larger prostates.59 The ability of systematic biopsies to detect cancer, particularly organ-confined disease, in men with file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_269.html[09.07.2009 11:53:32]

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normal DRE and serum PSA levels in the 2.5–4.0 ng/ml range has led

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Page 270 to calls to adopt lower PSA cut-offs for biopsy.60 This potentially increases the proportion of men without cancer requiring biopsy, and particularly includes those with BPH. Alhough serendipity again has been invoked in detection of cancer in men with normal PSA levels, detection of pathologically insignificant tumors does not seem to be increased by lower PSA cut-offs.61,62 The negative biopsy rate with PSA in the 2.5–4.0 ng/ml range may be reduced by restriction to a younger age cohort,34 or by using additional tests such as free PSA to improve specificity.63 However, as the efficacy of screening is unproven, the basis for assuming that a lower cut-off would be advantageous against the more widely adopted PSA standard has been hotly debated.64 The arguments center principally on the (unknown) differences in tumor control that would be attributable to further stage shift and the justification for further extending the scope for treatment where the extent of screening-induced bias on perceptions of clinical risk should already be a concern. To address these questions, indicators of biologic potential and prognosis are urgently required. Importance of prostatic malignancy in men with BPH As a raised serum PSA level, with or without abnormal DRE, may indicate an increased risk of prostatic malignancy, this necessitates biopsy for histologic diagnosis of cancer. Abnormal DRE without raised serum PSA levels may also suggest prostatic malignancy, and may be important in the diagnosis of a subset of tumors that characteristically do not express PSA and tend to be more aggressive and advanced at diagnosis. PSA and DRE are used together for detecting cancer in men with lower urinary tract symptoms (case finding),30 as well as for screening those with minimal or no symptoms for potentially curative treatment.31 BPH may present, therefore, through PSA elevation rather than symptoms. Radical therapy for early stage prostate cancer is unlikely to offer any significant survival advantage for men with life expectancy less than 10 years.65 This situation often coexists with BPH, becoming more common as age advances, parallel with increasing concomitant morbidities and their effects on life expectancy. Although the place for screening and radical treatment to achieve cure becomes increasingly limited beyond 70 years of age, prostate cancer is a common malignancy in men of this generation, and combination therapies including radiation and hormones may offer significant survival benefit for men with nonmetastatic high-risk disease.66 The potential benefits of early and adequate hormone intervention further reinforce the need for appropriate assessment and monitoring for cancer in elderly men.67 Since the introduction of PSA testing, various manipulations have been proposed to distinguish BPH and cancer in men with minor PSA elevation. These have taken into consideration patient age, prostate size, and changes in PSA concentration over time, but have not generally been adopted in clinical practice owing to their potentially adverse influence on the detection of cancer. Adjustment for transition zone volume may be more reliable than adjusting for total prostate volume, but both have the disadvantage of requiring transrectal ultrasound.68 Assays more selective for the different PSA fractions are available and that may reduce the negative biopsy rate or the need for repeat biopsy in the intermediate PSA range. The ratio of free to complexed PSA may reduce the number of negative biopsies in men with intermediate total PSA levels by up to one-third with minimal impact on the overall detection rate.69–71 Cleavage forms of free PSA such as ‘BPSA that may be specifically asso ciated with BPH and transition zone epithelium could further improve discrimination of cancer in men with prostatic enlargement.72 Future research is likely to bring potentially important diagnostic refinements to the clinical setting that will improve the ability to discriminate between benign and malignant prostatic disease without the need for biopsy. Other biochemical markers for cancer under evaluation including human kallikrein (hK2) and insulin-like growth factor (IGF) have not yet impacted on routine clinical practice.73,74 Histopathology The histopathologic diagnoses fall into three major groups: benign, premalignant, and malignant. Within the benign group a diagnosis of glandular hyperplasia is rarely made, as there is insufficient tissue to identify the nodular outline, which distinguishes hyperplasia from a normal gland (Fig. 19.1). In contrast, the morphology of stromal hyperplasia is distinctive and may be diagnosed in the absence of a nodular margin. Stromal nodules are virtually restricted to the suburethral tissue. Also included in the benign group are biopsies showing acute prostatitis, granulomatous prostatitis, and occasionally an area of infarction (Figs. 19.2–4). The latter may be associated with squamous metaplasia of the epithelium at the edge of the

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Figure 19.1 Normal prostatic glands. (a) Normal prostatic glands in a patient with benign prostatic hyperplasia, containing corpora amylacea within their lumen (400×magnification). (b) A group of normal prostatic glands, seen on routine hematoxylin and eosin stain (400×magnification). (c) The focus seen above (in panel (b)) is immunohistochemically stained with antibodies against cytokeratin 5/6, a basal cell marker, resulting in strong cytoplasmic staining in a majority of basal cells, but no staining in the inner luminal layer of epithelial cells. An intermittent staining pattern is commonly seen in benign prostatic glands (400×magnification). (d) The same focus is immunohistochemically stained with antibodies against p63, another basal cell marker, resulting in a nuclear pattern of staining in a majority of basal cells. Again, an intermittent pattern of staining is not uncommonly seen in benign prostatic glands (400×magnification). necrotic tissue. These conditions are important, as they may be associated with an abnormal DRE and/or elevated serum PSA. Premalignant lesions As more prostatic biopsies are prompted by a raised serum PSA, premalignant conditions will be diagnosed with increasing frequency, sometimes associated with co-existing cancer. There are two putative premalignant prostatic acinar lesions: atypical adenomatous hyperplasia (AAH) and prostatic intraepithelial neoplasia (PIN).75 The former is an architectural abnormality composed of clusters of small acini often within or related to a benign lobule. The relationship between AAH and adenocarcinoma is based on its similarity to the lower Gleason grades of carcinoma, its predominant occurrence in the transition zone, and some evidence of its spatial association with invasive tumor and some genetic similarities to prostate cancer. However, currently there is insufficient evidence for clinicians to treat this lesion as premalignant in terms of patient follow-up.76 The major importance of AAH lies in its potential morphologic confusion on biopsy with adenocarcinoma Gleason grades 1 and 2.77

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Figure 19.2 Acute and chronic inflammation of the prostate. (a) A focus of acute and chronic inflammation, composed of neutrophils and lymphocytes, seen adjacent to a prostatic gland (200×magnification). (b) The same focus seen at higher power, highlighting the presence of a multinucleate giant cell (400×magnification). (c) A nearby focus of chronic inflammation composed mainly of lymphocytes and plasma cells file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_272.html[09.07.2009 11:53:34]

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(400×magnification).

Figure 19.3 Granulomatous prostatitis. (a) A well-formed granuloma composed of epithelioid macrophages is seen next to a prostatic gland (400×magnification). (b) Groups of lymphocytes and eosinophils are seen surrounding and infiltrating into the epithelial cells of prostatic glands, disrupting the glandular architecture (400× magnification). (c) An occasional group of acute inflammatory cells (neutrophils) may also be seen infiltrating amongst the epithelial cells of a prostatic gland, in a case of granulomatous prostatitis (400× magnification).

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Figure 19.4 A healing prostatic infarct. (a) A localized, healing prostatic infarct showing the presence of squamous metaplasia of prostatic glandular epithelium, and replacement of prostatic muscle by fibrous tissue (200×magnification). (b) The same focus is seen at higher power (400× magnification). In contrast to AAH, PIN occurs within a normal, atrophic or, less frequently, hyperplastic architecture but has the cytologic features of malignancy and its differential diagnosis is shown in Table 19.1. It may be graded into three subgroups, but in practice the terms low-grade (grade 1) and high-grade (grades 2 and 3) PIN are used. The relationship between high-grade PIN and adenocarcinoma is well established in terms of morphologic identity, continuity, spatial distribution in the peripheral zone, and peak age. With respect to a variety of biochemical markers, PIN shows an intermediate position between benign prostatic epithelium and invasive adenocarcinoma.78,79 When high-grade PIN is found on biopsy in the absence of invasive carcinoma, concern relates to concomitant cancer as well as to the future development of malignancy. Repeat biopsy of patients with high-grade PIN initially produced a diagnosis of adenocarcinoma in 50–100% of patients.80 However, these series were highly selected and in recent studies the proportion of patients with carcinoma has fallen.81–84 In those with low-grade PIN, the incidence of invasive carcinoma on repeat biopsy is not significantly different from that in patients whose initial biopsies did not show PIN.85 Current urologic practice is to follow up and consider repeat biopsy in patients with elevated PSA and high-grade PIN. Prostatic adenocarcinoma Diagnosis of adenocarcinoma on biopsy is made against the background of other abnormalities within the gland that may resemble carcinoma either by forming small acini Table 19.1 Abnormalities mimicking prostatic intraepithelial neoplasia. Clear cell cribriform hyperplasia Atypical basal cell hyperplasia Reactive duct/acinar epithelium adjacent to inflammation Transitional cell carcinoma spreading within ducts and acini Table 19.2 Small acinar lesions mimicking adenocarcinoma. Atypical adenomatous hyperplasia Basal cell hyperplasia Sclerosing adenosis Atrophy Urethral nephrogenic adenoma Verumontanum glandular hyperplasia Hyperplasia of mesonephric remnants (Table 19.2) or showing cytologic abnormalities. Distinction between well-differentiated adenocarcinoma and the benign small acinar lesions is based on the presence of a double cell layer in the latter. Large nucleoli, intraluminal acid mucin, and crystals are all more frequently seen in carcinoma, but are also present in some

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Page 274 cases of AAH. Differentiation between invasive carcinoma and other lesions showing a degree of cytologic atypia is also dependent on the demonstration of an outer basal cell layer in the latter. If not apparent on hematoxylin and eosin (H & E) stain at high power, basal cells may be demonstrated by antibodies to high-molecular-weight cytokeratins. Conclusion Prostate needle biopsies currently have a limited place in the clinical management of BPH. Serum PSA, however, is acquiring increasing importance in the initial clinical assessment of BPH. In men with BPH, elevated PSA continues to serve as an indication for prostate biopsy for the detection of cancer, in spite of the diagnostic overlap. The importance of detecting cancer is entirely related to its subsequent clinical behavior and the success of available treatment. Early cancer may be curable by treatment, such as radical prostatectomy, but there are no morphologic or biochemical criteria for reliably defining tumors that will give rise to progressive symptomatic disease within the lifespan predicted for the patient. Men with BPH may, nevertheless, harbor detectable and clinically significant malignancy that eventually curtails their life expectancy. References 1. Tombal B, De Visccher L, Cosyns J P et al. Assessing the risk of unsuspected prostate cancer in patients with benign prostatic hypertrophy: a 13-year retrospective study of the incidence and natural history of T1a-T1b prostate cancers. BJU Int 1999; 84:1015–1020 2. Catalona W J, Hudson M A, Scardino P T et al. Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves. J Urol 1994; 152:2037– 2042 3. McNeal J, Noldus J. Limitations of transition zone needle biopsy findings in the prediction of transition zone cancer and tissue composition of benign nodular hyperplasia. Urology 1996; 48:751–756 4. Viglione M P, Potter S, Partin A W et al. Should the diagnosis of benign prostatic hyperplasia be made on prostate needle biopsy? Hum Pathol 2000; 33:796–800 5. Hochberg D A, Armenakas N A, Fracchia J A. Relationship of prostate-specific antigen and prostate volume in patients with biopsy proven benign prostatic hyperplasia. Prostate 2000; 45:315–319 6. Sakamoto W, Iwata H, Kamikawa S et al. Role of the transition zone for elevating serum prostatespecific antigen in benign prostatic hyperplasia. Int J Urol 1998; 5:163–166 7. Cadeddu J A, Pearson J D, Lee B R et al. Relationship between changes in prostate-specific antigen and the percent of prostatic epithelium in men with benign prostatic hyperplasia. Urology 1995; 45:795– 800 8. Roehrborn C G, Malice M, Cook T J, Girman C J. Clinical predictors of spontaneous acute urinary retention in men with LUTS and clinical BPH: a comprehensive analysis of the pooled placebo groups of several large clinical trials. Urology 2001; 58:210–216 9. Roehrborn C G, McConnell J, Bonilla J et al. Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR long-term efficacy and safety study. J Urol 2000; 163:13–20 10. Schroder F H, Wildhagen M F. Screening for prostate cancer: evidence and perspectives. BJU Int 2001; 88:811–817 11. Chagas M A, Babinski M A, Costa W S, Sampaio F J. Stromal and acinar components of the transition zone in normal and hyperplastic human prostate. BJU Int 2002; 89:699–702 12. Ichiyanagi O, Nakada T. Correlations between parameters in pressure-flow analysis and histological compositions in prostate in patients with benign prostatic hyperplasia. Urol Int 1997; 59:154–160 13. Zlota A, Sattar A A, Wespes E et al. Is one single prostate biopsy helpful for choosing a medical treatment of benign prostatic hyperplasia? A quantitative computerized morphometric study. Urology 1996; 47:329–334 14. Marks L S, Treiger B, Dorey F J et al. Morphometry of the prostate: I. Distribution of tissue components in hyperplastic glands. Urology 1994; 44:486–492 15. Robert M, Costa P, Bressolle F et al. Percentage area density of epithelial and mesenchymal components in benign prostatic hyperplasia: comparison of results between single biopsy, multiple biopsies and multiple tissue specimens. Br J Urol 1995; 75:317–324 16. Deering R E, Bigler S A, King J et al. Morphometric quantitation of stroma in human benign prostatic hyperplasia. Urology 1994; 44:64–70 17. Shapiro E, Becich M J, Hartanto V, Lepor H. The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostate hyperplasia. J Urol 1992; 147:1293–1297 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_274.html[09.07.2009 11:53:35]

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18. Schuster G A, Schuster T G. The relative amount of epithelium, muscle, connective tissue and lumen in prostatic hyperplasia as a function of the mass of tissue resected. J Urol 1999; 161:1168–1173 19. Price H, McNeal J E, Stamey T A. Evolving patterns of tissue composition in benign prostatic hyperplasia as a function of specimen size. Hum Pathol 1990; 21:578–585 20. Dorflinger T, England D M, Madsen P O, Bruskewitz R C. Urodynamic and histological correlates of benign prostatic hyperplasia. J Urol 1988; 140:1487–1490

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Page 275 21. Marks L S, Partin A W, Dorey F J et al. Long-term effects of finasteride on prostate tissue composition. Urology 1999; 53:574–580 22. Tewari A, Shinohara K, Narayan P. Transition zone volume and transition zone ratio: predictor of uroflow response to finasteride therapy in benign prostatic hyperplasia patients. Urology 1995; 45:258– 265 23. Ichiyanagi O, Sasagawa I, Ishigooka M et al. Morphometric analysis of symptomatic benign prostatic hyperplasia with and without bladder outlet obstruction. Urol Res 2000; 28:29–32 24. Shapiro E, Hartanto V, Lepor H. The response to alpha blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate 1992; 21:297–307 25. Kyprianou N, Litvak J P, Borkowski A et al. Induction of prostate apoptosis by doxazosin in benign prostatic hyperplasia. J Urol 1998; 159:1810–1815 26. Newman A J Jr, Graham M A, Carlton C E Jr, Lieman S. Incidental carcinoma of the prostate at the time of transurethral resection: importance of evaluating every chip. J Urol 1982; 128:948–950 27. Baron E, Angrist A. Incidence of occult adenocarcinoma of prostate after 50 years of age. Arch Pathol 1941; 32: 787–793 28. Lundberg S, Berge T. Prostatic carcinoma. An autopsy study. Scand J Urol Nephrol 1970; 4:93–97 29. Sakr W A, Grignon D, Haas G P et al. Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol 1996; 30:138–144 30. Cooner W H, Mosley B R, Rutherford C L Jr et al. Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol 1990; 143:1146–1152 31. Catalona W J, Richie J P, Ahmann F R et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994; 151: 1283–1290 32. Orozco R, Kunnel B, O’Dowd G J, Stamey T A. Positive prostate biopsy rate consistently increases with age at the same prostate-specific antigen level in patients with normal digital rectal examination. Urology 1998; 51:531–533 33. Weber J P, Oesterling J E, Peters C A et al. The influence of reversible androgen deprivation on serum prostatespecific antigen levels in men with benign prostatic hyper-plasia. J Urol 1989; 141:987– 992 34. Oesterling J E, Jacobsen S J, Chute C G et al. Serum prostate-specific antigen in a community-based population of healthy men. Establishment of age-specific reference ranges. J Am Med Assoc 1993; 270:860–864 35. Kane R A, Littrup P J, Babaian R et al. Prostate-specific antigen levels in 1695 men without evidence of prostate cancer. Findings of the American Cancer Society National Prostate Cancer Detection Project. Cancer 1992; 69: 1201–1207 36. Presti J C J, Chang J J, Bhargava V, Shinohara K. The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. J Urol 2000; 163:163–166 37. Hodge K K, McNeal J E, Terris M K, Stamey T A. Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 1989; 142: 71–75 38. Epstein J I, Walsh P C, Sauvageot J, Carter H B. Use of repeat sextant and transition zone biopsies for assessing extent of prostate cancer. J Urol 1997; 158:1886–1890 39. Norberg M, Egevad L, Holmberg L et al. The sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. Urology 1997; 50: 562–566 40. Stamey T A. Making the most out of six systematic sextant biopsies. Urology 1995; 45:2–12 41. Levine M A, Ittman M, Melamed J, Lepor H. Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 1998; 159:471–475 42. Durkan G C, Sheikh N, Johnson P et al. Improving prostate cancer detection with an extended-core transrectal ultrasonography-guided prostate biopsy protocol. BJU Int 2002; 89:33–39 43. Lui P D, Terris M K, McNeal J E, Stamey T A. Indications for ultrasound guided transition zone biopsies in the detection of prostate cancer. J Urol 1995; 153:1000–1003 44. Bott S R, Young M P, Kellett M J, Parkinson M C. Anterior prostate cancer: is it more difficult to diagnose? BJU Int 2002; 89:886–889 45. Bazinet M, Karakiewicz P I, Aprikian A G et al. Value of systematic transition zone biopsies in the early detection of prostate cancer. J Urol 1996; 155:605–606 46. Karakiewicz P I, Bazinet M, Aprikian A G et al. Outcome of sextant biopsy according to gland volume. Urology 1997; 49:55–59 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_275.html[09.07.2009 11:53:36]

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47. Crawford E D, Hirano D, Werahera P N et al. Computer modeling of prostate biopsy: tumor size and location—not clinical significance—determine cancer detection. J Urol 1998; 159:1260–1264 48. Naughton C K, Smith D S, Humphrey P A et al. Clinical and pathologic tumor characteristics of prostate cancer as a function of the number of biopsy cores: a retrospective study. Urology 1998; 52:808–813

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Page 276 49. Eskew L A, Woodruff R D, Bare R L, McCullough D L. Prostate cancer diagnosed by the 5 region biopsy method is significant disease. J Urol 1998; 160:794–796 50. Egevad L, Norberg M, Mattson S et al. Estimation of prostate cancer volume by multiple core biopsies before radical prostatectomy. Urology 1998; 52:653–658 51. Ung J O, San Francisco I F, Regan M M et al. The relationship of prostate gland volume to extended needle biopsy on prostate cancer detection. J Urol 2003; 169: 130–135 52. Chan T Y, Chan D Y, Stutzman K L, Epstein J I. Does increased needle biopsy sampling of the prostate detect a higher number of potentially insignificant tumors? J Urol 2001; 166:2181–2184 53. McNeal J E, Bostwick D G, Kindrachuk R A et al. Patterns of progression in prostate cancer. Lancet 1986; 1: 60–63 54. Epstein J I, Carmichael M J, Partin A W, Walsh P C. Small high grade adenocarcinoma of the prostate in radical prostatectomy specimens performed for nonpalpable disease: pathogenetic and clinical implications. J Urol 1994; 151:1587–1592 55. Terris M K, Haney D J, Johnstone I M et al. Prediction of prostate cancer volume using prostatespecific antigen levels, transrectal ultrasound, and systematic sextant biopsies. Urology 1995; 45:75–80 56. Graefen M, Augustin H, Karakiewicz P I et al. Can predictive models for prostate cancer patients derived in the United States of America be utilized in European patients? A validation study of the partin tables. Eur Urol 2003; 43:6–11 57. McNeal J E, Redwine E A, Freiha F S, Stamey T A. Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am J Surg Pathol 1988; 12:897–906 58. Greene D R, Egawa S, Neerhut G et al. The distribution of residual cancer in radical prostatectomy specimens in stage A prostate cancer. J Urol 1991; 145:324–28 59. Feneley M R, Landis P, Simon I et al. Today men with prostate cancer have larger prostates. Urology 2000; 56: 839–842 60. Catalona W J, Smith D S, Ornstein D K. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/ml and benign prostate examination. Enhancement of specificity with free PSA measurements. J Am Med Assoc 1997; 277:1452–1455 61. Meigs J B, Barry M J, Giovannucci E et al. High rates of prostate-specific antigen testing in men with evidence of benign prostatic hyperplasia. Am J Med 1998; 104: 517–525 62. Vis A N, Kranse R, Roobol M et al. Serendipity in detecting disease in low prostate-specific antigen ranges. BJU Int 2002; 89:384–389 63. Roehl K A, Antenor J A, Catalona W J. Robustness of free prostate specific antigen measurements to reduce unnecessary biopsies in the 2.6 to 4.0 ng./ml. range. J Urol 2002; 168:922–925 64. Carter H B. Rationale for earlier and less frequent prostate cancer screening. Urology 2001; 58:639– 641 65. Holmberg L, Bill-Axelson A, Helgesen F et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002; 347: 781–789 66. Bolla M, Collette L, Blank L et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360:103–106 67. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997; 79: 235–246 68. Djavan B, Zlotta A R, Remzi M et al. Total and transition zone prostate volume and age: how do they affect the utility of PSA-based diagnostic parameters for early prostate cancer detection? Urology 1999; 54:846–852 69. Partin A W, Catalona W J, Southwick P C et al. Analysis of percent free prostate-specific antigen (PSA) for prostate cancer detection: influence of total PSA, prostate volume, and age. Urology 1996; 48 (Suppl 6A): 55–61 70. Catalona W J, Partin A W, Slawin K M et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. J Am Med Assoc 1998; 279:1542–1547 71. Mettlin C, Chesley A E, Murphy G P et al. Association of free PSA percent, total PSA, age, and gland volume in the detection of prostate cancer. Prostate 1999; 39:153–158 72. Mikolajczyk S D, Millar L S, Wang T J et al. ‘BPSA, a specific molecular form of free prostate-specific antigen, is found predominantly in the transition zone of patients with nodular benign prostatic hyperplasia. Urology 2000; 55:41–45 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_276.html[09.07.2009 11:53:36]

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73. Partin A W, Catalona W J, Finlay J A et al. Use of human glandular kallikrein 2 for the detection of prostate cancer: preliminary analysis. Urology 1999; 54:839–845 74. Chan J M, Stampfer M J, Giovannucci E et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998; 279:563–566 75. Brawer M K. Prostatic intraepithelial neoplasia: a premalignant lesion. Hum Pathol 1992; 23:242–248 76. Helpap B, Bonkhoff H, Cockett A et al. Relationship between atypical adenomatous hyperplasia (AAH), pro static intraepithelial neoplasia (PIN) and prostatic adeno carcinoma. Pathologica 1997; 89:288–300

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Page 277 77. Bostwick D G, Srigley J, Grignon D et al. Atypical adenomatous hyperplasia of the prostate: morphologic criteria for its distinction from well-differentiated carcinoma. Hum Pathol 1993; 24:819–832 78. Parkinson M C. Preneoplastic lesions of the prostate. Histopathology 1995; 27:301–311 79. Sakr W A, Partin A W. Histological markers of risk and the role of high-grade prostatic intraepithelial neoplasia. Urology 2001; 57(Suppl 1): 115–120 80. Brawer M K, Bigler S A, Sohlberg O E et al. Significance of prostatic intraepithelial neoplasia on prostate needle biopsy. Urology 1991; 38:103–107 81. Kamoi K, Troncoso P, Babaian R J. Strategy for repeat biopsy in patients with high grade prostatic intraepithelial neoplasia. J Urol 2000; 163:819–823 82. O’Dowd G J, Miller M C, Orozco R, Veltri R W. Analysis of repeated biopsy results within 1 year after a noncancer diagnosis. Urology 2000; 55:553–559 83. Kronz J D, Allan C H, Shaikh A A, Epstein J I. Predicting cancer following a diagnosis of high-grade prostatic intraepithelial neoplasia on needle biopsy: data on men with more than one follow-up biopsy. Am J Surg Pathol 2001; 25:1079–1085 84. Vis A N, Hoedemaeker R F, Roobol M et al. The predictive value for prostate cancer of lesions that raise suspicion of concomitant carcinoma: an evaluation from a randomized, population-based study of screening for prostate cancer. Cancer 2001; 92:524–534 85. Keetch D W, Humphrey P, Stahl D et al. Morphometric analysis and clinical followup of isolated prostatic intraepithelial neoplasia in needle biopsy of the prostate. J Urol 1995; 154:347–351

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Page 279 20 Neurologic and neurophysiologic assessment C J Fowler K J O’Malley R S Kirby Introduction Symptomatic benign prostatic hyperplasia (BPH) is so prevalent that there is a tendency for urologists to assume that any lower urinary tract symptoms in a man over the age of 50 are likely to be the result of BPH. The usual investigations that have already been discussed—including digital rectal examination, prostate-specific antigen, ultrasound determination of postvoid residual urine, and urinary flow rates— may not distinguish between those male patients with uncomplicated BPH and those with neurologic disease producing a similar clinical picture. The neurologic disorders most often implicated as causing bladder symptoms include neurodegenerative diseases such as multiple system atrophy, idiopathic Parkinson’s disease, and other conditions that affect the autonomic nervous system. These include the autonomic neuropathy of diabetes mellitus, pelvic nerve injury secondary to procedures such as abdominoperineal resection of the rectum, or lesions causing cauda equina damage. Furthermore, patients with upper motor neuron lesions due to spinal cord disease, commonly multiple sclerosis, or diseases affecting the cerebral hemispheres such as cerebrovascular accidents (CVA), may complain of bladder symptoms that may closely mimic those of BPH. Finally, it must be remembered that as BPH is such a common condition it may well occur in men with established neurologic disease, although the decision whether to operate on such patients is often difficult The differentiation between neurogenic involvement of the bladder and bladder outflow obstruction due to BPH is important, as surgical reduction of outflow resistance by transurethral resection of the prostate (TURP) is inappropriate when the disease is primarily neurologic. Indeed, in circumstances such as multiple system atrophy or pelvic nerve injury following anteroposterior resection, where the distal sphincter mechanism is already denervated, surgery to the bladder neck and prostatic urethra is highly likely to cause postoperative urinary incontinence. Focused neurologic examination In many situations the astute urologist can, after taking a clinical history and making a brief but focused clinical examination, tentatively diagnose neurologic involvement of the bladder. In the past, neurologic examination of the perineum was stressed as being important in recognizing neurologic disease that was responsible for bladder dysfunction. In fact, cauda equina lesions, which may be detected by examining the somatic innervation of S2-S4, i.e. the perineum and the back of the thigh, are relatively rare compared with the much more commonly occurring suprasacral spinal pathologies. The neural programs that determine whether the bladder is in storage or voiding mode exist in centers in the dorsal tegmentum of the pons.1 For these programs to be effected there must be intact spinal connections between the pons and the sacral part of the spinal cord (which is the level of efferent and afferent neural connections to the lower urinary tract). Because the innervation of the bladder (Fig. 20.1) arises from cord segments lower than those which innervate the lower limbs, much can be learnt of spinal integrity by a

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Figure 20.1 The lower spinal segments innervating the bladder (parasympathetic) and pelvic floor (pudendal). The sympathetic innervation of the bladder neck, seminal vesicles, and prostate comes from the higher (T10−L1) thoracolumbar levels.

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Page 280 neurologic examination of the legs. Table 20.1 summarizes the sites of various lesions that can give rise to bladder dysfunction, together with the expected physical findings. It is unusual to have a lesion between the pons and the sacral part of the cord giving rise to a neurogenic bladder that does not also produce signs of an upper motor neuron lesion in the lower limbs. This is undoubtedly the case in patients with multiple sclerosis,2 but it also appears to hold for most other instances of spinal pathology unless the lesion is small and intramedullary. Moreover, although it might be predicted that a conus or cauda equina lesion affecting only S2-S4 would prove an exception to this rule, even such extreme caudal lesions are usually associated with neurologic abnormalities in the lower limbs, and foot deformities may be present if the problem is a longstanding one. The contribution of suprapontine pathology to neuro genic bladder dysfunction is quite extensive and diffuse, with the exception of quite localized areas in the frontal lobes. Patients with frontal lobe incontinence may have neuropsychologic impairment, including a change of personality, but are often not indifferent to their incontinence.3 Hydrocephalus can also cause bladder dysfunction, in combination with unsteadiness of gait and dementia.4 The suggestion is sometimes made that a patient’s peripheral neuropathy might be responsible for bladder dysfunction. Many forms of neuropathy are dependent on the length of the nerve fibers involved, the maximum deficit being evident in the longest fibers.5 Because the nerve fibers to the bladder are comparatively short, there should usually be clinical evidence of extensive disease with loss of both knee and ankle jerks and sensory impairment to a level well above the level of the ankles for its innervation to have been affected as part of a generalized neuropathy. Even if the neuropathy is selective for small fibers (i.e. autonomic function, pain, and temperature sensations), symptomatic bladder involvement occurs relatively late and only in patients with other profound neuropathic symptoms. Blood pressure measurement Every patient with suspected BPH should have his blood pressure measured in both the standing and sitting (or ideally standing and lying) position. The most common abnormality is hypertension. It has been one of the authors’ experience (RSK) that approximately 30% of patients entering BPH studies are found to be hypertensive if a definition of hypertension is taken as a diastolic blood pressure greater than 90 mmHg. There has been some suggestion recently that there may be some concomitance of hypertension and BPH,6 the rationale behind this suggestion being overactivity of the sympathetic nervous system in men beyond middle age. Postural hypotension is even more important to detect before initiating therapy for BPH, especially if α-blocking agents are being used in the treatment of this condition. Pre-existing postural hypotension, such as that which commonly occurs with diabetic autonomic neuropathy, will preclude the use of α-blocking agents. In the absence of diabetes mellitus, postural hypotension may be a sign of developing multiple system atrophy (MSA), which may be characterized by progressive autonomic failure. If a TURP is performed in the early stages of this disease, subsequent incontinence and erectile dysfunction may be incorrectly ascribed to the operating urologist when in fact they may be prodromal symptoms of the neurologic disease. Table 20.1 Neurologic conditions that can produce bladder symptoms. Nature/site of Physical signs lesion Spinal cord (tumor, Pathologically brisk knee and ankle jerks, extensor plantar responses vascular, MS, trauma) Cauda equina Absent ankle jerks and possibly loss also of knee jerks; wasting of calf muscles and intrinsic foot muscles; perineal sensory loss; lax anal sphincter Generalized Absent knee and ankle reflexes; impaired sensation in the feet peripheral neuropathy Multiple system History of erectile failure; parkinsonian features, particularly bradykinesia, often atrophy poorly responding to L-dopa; postural hypotension; quiet voice or laryngeal stridor; cerebellar ataxia Parkinson’s disease Lack of facial expression; resting tremor; akinesia-rigidity; shuffling, unstable gait MS, multiple sclerosis.

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Page 281

Figure 20.2 Cystometrogram in a patient with a lower motor neuron lesion of the bladder. Note the loss of compliance during bladder filling and the loss of the normal voiding reflex. However, recent studies of patients with MSA showed that urinary dysfunction is a more common and an earlier manifestation than postural hypotension, although subclinical cardiovascular abnormalities can appear early.7,8 Urodynamics The classic urodynamic appearances of bladder outflow obstruction due to BPH have been discussed in Chapter 17. Neurologic disorders of the bladder, especially upper motor neuron lesions, usually cause prominent detrusor overactivity with phasic unstable contractions. In a severe cord lesion there may be loss of the voiding reflex. In lower motor neuron lesions, an unstable filling pattern is still seen, but this is more often characterized by a slow progressive rise in bladder pressure during filling and, again, a loss of the normal voiding reflex (Fig. 20.2). In lower motor neuron lesions, such as a cauda equina lesion, the bladder neck is often open at rest (Fig. 20.3) and voiding is achieved by abdominal straining, leaving a considerable postmicturition residue. In addition to cystometry, studies have also indicated that urinary symptom scoring systems are useful.9–11 However, they are not specific and cannot differentiate between symptoms caused by neurologic disorders and those caused by BPH. In one study of patients with Parkinson’s disease it was found that the International Prostate Symptom Score (I-PSS) correlates with the

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Figure 20.3 An open bladder neck and slight stress incontinence seen in a male patient with a lower motor neuron lesion of the bladder. degree of neurologic disability and urinary complaints, in men and women.9 The value of scoring systems is in the screening of patients and an early assessment of the severity of bladder dysfunction.

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Page 282 Pelvic floor neurophysiology Electromyography Electromyography (EMG) of the pelvic floor and sphincters has been performed with two distinct aims: EMG in the urodynamic suite has been used to examine sphincteric activity during bladder filling and voiding, while in the neurophysiology laboratory EMG has usually been performed to assess the integrity of innervation of the sphincter muscle. For the latter studies a needle electrode can be used, but for kinesiologic studies various types of surface electrodes have been developed as alternatives to needles (see reference 12 for review). Sphincter EMG recorded during urodynamics Studies of detrusor and sphincter activity show that there is continuous EMG activity in the sphincters and pelvic floor throughout bladder filling and that EMG silence of the urethral sphincter is the first recordable event in normally coordinated voiding. If there is a spinal lesion interrupting the bulbospinal pathways, this normal pattern of behavior is lost and sphincter contraction occurs during detrusor contraction—the so-called detrusor-sphincter dyssynergia.13 In suprapontine lesions, such as those following CVA, there may be uninhibited detrusor activity but the pattern of detrusor sphincter behavior is normal. Concentric needle electrode EMG of the pelvic floor and urethral sphincter To record from the male urethral sphincter the patient lies in the left lateral position with knees and hips flexed and the needle is inserted percutaneously in the midline of the perineum and guided towards the apex of the prostate with the examiner’s finger in the rectum. The audio output of the EMG machine is essential for localizing the correct needle position, since on inserting the needle electrode into the striated muscle there is a burst of EMG activity which then reduces to a resting interference pattern made up of three or four tonically firing units. These units fire continuously at all times, even during sleep and light general anesthesia; the muscle becomes electrically silent only at the onset of micturition. Neuropathic units are of prolonged duration and polyphasic character and are readily distinguished from the less complex normal units found in control subjects (see reference 12 for review). It has been demonstrated that the EMG changes are equally prominent in the anal sphincter, and as that muscle is so much more accessible, it is usually studied when motor unit analysis is indicated.14 Multiple system atrophy The term MSA has been applied to a number of disease entities that have a common pathologic expression of neuronal atrophy in a variety of overlapping combinations. Shy-Drager syndrome, a term mostly now abandoned, referred to a late stage manifestation of the condition characterized by severe akinetic rigidity, autonomic failure, and urinary incontinence. MSA, in recognition of its varied presenting clinical picture, is now commonly divided into cerebellar (MSA-C) or parkinsonism (MSA-P) types. Disturbances of continence and micturition invariably accompany other neurologic changes in MSA and may be the presenting symptom.6,14 MSA usually begins in middle age with significantly higher prevalence rates over 55 years,15–17 and with a very high incidence of erectile dysfunction which usually precedes the onset of urinary symptoms.7 Some patients with MSA have undergone urologic surgery for BPH before the correct diagno sis had been made and the results of surgery are often transient or unfavorable due to the progressive nature of the disease.18 Much has been written in the neurologic literature about the presenting features of MSA, but the urologist should focus on general features and the patient’s gait in particular. A man with early MSA presenting with urinary symptoms is likely to be somewhat unsteady or ‘akinetic’, having recently been diagnosed as having ‘Parkinson’s disease’ (PD). He is also likely to have erectile dysfunction. Selective loss of the anterior horn cells in Onuf s nucleus occurs in MSA, resulting in denervation of the striated muscle of both anal and urethral sphincters. Sakuta et al.19 demonstrated the changes in the EMG of the anal sphincter in patients with MSA and compared them with such findings in patients with motor neuron disease. Kirby et al.20 examined motor units in the urethral sphincter and demonstrated marked prolongation and increased polyphasic potentials, indicating chronic reinnervation. In contrast, Onuf’s nucleus is spared in idiopathic PD and for this reason Eardley et al.21 proposed that sphincter EMG should be used to differentiate between MSA and PD patients with parkinsonism and bladder symptoms. There has subsequently been debate about this and a balanced view is that anal sphincter EMG abnormalities distinguish MSA from PD in the first 5 years after the onset of symptoms and signs, and from pure autonomic failure, as well as from cerebellar ataxias, if other causes for sphincter denervation have been ruled out.1 In a report of 121 men with MSA, cystometry showed detrusor hyperreflexia in 56%, low compliance in file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_282.html[09.07.2009 11:53:39]

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31%,

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Page 283 atonic curve in 5%, and detrusor-sphincter dyssynergia in 45%.7 The cystometric abnormality tended to change from hyperreflexia to low compliance, then to an atonic picture in repeated tests. Postmicturition residuals were noted in 74% of the patients. Parkinson’s disease The prevalence of urinary disturbances in PD has been claimed to be between 38% and 71%,18 although a substantial number of the earlier series included elderly patients, and many of the studies were published before the diagnosis of MSA was recognized. Furthermore, they were largely based on patients presenting to urology clinics with urinary symptoms. A recent study on PD patients diagnosed according to modern criteria found the prevalence of urinary symptoms to be 27%.22 Typically, patients present with longstanding neurologic disease, the bladder symptoms coming on years after the treatment for PD was started.18,22 Although it was thought to be unclear whether the symptoms related to the patient’s age, the duration of the disease, or the severity of the disease, a clear correlation with the neurologic disability has recently been shown.9 There are several possible neurogenic causes of bladder symptoms in PD. Urodynamics studies of several series of patients have found that detrusor overactivity is the most commonly observed abnormality (45–93%),22 but areflexia may also occur. The hypothesis that has been most widely proposed is that in healthy individuals the basal ganglia have an inhibitory effect on the micturition reflex, and with cell loss in the substantia nigra this is lost, and detrusor overactivity develops.23 Patients with PD complain of urgency and frequency, and urge incontinence particularly if poor mobility compounds their bladder disorder. Many male patients with PD will be in the age group in whom bladder outflow obstruction caused by BPH is a common coexistent disorder. These patients will complain of voiding symptoms, but may also have irritative symptoms since obstruction itself can cause overactivity. Urologic intervention is not contraindicated in men with PD, but it is reasonable to try these patients on anti-cholinergic medication initially if storage symptoms are prominent. If conservative measures fail then cystometry should be performed to demon-strate obstructed voiding before an outlet procedure is undertaken.24 Cauda equina lesions and pelvic nerve injury Like the EMG pattern of denervation and reinnervation seen in MSA, patients with cauda equina lesions show neuropathic motor units in the anal sphincter when an EMG needle is introduced. In these circumstances the demonstration of loss of motor units affecting this muscle has obvious implications in terms of continence if the urologist is considering prostatic resection. In circumstances such as urinary retention following an abdominoperineal resection of the rectum when the prostate is suspected to be enlarged, transurethral resection will reduce outflow resistance at the bladder neck and in the prostatic urethra, but if the urethral sphincter has been denervated by the surgical process then there is a substantial risk of urinary incontinence. Sacral reflexes and cortical evoked responses Sacral reflexes are reflex contractions of the striated muscle structures in the pelvic floor that occur in response to stimulation of the perineal genital region. Methods for neurophysiologic recordings of the bulbocavernosus reflex were described 30 years ago and, although this reflex is easier to elicit in men than in women, the intensity of stimulation needed to produce the reflex is very variable. Moreover, the presence or absence of a definite response does not always correlate with definite pathology.12 Cortical evoked potentials can be recorded following stimulation of the pudendal nerve, but it is unusual for this to be abnormal without an abnormality on clinical examination,25 and this test is now rarely used except in select cases.12 Conclusions Only a very small proportion of patients presenting with BPH will require the sophisticated neurophysiologic testing described above. However, all patients would benefit from a careful, focused neurologic examination and recording of blood pressure in the standing and lying positions. If neurologic disease is suspected, the authors recommend formal urodynamic studies and/or referral to a neurologist. References 1. Morrison J, Steers W D, Brading A et al. Neurophysiology and Neuropharmacology. In: Abrams P, Cardozo L, Khoury S, Wein A (eds). Incontinence, 2nd edn. Plymouth: Health Publication, 2002:83–163 2. Betts C D, D’Mellow M T, Fowler C J. Urinary symptoms and the neurological features of bladder dysfunction in multiple sclerosis. J Neural Neurosurg Psychiatry 1993; 56:245–250

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Page 284 3. Andrew J, Nathan P W. Lesions of the anterior frontal lobes and disturbances of micturition and defaecation. Brain 1964; 87:233–262 4. Fisher C M. Hydrocephalus as a cause of disturbances of gait in the elderly. Neurology 1982; 32:1358–1363 5. Sabin T. Classification of peripheral neuropathy: the long and short of it. Muscle Nerve 1986; 9:711– 719 6. Flack J M. The effect of doxazosin on sexual function in patients with benign prostatic hyperplasia, hypertension, or both. Int J Clin Prac 2002; 56:527–530 7. Sakakibara R, Hattori T, Uchiyama T et al. Urinary dysfunction and orthostatic hypotension in multiple system atrophy: which is the more common and earlier presentation? J Neurol Neurosurg Psychiatry 2000; 68:65–69 8. Kirchhof K, Apostolidis A N, Mathias C J, Fowler C J. Erectile and urinary dysfunction may be the presenting features in patients with multiple system atrophy: a retrospective study Int J Impot Res 2003; 15:293–298 9. Araki I, Kuno S. Assessment of voiding dysfunction in Parkinson’s disease by the international prostate symptom score. J Neurol Neurosurg Psychiatry 2000; 68:429–433 10. Lemack GE, Dewey RB Jr, Roehrborn CG et al. Questionnaire-based assessment of bladder dysfunction in patients with mild to moderate Parkinson’s disease. Urology 2000; 56:250–254 11. Sakakibara R, Shinotoh H, Uchiyama T et al. Questionnaire-based assessment of pelvic organ dysfunction in Parkinson’s disease. Auton Neurosci 2001; 92: 76–85 12. Benson JT, Craggs MD, Fowler C J et al. Clinical neurophysiology. In: Abrams P, Cardozo L, Khoury S, Wein A (eds). Incontinence, 2nd edn. Plymouth: Health Publication, 2002:389–424 13. Blaivas J G, Sinha H P, Zayed A A H, Labib K B. Detrusor-external sphincter dysynergia. J Urol 1981; 125: 542–545 14. Beck R O, Betts C D, Fowler C J. Genito-urinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J Urol 1994; 151:1336–1341 15. Wenning G, Ben Shlomo Y, Magalhaes Y et al. Clinical features and natural history of multiple system atrophy. Brain 1994; 117:835–845 16. Schrag A, Ben Shlomo Y, Quinn N. Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 1999; 354:1771–1775 17. de Rijk M C, Breteler M M, Graveland GA et al. Prevalence of Parkinson’s disease in the elderly: the Rotterdam study. Neurology 1995; 45:2143–2146 18. Chandiramani V A, Palace J, Fowler C J. How to recognize patients with parkinsonism who should not have urological surgery. Br J Urol 1997; 80:100–104 19. Sakuta M, Nakanishi T, Tohokura Y. Anal muscle electromyograms differ in amyotrophic lateral sclerosis and Shy-Drager syndrome. Neurology 1978; 28:1289–1293 20. Kirby R S, Fowler G J, Gosling J, Bannister R. Urethrovesical dysfunction in progressive autonomic failure with multiple system atrophy. J Neurol Neurosurg Psychiatry 1986; 49:554–562 21. Eardley I, Quinn N P, Fowler C J. The value of urethral sphincter electromyography in the differential diagnosis of parkinsonism. Br J Urol 1989; 64:360–362 22. Araki I, Kitahara M, Oida T, Kuno S. Voiding dysfunction and Parkinson’s disease. J Urol 2000; 164:1640–1643 23. Albanese A, Jenner P, Marsden C D, Stephenson J D. Bladder hyperreflexia induced in marmosets by 1-methyl4-phenyl-1, 2, 3, 6-tetrahydropyridine. Neurosci Lett 1988; 87:46–50 24. Chandiramani V A, Fowler C J. Urogenital disorders in Parkinson’s disease and multiple system atrophy. In: Fowler CJ (ed). Neurology of bladder, bowel, and sexual dysfunction, Vol 23 in Blue books of practical neurology. Boston: Butterworth Heinemann, 1999 25. Delodovici M L, Fowler C J. The clinical value of the pudendal somatosensory evoked potential is examined. Electroencephalogr Clin Neurophysiol 1995; 96:509–515

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Page 285 IV Medical Treatment

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Page 287 21 Medical management—watchful waiting P Hegurty J M Fitzpatrick R C Bruskewitz Introduction The spectrum of treatment options for benign prostatic hyperplasia (BPH) is matched by the spectrum of disease severity. New medications and minimally invasive modalities offer a greater range of choices to the urologist and the patient. This does not make treatment planning any easier. Despite these innovations the natural history of the condition with or without intervention is still unclear and can only be inferred from a number of studies. As BPH is rarely life-threatening, management is focused on quality of life. Provided it is safe to avoid surgery, watchful waiting (WW) can be offered to patients who are not bothered much by their symptoms. WW is an active process of patient monitoring, which allows for change to medical or surgical intervention as required. The patient must understand that it is not a passive process and that compliance with follow-up appointments is essential. This chapter describes WW as an active treatment option. The natural history of BPH appears to be one of waxing and waning. Only through knowing the natural history of the disease can we ascribe net benefit to any treatment. While the incidence of symptomatic BPH increases with age, it does not follow that the disease is not progressive in any one individual. Cohorts of untreated BPH are useful in describing the heterogeneity of the disease. As the studies have been carried out as the classification of the disease has evolved, it is difficult to compare results. Much of the work to date has compared WW to transurethral resection of the prostate (TURP), however the advent of novel medical and minimally invasive therapies has offered a ‘middle ground’, which must now be explored. Not only may these treatments improve symptoms, but there is also evidence that they may retard disease progression. The rate of TURP has dropped significantly with the introduction of αadrenergic antagonists and finasteride. This may reflect the lack of strong indications for TURP in the majority of patients, or indeed that these agents are in some way disease modifying. Although current guidelines recommend WW for patients with mild symptoms,1 or patients with more severe symptoms who are not bothered by them, medical management is also reducing the number of patients being assigned to WW, even for mildly symptomatic BPH.2 Large, randomized, controlled prospective trials using the American Urological Association (AUA) symptom score, urinary flow rates, and postvoid residual are necessary to allow valid comparison between the many treatments, including WW. Based on the available evidence, the indications for and logistics of WW are outlined. Baltimore longitudinal study of aging A large epidemiological study by Arrighi et al. was published in 1991.3 A cohort of 1371 volunteers was followed from 1958 with physical examination, digital rectal examination (DRE), and a self-administered questionnaire. Those with a history of prostate cancer or prostatectomy were excluded, leaving 1057 in the final analysis. The risk of prostatectomy increased with age. A man aged between 50 and 59 years had a 24% probability of undergoing prostatectomy in the subsequent 20 years. This risk increased to 39% for men over 60 years. Change in prostate size (determined on DRE) and obstructive symptoms increased the chance of prostatectomy. The increase in prostatectomy rates with age in this cohort may not reflect progression of the disease as historical comparison is skewed by prevailing attitudes of practicing urologists. Transrectal ultrasonography would improve the sensitivity of measuring changes in prostate size. Prospective study of patients with voiding symptoms Craigen et al. prospectively followed 251 patients with lower urinary tract symptoms (LUTS) for 4–6 years,4 Initially 39 patients had prostate cancer, 89 were in acute urinary retention, and 123 had prostatism. Of these 123 patients, 6.5% developed urinary retention and 39% required prostate surgery. Of the 67 patients who did not require surgery, 48% became symptom free. There was no difference in baseline symptoms, general health or age in those who did or did not require surgery. This study was limited by its nonspecific urinary symptoms and patient selection. However, it illustrates that of patients who do not require surgery, symptoms resolve in

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Page 288 48% of cases. In a more recent study, of 50 patients with an International Prostate Symptom Score (IPSS) score of less than 7, 81.2% were clinically stable at a mean followup of 17 months.5 Natural history of untreated ‘prostatism’ over 5 years Ball et al. described the 5-year follow-up of a cohort of 107 symptomatic patients for whom surgery was not indicated.6 Ten patients required surgery in the interim, two for acute retention and eight for worsening symptoms. Of the 97 untreated, 31 were subjectively improved, 50 unchanged, and 16 felt worse. This study included detailed urodynamic testing. The annual decrease in maximal flow rates of 1.2 ml/s was the same as that due to aging in the general population. Voiding pressure could safely remain above 70 cmH2O, though it tended to fall over the 5-year period. On average, the ten patients who required surgery had lower initial flow rates and increased prostatic length of profilometry. All ten were classified as obstructed on pressure-flow studies. On review of the initial assessment parameters, it was not possible to predict those who would subsequently require surgery. The simplest and least invasive test, the urinary flow rate, was as good a screening parameter as any other. This study demonstrated the safety of WW over a 5-year period. In an examination of the urodynamics of patients with bladder outlet obstruction (BOO) who underwent WW, it was possible to predict failure rate on the basis of obstruction grade, however.7 Treatment failure was defined as patients who did not wish to continue WW. Pressure-flow studies were conducted at baseline and again after 1 and 4 years. After 1 year, I-PSS had fallen at unchanged Q max and postvoid residual (PVR), and this did not change at 4 years. LUTS severity and failure rate increased over time in patients with severe BOO. The results indicate that prediction of failure is possible, which may allow a more precise prognosis for individual patients who prefer WW. The selection of patients for TURP, minimally invasive therapy, or WW on the basis of pressure-flow studies has also been shown to yield good symptomatic effects in terms of Q max, PVR, and I-PSS with less risk of complications.8 TURP waiting list Barham et al. reported in 1993 a study evaluating 118 patients on a waiting list for TURP.9 Surgery was indicated for symptoms of BPH in combination with an enlarged prostate on DRE. Patient mean age was 70 years (55–89 years), with a mean time on the waiting list of 3 years. Eleven of the original 118 patients were excluded because they had died, refused surgery, or had the procedure elsewhere, 107 patients were evaluated. Of these, 65% said symptoms were unchanged, 12% improved, and 22% deteriorated. Twenty-nine patients (27%) were kept on the waiting list for severe symptoms and a peak flow rate of less than 6 ml/s. The remaining 78 were re-evaluated. Of these, 51 (65%) were discharged from the waiting list due to mild symptoms, nine patients (12%) were kept under review for mild symptoms with objective evidence of severe obstruction (flow rate between 6 and 15 ml/s and residual volumes greater than 150 ml) and 18 (23%) stayed on the waiting list due to bothersome symptoms. In summary, of the original 107 patients evaluated, 47 (44%) were kept on the waiting list, nine (8%) remained under review, and 51 (48%) were discharged. This study demonstrated the fluctuations in BPH symptoms. The authors concluded that patients will opt to avoid surgery if reassured of the natural history of BPH. Like other studies, this study is limited by its definition of symptoms and indications for surgery. Prospective trial of TURP versus conservative management Kadow et al reported a randomized prospective trial of 38 patients with LUTS in 1988.10 Twenty-one patients were randomized to undergo TURP, and 17 WW. Patients were assessed by urodynamics and symptoms at baseline and 6 months after treatment. Of the WW group, 56% of patients were either symptom free or improved, compared to 71% following TURP Irritative symptoms decreased in both groups, with 79% of the TURP group and 50% of the WW group demonstrating improvement in detrusor instability on urodynamics. Peak flow increased from 8.5 to 19.0 ml/s in the TURP group, with little change in the WW group (9.8–11.2 ml/s). This demonstrates that, in a nonstratified group of patients, TURP is superior to WW in its urodynamic outcome and that with conservative management about half the patients improve over 6 months. Department of Veterans’ Affairs Cooperative Study The Department of Veterans’ Affairs (DVA) Cooperative Study compared TURP with WW in 556 men with moderate symptoms of BPH.11 Symptoms were assessed using the Madsen symptom score and bother to patients was measured by a qualify of life score. Exclusion criteria were

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Page 289 age less than 55, previous prostate surgery, bladder or prostate cancer, residual volume greater than 350 ml, or evidence of a neurogenic bladder; 280 patients were randomized to TURP and 276 to WW. Median age was 65, and there was no difference in the groups in their findings on examination, peak flow, residual volume, serum creatinine, or urinalysis at baseline. The follow-up period was 3 years. Flow rates and residual volumes were measured every 6 months, whereas symptom scores and quality of life scores were repeated annually. All patients were advised about aggravating factors such as medication, coffee, and alcohol. Treatment failure was defined as any of the following: death, urinary retention, residual urine more than 350 ml, development of a bladder calculus, new-onset persistent incontinence, or a Madsen symptom score of more than 24, or more than 21 on two consecutive visits. The values at baseline and after 3 years’ follow-up are listed in Table 21.1. The objective measurement of flow rate improved with TURP and was unchanged in the WW group. Postvoid residual volumes decreased to a greater extent in the TURP group over the WW cohort. Bother was ameliorated in both arms, however to a greater degree following TURP. General health and sexual performance remained stable in both groups. The treatment failures were greater in the WW group (17%) than in the TURP group (8%). Successful outcome with WW was more likely in those with high urinary flow rate, a low postvoid residual volume, and low bother score, whereas the only identifiable predictor of success in the TURP group was a high baseline bother score. This study demonstrates that TURP achieves better objective and subjective outcomes than WW in patients with moderate symptoms of BPH. However, patients with minimal bother can be managed safely by WW, as 82% do not experience treatment failure. Watchful waiting versus medical therapy The studies discussed so far have compared TURP to WW. A clinically more relevant question is the difference between medical management and WW. Direct comparison of outcomes of α-adrenergic blockade, finasteride, or WW showed improvement in symptoms and peak flow rates for all three approaches.12 However the actual degree of symptom improvement was greatest for the α-blockade group. In the Veterans’ Affairs Cooperative Studies published by Lepor et al. in 1996, the degree of improvement in AUA symptom score and peak flow rates was greatest among those on an α-adrenergic antagonist.13 In an examination of the effect of a variety of BPH treatments on sexual function, finasteride, αblockers, and TURP were associated with levels of improvement and deterioration in sexual function similar to WW.14 Although surgical intervention has been more closely associated with negative sexual effects in the past, these findings suggest that other factors, such as age, may be more influential.14,15 Current treatment patterns globally The variation between countries on patterns of treatment was the subject of six articles in a European Urology supplement in 1999.1,16–20 The different approaches to treating patients are quite striking. In particular, phytotherapeutics command 40% of the market share in France and Table 21.1 Baseline and 3-year follow-up values for patients in the DVA Cooperative Study.   WW TURP Parameter Baseline 3-year follow-up Baseline 3-year follow-up Peak urinary flow rate (ml/s)* 12.3 12.7 11.6 17.8 Residual urine volume (ml)* 113 72 110 51 Symptom score (points)* 14.6 94 14.5 4.9 Bother from urinary difficulties (points†)* 48.0 57.6 46.4 75.7 Sexual performance (points†) 38.6 35.6 40.0 36.0 General well-being (points†) 71.3 71.4 73.2 76.2 *Changes on transurethral resection of the prostate (TURP) significantly different ( p <0.01) from changes on watchful waiting (WW). †Scale ranges from 0 (most impaired) to 100 (least impaired). (Adapted from ref. 4 with permission.)

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Page 290 Germany.17,18 This is despite the lack of evidence of their efficacy over placebo.21 These papers also describe the widening range of physicians caring for men with BPH. This has occurred with the advent of medical management and the fall-off in the TURP rate occurring in most countries (except the UK).20 The prescribing of α-adrenergic antagonists in combination with finasteride is still prevalent, and may increase following recent positive findings regarding the combination of doxazosin and finasteride;22 however, there is also evidence showing no benefit over α-adrenergic antagonist alone.13 In a telephone survey of 502 American urologists, 20% said they favored medical management over WW in patients with only mild LUTS.23 Thus it is evident that in recent years medical management has reduced both the TURP and WW rates. Treatment preferences The influence of urologist preference is well described in a paper published in 1999 by Stoevelaar et al.24 The preferences of 39 urologists were evaluated in treating 670 consecutive patients, in 13 Dutch hospitals. The majority of patients (67.8%) belonged to the gray area for which, according to the study guidelines, management should be based on patient choice and urologist preference. Patients with high urinary flow rate, low residual volume, or mild irritative symptoms were more likely to undergo WW. Controling for patient characteristics, the urologist’s preference could more than double the likelihood of surgery. The number of years’ experience also influenced treatment choice, in that younger urologists were less likely to recommend WW. Patient preference should predominate in deciding treatment.25,26 However,27,28 since the advent of medical and minimally invasive therapies, this decision has become more difficult. When patients were shown an educational video program, those who had previously chosen an invasive therapy changed to a less invasive option.29 Based on AUA symptom scores, 35% of patients with severe symptoms preferred WW to medical or surgical intervention.12 This indicates that factors other than disease severity are important in the decision-making process. Indications When TURP was introduced over 70 years ago, the mortality and morbidity were high.30 The procedure was reserved for life-threatening conditions such as hemorrhage, uremia and sepsis. With the gradual reduction in mortality, the indications for TURP have greatly expanded.31 The availability of medical and minimally invasive therapies has also altered indications for treatment.32–36 Strong indications for treatment or watchful waiting The absolute indications for intervention are easy to define. Surgery is recommended for (1) refractory urinary retention, patients who have at least one trial without catheter with or without α-adrenergic blockade, (2) recurrent urinary tract infection caused by bacterial prostatitis, refractory to medical treatment, (3) bladder calculi, (4) renal insufficiency due to BOO, (5) severe hematuria from BPH. Other indications for TURP are relative. There is no strong indication for WW, however a strategy of WW is recommended for patients with mild symptoms of BPH.1 Moderate indications for treatment or watchful waiting Management of patients with moderate symptoms of BPH is controversial. Such patients need to be informed of the current evidence regarding the available treatments, so that potential side-effects can be weighed against the natural history of the disease. Many patients, however, seek the opinion of a specialist, in which case it is appropriate to select the optimal treatment. This is based on clinical findings and a number of tests. For WW these include (1) the patient’s bother from urinary symptoms, (2) postvoid residual volume, and (3) uroflowmetry. Bother Two patients with the same AUA symptom score might be bothered by their symptoms to different degrees. Bother is ameliorated to a greater extent by TURP than by WW.11 The interference by the disease in the day-to-day activities of patients can be measured using the BPH impact index.37 Postvoid residual Patients with higher residual volumes fare less well with a WW strategy than with TURP.10 There is no strict cut-off volume at which intervention is recommended. Uroflowmetry Objective evidence of obstruction is gained with uroflowmetry, with the maximal flow rate being the best predictor of surgical outcome.38–40 Patients with a flow

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Page 291 Table 21.2 Indications for therapeutic intervention vs watchful waiting in BPH. Strength Strategy of Watchful waiting Therapeutic intervention indication Strong Mild symptoms (AUA score ≤7) Recurrent urinary retention (more than a single episode) Recurrent urinary tract infections Recurrent gross hematuria Bladder stones Renal insufficiency due to BPH Moderate Moderate symptoms (AUA score ≥8 and ≤19) Moderate to severe symptoms (AUA score but not bothersome (low BPH Impact Score) ≥8) and bothersome (high BPH Impact Score) Higher peak urinary flow rate (rate not High post-voiding residual and low peak specified) urinary flow rate (volume and rate not specified) Low post-void urinary residual (volume not   specified) rate greater than 15 ml/s demonstrate poorer outcomes following TURP than those with maximal flow rates less than 15 ml/s.40–41 Conclusions Low bother score, high urinary flow rates, and low postvoid residual volumes favor management by WW, but the decision should not be based on these factors alone. The indications for WW versus other intervention are listed in Table 21.2.5 Strategy Patients being followed in a strategy of WW must understand that this is an active program. The patient’s symptoms and clinical course are monitored, usually on an annual basis. More (or less) frequent review periods have yet to be defined by research. Patients should receive advice with regard to aggravating factors such as diuretic dose scheduling and coffee and alcohol consumption. On review, the patient should be asked about his satisfaction with this approach. Symptoms should be reassessed, along with physical examination and routine laboratory testing (serum creatinine, urinalysis). Repeat of uroflowmetry and residual urine measurement should be considered. Medical or surgical treatment can be offered to those who deteriorate or those substantially bothered by a lack of improvement. The WW program can be delivered in a shared care setting, provided the system is based on good information and mutual confidence.42 Conclusions Urologists tend to measure outcome by means of symptom score and urinary flow rates. This is balanced against the side-effect profile of any treatment. A minor risk of even a serious side-effect such as incontinence is considered acceptable if the chance of success (as measured by symptom score or urinary flow) is high. From the patient’s aspect, the prime factor is whether the degree of bother is worth risking the morbidity of undergoing treatment. The risk of harm may outweigh the anticipated improvement. Guidelines recently issued by the AUA recommend that patients with mild symptoms (AUA score ≤7), or moderate to severe symptoms who are not significantly bothered by them, be ‘treated’ with WW. From the evidence in this chapter, it is appropriate to recommend WW for patients with mild symptoms. Patients with moderate or severe symptoms can be considered for WW, if their symptoms do not interfere with their activities of daily living. Large, prospective, randomized controlled studies of WW versus medical and surgical treatments are necessary to develop clearer indications for each modality Further research is necessary to outline precise follow-up schedules, the need for repeated renal function tests, and how much postvoid residual is excessive. Allowing patients with BPH to participate in the decision process makes for better compliance and optimal care. References 1. de la Rosette J J, Alivizatos G, Madersbacher S et al. European Association of Urology. EAU Guidelines on benign prostatic hyperplasia (BPH). Eur Urol 2001; 40: 256–263; discussion 264 2. Bruskewitz R C. Management of symptomatic BPH in the US: who is treated and how? Eur Urol 1999; 36 (Suppl 3): 7–13

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Page 292 3. Arrighi H M, Metler E J, Guess H A et al. Natural history of benign prostatic hyperplasia and risk of prostatectomy. Urology 1991; 38:4–8 4. Craigen A A, Hickling J B, Saunders C R et al. Natural history of prostatic obstruction. J R Coll Gen Pract 1969; 18:226–232 5. Netto N R Jr, Lima M L, Netto M R, D’Ancona C A L. Evaluation of patients with bladder outlet obstruction and mild international prostate symptom score followed up by watchful waiting. Urology 1999; 53:314–316 6. Ball A J, Feneley R C L, Abrahams P H. The natural history of untreated ‘prostatism’. Br J Urol 1981; 53:613–616 7. Knutson T, Schafer W, Fall M et al. Can urodynamic assessment of outflow obstruction predict outcome from watchful waiting?—a four-year follow-up study Scand J Urol Nephrol 2001; 35:463–469 8. Knutson T, Pettersson S, Dahlstrand C. Pressure-flow studies for patient selection in the treatment of symptomatic BPH—a one-year follow-up study Scand J Urol Nephrol 2001; 35:470–475 9. Barham C P, Pocock R D, Jamed E D. Who needs a prostatectomy? Review of a waiting list. Br J Urol 1993; 72: 314–317 10. Kadow C, Feneley R C L, Abrahms P H. Prostatectomy or conservative management in the treatment of benign prostatic hypertrophy? Br J Urol 1988; 61:432–434 11. Wasson J H, Reda D J, Bruskewitz R C et al. Comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. N Engl J Med 1995; 332:75–79 12. McConnell J D, Barry M J, Bruskewitz R C et al. Benign prostatic hyperplasia diagnosis and treatment. Clinical practice guideline No 8 AHCPR publication No 94–0582. Rockville: Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services, 1994 13. Lepor H, Williford W O, Barry M L et al. The impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. J Urol 1998; 160:1358–1367 14. Leliefeld H H, Stoevelaar H J, McDonnell J. Sexual function before and after various treatments for symptomatic benign prostatic hyperplasia. BJU Int 2002; 89:208–213 15. Kassabian V S. Sexual function in patients treated for benign prostatic hyperplasia. Lancet 2003; 361:60–62 16. Speakman M J. Who should be treated and how? Evidence based medicine in symptomatic BPH. Eur Urol 1999; 36 (Suppl 3):40–51 17. Lukacs B. Management of symptomatic BPH in France: who is treated and how? Eur Urol 1999; 36 (Suppl 3): 14–20 18. Berges R R, Pientka L. Management of symptomatic BPH in Germany: who is treated and how? Eur Urol 1999; 36 (Suppl 3):21–27 19. Tubaro A, Montanari E. Management of symptomatic BPH in Italy: who is treated and how? Eur Urol 1999; 36 (Suppl 3):28–32 20. McNicholas T. Management of symptomatic BPH in the UK: who is treated and how? Eur Urol 1999; 36 (Suppl 3): 33–39 21. Fitzpatrick J M, Lynch T H. Phytotherapeutic agents in the management of symptomatic benign prostatic hyperplasia. Urol Clin North Am 1996; 22:407–412 22. McConnell J D and the MTOPS Steering Committee. The impact of medical therapy on the clinical progression of BPH: results of the MTOPS trial. J Urol 2002; 167 (Suppl 4): abstract 1042 (updated) 23. Gee W F, Holgrewe H L, Albertsen P C et al. 1997 American Urological Association Gallup Survey: changes in diagnosis and management of prostate cancer and benign prostatic hyperplasia, and other practice trends from 1994–1997. J Urol 1998; 160:1804–1807 24. Stoevelaar H J, Van De Beek C, Casparie A F et al. Treatment choice for benign prostatic hyperplasia: a matter of urologist preference? J Urol 1999; 161:133–138 25. Barry M J, Mulley A G Jr, Fowler F J et al. Watchful waiting vs immediate transurethral resection for symptomatic prostatism: the importance of patient preferences. J Am Med Assoc 1988; 259:3010–3017 26. Kaplan S A, Golubluff E T, Olsson C A et al. Effect of demographic factors, urinary peak flow rates, and Boyarsky symptom scores on patient treatment choice in benign prostatic hyperplasia. Urology 1995; 45:398–405 27. Speakman M J. Initial choices and final outcomes in lower urinary tract symptoms. Eur Urol 2001; 40 (Suppl 4): 21–30 28. Teillac P. Benign prostatic hyperplasia: patients’ perception of medical treatment and their expectations. Results of a French survey involving patients treated with finasteride [in French]. Therapie file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_292.html[09.07.2009 11:53:44]

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2002; 57:473–483 29. Kasper J F, Mulley A G Jr, Wennberg J E. Developing shared decision-making programs to improve the quality of health care. Qual Rev Bull 1992; 18:183–190 30. Perrin P, Barnes R, Hedley H et al. Forty years of transurethral resections. J Urol 1976; 16:757–758 31. Mebust W K, Holtgrewe H L, Cockett A T K et al. Immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol 1989; 141:243–247 32. Fitzpatrick J M. Current management and future trends in benign prostatic hyperplasia (BPH). Ir Med J 1997; 90: 256–258

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Page 293 33. Debruyne F M, Witjes W P, Fitzpatrick J M et al. The international terazosin trial: a multicentre study of the long-term efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. The ITT group. Eur Urol 1996; 30:369–376 34. Fitzpatrick J M. Alternative instrumental treatments in BPH. Introduction. Eur Urol 1999; 35:117–118 35. Hegarty N J, Fitzpatrick J M. High intensity focused ultrasound in benign prostatic hyperplasia. Eur J Ultrasound 1999; 9:55–60 36. Ramon J, Lynch T H, Eardley I et al. Transurethral ablation of the prostate for the treatment of benign prostatic hyperplasia: a collaborative multicentre study. Br J Urol 1997; 80:128–134 37. Barry M J, Fowler F J, O’Leary M P et al. Measuring disease-specific health status in men with benign prostatic hyperplasia. Med Care 1995; 33: AS145-AS155 38. Jensen K M E, Bruskewitz R C, Iversen P et al. Spontaneous uroflowmetry in prostatism. Urology 1984; 24:403–409 39. Jensen K M E, Jorgensen J B, Morgensen P. Urodynamics in prostatism I. Prognostic value of uroflowmetry. Scand J Urol Nephrol 1988; 22:109–117 40. Abrahms P H. Prostatism and prostatectomy: the value of urine flow rate measurement in the preoperative assessment for operation. J Urol 1977; 117:70–71 41. Jensen K M E. Clinical evaluation of routine urodynamic investigations in prostatism. Neurourol Urodyn 1989; 8: 545–578 42. Kirby R S, Chisholm G, Chapple C R et al. Shared care between general practitioners and urologists in the management of benign prostatic hyperplasia: a survey of attitudes among clinicians. J R Soc Med 1995; 88:284–288

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Page 295 22 The placebo effect in the treatment of benign prostatic hyperplasia C G Roehrborn ‘The principal quality of a physician, as well as of a poet (for Apollo is the God of physics and poetry), is that of fine lying, or flattering the patient… And it is doubtless as well for the patient to be cured by the working of his imagination, or a reliance upon the promise of his doctor, as by repeated doses of physics.’1 ‘Is it ethical to use a placebo? The answer to this question will depend, I suggest, upon whether there is already available an orthodox treatment of proven or accepted value. If there is such an orthodox treatment the question will hardly arise, for the doctor will wish to know whether a new treatment is more, or less, effective than the old, not that it is more effective than nothing.’2 Placebo and placebo effect: definitions and theoretical considerations It has long been recognized by practicing physicians that procedures that offer patients reassurance or the expectation of help may lead to marked improvement in their clinical status,3 and many doctors believe that placebo intervention has an ethically acceptable place in clinical practice.4 The Latin-derived term ‘placebo’ originally appears in the Bible ( placebo domino in regione vivorum, Psalm 116, Verse 9), where it may be literally translated as ‘I shall please’. This original meaning of please is still found in the first medical definition of the term in Hooper’s medical dictionary in the early nineteenth century: ‘quality ascribed to any drug prescribed to please the patient rather than being useful’. The first article dedicated to the placebo effect did not appear until 1945: A note on placebo’ by Pepper.5 The potency of belief and expectation in affecting health is also underscored by such dramatic harmful effects as voodoo death, which in contrast can be referred to as a ‘nocebo’ (‘I shall harm’) effect.6 In clinical context, placebo has come to denote a deceptive practice, a view that originates from the practice of singing vespers for pay. This negative connotation of placebo has come to dominate contemporary thinking due to the emergence of double-blind, placebo-controlled drug studies, in which the differentiation of effects due to the pharmacologic action of a compound from other unspecified effects is a primary consideration. Placebo effects are so omnipresent that if they are not controlled for in therapeutic studies, the findings are considered unreliable. Conditions in which placebo effects have been described include cough, mood changes, angina pectoris, headache, anxiety, hypertension, asthma, depression, lymphosarcoma, gastric motility, dermatitis, and pain from a variety of sources.7 A prevalent view of placebo is that its use is mandatory in clinical trials, but unethical in clinical practice, a view that may be challenged on both accounts.7 One of the most influential writers in the field of placebo research is Arthur K. Shapiro who offers the following definition: ‘A placebo is defined as any therapy or component of therapy that is deliberately used for its nonspecific, psychological, or psychophysiological effect, or that is used for its presumed specific effect, but is without specific activity for the conditions being treated. A placebo effect is defined as the psychological or psychophysiological effect produced by placebos.’8 Others have suggested definitions different from the one quoted above,9 or further deliberated on Shapiro’s theory. Grünbaum developed a diagram to illustrate his definition of placebo (Fig. 22.1).10 If a therapeutic theory recommends a therapy ‘t’ for a condition, this treatment usually consists of a spectrum of factors, namely characteristic factors ‘F’ and incidental treatment factors ‘C’. These incidental treatment factors may be known or unknown. The patient’s life activities and functions are subdivided into two parts: the target disorder ‘D’, e.g. BPH, and other aspects of the patient’s life functions or health. The arrows in Fig. 22.1 illustrate the possible causations (effects). The characteristic factors ‘F’ may have a positive or a negative effect on the target disorder (or it may have no effect whatsoever). Similarly, the factors ‘F’ may have similar influences, good or bad, on other aspects of the patient’s life, which are known as side-effects. The incidental treatment factors ‘C’ may have sideeffects, but they may also affect the target disorder, in which case it is referred to as a placebo effect. For example, let the target disorder be BPH and the therapeutic theory the administration of α-blocking drugs

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Figure 22.1 Illustration of a therapeutic theory used to clarify the definition of ‘placebo’. For further explanation see text. (Adapted from reference 10.) by a physician who evaluates the patient at regular intervals. The relaxation of the smooth muscle in the bladder neck and prostate positively affects the symptoms of BPH (nonplacebo effect), but it also causes side-effects, namely a lowering of the blood pressure (positive) and asthenia (negative). An incidental treatment factor is the dispensation of the drug by the physician. If he expresses his confidence in the medication it may result in a positive placebo effect, if he is neutral or makes a comment like: ‘We might try this for a while before we have to do something more serious’, it may result in a negative placebo effect. Obviously, the frequent visits to the physician’s office have an impact on the patient’s life functions as well by forcing him to make time for the visits, etc. (negative sideeffect of incidental treatment factors). Recent research has suggested that the dopaminergic reward mechanisms of the brain are responsible for mediating the placebo effect.11 Brody listed three possibilities to explain why a patient improves after a certain therapy is instituted:12 • The patient got better due to the natural history of the condition in an organism with intact healing and recuperative powers. • The patient got better due to the symbolic effect of the treatment, that is its impact on his or her imagination, beliefs, and/or emotions. • The patient got better due to some specific or characteristic feature of the treatment that can be studied, isolated, and predicted within the context of contemporary medical theory. A positive placebo effect (the second of the above list) is most likely to occur when three factors are present:12 • The meaning of the illness experience for the patient is altered in a positive manner, given the patient’s belief system and world view. • The patient is supported by a caring group. • The patient’s sense of mastery or control over the illness is restored or enhanced. This theory, emphasizing the importance of the patient’s belief system and his or her expectations, highlights the cultural dimension of the placebo phenomenon and the importance of cross-cultural studies in placebo research. White et al.7 pointed out that there is no single placebo effect with a single mechanism and efficacy, but rather a multiplicity of effects with differential efficacy and mechanisms, and they provide a list of placebogenic variables or determinants of a placebo response (Table 22.1). Turner et al.,13 in a review of the importance of the placebo effect in pain treatment and research, listed similar factors influencing the placebo response. Among the patients’ factors contributing to a high placebo response rate were anticipation and expectations, a positive attitude toward provider and treatment, anxiousness and compliance with the prescribed treatment. As an example for the latter, a randomized trial to evaluate the efficacy of a lipid-lowering drug in the therapy of coronary heart disease may be mentioned. Patients in the placebo arm were stratified by whether they took more or less than 80% of the placebo tablets.14 Even after controling for 40 known or suspected risk factors, the noncompliers had a 57% higher 5-year mortality rate than the compliant patients. Either the placebo lowered mortality, or patients’ compliance related to other characteristics associated with mortality, which was not assessed in this study. Among the

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Page 297 Table 22.1 Biopsychosocial determinants of placebo response. (Reproduced with permission from White et al.7) Cultural context Belief system Faith Environmental milieu instruction Suggestion Preparation characteristics Doctor-patient relationship Patient’s expectations and beliefs Patient’s personality Psychological state Symptom severity Discomfort severity Anxiety and stress Central evaluative processes Cognitive processes Cognitive schema Self-schema Self-control Expectancy Outcome expectancy Efficacy expectations Operant behavior Symbolic processes Imagination Covert rehearsal Emotions Central nervous system influences upon physiology Immune system Stress mechanism Endogenous opiates Classical conditioning Spontaneous remissions providers’ factors they listed warmth, friendliness, interest, sympathy, empathy, prestige, and, again, a positive attitude towards the patient and the treatment. These considerations all address the issue of a ‘placebo treatment’ and the ‘placebo effect’ in the usually understood sense of a medical treatment with a drug. Placebo effects, however, are equally important to consider when the treatment consists of a procedure or surgical therapy. Instead of using an inactive preparation, a procedure or surgery is performed which is similar in all respects to the active procedure or surgery, but different in that the key aspect of the procedure, which is believed to convey the main therapeutic benefit, is omitted. Such procedures are referred to as ‘sham treatment’ and the incidental causes or effects as ‘sham effects’. Throughout this chapter, the term ‘placebo/sham’ will be used to indicate the pertinence of the observation to both medical (drug) treatments and procedural (surgical) interventions. Rationale for placebo/sham controlled trials The value of controlled clinical trials in the determination of the safety and effectiveness of a new intervention is largely undisputed. The US Food and Drug Administration (FDA) recognizes four types of comparative trials: • No treatment, which involves a comparison of the results in comparable concurrent groups of treated and untreated patients, This type of control is utilized when objective measurements of effectiveness are available and placebo effect or spontaneous improvement of the condition is negligible. • Placebo control, which involves a comparison of the results of a particular therapy with an inactive preparation or a sham procedure. • Active treatment control, which involves a comparison of the results from the new intervention with those from a treatment known to be effective. • Historical control, which involves comparison of the results from a new intervention with prior experience obtained in a comparable group of patients receiving no therapy or a known effective file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_297.html[09.07.2009 11:53:46]

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regimen. The caveat listed in the first paragraph is of great relevance in BPH treatment trials. While better objective outcome measures are being developed and utilized, there is certainly a placebo effect and the natural history of the disease is such that spontaneous remissions are quite common. Thus, in clinical BPH research the only alternatives are placebo/sham-controlled trials, or active treatmentcontrolled trials. Active control trials might substitute for placebo-controlled trials (1) when there is reasonable certainty that a new treatment will be more effective than other agents known to be effective; (2) when the effectiveness of the new treatment is self-evident; or (3) where the nature of the therapy or procedure is such that it is not possible to blind the patients or the observers.15 While the

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Page 298 first two arguments rarely are true in BPH treatment trials, the third argument demands a closer look. Experience has shown that it is feasible to blind both patients and observers responsible for outcome assessment regarding the randomization in a trial comparing balloon dilatation of the prostate with a sham procedure (cystoscopy).16 As will be discussed below, blinding is also possible in treatment trials using microwave-induced heat and other minimally invasive treatments. Whether or not true blinding could be achieved in a trial comparing transurethral resection of the prostate (TURP) with a sham procedure is more questionable because of the need for catheterization, the bleeding, and the irrigation necessary following the TURP, Despite the absence of any such trial, TURP is currently considered the gold standard of BPH treatments, and, in fact, it serves occasionally as an active-treatment control for other invasive treatment modalities. Despite the general acceptance of placebo/sham controls in medical research,17 others have warned against the ‘continuing unethical use of placebo controls’,18 stating that in many cases the use of placebo control groups is in direct violation of the Declaration of Helsinki. The Declaration states that: ‘The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.’19 Thus, Rothman and Michels argue that the use of a placebo is unethical whenever there is a proven therapy available according to the Declaration of Helsinki.18 The two ethical counter arguments which can be made are the notion that withholding of active treatment may not lead to any harm on the part of the patient depending on the underlying condition, and second, that patients in fact give their informed consent, after being fully informed, to participate in a placebo/sham controlled trial. In the field of clinical BPH research, the American Urological Association (AUA), the US FDA, and the World Health Organization (WHO) advocate rather strictly the use of placebo controls. The AUA BPH Clinical Trials Subcommittee is currently preparing a blueprint for the design and reporting of clinical trials in BPH. It is noted that BPH is a disease characterized by a somewhat unpredictable natural history. A significant minority of patients experience stabilization of symptoms or actual improvement. Moreover, improvements in symptoms and uroflow are seen in patients treated with placebo. This makes a randomized, placebo- (or sham-) controlled design mandatory. New surgical technologies should be compared to standard surgical treatments, such as TURP or transurethral incision of prostate (TUIP), utilizing a randomized design. For BPH medical therapies and minimally invasive technolo gies, efficacy relative to placebo or sham must be established (J.D.McConnell, personal communication). The document furthermore stipulates that patients have to be blinded towards the assigned treatment, and that preferentially the treating physician should also be blinded (double-blind). The FDA circulated a draft guidance for the clinical investigation of hyperthermia devices used for the treatment of BPH. This document stipulates that the study protocol should include a randomized active control which best can be accomplished by a blinded, shamtreated control. The FDA specifically discusses the use of a watchful waiting control or historical controls, and expresses concern regarding both these suggestions. The watchful waiting control does not assess the placebo effect of repeated catheterization which is part of the heat treatment, and the historical TURP control group might not be well matched due to different selection criteria and evaluation methodologies. However, the use of an active, randomized, concurrent TURP control group is recommended to further enhance the evaluation of hyperthermia therapy. This draft guidance document has not yet been finalized, but it is widely used in the design of trials for hyperthermia devices or other minimally invasive treatment modalities (thermotherapy, transurethral needle ablation of the prostate (TUNA), high-intensity focused ultrasound (HIFU), etc.). The International Consultation on BPH has published under the patronage of the WHO five consensus documents which address the standardization of the evaluation of treatment modalities. Similar recommendations were made in the proceedings from the 1991, 1993, 1995, and 1997 meetings.20 The 2000 consensus recommendations state that all new drugs and devices intended for the use in LUTS and BPH should undergo rigorous testing in phase III trials of at least 12 months’ duration in which they are compared with either standard treatments or placebo/sham treatments to document their efficacy.21 Despite the ethical concerns voiced by some, in regards to BPH treatment trials there appears to be unanimity between physicians, industry, the government (FDA), and the WHO regarding the mandatory use of placebo/sham control groups, at least in those trials considered pivotal for a new treatment.

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Page 299 In November 2000 the National Center for Complementary and Alternative Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) convened a consensus conference in Bethesda, MD (USA) on the NIH campus regarding The science of the placebo: towards an interdisciplinary research agenda’. The tremendous response and participation of researchers and clinicians from a wide variety of backgrounds highlighted the urgent need to improve our understanding of the placebo effect and its role in bio medical research. Placebo effects in other fields of medicine Blackwell et al. chose the setting of a medical school class to demonstrate the range of possible placebo effects.22 Fifty-six second-year medical student volunteers were conditioned to expect either stimulative or sedative effects, but in fact all received placebo in either one or two blue or pink capsules, without knowing that in fact the number and color of the dispensed capsules differed between the volunteers. Following the ingestion of the study medication, 30% of participants reported drug-associated changes, which were severe in one or two of the participants. Two capsules produced more changes than one, and blue capsules were associated with more sedative effects than the pink capsules. Physicians are powerful therapeutic agents, and their (placebo) influence can be felt to a greater or lesser degree at every consultation. In an unusual study, 200 patients with nonspecific symptoms but no definite diagnosis were selected for one of four consultations: a positive consultation with therapy (thiamine hydrochloride 3 mg tablets) or without treatment, or a negative consultation with or without treatment.23 In a positive consultation the patient was given a firm diagnosis and told that he would be better in a few days. If no treatment was given, he was told he needed none. If treatment was given, he was told that the treatment would make him better with certainty. In a negative consultation the doctor stated that he could not be sure about the diagnosis, and that therefore no treatment was given (no treatment group), or that a treatment would be tried without assuring that it would help (treatment group). During the follow-up visit, 64% of patients in the positive consultation group got better versus 39% in the negative consultation group ( p =0.001). However, there was no significant difference between the treated (53%) and the not treated (50%) patients ( p =0.5). In this example the physicianrelated placebo effect was clearly stronger than the effect conveyed by the medication given. The largest body of literature regarding placebo effects exists in the area of pain treatment. Turner et al.13 identified over 150 articles describing placebo effects in pain treatment and research. They found that placebo response rates vary greatly. Frequently they were found to be higher than the widely accepted one-third placebo response rate based on the classic article by Beecher.24 Placebos have timeeffect curves, and peak, cumulative, and carry-over effects similar to those of active medications. A certain placebo-responder personality could not be identified, and the role of anxiety, expectations, and learning were emphasized. The authors concluded that placebo effects plus natural history and regression to the mean25 may result in high rates of good outcomes in pain treatment, which may be misattributed to specific treatment effects. The important role of the physician as administrator of the treatment for pain, be it active or placebo, was emphasized by Gracely et al.26 Dental patients were told that they would receive either a placebo, a narcotic analgesic, or a narcotic antagonist, and that this treatment might increase, decrease, or have no effect on their pain. The physicians administering the drugs knew, however, that one group of patients would receive either placebo or the narcotic antagonist but not the narcotic analgesic (group A), while another group would receive any one of the three agents (group B). Thus, the two groups of placebo-treated patients in groups A and B did only differ in the clinician’s knowledge of the range of possible double-blind treatments, including the knowledge that patients in the group A had no chance of receiving active pain medication. Nonetheless, the placebotreated patients in group B had significantly less pain than those in group A. This experiment shows clearly that analgesia does not only depend on the action of the administered treatment, but also on the expectations of the patient and, most surprisingly, on those of the physician, who may influence the patient’s responsiveness by a subtle behavioral change. This phenomenon of expectation and anticipation of analgesia must be taken into account when designing a cross-over study, as the patient’s past experience of pain relief (i.e. during phase I of a cross-over trial) may influence his/her subsequent (i.e. during phase II of a cross-over trial) response to treatment.27 Surgical procedures may also have a very strong placebo effect as described earlier by Beecher.28 A most striking

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Page 300 and classic example is the history of internal mammary artery ligation for the treatment of angina pectoris, which was popular in the first half of the twentieth century as a means to increase blood flow to the coronary circulation. Beecher analyzed the early experience and divided the reports into those written by ‘enthusiasts’ versus ‘sceptics’. The former group found complete relief of chest pain in 71/213 patients (38%) while the latter in only 6/56 (10%).28 Cobb et al.29 and Diamond et al.30 performed a double-blinded study (the cardiologist was blinded as to the procedure performed by the cardiac surgeon) of internal mammary artery ligation versus a sham procedure, namely skin incision only, and published remarkably similar results. Cobb et al. reported a 63% significant improvement and 34% decrease in the use of nitroglycerine in the ligation group versus a 56% improvement and 42% decrease in nitroglycerine use in the sham group. Diamond et al. reported a 100% improvement in both groups regarding exercise tolerance, nitroglycerine use, and angina pain. During the year after surgery, 69% of patients reported over 50% improvement in pain in the ligation group versus 100% who experienced greater than 50% improvement in the sham group. In a review, Johnson31 discussed the possible placebo effect of extracorporeal shock wave lithotripsy (ESWL) for gallstones. In a randomized trial comparing ESWL with open cholecystectomy the symptomatic response was similar in both groups but, surprisingly, the symptomatic response in the ESWL group was identical whether or not the stones had actually been cleared. Thus, the symptomatic response might at least partially be triggered by a placebo effect. Comparatively little is known about the placebo effects on healthy volunteers in clinical pharmacology trials. Rosenzweig et al.27 reviewed adverse events reported during placebo administration in 109 double-blind, placebo-controlled studies involving 1228 volunteers. The overall incidence of adverse events was 19%, and complaints were more frequent after repeated dosing (28%) and in elderly subjects (26%). The most frequent adverse events were headache (7%), drowsiness (5%), and asthenia (4%). The overall incidence and distribution of adverse events also appeared to depend on the nature of the active investigational drug in the young volunteers in single-dose studies. The highest incidence for all adverse events was noted when the active drug had a central nervous system effect (16.7%). The incidence was lower when the active drug had miscellaneous effects (16.2%) or a cardiovascular system effect (6.1%). Natural history, watchful waiting, versus placebo effect The importance of placebo/sham-controlled trials in BPH research is emphasized by the highly variable natural history of the disease, and the tendency towards spontaneous improvement and regression documented in several watchful waiting studies, and, to a lesser degree in longitudinal studies of the natural history of the disease. While natural history studies refer to the longitudinal study of a cohort of men with signs and symptoms of BPH over time without any kind of treatment intervention, the watchful waiting studies usually entail at least a yearly follow-up visit with a ‘treating’ physician. According to the discussion above, this consultation may have a profound impact on the ‘natural history’ of the disease process depending on the attitude and behavior of the physician. It is probably reasonable to expect that at the end of each visit the physician would tell the patient that ‘he is doing well and does not need any [additional or active] treatment’, a statement that carries with it a considerable placebo effect. Even in a natural history study the members of the study population have to be seen, interviewed, and examined at regular intervals, thus providing for the possibility of a placebo effect. Longitudinal natural history studies may provide nonetheless the best information about the ‘background activity’ of the disease process. Watchful waiting studies add at least one known and powerful placebo effect, and they carry with them the possibility of ‘treatment failure’ and conversion to a presumably more active treatment. Lastly, placebo/sham control groups add additional nonspecific effects and, thus, their outcomes theoretically should be superior to watchful waiting and natural history studies. Regression to the mean Placebo control arms differ in at least one other very important characteristic from natural history studies. In general, patients are selected to participate in studies based on inclusion/exclusion criteria, usually eliminating patients perceived to be less symptomatic, i.e. those with lower symptom scores and higher peak flow rates. By the principle of trial conduct, patients then repeat the symptom and flow rate assessment during and after therapy in both active and placebo groups. However, the same inclusion/exclusion criteria are not applied to those measurements. To determine the effect that the stringency of pretrial screening has on the outcome of placebo treatment, a cohort of 145 volunteers were invited to fill in the I-PSS score and perform a flow rate recording twice within a

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Page 301 month without receiving any therapy or instructions whatsoever.32 Although many patients experienced either an increase or a decrease in both parameters, the mean values did not change significantly (I-PSS 12.1 vs 11.7 points, peak flow rate 17.7 vs 17.4 ml/s; not significant). However, when typical BPH trial conditions were applied and only those patients considered for analyses who had an I-PSS score above (>7, >10, >15) and a flow rate below a certain threshold (<15, <12, <10 ml/s), a unilateral regression to the mean took place, by which the ‘more’ symptomatic volunteers (i.e. patients) experienced still considerable natural variability on the occasion of the second assessment, but the net effect was towards ‘improvement’, i.e. lower scores and higher flow rates. For example, when only considering patients with I-PSS scores >10 points, the mean difference between first and second assessment was between 19.9 and 18.9 points or −1.1 ( p <0.05). Similarly, when only patients with a peak flow rate <12 ml/s were considered, the mean difference between the first and second assessments was 9.3 vs 10.9 ml/s or +1.6 ml/s ( p <0.01) (Tables 22.2 and 22.3). This experiment clearly illustrates that a unilateral regression to the mean induced and controlled by the stringency of the inclusion criteria can result in a significant ‘improvement’ in any parameter for which a threshold is set at the baseline screening. Such purely mathematical effect is probably at work in many if not all studies where the outcome parameters are measured using a numerical scale of some sort, and where baseline screening criteria are applied. This effect, however, is by definition not at work in a longitudinal natural history study where no baseline inclusion criteria are applied, but rather all patients independent of the numerical value of the measured parameter are followed. Table 22.2 Mean±SD and range for AUA symptom index for tests 1 and 2, mean difference between the two tests and the 95% confidence interval (CI) for the difference, for all subjects, and for subjects censored based on test 1>7 points, >10 points, and >15 points. Statistical comparison between tests 1 and 2 by t-test. Note the reduction in the number of patients available for follow-up due to censoring which affects the power of the statistical test. Selection   Mean±SD Range Mea Mean difference 95% CI t-Test n All subjects 1 12.1±8.8 0–32 −0.39       2 11.7±9.0 0–32 −1.1 to 0.29 0.133 145 >7 at 1 1 17.8±6.5 9–32 −0.97       2. 16.8±7.7 0–32 −2.0 to 0.08 0.035* 88 >10 at 1 1 19.9±5.6 11–32 −1.1       2 18.9±6.9 0–32 −2.2 to 0.1 0.036* 70 >15 at 1 1 22.0±4.6 16–32 −1.4       2 20.6±6.6 0–32 −2.8 to 0.0.1 0.026* 54 *p <0.05. Table 22.3 Mean±SD and range for peak flow rate for tests 1 and 2, mean difference between the two tests and the 95% confidence interval (CI) for the difference, for all subjects, and for subjects censored based on test 1<15 ml/s, <12 ml/s, and <10 ml/s. Statistical comparison between tests 1 and 2 by t-test. Note the reduction in the number of patients available for follow-up due to censoring which affects the power of the statistical test. Selection   Mean±SD Range Mean difference 95% CI t-Test n All subjects 1 17.7±8.2 5.1–47.5 −0.18       2 17.4±8.4 4.7–61.0 −1.2 to 0.82 0.36 145 <15 at 1 1 10.7±2.5 5.1–14.6 1.5       2 12.2±4.6 4.7–25.5 0.47 to 2.6 0.002* 65 <12 at 1 1 9.3±2.1 5.1–11.8 1.6       2 10.9±4.8 4.7–25.5 0.06 to 3.1 0.021* 40 <10 at 1 1 7.3±1.6 5.1–9.9 1.7       2 9.0±3.7 4.7–17.4 0.4 to 3.8 0.05* 17 *p <0.05.

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Page 302 Natural history of BPH The most informative natural history study to date is the Olmsted County study of urinary symptoms and health status among men, which has given us much information about prevalence and severity of urinary symptoms, bother, worry, and embarrassment, quality of life due to symptoms, and the relationship between symptoms and other parameters such as flow rates, prostate volume, and prostate-specific antigen (PSA).33–41 With continued follow-up of this cohort, data have emerged regarding the longitudinal changes in symptoms and flow rate over time in this population-based study. Of 904 men reporting none to mild symptoms (AUASI 0–7 points) at baseline, 118 reported moderate to severe symptoms (AUASI >7 points) at 18 months’, and 196 at 42 months’ follow-up.42 However, 47 men who had developed moderate to severe symptoms at 18 months, had none to mild symptoms at 42 months. At 42 months of follow-up an average increase in the I-PSS of 0.18 (95% confidence interval 0.13 to 0.24) points per year of followup was recorded. The average annual symptom score slope and variability in slope increased with patient age at baseline from a mean of 0.05±1.06 (standard deviation) per year among men in their forties to 0.44±1.35 per year for men in their sixties, and decreased to 0.14±1.42 per year for men in their seventies.43 More recently, 92 months’ data showed an annual change of 0.34 points/year, with 31% of all men reporting at least a 3-point increase. The greatest annualized increase was observed in men in their sixties with 0.6 points/year.44 In addition, 6-year follow-up data on peak flow rate measurements in a subset of about 500 men showed a median peak urinary flow rate slope decrease of −2.1% per year (25th centile −4.0, 75th centile −0.6). Peak urinary flow rate declined more rapidly with decreasing baseline rate, and increasing baseline age, prostate volume, and symptom severity (all p =0.001). When the variables were simultaneously adjusted for each other, a rapid decline (negative slope 4.5% or greater per year) was more likely in men 70 years old or older and in those with a rate less than 10 ml/s at baseline compared to those 40 to 49 years old and those with a rate of 15 ml/s or greater, respectively. Prostate volume and symptom severity were not statistically significant predictors of a rapid decline in peak urinary flow rate when variables were considered simultaneously.45 Based on transrectal ultrasonography (TRUS), the growth of the prostate in the men aged 40–79 years was estimated to be about 0.6 ml per year or 6 ml per decade of life. However, prostate growth followed an exponential growth pattern, with a slope estimate of 0.4 ml per year for men aged 40–59 years at baseline and of 1.2 ml per year for those aged 60–79 years at baseline.46 An updated analysis revealed a median growth rate of about 1.9%/year independent of age and symptoms. However, a higher baseline serum PSA and larger prostate volume predicted greater annualized volume increases (Fig. 22.2).47 Diokno et al.48 provided estimates of the prevalence, incidence, and remission of lower urinary tract symptoms in 803 community-dwelling men aged 60 years or older. The annual incidence of prostate surgery was 2.6% and 3.3% during years 1 and 2 of follow-up. The prevalence of at least one symptom was 35%, with annual incidence rates during years 1 and 2 of follow-up being 16.4% and 16.1%. Remission was also noted in that 22.9% of those having severe symptoms at baseline were asymptomatic at follow-up. Table 22.4 details the changes in symptom severity from one survey to the next. The tendency for fluctuation and spontaneous remission of symptoms as well as the regression to the mean become evident from an analysis of these data. Watchful waiting studies In the absence of other longitudinal natural history studies, several watchful waiting studies are available for review. Most of these studies have significant shortcomings. Inclusion and exclusion criteria are poorly defined, follow-up is loose, assessment instruments are either not defined or insufficient, and patient accounting is incomplete. Five such studies, reported between 1919 and 1988 and totaling 456 patients with follow-up ranging from 3 to 6 years,49–53 were analyzed for the AHCPR BPH Guidelines.54 A change in symptom status was reported for all 456 patients, while none of the studies utilized a quantitative symptom severity scale. Data on urinary flow rate and residual urine were available for 223 and 197 patients, respectively. The peak urinary flow rate deteriorated in 66% and improved in 20%. Residual urine increased (35%), decreased (37%), and remained unchanged (28%) in about the same number of all patients. The mean change in peak flow rate (in those patients for whom data are available) was 2.2 (from a mean of 9.0 to 11.2) ml/s or 24%, while the mean change in residual urine was +37 (from a mean of 115 to 152) ml or 32%. The data on symptom improvement were dichotomized (improved versus not improved). The probability for symptom improvement was then calculated using the confidence profile method (CPM) file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_302.html[09.07.2009 11:53:49]

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described by David Eddy55 (Fig. 22.3). The mean probability for

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Figure 22.2 Per cent annual increase in prostate volume by baseline prostate volume (a) and baseline serum PSA (b) in participants of Olmsted County study of urinary symptoms in men. (Adapted from reference 47.) Table 22.4 Changes in status of obstruction severity from one survey to the next (adapted from reference 48). Patients who underwent prostatectomy in the preceding year were excluded from the next survey. Severity Year No Severity in following year (%) None Mild Moderate Severe None Baseline 293 83.6 12.3 2.7 1.4   Year 1 223 83.9 9.0 2.2 4.9 Mild Baseline 88 18.2 55.7 11.4 14.8   Year 1 84 33.3 52.4 8.3 6.0 Moderate Baseline 38 7.9 31.6 26.3 34.2   Year 1 27 3.7 33.3 22.2 40.7 Severe Baseline 35 22.9 17.1 11.4 48.6   Year 1 31 9.7 22.6 12.9 54.8

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Page 304 improvement in symptom severity was estimated to be 42.5% (90% CI 30.8 to 54.8), surprisingly similar to the probability for improvement noted in the placebo arms, and in a carefully designed, prospective study to be discussed below. It must, however, be recognized that, because of limitations of the dataset, the magnitude of the improvement cannot be estimated. In updated guidelines for the management of BPH, published by the AUA,56 watchful waiting is recommended for patients with mild symptoms (AUA symptom score ≤7) or moderate to severe BPH in patients who are not bothered by their symptoms. Watchful waiting is therefore an appropriate early treatment strategy for most men with BPH. A randomized study with a 3-year follow-up was reported comparing watchful waiting with TURP in 556 men with symptoms of BPH57. Inclusion criteria included a Madsen-Iversen symptom score between 10 and 20 points (0–27 point scale), thus limiting the informational value of the watchful waiting arm of the study to patients with moderate lower urinary tract symptoms. There were 47 treatment failures (defined as death, recurrent infection, residual urine volume over 350 ml, development of bladder calculus, incontinence, a symptom score of 24 or higher, or a doubling of serum creatinine from baseline) in the watchful waiting arm ( n =276) versus 23 in the surgery arm ( n =280) over 3 years of follow-up (relative risk 0.48; 95% CI 0.3–0.77). Sixty-five (24%) men assigned to watchful waiting underwent surgery during follow-up, 20 of them for treatment failure. The majority of these men

Figure 22.3 Probability of achieving symptom improvement following various treatment interventions. Mean probability and 90% confidence interval calculated with the confidence profile method55 using hierarchical Bayes’. were classified as more bothered at baseline (Fig. 22.4). It should be noted that about 40% of patients in this category experienced improvement in the degree of bother from urinary difficulties (Fig. 22.4). The changes from baseline for the watchful waiting patients are shown in Table 22.5. It should be noted that the mean changes represented in almost all categories an improvement for those men who were followed in the assigned treatment arm (watchful waiting) over 3 years. The magnitude of the improvement, however, was less than that realized by surgery in almost all categories ( p values in Table 22.5). Furthermore, this analysis obviously excludes those men who were categorized as treatment failures, underwent surgery (cross-over), or were lost to follow-up. Placebo arms of controlled medical treatment trials for BPH For the AHCPR BPH guidelines, data on 1417 patients treated in 45 placebo arms of placebo-controlled trials were analyzed.54 Table 22.6 and Figure 22.3 allow a direct comparison between the watchful waiting and the placebo studies. A significant difference between the two treatment modalities cannot be identified for any of the examined parameters. However, several points deserve discussion. As opposed to the long-term follow-up in the watchful waiting studies, the placebo studies are part of

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Figure 22.4 Degree of bother from urinary difficulties after 3 years of follow-up among men with LUTS and BPH managed with TURP or watchful waiting stratified by more or less bother at baseline.57 , Improved; worse or no change; , cross-over to surgery.

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Page 305 Table 22.5 Changes from baseline for men followed over 3 years in a watchful-waiting protocol (Adapted from reference 57.) Outcome Baseline* Follow-Up** Mean change ±SD p Value† Symptom Score (0–27) 14.6 9.1 −5.5±5.2 <0.001 Residual urine (ml) 113 72 −41±90 0.015 Peak flow rate (ml/s) 12.5 12.7 0.4±9.2 <0.001 Bother from urinary difficulties‡ 46.3 57.6 9.6±29.7 <0.001 Sexual performance‡ 42.5 35.6 −3.2±26.6 0.92 Activities of daily living‡ 69.0 75.6 6.4±30.3 <0.001 General well-being‡ 71.2 71.4 0.1±28.3 0.217 Social activities‡ 74.2 73.1 −1.7±23.5 0.945 *n =276; **only patients who were followed over 3 years excluding cross-overs, failures etc.; †for difference between treatment groups (surgery versus watchful waiting); ‡on a scale from 0 (greatest impairment) to 100 (least impairment). Table 22.6 Comparison of outcomes following watchful waiting and placebo treatment. (Adapted from reference 54.) Outcomes Watchful waiting Placebo Total number of patients in database 456 1417 Peak flow rate Probability for flow rate increase 19.7% 35.8% Probability for no change in flow rate 14.2% 41.1% Probability for flow rate decrease 66.1% 23.1% Mean pretreatment flow rate (ml/s) 9.0 9.1 Mean. posttreatment flow rate (ml/s) 11.2 9.7 Difference (ml/s) +2.2 +0.6 Per cent change in peak flow rate +24.4% +6.6% Residual urine Probability for decrease in residual urine 35.0% 38.0% Probability for residual urine to remain unchanged 28.0% 26.1% Probability for increase in residual urine 37.0% 35.9% Mean pretreatment residual urine (ml) 115 87 Mean posttreatment residual urine (ml) 152 76 Difference (ml) +37 −11 Per cent change in residual urine +32.2% −12.6% Symptom improvement Probability for symptom improvement 41.7% 41.7% Probability for symptoms to remain unchanged 25.8% 53.5% Probability for symptom worsening 32.4% 4.7% Mean probability for symptom improvement* 41.7% 41–7% 90% Confidence interval for symptom improvement* 30.8 to 54.8% 26.3 to 65.1% *Calculated by confidence profile method using hierarchical Bayes’.55 short- to mid-term medical treatment trials ranging from 3 days to 52 weeks in duration (mean 13 weeks). In all these studies the patients are blinded as to the treatment arm, and thus have in most cases at least a 50:50 (or better in case of 2:1 or 3:1 randomization) chance of receiving active drug. Dropping out of such studies because of failure does not have the same ramification as it does in watchful waiting studies where the patients willingly assume a conservative treatment approach knowing that it might fail (i.e. they might fail and go on to active treatments). In contrast, in some placebocontrolled studies a promise—either tacit or openly—is made stating that

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Figure 22.5 Percentage changes in peak flow rate and residual urine (left y-axis), and percentage of patients reporting improvement in symptoms (right y-axis) following various treatment interventions. (Adapted from reference 54.) following the conclusion of the trial the patient would be eligible for either ‘free’ active treatment or he would be ‘moved up’ on the surgical waiting list (this phenomenon is unique to those studies conducted in the UK). The inactive preparation given should theoretically add to the placebo effect and, thus, improve the outcome above those noted for watchful waiting studies. The probability for a patient to experience improvement, however, is estimated to be about 40% in the uncontrolled watchful waiting studies, the randomized watchful waiting versus TURP study, and the combined placebo arms. The changes in peak flow rate and residual urine are similar, and similarly small, for these three groups as well (see Tables 22.5 and 22.6). Figure 22.5 shows a comparison of the percentage changes in peak flow rate and residual urine as well as the percentage of patients experiencing symptom improvement between various treatment modalities. It becomes evident that a 40% rate of patients reporting improvement and the minimal fluctuation of peak flow rate and residual urine represent the ‘placebo effect’ background against which the more substantial changes in these parameters achieved by active treatment modalities must be seen. With the advent of symptom severity assessment tools or symptom scores it is possible to quantitatively describe the response of patients treated by a variety of treatment interventions including placebo and watchful waiting (see Chapter 21). Unfortunately, the different symptomscoring instruments differ regarding their foot points (0 or different from 0), their scale, and occasionally even their direction (increasing or decreasing severity of symptoms with increasing score). While currently the AUASI or International Prostate Symptom Score (I-PSS),58–63 with its scale from 0 to 35 points, is the most widely utilized instrument, thus facilitating direct comparisons between studies, in the years past different scores with different scales were used. The only way to compare symptom improvement in different trials quantitatively in such cases is to rescale the individual scales to a 100% scale, and to express the changes as the drop in percentage symptom score from before to after treatment. Using this technique, seven placebo-controlled trials were reanalyzed and compared to the most significant watchful waiting study57 (Fig. 22.6). These seven trials enrolled between 11 and 267 subjects per arm, lasted from 4 to 24 weeks, and utilized an injectable steroid hormone (norprogesterone),64 a prolactin inhibitor (bromocriptine),65 an H2 blocker (cimetidine),66 an α-blocker (alfuzosin) ,67 or candicin68–70 as the ‘active’ drug. Each study is represented by its active and the placebo arm side by side.

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Figure 22.6 Improvements noted using a quantitative symptom score in seven placebocontrolled trials and a watchful waiting study. Due to the different scales used, all scores were rescaled to a 100% scale and the reported changes expressed as mean pretreatment and mean posttreatment per cent symptom score. The number above the vertical bar indicates the change noted following treatment (expressed as per cent). Several points are noteworthy. The pretreatment symptom severity score expressed as percentage of achievable score on a 100% scale ranges from 35% to almost 60%, and the drop in symptom severity from 7% to 33% for the placebo arms. Moreover, the pre- to posttreatment symptom score range does not even overlap between some of the trials listed, indicating that vastly different patient populations were treated. Specifically addressing the three placebo-controlled, double-blinded trials using candicin as the active drug, the drops in symptom score were 9, 15, and 33% (placebo), and 6, 26, and 22% (candicin). With the exception of the bromocriptine trial, the baseline symptom severity was reasonably similar between the placebo and the active treatment arm, and in all such cases the placebo response closely matched the active drug response. These observations allow several conclusions: • There is a strong placebo response noted in medical treatment trials for BPH when quantitative symptom severity scores are used. • The placebo response in medical treatment trials for BPH depends largely on the pretreatment characteristics of the treated cohort. • Even when the baseline symptom severity is similar between two trials (A and B), the response of the placebo group in trial A matches more closely its actively treated cohort than the placebo group in trial B. • The latter fact indicates that factors other than the active drug or placebo are most responsible for the placebo effect. These factors may include patient selection criteria (solicitation, advertising), design and duration of study, incentives offered to patients (financial or otherwise), conduct and attitude of treating physician or research coordinator (sympathetic versus unsympathetic, friendly versus unfriendly, positive versus negative), and other unrecognized factors. In fact, given the parallel changes in both treatment groups in most trials, the latter factors, which are provider factors, are more likely to be responsible than the previously mentioned patient factors. It could be reasoned that placebo-treated patients enrolled with similar inclusion and exclusion criteria into clinical trials using the same class of active drugs might have a similar placebo response. A comparison of three α1-receptor-blocker trials allows this hypothesis to be tested. Eighty-two patients were treated with doxazosin

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Page 308 versus placebo over 16 weeks,71 2064 patients with terazosin versus placebo over 52 weeks,72 and 296 patients with tamsulosin versus placebo over 12 weeks.73 In all three trials a different symptom score was used. In the doxazosin trial, the scale ranged from 0 to 30 points, in the terazosin trials from 0 to 35 points (AUASI), and in the tamsulosin trial from 0 to 27 (Boyarsky score). In Figure 22.7 all scores are rescaled to a 100% scale and the preand posttreatment mean scores are expressed as a percentage of the 100% scale. Although the pretreatment symptom severity is different in the three trials, the placebo responses are very similar, ranging from 8.1 to 10.6% on the 100% scale, roughly half of the active drug cohort in each trial. Improvements in peak urinary flow rates are also similar between these three drug trials, ranging from 0.4 to 0.8 ml/s in the three placebo groups, despite the fact that the baseline mean peak flow rates are rather different (Fig. 22.8). It should be noted that this improvement in peak flow rate is very similar to the mean changes noted in the combined placebo arm analysis of the AHCPR guidelines (0.6 ml/s) and the watchful waiting study (0.4 ml/s) by Wasson et al.57 The percentage improvement calculated for the combined placebo arms (6.6%) falls also in the range of improvements seen in these three α-blocker trials (3.8 to 8.3%). Sham arms of controlled-device treatment trials for BPH In recent years a multitude of minimally invasive device treatments for BPH have been developed and tested in randomized, sham-controlled, open, single-, or even double-blinded trials. While the majority of these trials compare various types of heat treatments (transrectal or transurethral hyperthermia or thermotherapy) with a sham treatment, one investigator compared balloon dilatation with ‘sham’ cystoscopy alone in a randomized, double-blinded trial involving 33 men with BPH.74 Blinding of the patients was effective in that an equal number of patients in each arm thought they had undergone balloon dilatation. After 3 months, 40% of balloon dilated patients noted marked improvement, while 27% noted no change. After cystoscopy, 63% had marked improvement and 12% no change. The changes in symptom score were significant at 3 months in both groups, while the peak urinary flow rate changes were not significant from baseline in either group (Table 22.7). Most importantly, there was no difference in the symptom score or peak flow rate data at 3 months between the ‘active’ and the ‘sham’ treatment. This study is widely used to support the notion that balloon dilatation has no role in the treatment of BPH, and is not better than placebo/sham treatment.

Figure 22.7 Pre- and posttreatment mean symptom scores (upper and lower tickmark of vertical bar, respectively) rescaled to 100% for activedrug- and placebo-treated cohorts in three randomized α-blocker trials (for details see text). The number at the bottom of the graph represents the per cent improvement achieved.

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Figure 22.8 Pre- and posttreatment mean peak flow rates (Qmax) (lower and upper tickmark of vertical bar) for active-drug- and placebotreated cohorts in three randomized α-blocker trials (for details see text). The number at the bottom at the vertical line indicates the per cent improvement in mean peak flow rate, while, the number at the bottom of the graph represents the absolute mean improvement. Table 22.7 Outcomes at 3 months following balloon dilatation or cystoscopy in a randomized, double-blinded study. (Reproduced with permission from Lepor et al.74)   Baseline 3 p Value; baseline versus 3 p Value: cystoscopy versus balloon dilatation months months at 3 months Peak flow rate Cystoscopy 10.5 12.9 NS   Balloon 92 11.5 NS p =0.48 dilatation Symptom score Cystoscopy 11.9 8.8 <0.01   Balloon 12.4 7.5 <0.05 p =0.33 dilatation Figures 22.9 and 22.10 analyze the outcomes of the balloon dilatation versus cystoscopy trial, one multiright trial using transrectal or transurethral hyperthermia in comparison with a sham control,75 and five transurethral microwave thermotherapy (TUMT) trials and their respective sham-control arms.76–79 The following observations can be made. The baseline or pretreatment mean symptom severity expressed as a percentage of total achievable severity (rescaled to 100%) is different from trial to trial. The mean improvements in symptom severity in the sham groups ranged from 5.2 to 15.6% (on a 100% scale), while the active thermotherapy-treated patients had improvements ranging from 27.0 to 37.8%, or in most cases twice the improvement compared to the sham control. The multiright hyperthermia trial represents the exception, in that the actively treated cohort has an improvement similar to the sham control, which is well within the range of the other sham control trials. The changes in peak urinary flow rate follow a similar pattern (Fig. 22.10). With the exception of TUMT trials 2 and 4, the changes in peak flow rate are either very modest improvements or deteriorations (0.5, 0.6, −0.2, −1.0 ml/s), while the active-treatment arms report substantial improvements, with the exception of the hyperthermia trial. The changes noted in the sham arms (and the largely ineffective hyperthermia treatment arm) are very similar to those observed after α-blocker therapy (see Figs. 22.7 and 22.8). Both thermotherapy trial 5 and the terazosin trial have similar entry criteria and baseline mean symptom severity. The improvements noted in the placebo and

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Figure 22.9 Pre- and posttreatment (3 months) mean symptom scores (upper and lower tickmark of vertical bar) rescaled to 100% for activetreated and sham-treated patients in a multicenter hyperthermia trial, five transurethral microwave thermotherapy (TUMT) trials, and a balloon dilatation versus cystoscopy trial The improvement in per cent is noted above the horizontal tickmark.

Figure 22.10 Pre- and posttreatment (3 months) mean peak urinary flow rates (lower and upper tickmark of vertical bar) for active-treated and sham-treated patients in a multicenter hyperthermia trial, five transurethral microwave thermotherapy (TUMT) trials, and a balloon dilatation versus cystoscopy trial The changes in per cent are noted below the horizontal tickmark and the absolute improvement (deterioration) at the bottom of the graph. file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_310.html[09.07.2009 11:53:53]

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Page 311 sham arms were 3.3 points (10.6%) and 2.6 points (6.4%), respectively, while in the active-treatment arms the improvements were 7.6 points (21.7%) and 12.1 points (34.6%), respectively. Placebo/sham effect and baseline symptom severity An area of considerable interest is the question to what degree the placebo/sham effect depends on the baseline status of the patients. This could pertain to baseline symptom severity, baseline bother, quality of life, baseline flow rate, and all other imaginable parameters. Although very few investigators have thus far reported data stratified by baseline parameters, results from a multicenter, placebocontrolled, 12-month α-blocker trial (terazosin) can be analyzed.80 Figure 22.11 shows the absolute and percentage improvement in AUA symptom score for the placeboand drug-treated patients stratified in six strata by symptom severity. While the active drug-treated cohort has almost twice the improvement within each stratum, the placebo-treated patients had improvements ranging from 1.4 points (4.6%) to 7.5 points (21.4%). The placebo improvements for the entire placebo cohort were 3.3 points (10.6%). A similar increase in the placebo effect with increasing baseline symptom severity has been reported for patients treated with finasteride in the phase III trials.81 It might be speculated that the baseline symptom severity may also affect the sham effect seen in device trials. This phenomenon might be due to increased expectations in patients with more severe baseline symptoms, or simply due to a regression to the mean. Natural history of disease progression in long-term placebo arms The distinction between placebo response in controlled studies versus the natural history of the disease itself observed in population-based studies becomes blurred when the placebo control is carried out over a period of time long enough to allow natural history changes to take place and confound the situation. The Proscar Long Term Efficacy and Safety Study (PLESS) followed a cohort of over 3000 men with moderate symptoms and enlarged prostate glands randomized to treatment with finasteride 5mg daily versus placebo over 4 years.82,83 While in most

Figure 22.11 Improvements in symptom score expressed recorded in a placebo-controlled, 12-month α-blocker treatment trial for patients stratified in six baseline symptom severity strata (along x-axis labeled as P=placebo- and T=terazosin-treated). The per cent improvement (100% scale) and the absolute changes (at bottom of graph) are shown.

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Figure 22.12 Mean ±95% CI for symptom (a) and peak flow rate (b) in placebo-treated patients in PLESS study stratified by baseline serum PSA levels. placebo arms of controlled trials lasting 12 months or less the combined placebo effect is maintained for the entire duration of the study, in this trial, both the mean symptom score and peak flow rate slowly drifted back to baseline after a typical initial placebo response, without quite reaching baseline levels, however.83 The almost 1500 men in the placebo arm of this trial allowed for a detailed analysis of the placebo response and the subsequent natural history stratified by baseline parameters. By far the most powerful of these parameters proved to be unexpectedly the baseline serum PSA level. When stratifying the population by serum PSA into tertiles or thirds of patients with PSA levels from 0–1.3, 1.4–3.2, and 3.3– 10 ng/ml, three distinctly different pat terns emerged (Fig. 22.12).82 While the initial placebo response in the lowest PSA tertile for both symptom and flow rate was maintained over the entire 4 years of followup, the middle tertile experienced a slow deterioration of symptoms back to baseline and in essence the natural history and progression of disease eliminated any flow rate gains. In the highest PSA tertile the symptom score increased steadily over time following an initial placebo response by −1.5 points. Over the subsequent years, the score increased by 0.5 points/year, bringing it at the end of the study back to the original baseline level. The initial response in terms of flow rate improvement was completely negated by the progression/natural history after 2 years, and at the end of the study, this group of patients

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Page 313 registered a net worsening of the flow rate by a mean of −1.0 ml/s (Fig. 22.12b). For the first time, the PLESS study and its placebo control group allowed the study of natural history and disease progression in a cohort selected for moderate symptoms and other evidence of disease (in contrast to a population-based study) on the background of the initial combined placebo responses. Relationship between placebo/sham effect and perception of improvement Barry et al. reported an important observation by assessing the relationship between changes in the AUASI and patients’ global rating of improvement in over 1200 men treated in a medical treatment trial for BPH.84 They noted that a mean decrease in AUASI of 3.1 points was associated with a slight improvement; however, this relationship was strictly dependent on the baseline AUASI (Fig. 22.13). For patients to perceive a slight, moderate, or marked improvement, increasing drops in AUASI were required with increasing baseline symptom severity. In Figure 22.13 this relationship is illustrated graphically for slight, moderate, and marked improvement. The symbols indicate the improvement in AUASI noted in the alreadymentioned α-blocker trial active-drug and placebo arms.72 It is evident, that for every symptom severity stratum, the improvement in the placebo arm fell roughly on the ‘slight’ improvement line, which is the minimum improvement noticeable to patients. Thus, for each baseline symptom severity level, patients treated with placebo would have a noticeable symptom improvement. However, the patients treated with active drug experienced in all strata analyzed at least a ‘moderate’ improvement. Summary and conclusions The data discussed demonstrate rather convincingly that in both medical and minimally invasive-device treatment trials for BPH, a placebo/sham effect must be expected, in addition to a regression to the mean effect, the magnitude of which depends on the chosen thresholds for inclusion and exclusion (i.e. the more restrictive, the greater the effect). The combined regression to the mean and placebo/sham effect is surprisingly stable across different trials and different treatment modalities. About 40% of

Figure 22.13 Relationship between baseline (x-axis) symptom score and absolute changes in scores for subjects rating global improvement as slight, moderate, or marked (adapted from reference 85). The symbols indicate the absolute drops in symptom scores from baseline for patients treated in a placebo-controlled, 12-month α-blocker treatment trial stratified in six. strata by baseline symptom severity (placebo=triangle; α-blocker=circle).

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Page 314 patients experience some unspecified degree of improvement, albeit marginal, in watchful waiting and placebo/sham control cohorts. Improvements in symptom severity scores range from 5 to 15% (about 2 to 5 points using the AUASI ranging from 0 to 35 points) for placebo/sham-treated cohorts, while changes in peak urinary flow rate are in general more modest, ranging from actual deterioration to improvements of 1.0 ml/s with few exceptions. The magnitude of this effect is similar to that seen in watchful waiting studies. Of great importance is the observation that the magnitude of the improvement correlates directly with the baseline symptom severity. Patients’ perception of improvement also correlates with baseline symptom severity and, in general, a larger drop in symptom score is associated with a global rating of a slight, moderate, or marked improvement with increasing baseline symptom score. In the limited datasets available the placebo effect for each symptom severity stratum is of a magnitude associated with a global perception of slight improvement. The statement that treatment for BPH is associated with a ‘40% placebo/sham effect’ is clearly an inadequate oversimplification. More detailed and sophisticated analyses of responses in placebo/shamtreated cohorts of men with BPH are needed to further our understanding of the complex relationship between patients’ expectations, baseline symptom severity, bother, quality of life, nature and invasiveness of the active treatment arm, and the responses noted in regards to symptom, bother, quality of life, and indirect outcomes such as urinary flow rates. Only once a matrix of these responses and their predictors has been established will we be able to judge newly developed treatments for BPH against the backdrop of their associated placebo/sham effects. References 1. Shaw P. The reflector: representing human affairs, as they are; and may be improved. 1750. Cited in: Drugs and Human Behavior. London: 1970 2. Hill A B. Medical ethics and controlled trials. B Med J 1963; 1:1043–1049 3. Macedo A, Farre M, Banos J E. Placebo effect and placebos: what are we talking about? Some conceptual and historical considerations. Eur J Clin Pharmacol 2003; 59: 337–342 4. Hrobjartsson A, Norup M. The use of placebo interventions in medical practice—a national questionnaire survey of Danish clinicians. Eval Health Prof 2003; 26:153–165 5. Pepper O H P. A note on placebo. Ann J Pharmacol 1945; 117:409–412 6. Kennedy W P. The nocebo reaction. Med Word 1961; 344:203–205 7. White L, Tursky B, Schwartz G E. Placebo in perspective. In: White L, Tursky B, Schwartz G E (eds). Placebo. Theory, research, and mechanism. New York: The Guilford Press, 1985:3–6 8. Shapiro A K, Morris L A. The placebo effect in medical and psychological therapies. In: Garfield S L, Bergin A E (eds). Handbook of psychotherapy and behavior change. New York: Wiley, 1978:371 9. Brody H. Placebos and the philosophy of medicine. Chicago: University of Chicago Press, 1977 10. Grünbaum A. Explication and implications of the placebo concept. In: White L, Tursky B, Schwartz GE (eds). Placebo. Theory, research, and mechanisms. New York: The Guilford Press, 1985:9–36 11. de la Fuente-Fernandez R, Schulzer M, Stoessl A J. The placebo effect in neurological disorders. Lancet Neurol 2002; 1:85–91 12. Brody H. Placebo effect: an examination of Grünbaum’s definition. In: White L, Tursky B, Schwartz G E (eds). Placebo. Theory, research, and mechanisms. New York: The Guilford Press, 1985:37–58 13. Turner J A, Deyo R A, Loeser J D et al. The importance of placebo effects in pain treatment and research. J Am Med Assoc 1994; 271:1609–1614 14. Coronary Drug Project Research Group. Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med 1980; 303:1038–1041 15. Finkel M J. Placebo controls are not always necessary. In: White L, Tursky B, Schwartz G E (eds). Placebo. Theory, research, and mechanisms. New York: The Guilford Press, 1985:419–428 16. Lepor H, Sypherd D, Machi G et al. Randomized doubleblind study comparing the effectiveness of balloon dilation of the prostate and cystoscopy for the treatment of symptomatic benign prostatic hyperplasia. J Urol 1992; 147: 639–42; discussion 642–644 17. Moyad MA. The placebo effect and randomized trials: analysis of conventional medicine. Urol Clin North Am 2002; 29:125–33, ix-x 18. Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med 1994; 331:394–398 19. Zion D, Gillam L, Loff B. The Declaration of Helsinki, CIOMS and the ethics of research on vulnerable populations. Nat Med 2000; 6:615–617 20. Denis L, McConnell J D, Yoshida O et al. Recommendations of the International Scientific Committee: the evaluation and treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_314.html[09.07.2009 11:53:55]

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obstruction. In: Denis L, Griffiths K, Khoury S et al. (eds).

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Page 315 4th international consultation on benign prostatic hyerplasia (BPH). Plymouth: Health Publication, 1997: 669–684 21. Recommendations of the International Scientific Committee. Evaluation and treatment of LUTS in older men. In: Chatelain C, Denis L, Foo K T et al. (eds). 5th International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth, UK: Health Publication, 2001:519–534 22. Blackwell B, Bloomfield S S, Buncher C R. Demonstration to medical students of placebo responses and non-drug factors. Lancet 1972; 294:1279–1282 23. Thomas K B. General practice consultations: is there any point in being positive? Br Med J 1987; 294:1200–1202 24. Beecher H K. The powerful placebo. J Am Med Assoc 1955; 159:1602–1606 25. Whitney C W, Von Korff M. Regression to the mean in treated versus untreated chronic pain. Pain 1992; 50: 281–285 26. Gracely R H, Dubner R, Deeter W R et al. Clinicians’ expectations influence placebo analgesia. Lancet 1985; 294:43 27. Rosenzweig P, Brohier S, Zipfel A. The placebo effect in healthy volunteers: influence of experimental conditions on the adverse events profile during phase I studies. Clin Pharmacol Therapeut 1993; 54:578–583 28. Beecher HK. Surgery as placebo. J Am Med Assoc 1961; 176:1102–1107 29. Cobb LA, Thomas GI, Dillard DH et al. An evaluation of internal-mammary-artery-ligation by a double-blind technic. N Engl J Med 1959; 260:115–118 30. Diamond E G, Kittle C F, Crockett J E. Comparison of internal mammary ligation and sham operation for angina pectoris. Am J Cardiol 1960; 5:483–486 31. Johnson A G. Surgery as placebo. Lancet 1994; 344: 1140–1142 32. Sech S M, Montoya J D, Bernier P A et al. The so-called ‘placebo effect’ in benign prostatic hyperplasia treatment trials represents partially a conditional regression to the mean induced by censoring. Urology 1998; 51:242–250 33. Oesterling J E, Jacobsen S J, Chute C G et al. Serum prostate-specific antigen in a community-based population of healthy men. Establishment of age-specific reference ranges [see comments]. J Am Med Assoc 1993; 270: 860–864 34. Guess H A, Chute C G, Garraway W M et al. Similar lev els of urological symptoms have similar impact on Scottish and American men—although Scots report less symptoms. J Urol 1993; 150:1701– 1705 35. Jacobsen S J, Girman C J, Guess H A et al. Natural history of prostatism: factors associated with discordance between frequency and bother of urinary symptoms. Urology 1993; 42:663–671 36. Oesterling J E, Girman C J, Panser L A et al. Correlation between urinary flow rate, voided volume, and patient age in a community-based population. Prog Clin Biol Res 1994; 386:125–139 37. Girman C J, Epstein R S, Jacobsen S J et al. Natural history of prostatism: impact of urinary symptoms on quality of life in 2115 randomly selected community men. Urology 1994; 44:825–831 38. Sarma A V, Wei J T, Jacobson D J et al. Olmsted County Study of Urinary Symptoms and Health Status; Flint Men’s Health Study. Comparison of lower urinary tract symptom severity and associated bother between community-dwelling black and white men: the Olmsted County Study of Urinary Symptoms and Health Status and the Flint Men’s Health Study. Urology 2003; 61:1086–1091 39. Sarma A V, Jacobsen S J, Girman C J et al. Concomitant longitudinal changes in frequency of and bother from lower urinary tract symptoms in community dwelling men. J Urol 2002; 168:1446–1452 40. Roberts R O, Jacobson D J, Girman C J et al. Prevalence of prostatitis-like symptoms in a community based cohort of older men. J Urol 2002; 168:2467–2471 41. Roberts RO, Jacobsen SJ, Rhodes T et al. Cigarette smoking and prostatism: a biphasic association? Urology 1994; 43:797–801 42. Jacobsen S J, Girman C J, Guess H A et al. Natural history of prostatism: four-year change in urinary symptom frequency and bother. J Urol 1995; 153:300A 43. Jacobsen S J, Girman C J, Guess H A et al. Natural history of prostatism: longitudinal changes in voiding symptoms in community dwelling men. J Urol 1996; 155: 595–600 44. Rhodes T, Girman C, Jacobson D et al. Longitudinal prostate volume in a community-based sample: 7-year followup in the Olmsted County Study of Urinary Symptoms and Health Status among Men. J Urol 2000; 163:249 45. Roberts R O, Jacobsen S J, Jacobson D J et al. Longitudinal changes in peak urinary flow rates in a file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_315.html[09.07.2009 11:53:56]

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community based cohort. J Urol 2000; 163:107–113 46. Rhodes T, Girman C J, Jacobsen S J et al. Longitudinal measures of prostate volume in a communitybased sample: 3.5 year followup in the Olmsted County study of health status and urinary symptoms among men. J Urol 1995; 153:301A 47. Rhodes T, Girman C J, Jacobsen S J et al. Longitudinal prostate growth rates during 5 years in randomly selected community men 40 to 79 years old. J Urol 1999; 161: 1174–1179 48. Diokno A C, Brown M B, Goldstein N et al. Epidemiology of bladder emptying symptoms in elderly men. J Urol 1992; 148:1817–1821

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Page 316 49. Clarke R. The prostate and the endocrines. 1919: 254–271 50. Craigen A A, Hickling J B, Saunders C R et al. Natural history of prostatic obstruction. J R Coll Gen Pract 1969; 18:226–232 51. Birkhoff J D, Wiederhorn A R, Hamilton M L et al. Natural history of benign prostatic hypertrophy and acute urinary retention. Urology 1976; 7:48–52 52. Ball A J, Feneley R C, Abrams P H. The natural history of untreated ‘prostatism’. Br J Urol 1981; 53:613–616 53. Kadow C, Feneley R C, Abrams P H. Prostatectomy or conservative management in the treatment of benign prostatic hypertrophy? Br J Urol 1988; 61:432–434 54. McConnell J D, Barry M J, Bruskewitz R C et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical practice guideline, number 8. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services, 1994 55. Eddy D M, Hasselblad V. FAST*PRO. Software for metaanalysis by the confidence profile method. Boston: Academic Press, 1992 56. AUA BPH Guideline Update Panel. The management of BPH, 2003. https://shop.auanet.org/timssnet/products/guidelines/bph_management.cfm 57. Wasson J H, Reda D J, Bruskewitz R C et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans’ Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995; 332:75–79 58. O’Leary M P, Barry M J, Fowler F J Jr. Hard measures of subjective outcomes: validating symptom indexes in urology. J Urol 1992; 148:1546–1548; discussion 1564 59. Barry M J, Fowler F J Jr, O’Leary M P et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992; 148: 1549–1557; discussion 1564 60. Barry M J, Fowler F J Jr, O’Leary M P et al. Correlation of the American Urological Association symptom index with self-administered versions of the Madsen-Iversen, Boyarsky and Maine Medical Assessment Program symptom indexes. Measurement Committee of the American Urological Association. J Urol 1992; 148:1558–1563; discussion 1564 61. Schneider H, Ludwig M, Weidner W, Brahler E. Experience with different questionnaires in the management of patients with CP/CPPS: GPSS, IPSS and NIHCPSI. World J Urol 2003; 21:116–118 62. Kok E T, McDonnell J, Stolk E A et al.; Triumph Research Group; Pan-European Expert Panel. The valuation of the International Prostate Symptom Score (IPSS) for use in economic evaluations. Eur Urol 2002; 42:491–497 63. Porru D, Jallous H, Cavalli V et al. Prognostic value of a combination of IPSS, flow rate and residual urine volume compared to pressure-flow studies in the preoperative evaluation of symptomatic BPH. Eur Urol 2002; 41: 246–249 64. Aubrey D A, Khosla T. The effect of 17-α-hydroxy-19-norprogesterone caproate (SH582) on benign prostatic hypertrophy. Br J Surg 1971; 58:648–652 65. Van Poppel H, Boeckx G, Westelinck K J et al. The efficacy of bromocriptine in benign prostatic hypertrophy. A double-blind study. Br J Urol 1987; 60:150–152 66. Lindner A, Ramon J, Brooks M E. Controlled study of cimetidine in the treatment of benign prostatic hypertrophy. Br J Urol 1990; 66:55–57 67. Jardin A, Bensadoun H, Delauche-Cavallier M C et al. Alfuzosin for treatment of benign prostatic hypertrophy. The BPH-ALF Group [see comments]. Lancet 1991; 337: 1457–1461 68. Abrams P H. A double-blind trial of the effects of candicidin on patients with benign prostatic hypertrophy. Br J Urol 1977; 49:67–71 69. Jensen KM, Madsen PO. Candicidin treatment of prostatism: a prospective double-blind placebocontrolled study. Urol Res 1983; 11:7–10 70. Madsen P O, Dorflinger T, Frimodt-Moeller P C et al. Candicidin in treatment of benign prostatic hypertrophy. J Urol 1984; 132:1235–1238 71. Gillenwater J Y, Conn R L, Chrysant S G et al. Doxazosin for the treatment of benign prostatic hyperplasia in patients with mild to moderate essential hypertension: a double-blind, placebo-controlled, dose-response multicenter study. J Urol 1995; 154:110–115 72. Roehrborn C G, Oesterling J E, Auerbach S et al. The Hytrin Community Assessment Trial study: a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. HYCAT Investigator Group. Urology 1996; 47:159–168 73. Abrams P, Schulman C C, Vaage S. Tamsulosin, a selective alpha 1c-adrenoceptor antagonist: a file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_316.html[09.07.2009 11:53:56]

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randomized, controlled trial in patients with benign prostatic ‘obstruction’ (symptomatic BPH). The European Tamsulosin Study Group. Br J Urol 1995; 76:325–336 74. Lepor H, Sypherd D, Machi G et al. Randomized doubleblind study comparing the effectiveness of balloon dilation of the prostate and cystoscopy for the treatment of symptomatic benign prostatic hyperplasia. J Urol 1992; 147: 639–642. 75. Abbou C C, Colombel M, Payan C et al. The efficacy of microwave induced hyperthermia in the treatment of BPH: The Paris Public Hospitals’ experience. In: Kurth K H, Newling D W W (eds). Benign prostatic hyperplasia. Recent progress in clinical research and practice. New York: Wiley-Liss, 1994:449– 454

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Page 317 76. Ogden C W, Reddy P, Johnson H et al. Sham versus transurethral microwave thermotherapy in patients with symptoms of benign prostatic bladder outflow obstruction. Lancet 1993; 341:14–17 77. Blute M L, Tomera K M, Hellerstein D K et al. Transurethral microwave thermotherapy for management of benign prostatic hyperplasia: results of the United States Prostatron Cooperative Study [see comments]. J Urol 1993; 150:1591–1596 78. de la Rosette J J, de Wildt M J, Alivizatos G et al. Transurethral microwave thermotherapy (TUMT) in benign prostatic hyperplasia: placebo versus TUMT. Urology 1994; 44:58–63 79. Bdesha A S, Bunce CJ, Snell M E et al. A sham controlled trial of transurethral microwave therapy with subsequent treatment of the control group. J Urol 1994; 152:453–458 80. Roehrborn CG, Oesterling JE, Auerbach S et al. Effectiveness and safety of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia in the HYCAT study. Urology 1996; 47: 159–168 81. Gormley G J, Stoner E, Bruskewitz R C et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med 1992; 327: 1185–1191 82. Roehrborn C G, Boyle P, Bergner D et al. Serum prostatespecific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology 1999; 54:662–669 83. McConnell J D, Bruskewitz R, Walsh P et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign pro static hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 1998; 338 :557–563 84. Barry M J, Williford W O, Chang Y et al. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients? [see comments]. J Urol 1995; 154:1770–1774 85. Barry M J, Williford W O, Chang Y C et al. BPH-specific health status measures in clinical research: how much change in AUA symptom index and the BPH impact index is perceptible to patients? J Urol 1995; 154: 1770–1774

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Page 319 23 Dutasteride in the treatment of the BPH patient J D McConnell C G Roehrborn Introduction Benign prostatic hyperplasia (BPH) and the lower urinary tract symptoms (LUTS) associated with the condition are becoming increasingly prevalent as the Western male population ages and healthcare provision worldwide improves. The need for new and improved treatments for the condition is therefore ongoing and likely to increase. BPH develops due to a combination of testicular androgens and aging. The main androgen present in the prostate is dihydrotestosterone (DHT). The role of DHT and the enzyme responsible for its reduction, 5α-reductase, in the development of BPH has long been established, and the clinical potential of inhibitors of the enzyme has been proven. Limitations of inhibitors with a selective action on one of the isoforms of 5α-reductase have been described, however. Inhibition of both 5α-reductase isozymes has therefore been suggested as a means of increasing clinical response in terms of reducing prostate volume and thereby improving urinary symptoms and limiting risk of acute urinary retention (AUR) and BPH-related surgery. The selective 5α-reductase type II inhibitor finasteride has been available for the treatment of BPH for over 10 years, and this is testament to its efficacy in reducing symptoms of the condition in patients over an extended period of time. However, dual inhibition of 5α-reductase has been predicted to expand and enhance response in both finasteride responders and nonresponders. Development of BPH and role of DHT The prevalence of BPH increases in a linear fashion alongside age. At the age of 40, approximately 23% of men suffer from BPH, while 88% of men in their nineties are thought to have the condition.1 Androgen stimulation is necessary for the initial growth and development of the prostate and for the maintenance of its integrity, as well as the development of the obstructive urinary symptoms associated with BPH.2 Although the mechanisms underlying the development of BPH have not been fully established, testicular androgens, particularly DHT, are recognized as integral to the process. The influence of DHT in initial prostatic development has been determined, with the hormone found to be responsible for the embryonic differentiation of the prostate and the formation of external genitalia in the male.3 Fetal castration results in inhibited formation of the gland,4 and the continued role of testicular androgens in later life is evidenced by the lack of BPH development among men who have undergone castration prior to puberty.5 DHT, which is reduced by 5α-reductase from testosterone (Fig. 23.1), has been identified as the predominant androgen contained in the prostate,2 and its permissive if not causative role in hyperplastic prostatic growth has been outlined in several studies.6,7

Figure 23.1 Reduction of testosterone to dihydrotestosterone by 5α-reductase.

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Page 320 DHT binds to androgen receptors contained within the epithelium of the prostate.6,7 These receptors are upregulated during puberty, leading to increased androgen sensitivity and, although the receptors may also bind testosterone, DHT has much greater affinity, indicating that this hormone is the main driver of subsequent genetic modulation in the prostate.8 Although downregulation of many androgen receptors occurs after puberty at other sites, this does not occur in the prostatic epithelium. Coupled with the fact that DHT levels remain constant after puberty, when testosterone levels fall, this explains the continued growth-promoting influence of DHT and the DHT-receptor complex in the prostate. The formation of this complex stimulates the expression of a range of growth factor promoters, such as epidermal growth factor (EGF), basic fibroblast growth factor, keratinocyte growth factor (KGF), and insulin-like growth factor (IGF), leading to cellular proliferation,9,10 and inhibitors, such as transforming growth factor-β (TGF-β), which increases levels of apoptosis.11–13 Homeostasis is therefore achieved by the normally functioning prostate. Increased stimulation by DHT leads to increased expression of growth factor promoters and hyperplastic growth. Removal of the stimulus, through surgical or chemical means, leads to the opposite scenario, with a general move towards increased expression of cell growth inhibitors, such as TGF-β. A lack of DHT, due to deficiency of the enzyme responsible for its formation from testosterone, i.e. 5αreductase, has been identified in men with pseudohermaphroditism.14,15 The clinical and pathologic sequelae observed in these individuals provide further evidence of the role of androgens, specifically DHT, in the prostate. Men affected by 5α-reductase deficiency experience normal or partial virilization at puberty, due to the action of testosterone; however, the prostate itself remains underdeveloped, small, and unpalpable on digital rectal examination. The normal development of the prostate, and its hyperplastic growth during BPH, are therefore predominantly attributed to the reduction of testosterone to DHT by 5α-reductase. 5α-Reductase The increased cell proliferation that takes place during hyperplastic prostatic growth mainly occurs in the stroma of the prostate and a strong positive association of 5α-reductase activity with stroma and a negative correlation with epithelium has been recently identified.16 Two isozymes of the highly lipophilic enzyme 5α-reductase have been identified to date. These proteins are encoded by different genes, that for type I being located on chromosome 5 and that for type II on chromosome 2.17 The distribution of the 5α-reductase isozymes differs significantly, with type I predominating in the liver, scalp, and skin, with low levels found in the prostate, while type II mainly occurs in the prostate and other genital tissues and is found to a lesser extent elsewhere.2 The 5α-reductase deficiency observed in pseudohermaphroditic men involves type II 5α-reductase alone; type I 5α-reductase deficiency has not been identified to date in humans. In 5α-reductase deficient men, virilization at puberty is accompanied by increased expression of 5α-reductase type I in the skin,18 suggesting that DHT has paracrine effects, and that dual inhibition is necessary for complete control of the hormone. It may also explain why finasteride, which inhibits the action of type II 5α-reductase alone, only succeeds in reducing prostatic DHT by 85–90% and often fails to significantly reduce the urinary symptoms of BPH.19,20 The need for a dual 5α-reductase inhibitor The efficacy of the type II 5α-reductase inhibitor, finasteride, has been described in several short- and long-term clinical trials.21–25 Mainly through a reduction in prostate volume, the drug has been shown to significantly reduce risk of AUR and BPH-related surgery and improve urinary symptoms and peak urinary flow ( Q max) in both younger and older men, with positive consequences for quality of life scores. Since its launch in 1992, the drug has been used to treat millions of men worldwide, with good reported success in responders. Stratification of the results of clinical trials has suggested that men with larger prostates are more likely to respond to finasteride therapy than those with smaller glands.26 A meta-analysis of six clinical trials indicated that significantly greater improvements in Q max and symptom score were experienced by men with prostates larger than 60 ml compared to those with prostates of 20 ml or smaller. The authors concluded that finasteride was most appropriate for men with prostates of 40 ml or greater. Severity of symptoms does not necessarily correlate with prostate volume, however,27 and the effects of a greater reduction in prostate volume than that seen with finasteride have yet to be determined. It has been suggested that finasteride falls short of initial expectations due to the simultaneous occurrence of BPH with symptoms unrelated to prostatic growth,28

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Page 321 heterogeneity of the disease,29 and the effect of the increase in levels of testosterone8 as well as the influence of the DHT that continues to circulate despite 5α-reductase type II inhibition, i.e. that originating from type I reduction. Between 20 and 40% of baseline DHT remains in men treated with finasteride.30–32 The exact role of DHT reduced by type I 5α-reductase is not known and the level of entry of this protein to the prostate has not been established. Therefore, even though finasteride successfully reduces levels of DHT in the prostate, it can be postulated that systemic DHT maintains levels high enough to allow continued cell proliferation or negate the normal ongoing apoptosis of prostatic cells. On this basis, obstructive urinary symptoms may therefore persist, particularly in men with smaller prostates. A dual inhibitor of both 5α-reductase isoforms, producing greater reductions in prostatic and circulating DHT, would reduce this possibility. Over the last decade, the principle of 5α-reductase inhibition in terms of reducing prostate volume and thereby alleviating symptoms has been shown to have considerable clinical benefit; however, selective inhibition of one isozyme alone may limit the magnitude of the clinical response. Preclinical development of dutasteride The assumption that inhibition of both type I and type II 5α-reductase could improve the urinary symptoms of BPH over and above mono-inhibition with finasteride led to the development of the 6azasteroid molecule 17β-N -(2,5-bis(trifluoromethyl) phenylcarbamoyl)-4-aza-5α-androst-1-en-3one (dutasteride, Fig. 23.2). A range of dual 5α-reductase inhibitors was developed simultaneously;33 however, dutasteride was found to have a particularly high affinity for both 5α-reductase isozymes. In vitro, the compound was 60 times more powerful at inhibiting type I 5α-reductase and 10 times more powerful at inhibiting type II 5α-reductase than finasteride.34 Trials of the drug in humans revealed type I inhibition to be 100-fold higher and type II inhibition 3-fold higher than finasteride.35 Investigation of dutasteride’s mechanism of inhibition in rats revealed that the drug affects type I 5αreductase differently to type II.36 The drug inhibits type I 5α-reductase in a classically competitive manner, forming a dissociable complex with this isozyme. In contrast, the inhibition of type II 5αreductase is time-dependent. In this analysis, which compared the actions of finasteride and dutasteride in rats, the latter was found to be 20 times as

Figure 23.2 Structure of dutasteride. powerful an inhibitor as finasteride of 5α-reductase type I, and 10 times as powerful with type II. Previous studies in rats have indicated that finasteride acts as a dual inhibitor of 5α-reductase in these animals, so the beneficial effects of the drug may in fact be overestimated.37 However, this model allows the direct comparison of finasteride and dutasteride in terms of overall potency. An additional animal study of dutasteride indicated that its half-life is considerably longer than that of finasteride. Examination of the pharmacokinetic and pharmacodynamic properties of dutasteride revealed a greater terminal half-life compared to finasteride, at 14 hours versus 1 hour in the rat, and 65 hours versus 4 hours in the dog. Total body clearance in the dog was found to be 0.5 mg/min per kg and volume of distribution was high, at 3 liters/kg. In man, a single dose was found to have a terminal half-life of around 240 hours. Levels of DHT were found to be reduced to a significantly greater level after a 10 mg dose of dutasteride compared to a 5 mg dose of finasteride.38 The extended half-life of dutasteride, in addition to its dual-inhibitor nature and decreased total body clearance, is considered to underpin the greater inherent potency of this drug compared to selective 5α-

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reductase inhibitors.38 Clinical experience with dutasteride Clinical experience involving dutasteride is relatively limited due to its recent availability on the market, and comparison studies are lacking. What evidence there is, however, indicates that the drug consistently reduces

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Page 322 prostate volume, improves urinary symptoms and Q max, and reduces risk of AUR and BPH-related surgery.39 The pooled analysis of three phase III randomized, placebo-controlled studies of dutasteride, each lasting 24 months, has substantiated the potential of the drug in the treatment of LUTS in BPH patients. A total of 4325 men aged over 50 with moderate to severe symptoms of BPH (American Urological Association symptom index (AUASI) ≥12, Q max ≤15 ml/s, prostate volume ≥30 ml, as measured using transurethral ultrasound) took part in the trials, which took place at 400 sites in 19 countries. After a 1month placebo run-in period, participants were randomized to receive 0.5 mg dutasteride or placebo. Assessment, involving AUASI, Q max, and PSA measurement, took place at 1, 3, 6, 12, 18, and 24 months and testosterone and DHT levels were measured at 12 and 24 months. Total prostate volume was assessed at regular intervals and transition zone volume was determined in two of the trials. In total, 68% (2951) of participants completed the 24month study period, with discontinuation rates similar between the active and placebo groups ( n =657 and n =717, respectively). DHT levels fell by a mean of 90.2% in the active group compared to a mean increase of 9.6% in the placebo group (Fig. 23.3). Prostate volume fell significantly compared to placebo after just 1 month and this difference increased over the course of the study period. Total prostate volume fell by a mean of 25.7% and transition zone volume by 20.4% from baseline in the active groups; AUASI fell by 4.5 points compared to 2.3 points with placebo, reaching significance in the pooled results after 6 months; Q max increased by 2.2 ml/s compared to 0.6 ml/s with placebo, with a significant difference between active and placebo arms after 3 months; PSA increased by 15.8% in the placebo group and decreased by 52.4% with dutasteride. AUR occurred in less than half the number of dutasteride-treated patients compared to placebo (39 versus 90), representing a reduction in risk of 57% ( p =0.001). BPH-related surgery was performed in 47 and 89 patients, respectively, indicating a reduction in risk of 48% ( p =0.001) with dutasteride. Adverse event rates were similar between groups, at 77% for dutasteride-treated patients and 75% in those receiving placebo. Drug-related adverse event rates were 14% and 19%, respectively, with sexual dysfunction being the most commonly reported in both groups (Fig. 23.4). Prostate cancer was identified in 1.9% and 1.1% of the groups, respectively. The results indicate that impressive clinical benefits are associated with dual 5α-reductase inhibition. Comparison of these results with those reported for other types of medical therapy for BPH indicates that the improvement in symptom score for dutasteride described here compares favorably with that reported for finasteride

Figure 23.3 Changes in efficacy parameters at 24 months (expressed as a percentage change of baseline measurements, all changes for dutasteride are statistically significant (p<0.001) versus placebo).

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Figure 23.4 Sexual dysfunction adverse events: incidence (percentage of patients) over the entire study (2 years). Statistically significant for all disorders (p<0.001), dutasteride versus placebo. and many α-blockers.20,40 A review of the different medical treatments available for the management of BPH revealed symptom improvements compared to placebo of 9–40% for alfuzosin, 2–34% for terazosin, 3–19% for doxazosin, and 2–20% for tamsulosin.41 In the study described above, an improvement of 13% over placebo was observed, indicating similar results compared to these alternative therapies. The decrease in risk of AUR and BPH-related surgery adds an additional dimension to the benefits of dutasteride; 23% of men surviving to 80 years are likely to suffer AUR and BPH-related surgery is needed in 29% of all men.42,43 The reduction in risk observed here is therefore extremely significant. Similar results have been shown for finasteride,22 indicating the influence of 5α-reductase inhibitors on this aspect of BPH. Direct clinical comparisons of dutasteride with finasteride are lacking, due to the recent release of the former drug. However, a phase II clinical trial, involving 399 BPH patients (mean age 62.6–65.6 across treatment group, mean prostate volume 41.9–47.3 ml) did compare a variety of doses of dutasteride (0.01, 0.05, 0.5, 2.5, and 5.0 mg) to 5 mg finasteride or placebo over a period of 24 weeks.44 A clear dose-response relationship was observed with dutasteride, with 98.4±1.2% DHT reduction observed with the highest dose compared to a mean decrease of 70.8±18.3% with 5.0 mg finasteride (Fig. 23.5). Significantly greater decreases in DHT were observed at dutasteride doses of 0.5, 2.5 and 5.0 mg com pared to both placebo ( p =0.001) and finasteride ( p =0.001). If, as thought, the reduction in DHT is the mechanism responsible for the improvement in symptoms seen with finasteride, it may be expected that a greater fall in DHT would be accompanied by greater improvements in symptomatology. Other considerations Prostate-specific antigen The reductions in prostate-specific antigen (PSA) levels observed with finasteride therapy have been mirrored in clinical trials of dutasteride,39 and it has been suggested that this may have implications for prostate cancer screening. However, in vivo studies have shown that complexed-to-total and free-tototal ratios remain constant with finasteride treatment, indicating that proportional reduction in all molecular forms of PSA occurs with 5α-reductase inhibition.45–47 If similar results are found for dutasteride, measurement of these PSA forms could potentially be used to screen for prostate cancer and the use of PSA in cancer screening would not be compro-mised. In addition, investigation of PSA levels in men included in phase III trials of dutasteride revealed reductions in PSA of around 50%. Multiplication of these scores by 2 showed levels of PSA that were superimposable on curves observed at baseline, suggesting that this simple method could allow continued screening using total PSA levels. Again, free-to-total ratio did not change in these patients.

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Figure 23.5 Comparative changes in serum DHT and testosterone following 24 weeks’ treatment with dutasteride (0.5 mg), finasteride (5 mg), or placebo (serum DHT suppression significant for dutasteride versus finasteride, p<0.001). Hematuria Finasteride and other anti-androgens have been shown to have potential clinical applications in the prevention of hematuria,48–50 possibly due to decreased expression of vascular endothelial growth factor (VEGF), which lowers microvessel density in the prostatic suburethra.51,52 It may be postulated that the decrease in VEGF will be greater following dutasteride treatment, indicating an even greater anti-hematuric effect; however, such aspects remain to be investigated. Combination therapy The combination of 5α-reductase inhibitors and α-blockers has recently been investigated,53 and the addition of doxazosin to 5α-reductase therapy was found to result in significantly greater benefits in terms of disease progression and symptom score than either treatment alone. The greater efficacy of dutasteride in terms of DHT reduction suggests that the combination of an α-blocker with this drug may hold even more promise. However, long-term, randomized, placebo-controlled trials are needed to investigate this theory. Conclusions The results of pharmacokinetic, pharmacodynamic, and clinical studies have indicated that dutasteride is the most powerful suppressor of DHT on the market. The drug effectively inhibits type II 5α-reductase activity to a greater extent than finasteride, with the additional benefit of completely inhibiting type I 5αreductase. The net effect is a reduction in prostatic and circulating DHT to virtually zero. Greater reductions in prostate volume may therefore be expected with dual 5α-reductase inhibition than with selective inhibition, with positive clinical consequences with respect to urinary symptoms, AUR, BPHrelated surgery risk and quality of life. Dutasteride therefore builds on the well-documented long-term safety and tolerance of 5α-reductase inhibitors, but potentially could provide additional clinical benefit to that observed with finasteride due to more effective DHT suppression. However, a direct comparison of finasteride and dutasteride is now needed to determine the relative clinical benefits of selective and dual isozyme inhibitors as monotherapy or in combination with other classes of drug. References 1. Berry S J, Coffey D S, Walsh P C, Ewing L L. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474–479 2. Lee C, Kozlowski J M, Grayhack J T. Aetiology of benign prostatic hyperplasia. Urol Clin N Am 1995; 22:237–246 3. Wilson J D. Androgens. In: Hardman J G, Limbird L E (eds). Goodman & Gilman’s The pharmacological basis of therapeutics, 10th edn. New York: McGraw-Hill, 2001: 1441–1458

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Page 325 4. Cunha G R, Donjacour A M, Cooke P S et al. The endocrinology and developmental biology of the prostate. Endocr Rev 1987; 8:338–362 5. Wu C P, Gu F L. The prostate in eunuchs. EORTC Genitourinary Group Monograph 10. Urologic oncology: reconstructive surgery, organ preservation and restoration of function. New York: Wiley-Liss, 1992; 249–255 6. Walsh P C, Hutchins G M, Ewing L L. Tissue content of dihydrotestosterone in human prostatic hyperplasia is not supranormal. J Clin Invest 1983; 72:1772–1777 7. Traish A M, Wotiz H H. Prostatic epidermal growth factor receptors and their regulation by androgens. Endocrinology 1987; 121:1461–1467 8. Grino P B, Griffin J E, Wilson J D. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology 1990; 126:1165–1172 9. Saez C, Gonzalez-Baena A C, Japon M A et al. Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride. Prostate 1999; 40:83–88 10. Crescioli C, Villari D, Forti G et al. Des (1–3) IGF-I-stimulated growth of human stromal BPH cells is inhibited by a vitamin D(3) analogue. Mol Cell Endocrinol 2002; 198: 69–75 11. Farnsworth W E. Prostate stroma: physiology. Prostate 1999; 38:60–72 12. Niu Y, Xy Y, Zhang J et al. Proliferation and differentiation of prostatic stromal cells. BJU Int 2001; 87:386–393 13. Kim I Y, Zelner D J, Sensibar J A et al. Modulation of sensitivity to transforming growth factor-beta 1 and the level of type II TGF-β receptor in LNCaP cells by dihydrotestosterone. Exp Cell Res 1996; 222:103–110 14. Walsh P C, Madden J D, Harrod M J et al. Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974; 291:944–949 15. Imperato-McGinley J, Guerrero L, Gautier T, Peterson R E. Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 1974; 186: 1213–1215 16. Sherwood J B, McConnell J D, Vazquez D J et al. Heterogeneity of 5 alpha-reductase gene expression in benign prostatic hyperplasia. J Urol 2003; 169:575–579 17. Russell D W, Wilson J D. Steroid 5α-reductase: two genes/two enzymes. Annu Rev Biochem 1994; 63:25–61 18. Thipen A E, Silver R I, Guileyardo J M et al. Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression. J Clin Invest 1993; 92:903–910 19. Bartsch G, Rittmaster R S, Klocker H. Dihydrotestosterone and the concept of 5 alpha-reductase inhibitors in human benign prostatic hyperplasia. Eur Urol 2000; 37:367–380 20. Lepor H, Williford W O, Barry M J et al. for The Veterans’ Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. The efficacy of terazosin, finasteride or both in benign prostatic hyperplasia. N Engl J Med 1996; 335: 533–540 21. McConnell J D, Bruskewitz R, Walsh P et al. for the Finasteride Long-term Efficacy and Safety Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998; 338: 557–563 22. Roehrborn C G, Bruskewitz R, Nickel G C et al. Urinary retention in patients with finasteride or placebo over 4 years. Characterization of patients with ultimate outcomes. The PLESS Study Group. Eur Urol 2000; 37: 528–536 23. Vaughan D, Imperato-McGinley J, McConnell J et al. Long-term (7 to 8-year) experience with finasteride in men with benign prostatic hyperplasia. Urology 2002; 60: 1040–1044 24. Ekman P and the Scandinavian Finasteride Study Group. Maximum efficacy of finasteride is obtained within 6 months and maintained over 6 years: follow-up of the Scandinavian Open-Extension Study. Eur Urol 1998; 33: 312–317 25. Lam J S, Romas N A, Lowe F C. Long-term treatment with finasteride in men with symptomatic benign prostatic hyperplasia: 10-year follow-up. Urology 2003; 61: 354–358 26. Boyle P, Gould A L, Roehrborn C G. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48:398– 405 27. Christensen M M, Bniskewitz R C. Clinical manifestations of benign prostatic hyperplasia and indications for therapeutic intervention. Urol Clin North Am 1990; 17: 509–516 28. Barry M J, Cockett A T K, Holtgrewe H L et al. Relationship of symptoms of prostatism to commonly file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_325.html[09.07.2009 11:54:01]

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used physiological and anatomical measure of the severity of benign prostatic hyperplasia. J Urol 1993; 150:351–358 29. Shapiro E, Becich M G, Hartanto V, Lepor H. The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostatic hyperplasia. J Urol 1992; 147:1293–1297 30. Gormley G L, Stoner E, Rittmaster R S et al. Effects of finasteride (MK-906), a 5α-reductase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab 1990; 70:1136–1141 31. Ohtawa M, Morikawa H, Shimazaki J. Pharmacokinetics and biochemical efficacy after single and multiple oral

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Page 326 administration of N -(2-methyl-2-propyl)-3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-carboxamide, a new type of specific competitive inhibitor of testosterone 5 alpha-reductase, in volunteers. Eur J Drug Metab Pharmacokinet 1991; 16:15–21 32. De Schepper P J, Imperato-McGinley J, Van Hecken A et al. Hormonal effects, tolerability, and preliminary kinetics in men of MK-906, a 5 alpha-reductase inhibitor. Steroids 1991; 56:469–471 33. Frye S V. Inhibitors of 5 alpha-reductase. Curr Pharm Design 1996; 2:59–84 34. Tian G, Mook R A, Moss M L, Frye S V. Mechanism of time-dependent inhibition of 5 alphareductases by 4-azasteroids: towards perfection of rates of time-dependent inhibition by using ligandbinding energies. Biochemistry 1995; 34:13453–13459 35. Clark R V, Hermann D J, Gabriel H et al. Effective suppression of dihydrotestosterone (DHT) in men by GI198745: a novel dual 5 alpha-reductase inhibitor. Abstract S1737. J Urol 1999; 164 (Suppl 4): 268 36. Stuart J D, Lee F W, Noel D S et al. Pharmacokinetic parameters and mechanisms of inhibition of rat type 1 and 2 steroid 5 alpha-reductases: determinants for different in vivo activities of GI198 745 and finasteride in the rat. Biochem Pharmacol 2001; 62:933–942 37. Levine A C, Wang J P, Ren M et al. Immunohistochemical localization of steroid 5α-reductase in human male fetal reproductive tract and adult prostate. J Clin Endocrinol Metab 1996; 81:384–389 38. Bramson H N, Hermann D, Batchelor K W et al. Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR. J Pharmacol Exp Ther 1997; 282: 1496–1502 39. Roehrborn C G, Boyle P, Nickel J C et al. on behalf of the ARIA3001, ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5 alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002; 60:434–441 40. Kirby R, Boyle P, Roehrborn C. Results of PREDICT (Prospective Randomized European Doxazosin and Combination) study of medical therapy for BPH (abstract). Br J Urol 1999; 83:83 41. Clifford F, Farmer R. Medical therapy for benign prostatic hyperplasia: a review of the literature. Eur Urol 2000; 38: 2–19 42. Boyle P. Some remarks on the epidemiology of acute urinary retention. Arch Ital Urol Nefrol Androl 1998; 70: 77–82 43. Glynn R J, Campion E W, Bouchard G R et al. The development of benign prostatic hyperplasia among volunteers in the Normative Aging Study. Am J Epidemiol 1985; 121: 78–90 44. Clark R, Hermann D, Gabriel H et al. Effective suppression of dihydrotestosterone (DHT) by GI198 745, a novel, dual 5 alpha-reductase inhibitor. J Urol 1999; 161:1037 45. Espana F, Martinez M, Royo M et al. Changes in molecular forms of prostate-specific antigen during treatment with finasteride. Br J Urol Int 2002; 90:672–677 46. Brawer M K, Lin D W, Williford W O et al. Effects of finasteride and/or terazosin on serum PSA: results of VA Cooperative Study #359. Prostate 1999; 39:234–239 47. Tarle M, Kraus O, Trnski D et al. Early diagnosis of prostate cancer in finasteride treated BPH patients. Anticancer Res 2003; 23:693–696 48. Kashif K M, Foley S J, Basketter V, Holmes S A. Haematuria associated with BPH—natural history and a new treatment option. Prostate Cancer Prostatic Dis 1998; 1:154–156 49. Perimenis P, Gyftopoulos K, Markou S, Barbalias G. Effects of finasteride and cyproterone acetate on hematuria associated with benign prostatic hyperplasia: a prospective, randomized, controlled study. Urology 2002; 59:373–377 50. Kearney M C, Bingham J B, Bergland R et al. Clinical predictors in the use of finasteride for control of gross hematuria due to benign prostatic hyperplasia. J Urol 2002; 167:2489–2491 51. Pareek G, Shevchuk M, Armenakas N A et al. The effect of finasteride on the expression of vascular endothelial growth factor and microvessel density: a possible mechanism for decreased prostatic bleeding in treated patients. J Urol 2003; 169:20–23 52. Haggstrom S, Torring N, Moller K et al. Effects of finasteride on vascular endothelial growth factor. Scand J Urol Nephrol 2002; 36:182–187 53. McConnell JD, Roehrborn CG, Bautista OM et al. Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 18; 349:2387–2398

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Page 327 24 Finasteride in the treatment of benign prostatic hyperplasia J D McConnell Introduction The androgen dependency of the prostate is responsible both for the development of benign prostatic hyperplasia (BPH) in older men and the reduction in symptoms associated with finasteride therapy. Dihydrotestosterone (DHT), which is converted from testosterone by two 5α-reductase isozymes, accounts for around 90% of all intraprostatic androgens. Finasteride is an inhibitor of the type II isozyme of 5α-reductase, which effectively reduces testosterone conversion to DHT in the prostate and thereby improves the urinary symptoms associated with BPH. The use of finasteride since its approval over a decade ago is supported by a wealth of clinical experience, with long-term studies indicating that the drug not only prevents acute urinary retention (AUR) but may delay the need for invasive therapy indefinitely or negate it altogether in responders. It has been suggested that men with larger prostates are more likely to respond to treatment with finasteride than those with smaller glands. Reductions in libido and other sexual effects have also been reported in a minority of patients, and the reduction in prostate-specific antigen (PSA) levels may also have a bearing on the use of the drug. The clinical relevance of these assumptions will be examined in this chapter. BPH affects the majority of older Western men and, as the age of the general population increases and improvements in healthcare provision occur in the developing world, the prevalence of this disease will grow. Pharmacologic treatments with a range of mechanisms of action are therefore desirable. Effective patient selection and the use of finasteride as monotherapy or in combination with other preparations also ensure the continued place of the drug in the armory of anti-BPH agents. DHT and 5α-reductase The prostate is highly dependent on testicular androgens for its development and functional integrity. BPH develops in older men as a function of sensitivity to these testicular androgens, specifically DHT.1 Serum and prostatic DHT levels remain stable, unlike testosterone, which falls over time. The role that androgens play in hyperplastic and normal prostatic growth is governed by the levels of DHT that bind to androgen receptors within the epithelium of the prostate. This complex plays a critical role in stimulating androgen-mediated prostatic growth.2,3 The characteristic reduction in androgendependent growth observed with aging in some other tissues does not occur in the prostate.4 Testosterone is reduced to DHT through the action of 5α-reductase. Two forms of this enzyme have been identified: type I, which is found in greater proportions in the skin and liver, and type II, which is the predominant isozyme contained in the prostate.1 The role of DHT and, by definition, the protein responsible for its reduction, in the development of BPH was determined following the identification of 5α-reductase deficiency in a group of individuals with pseudohermaphroditism5–7. Virilization occurred at puberty in these individuals, although their prostates remained nonpalpable, and male sexuality was in evidence alongside normal muscular composition. This, plus the observation that men with castrate levels of testosterone do not develop BPH and have very low levels of DHT, indicated that blockade of prostate-specific androgens could reduce the size of the prostate, thereby relieving obstructive urinary symptoms with limited adverse sexual or physical implications. The development of finasteride The above observations led to the development of synthetic 4-azasteroid α-reductase inhibitors. These agents were designed to reduce levels of type II 5α-reductase, the isozyme that predominates in the prostate (Fig. 24.1). One compound, N -(2-methyl-2-propyl)-3-oxo-4-aza-5-α-androst-1-ene-17-β-carboxamide (finasteride), was found to reduce levels of DHT in the canine prostate and reduce prostatic volume by up to 64%.8 Further studies showed that testosterone levels were unaffected by the drug, indicating that sexual function should be maintained.9,10

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Page 328 As anticipated, intraprostatic testosterone levels were elevated, however, and serum and prostatic DHT were not completely inhibited, due to formation via the uninhibited type I 5α-reductase.11 Mode of action Finasteride, which reduces serum DHT by around 70% and prostatic DHT by 85–90% (Fig. 24.2), 12 is thought to act predominantly on the epithelium of the prostate, exerting its beneficial clinical effect by altering prostatic

Figure 24.1 Structure of finasteride.

Figure 24.2 Action of finasteride. Free testosterone (T), predominantly manufactured by the testes, enters the prostate where it binds to an androgen receptor (AR) or is converted to dihydrotestosterone (DHT) by 5α-reductase (5α). DHT will also bind to the androgen receptor, with a greater affinity than testosterone. T or DHT then influences DNA transcription. tissue composition and inhibiting cell proliferation.13–16 A 24- to 30-month open-label extension study of finasteride in a group of 19 men whose prostates were assessed by magnetic resonance imaging (MRI) and biopsy revealed a reduction in symptoms, PSA, DHT, and prostate volume after 6 months.14 The percentage of prostate volume attributed to epithelium shrank significantly from 19.2% to 12.5% at intermediate follow-up and to 6.4% at longterm follow-up. Changes in the transforming growth factor beta (TGFβ) signaling system, in terms of upregulation of TGFβ signaling receptors and a subsequent increase in epithelial apoptosis, may be instrumental in this process. The inhibition of prostatic cell proliferation has been demonstrated in several studies.15,16 Stromal and epithelial prostate cells from hyperplastic and normal glands treated in vitro with finasteride in the presence of labeled thymidine revealed that normal stromal cells incorporated more thymidine than epithelial cells. Finasteride treatment resulted in 80±3% and 55±10% thymidine incorporation in stromal and epithelial cells, respectively, while rates of 70±4% and 74±4% were observed in hyperplastic tissue. Measurement of 5α-reductase activity showed that type II activity was reduced 100-fold while type I activity was reduced 5-fold, demonstrating the selectivity of finasteride for the former isozyme.16 The incomplete inhibition of cell proliferation observed indicates the action of factors other than DHT in prostate cell proliferation, however.15 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_328.html[09.07.2009 11:54:03]

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Locally produced growth factors, such as basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF), and keratinocyte growth factor (KGF), may also have an impact on prostatic enlargement,17,18 stimulating an increase in levels of mitosis in the prostatic stroma (Fig. 24.3). Analysis of bFGF expression and that of fibroblast growth factor receptor types 1 and 2 (FGFR1, FGFR2) in finasteridetreated and untreated BPH patients revealed strong bFGF immunoreactivity in the stroma and weaker immunoreactivity in the epithelium of the untreated patients, and virtually no immunoreactivity in the epithelium and lower stromal immunoreactivity in finasteridetreated patients. This suggests that finasteride treatment leads to downregulation of bFGF activity, thereby limiting the growth-stimulating action of this protein. Epidermal growth factor (EGF) appears to be unaffected by finasteride treatment, however, with only small changes observed in levels of TGF-α and EGF receptors after treatment, indicating a potential means of continued growth of androgen-independent basal prostatic epithelial cells.19

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Page 329 Clinical experience with finasteride Finasteride was first launched in 1992 and is currently prescribed in developed countries worldwide. The duration of its clinical usage means that a range of long-term studies and meta-analyses are available as evidence of its safety and efficacy (Table 24.1). Men treated with 5 mg finasteride have been consistently shown to exhibit significant improvements in peak urinary flow ( Q max) and reductions in obstructive symptoms and prostatic volume in both older and younger men.20–28 Incidence of sexual dysfunction, in terms of lower libido, ejaculatory dysfunction, and impotence, is greater in men who receive the drug, although the majority of patients remain unaffected. The Proscar (finasteride) Long-term Efficacy and Safety Study (PLESS) investigated the effects of finasteride relative to placebo over a 4-year period.22 Over 3000 men aged 45–78 with moderate to severe BPH were randomized to receive either 5 mg finasteride or placebo. Risk of acute urinary retention (AUR) or BPH-related surgery was significantly lower (−55–57% relative risk) in the finasteride group compared to placebo over the study period (Fig. 24.4). Quasi-AUA symptom score improved in this group (3.3 versus 1.3 points) and prostate volume fell (−18% versus +14% for placebo). In 4 years, 6.6% of the placebo group experienced AUR compared to 2.8% of the finasteride group ( p =0.001).23 As a result of AUR,

Figure 24.3 Locally produced growth factors influence prostatic cell proliferation and apoptosis.

Figure 24.4 Reduced risk of acute urinary retention (AUR) and BPH-related surgery with finasteride.

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Page 330 Table 24.1 Long-term finasteride trials. Study DurationRegimen Reduction Reduction in in AUR BPH-related risk surgery risk Roehrborn4 years 5 mg 57% 55% et al.23 FIN/day or placebo Vaughan 7–8 5 mg — — et al.25 years FIN/day (or 10 mg 1st year) Ekman et 6 years 5 mg al.26 FIN/day

—

—

Lam et al.27

—

—

10 years5 mg FIN/day

Boyle et al.42

ProstateQ max volume

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Symptom score

Side-effects

−18% +1.9ml/s−3.3

ED 8.1% L LIB 6.4% EJD 3.7% −25% +20% 1-year 1st year, ED improvement6.4% maintained L LIB 10.9% EJD 5.8% few new cases thereafter −21% 4–2.2 ml 30% 0.6–1.7% dropimprovementout to SD each year — — 55.8% Treatment treatment duration not success linked to sideeffects — 0.89– +1.8–2.8* — 1.84 ml*

N/A — — — metaanalysis * Depending on prostate volume; larger prostates linked to greater improvement. ED, erectile dysfunction; FIN, finasteride; L LIB, lowered libido; EJD, ejaculatory dysfunction; SD, sexual dysfunction.

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Page 331 surgery was then performed in 75% of the former and 40% of the latter group ( p =0.01), Prostate volume and PSA level were powerful predictors of risk of AUR or BPH-related surgery in this patient group.27 Risk of AUR or surgery ranged from 8.9% to 22%, depending on prostate volume, and from 7.8% to 19.9% depending on PSA level. In PLESS, only three drug-related side-effects occurred within the first year with an incidence of >1%: impotence (8.1% versus placebo 3.7%); decreased libido (6.4% versus 3.4%), and decreased ejaculate volume (3.7% versus 0.8%). Further analysis of PLESS data showed that finasteride was effective and safe in both older (≥65 years) and younger (45–64 years) patients, with no additional risk of drug-related adverse events in the older cohort.24 Spine bone mineral density, for example, was unaffected by 4-year finasteride administration.29 Longer-term studies indicate that the efficacy of finasteride is durable and that, in responders, the drug negates the need for prostatic surgery altogether.25,27 Men prescribed open-label finasteride for a 7- to 8-year period ( n =71) after taking part in two short-term phase II trials were found to maintain the reductions in Boyarsky symptom score seen after 1 year over the following 6 years.25 Baseline DHT fell by 85% over the study period while serum PSA fell by 45%. Prostate volume fell by 25% from average baseline 61.2 g after 1 year and this was sustained after 7 years. Sexual side-effects (impotence, abnormal ejaculation, and low libido) occurred most often during the first year of extension and decreased over the extension period. Discontinuation due to such effects was 1.9% in year 1 and 0% after year 4. Likewise, only minor reductions in sexual function were observed in a 6-year extension study of the drug.26 A 10-year follow-up study suggested that appropriately selected patients, often with larger prostates, could be effectively treated for BPH symptoms with finasteride over this extended time period.27 Of an original 43 patients who entered phase III 12-month double-blind trials, 41 completed the year and 30 continued to take the drug for a further 4 years. Twenty-two continued treatment for a further 10 years, indicating a 48.8% overall discontinuation rate, but only 26.7% between 5 and 10 years. In total, 24 (56%) were judged to be successfully treated over the 10-year follow-up. The majority of withdrawals due to treatment failure occurred in the first 1 or 2 years, suggesting continued therapeutic success in initial responders. The adverse event profiles in the 1-year, placebo-controlled, phase III studies, the 5-year open extension study, and PLESS are similar. Overall, therefore, there is no evidence of increased side-effects with increased duration of treatment. Adverse treatment effects are, by and large, limited to sexual dysfunction;25,26 however, few patients report such effects overall and superficial analysis would appear to indicate that numbers are similar across alternative treatment options30 (Fig. 24.5). A study of 670 BPH patients treated with a range of medical and surgical options and watchful waiting ( n =90 (α-blocker 43, finasteride 47), 207, and 234, respectively involved assessment of sexual effects by questionnaire 9 months after surgery or the initiation of therapy. Libido, sexual activity, potency, and penile rigidity were determined. An improvement of between 7 and 14% was reported for libido for all treatments (α-blocker 3%, finasteride 8%) and deterioration in libido was reported by between 7 and 14% (α-blocker 14%, finasteride 8%) of all participants. Similar results were observed for sexual activity and erectile capacity; however, complete results for rigidity were not available for finasteride-treated patients. A similar degree of improvement in urinary symptoms and quality of life has been reported in some studies of 5α-reductase inhibitors and α-blockers. For example, a randomized study of tamsulosin (0.2 mg) and finasteride (5 mg) showed both drugs to result in similar improvements in a group of Korean BPH patients ( n =205) after a period of 24 weeks. I-PSS, Q max, and quality of life improved in both groups with no significant difference between scores at endpoint; however, analysis at 4 weeks showed tamsulosin to have a swifter time to onset.31 Combination studies The different mode of action of 5α-reductase inhibitors and α-blockers has led to the assumption that a combination of both drug types may increase clinical improvement in BPH patients, due to the dual effects of inhibiting cell proliferation and altering the smooth muscle tone of the prostatic stroma and detrusor. The most comprehensive evaluation of the clinical potential of combination therapy has been the Medical Therapy Of Prostatic Symptoms (MTOPS) study. This trial indicated that the combination of finasteride with doxazosin both slows the progression of BPH and reduces risk of AUR to a greater extent than either type of therapy alone.32 This study involved a total of 3047 BPH patients who received file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_331.html[09.07.2009 11:54:04]

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monotherapy, placebo, or combination therapy for an average of 5 years. Finasteride or doxazosin monotherapy brought about reductions in risk of disease progression of 34% and 39%, respectively, while

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Page 332 combination therapy was associated with a 67% reduction in risk (Fig. 24.6). AUR risk was cut by 79% in this group compared to 67% in the finasteride group and 31% in the doxazosin group. Reductions in risk of BPH surgery were 69%, 64%, and 8% relative to placebo in each group, respectively. No increase in side-effects was observed with combination treatment. The results suggest that enlargement of the prostate is slowed by finasteride while the symptoms of BPH are directly reduced by doxazosin. Investigation of baseline characteristics and subsequent progression of the men in the MTOPS placebo group ( n =737) indicated that easily obtainable measures, such as PSA level, Q max, postvoid residual urine, and prostate volume, correlate significantly with disease progression and the need for surgery.33 Such an approach may allow improved patient selection to ensure optimum clinical results.

Figure 24.5 Percentage of patients with improved and reduced sexual function following BPH treatment.

Figure 24.6 MTOPS—reductions in disease progression with combination treatment. AUR, acute urinary retention.

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Page 333 Additional research has suggested that it may be possible to discontinue combination therapy after 1 year with no compromise in clinical benefit.34 A group of BPH patients ( n =270) were prescribed 2, 4, or 8 mg doxazosin alongside 5 mg finasteride for a period of 3, 6, 9, or 12 months, after which the αblocker was discontinued. Of those who discontinued doxazosin at 12 months, 84% of the 2 mg group, 85% of the 4 mg group, and 87% of the 8 mg group experienced no increase in AUA symptom score and reported no desire to resume taking doxazosin 1 month later. In studies of generally shorter duration and reduced patient numbers the results with combinations have not been as conclusive. The addition of finasteride to terazosin in the Veterans’ Affairs Cooperative Studies BPH Study Group, which involved 1229 patients, conveyed no additional benefit compared to terazosin monotherapy after 1 year.35 The relatively low average prostate volume of the men involved in this study (36.2–38.4 ml) could explain the limited improvement observed in patients treated with finasteride alone, due to the correlation between gland size and clinical response observed in several studies.36,37 Pharmacokinetic interactions between finasteride and terazosin, but not doxazosin may also have a bearing on clinical response to different combination therapy regimens.38 A 6-month trial of sustained-release alfuzosin (5 mg), finasteride (5 mg), or both drugs in 1051 men yielded similar findings to the VA Cooperative trial, with higher symptom improvement observed in patients who received α-blockade or combination therapy.39 The short-term nature of this trial precludes any definitive conclusions, however. An additional 1-year randomized placebo-controlled study involved 1007 men who received finasteride (5 mg) or doxazosin (1–8 mg, titrated) monotherapy, combination therapy, or placebo. Results indicated no additional benefit of finasteride to doxazosin therapy.40 Again, mean prostate size was relatively small, at 36.3 g, which may explain the lack of observed efficacy of finasteride. No stratified analysis based on prostate volume was performed. The role of prostate volume is illustrated by a further trial of finasteride, alfuzosin, or a combination of both in a group of 138 men with I-PSS >13 and prostate volume of at least 60 ml. Overall, 96% of patients in the combination group showed improved Q max and I-PSS, compared to 84% in the αblocker alone group and 74% in the finasteride group.41 Meta-analysis of six randomized clinical trials involving finasteride (Table 24.2) provides further evidence of the role of prostate volume in response to therapy, with men with larger prostates showing particularly good response to treatment with finasteride.42,43 Over 2600 individuals were included in this study, which included all finasteride studies and phase III trials plus a number of other trials including the VA Cooperative Study. Men with prostates smaller than 20 g were less likely to show clinical improvement in quasi-I-PSS symptom score and Q max compared to those with prostates larger than 60 g (1.8 versus 2.8 points and 0.89 ml versus 1.84 ml, respectively). Improvements were judged to become significant in men with prostates greater than 40 ml, i.e. 50% of the entire population, and the results indicate that prostate volume is a significant predictor of response to therapy. Additional considerations Hematuria Hematuria, which often emerges secondary to BPH, is associated with significant morbidity, including anemia and clot retention. Recent research has shown that the Table 24.2 Studies included in meta-analysis of finasteride. Study Patients Age Prostate volume (mean Peak flow (mean Quasi-I-PSS (n) (mean) ml) ml) (mean) Gormley et al.20 567 64.1 59.9 9.6 12.1 The Finasteride Study 447 65.5 48.1 8.9 11.8 Group59 Andersen et al.60 384 65.3 41.3 10.2 10.1 Lepor et al.35 601 65.7 37.5 10.4 13.4 Nickel et al.61 554 63.3 45.9 11.0 12.4 Bonilla et al.62 188 56.4 41.6 15.8 9.3

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Page 334 condition may be successfully treated with finasteride and other anti-androgens.44–46 Although the exact mechanism is not understood, histochemical studies have suggested that this is due to decreased expression of vascular endothelial growth factor (VEGF) following finasteride treatment which, as a consequence, lowers microvessel density in the prostatic suburethra.47,48 Such mechanisms could explain the reduction in hematuria and intraoperative blood loss observed when patients due to undergo transurethral resection of the prostate (TURP) receive finasteride treatment preoperatively.49,50 Investigation of potential predictors of clinical response to finasteride treatment in patients with gross hematuria revealed that 94% responded to treatment and that 77% suffered no further bleeding while taking the drug.46 Treatment was effective in patients taking a range of anticoagulants. Recurrent but lower-grade bleeding and slower response time were identified in men with larger prostates. Men with smaller prostates and those who had undergone previous prostatectomy had more rapid responses to treatment (2.7 days in men with glands <40 g versus 45 days in those with glands 100–150 g and 5.5 days in men who had undergone prostatectomy versus 18.6 days in those who had not). PSA PSA levels have been found to fall following application of finasteride to prostate cells treated in vitro with testosterone.51 In vivo studies have shown that plasma and serum complexed-to-total and free-tototal ratios remain constant with finasteride treatment, indicating that proportional reduction in all molecular forms of PSA occurs with finasteride treatment.52–54 Measurement of these PSA forms could potentially be used to screen for prostate cancer in men receiving finasteride, but this requires further investigation.54,55 The effect of finasteride on overall PSA levels has implications for prostate cancer screening but may also impact upon actual risk of prostate cancer. A case-control study of the medication use in 639 men with prostate cancer and 659 tumor-free controls indicated that, after adjustment for confounders, finasteride has a protective role against prostate cancer while nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) have no protective influence.56 Further evidence of the potential preventative role of finasteride has been recently highlighted in a large-scale study of the incidence of prostate cancer among men aged ≥55 years prescribed finasteride or placebo over 7 years.57 Men who received the active agent were significantly less likely to develop prostate cancer during the study than those prescribed placebo ( p =0.001), although when cancer did develop in this group, it was more likely to be of a higher Gleason grade than in the placebo group. Whether the benefits of reduced likelihood of prostate cancer development and urinary symptoms outweigh the risks of higher-grade tumor development and sexual side-effects requires further investigation. Conclusions Patient perception of finasteride has been shown to be excellent. In a survey of French BPH patients, the primary preoccupations were reported as a reduced risk for urological complications and need for surgery, with improved symptoms and quality of life of secondary importance. These expectations were easily met by finasteride in the majority of cases, and 89% of participants reported good or extremely good improvement of symptoms, with very few tolerability issues.58 The studies outlined here indicate that finasteride is an effective long-term treatment option for BPH. The benefit of finasteride over placebo has been repeatedly proven in well-designed large-scale clinical trials and comparison studies have shown the drug to be of similar efficacy in terms of AUR prevention and necessity for BPH surgery to α-blockers in well-chosen patient groups. Men with larger prostates appear to benefit particularly from finasteride therapy. Response to therapy has been shown to have exceptionally long duration in responders, exceeding 10 years in many cases. The data from the MTOPS study indicate that the drug has further potential when used in combination with α-blockers. On this basis, future treatment algorithms could include both a 5α-reductase inhibitor and α-receptor antagonist, depending on the initial clinical presentations. The effects of finasteride on PSA level have been frequently documented; however, recent findings regarding the lack of effect of the drug on free-to-total PSA ratio may mean that suggestions that prostate cancer detection may be compromised can largely be dismissed. Further investigation of this aspect is required, however. References 1. Lee C, Kozlowski J M, Grayhack J T. Aetiology of benign prostatic hyperplasia. Urol Clin North Am 1995; 22: 237–246 2. Walsh P C, Hutchins G M, Ewing L L. Tissue content of dihydrotestosterone in human prostatic hyperplasia is not supranormal. J Clin Invest 1983; 72:1772–1777 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_334.html[09.07.2009 11:54:06]

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Page 335 3. Traish A M, Wotiz H H. Prostatic epidermal growth factor receptors and their regulation by androgens. Endocrinology 1987; 121:1461–1467 4. Wilson J D. The pathogenesis of benign prostatic hyperplasia. Am J Med 1980; 68:745–756 5. Walsh P C, Madden J D, Harrod M J et al. Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974; 291:944–949 6. Imperato-McGinley J, Guerrero L, Gautier T, Peterson R E. Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 1974; 186: 1213–1215 7. Thigpen A E, Davis D L, Milatovich A et al. Molecular genetics of steroid 5α-reductase 2 deficiency. J Clin Invest 1992; 90:799–809 8. Brooks J R, Berman C, Garnes D et al. Prostatic effects induced in dogs by chronic or acute oral administration of 5 alpha-reductase inhibitors. Prostate 1986; 9:65–75 9. Rittmaster R S, Stoner E, Thompson D L et al. Effect of MK-906, a specific 5α-reductase inhibitor, on serum androgens and androgen conjugates in normal men. J Androl 1989; 10:259–262 10. Vermeulen A, Giagulli C A, Schepper P D et al. Hormonal effects of an orally active 4-azasteroid inhibitor of 5α-reductase in humans. Prostate 1989; 14:45–53 11. Thigpen A E, Silver R I, Guileyardo J M et al. Tissue distribution and ontogeny of steroid 5 alphareductase isozyme expression. J Clin Invest 1993; 92:903–910 12. Bartsch G, Rittmaster R S, Klocker H. Dihydrotestosterone and the concept of 5 alpha-reductase inhibitors in human benign prostatic hyperplasia. Eur Urol 2000; 37:367–380 13. Marks L S, Partin A W, Dorey F J et al. Long-term effects of finasteride on prostate tissue composition. Urology 1999; 53:574–580 14. Saez C, Gonzalez-Baena A C, Japon M A et al. Regressive changes in finasteride-treated human hyperplastic prostates correlate with an upregulation of TGF-beta receptor expression. Prostate 1998; 37:84–90 15. Lobaccaro J M, Boudon C, Lechevallier E et al. Effect of finasteride (Proscar) on the proliferation of cultured epithelial and stromal cells from normal and hyperplastic human prostates. Cell Mol Biol (Noisyle-grand) 1996; 42:511–518 16. Feneley M R, Span P N, Schalken J A et al. A prospective randomized trial evaluating tissue effects of finasteride therapy in benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 1999; 2:277–281 17. Saez C, Gonzalez-Baena A C, Japon M A et al. Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride. Prostate 1999; 40:83–88 18. Crescioli C, Villari D, Forti G et al. Des (1–3) IGF-I-stim-ulated growth of human stromal BPH cells is inhibited by a vitamin D(3) analogue. Mol Cell Endocrinol 2002; 198: 69–75 19. Torring N, Moller-Ernst Jensen K, Lund L et al. Possible autocrine loop of the epidermal growth factor system in patients with benign prostatic hyperplasia treated with finasteride: a placebo-controlled randomized study. BJU Int 2002; 89:583–590 20. Gormley G J, Stoner E, Bruskewitz R C et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med 1992; 327: 1185–1191 21. Byrnes C A, Liss C L, Tenover J L et al. Combined analysis of two multicenter studies of finasteride 5 mg in the treatment of symptomatic benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 1997; 1:26–31 22. McConnell J D, Bruskewitz R, Walsh P et al. for the Finasteride Long-term Efficacy and Safety Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998; 338: 557–563 23. Roehrborn C G, Bruskewitz R, Nickel G C et al. Urinary retention in patients with finasteride or placebo over 4 years. Characterization of patients with ultimate outcomes. The PLESS Study Group. Eur Urol 2000; 37: 528–536 24. Kaplan S A, Holtgrewe H L, Bruskewitz R et al. for the Proscar Long-Term Efficacy and Safety Study Group. Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia. Urology 2001; 57:1073–1077 25. Vaughan D, Imperato-McGinley J, McConnell J et al. Long-term (7 to 8-year) experience with finasteride in men with benign prostatic hyperplasia. Urology 2002; 60: 1040–1044 26. Ekman P and the Scandinavian Finasteride Study Group. Maximum efficacy of finasteride is obtained within 6 months and maintained over 6 years: follow-up of the Scandinavian Open-Extension Study. Eur Urol 1998; 33: 312–317 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_335.html[09.07.2009 11:54:06]

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27. Lam J S, Romas N A, Lowe F C. Long-term treatment with finasteride in men with symptomatic benign prostatic hyperplasia: 10-year follow-up. Urology 2003; 61: 354–358 28. Roehrborn C G, McConnell J D, Lieber M et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group. Urology 1999; 53:473–480

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Page 336 29. Matsumoto A M, Tenover L, McClung M et al. Pless Study Group. The long-term effect of specific type II 5alpha-reductase inhibition with finasteride on bone mineral density in men: results of a 4-year placebo controlled trial. J Urol 2002; 167:2105–2108 30. Leliefeld H H, Stoevelaar H J, McDonnell J. Sexual function before and after various treatments for symptomatic benign prostatic hyperplasia. BJU Int 2002; 89:208–213 31. Lee E. Comparison of tamsulosin and finasteride for lower urinary tract symptoms associated with benign prostatic hyperplasia in Korean patients. J Int Med Res 2002; 30: 584–590 32. McConnell JD, Roehrborn CG, Bautista OM et al. Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 23; 349:2387–2398 33. McConnell J F, Roehrborn C G, Slawin K M et al. Baseline measures predict the risk of benign prostatic hyperplasia clinical progression in placebo-treated patients. J Urol 2003; 169 (Suppl 4): abstract 1287 34. Baldwin K C, Ginsberg P C, Roehrborn C G, Harkaway R C. Discontinuation of alpha-blockade after initial treatment with finasteride and doxazosin in men with lower urinary tract symptoms and clinical evidence of benign prostatic hyperplasia. Urology 2001; 58:203–209 35. Lepor H, Williford W O, Barry M J et al. for The Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. The efficacy of terazosin, finasteride or both in benign prostatic hyperplasia. N Engl J Med 1996; 335: 533–540 36. Boyle P, Gould A L, Roehrborn C G. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48:398– 405 37. Roehrborn C G, Boyle P, Bergner D et al. for the PLESS Study Group. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. Urology 1999; 54: 662–669 38. Vashi V, Chung M, Hilbert J et al. Pharmacokinetic interaction between finasteride and terazosin, but not finasteride and doxazosin. J Clin Pharmacol 1998; 38: 1072–1076 39. Debruyne F M, Jardin A, Colloi D et al. Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. European ALFIN Study Group. Eur Urol 1998; 34:169–175 40. Kirby R S, Roehrborn C G, Boyle P et al. for the PRE-DICT Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 2003; 61:119–126 41. Loran O B, Pushkar’ Dlu, Rasner P I. [Comparative evaluation of the effectiveness and safety of combined drug therapy of patients with benign prostatic hyperplasia with finasteride and alfuzozine] [in Russian]. Urologiia 2002; 1: 19–22 42. Boyle P, Gould A L, Roehrborn C G. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48:398– 405 43. Roehrborn C G. Meta-analysis of randomized clinical trials of finasteride. Urology 1998; 51 (Suppl 4A): 46–49 44. Kashif K M, Foley S J, Basketter V, Holmes S A. Haematuria associated with BPH—natural history and a new treatment option. Prostate Cancer Prostatic Dis 1998; 1:154–156 45. Perimenis P, Gyftopoulos K, Markou S, Barbalias G. Effects of finasteride and cyproterone acetate on hematuria associated with benign prostatic hyperplasia: a prospective, randomized, controlled study. Urology 2002; 59:373–377 46. Kearney M C, Bingham J B, Bergland R et al. Clinical predictors in the use of finasteride for control of gross hematuria due to benign prostatic hyperplasia. J Urol 2002; 167:2489–2491 47. Pareek G, Shevchuk M, Armenakas N A et al. The effect of finasteride on the expression of vascular endothelial growth factor and microvessel density: a possible mechanism for decreased prostatic bleeding in treated patients. J Urol 2003; 169:20–23 48. Haggstrom S, Torring N, Moller K et al. Effects of finasteride on vascular endothelial growth factor. Scand J Urol Nephrol 2002; 36:182–187 49. Kamalov A A, Riaboi A V, Ignashin N S et al. [Use of proscar in preoperative preparation of patients with benign prostatic hyperplasia before transureteral resection] [in Russian]. Urologiia 2002; 5:16–18 50. Sandfelt L, Bailey D M, Hahn R G. Blood loss during transurethral resection of the prostate after 3 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_336.html[09.07.2009 11:54:07]

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months of treatment with finasteride. Urology 2001; 58:972–976 51. Lopez Munnoz A, Larran Lopez J, Aparicio Patino J et al. Assessment of the effect of a 5-alphareductase inhibitor on cultured explants of human prostate. [in Spanish]. Actas Urol Esp 1996; 20:316– 322 52. Espana F, Martinez M, Royo M et al. Changes in molecular forms of prostate-specific antigen during treatment with finasteride. BJU Int 2002; 90:672–677 53. Brawer M K, Lin D W, Williford W O et al. Effects of finasteride and/or terazosin on serum PSA: results of VA Cooperative Study #359. Prostate 1999; 39:234–239

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Page 337 54. Tarle M, Kraus O, Trnski D et al. Early diagnosis of prostate cancer in finasteride treated BPH patients. Anticancer Res 2003; 23:693–696 55. Keetch D W, Andriole G L, Ratliff T L, Catalona W J. Comparison of percent free prostate-specific antigen levels in men with benign prostatic hyperplasia treated with finasteride, terazosin or watchful waiting. Urology 1997; 50:901–905 56. Irani J, Ravery V, Pariente J L et al. Effect of nonsteroidal anti-inflammatory agents and finasteride on prostate cancer risk. J Urol 2002; 168:1985–1988 57. Thompson I M, Goodman P J, Tangen C M et al. The influence of finasteride on the development of prostate cancer. Published at www.nejm.org 24 June, 2003 (doi: 10.1056/NEJMoa030660) 58. Teillac P. Benign prostatic hyperplasia: patients’ perception of medical treatment and their expectations. Results of a French survey involving patients treated with finasteride [in French]. Therapie 2002; 57:473–483 59. The Finasteride Study Group. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. Prostate 1993; 22:291–299 60. Andersen J T, Ekman P, Wolf H et al. and the Scandinavian BPH Study Group. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. Urology 1995; 46:631–637 61. Nickel J C, Fradet Y, Boake R C et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. CMAJ 1996; 155:1251–1259 62. Bonilla J, Stoner E, Grino P et al. Intra- and interobserver variability of MRI prostate volume measurements. Prostate 1997; 31:98–102

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Page 339 25 Combination therapy in the treatment of BPH C G Roehrborn Introduction Treatment for benign prostatic hyperplasia (BPH) in recent years has been characterized by a fall in the use of surgical procedures, mainly transurethral resection of the prostate (TURP), and a rise in the use of minimally invasive treatments and, particularly, medical therapy.1–3 Up to 90% of men in their eighties are estimated to suffer from BPH to some extent and prevalence of the disease is growing.4 Development of the associated symptomatology is androgen-dependent, and castration before or during puberty prevents its occurrence. Lower urinary tract symptoms (LUTS) secondary to BPH occur due to increased sensitivity to circulating androgens in the prostate. Increased cell proliferation, mainly in the transition zone of the prostate, occurs alongside a rise in the smooth muscle tone of both the prostate and bladder neck. Symptoms of reduced urinary flow and urinary retention, increased urinary frequency, and nocturia are particularly common.5 Pharmacologic therapies available for the treatment of LUTS include α-adrenoceptor antagonists (αblockers), such as terazosin, doxazosin, alfuzosin, and tamsulosin, and the 5α-reductase inhibitors, finasteride and dutasteride. Other strategies, such as plant-derived medication or watchful waiting, are applied to varying extents. Alpha-blockers act on the α-adrenoceptors of the prostate and bladder neck, thereby reducing the sympathetic nervous system controlled tone of the smooth muscle. Many placebo-controlled trials of αblockers have shown them to increase urinary flow and relieve irritative and obstructive symptoms, often within as little as 2 weeks of treatment.6–11 In contrast, 5α-reductase inhibitors reduce the formation of dihydrotestosterone (DHT) from testosterone in the prostate and thereby increase rates of apoptosis and reduce rates of cell proliferation. Enlarged prostate glands therefore shrink, causing alleviation of BPH symptoms and urinary flow in the process,12–14 as proven by placebocontrolled trials.15–17 More recently, it has been shown that the risks of acute urinary retention (AUR) and BPHrelated surgery are reduced in men receiving finasteride by 55% and 57%,15 respectively. However, symptom improvement may only be observed after up to 6 months of treatment15,16 and, indeed, it has been suggested that the clinical benefit is limited to men with larger prostates.16,18 The recent development of diverse formulations of pharmacologic therapies, such as the doxazosin gastro intestinal therapeutic system (GITS) and doxazosin XL, has increased patient and physician treatment choice.10 Further alterations in the pharmacokinetic profiles of available drugs are possible, however such avenues may be limited. In real terms we may have reached the limit of clinical benefit that can be achieved by monotherapy. Alternative pharmacologic treatment strategies for targeting BPH are therefore desirable. Given the different mechanisms of action of α-block-ers and 5α-reductase inhibitors, a combination of each of the drug classes in a single drug regimen might logically be expected to convey cumulative benefit to BPH patients.19 Several large-scale studies have been performed in recent years to determine whether the administration of an α-blocker in combination with a 5α-reductase inhibitor leads to greater improvement in BPH symptoms than either one individually and whether the side-effects documented with each drug class occur with greater frequency in combination. The following represents a summary of the salient findings from the most important combination studies that have been completed. Terazosin and finasteride VA Cooperative Study The first large-scale trial established to examine the potential benefits of combining an α-blocker with a 5α-reductase inhibitor was the Veterans’ Affairs (VA) Cooperative Study.6 This multicenter trial compared the use of terazosin and finasteride individually and in combination. The double-blind, placebo-controlled trial involved 1229 men (87% white, 11% black, 1% Asian/Pacific Islanders, 0.5% Native Americans) aged 45–80 suffering from symptomatic BPH. Baseline measures were obtained during an initial 1-month wash-out period and included American Urological Association (AUA) symptom score, peak urinary flow ( Q max), and volume of postvoid residual

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Page 340 urine (PVR). Prostate-specific antigen (PSA) levels were recorded and transurethral ultrasound examination of the prostate was also performed. Participants had an AUA symptom score of ≥8, Q max of 4–15 ml/s, minimal voided volume of 125 ml and PVR of <300 ml. After the wash-out period, they were randomized to receive 5 mg finasteride, terazosin titrated to 10 mg, a combination of both drugs, or placebo for a period of 1 year. Clinical evaluation, in terms of uroflowmetry, symptom score, PVR, and adverse effects, took place at 2, 4, 13, 26, 39, and 52 weeks. Transrectal ultrasound examination took place at the half-way point and on completion of the study. PSA was recorded at the end of the study period. Drop-out rates were similar between groups after 1 year, although discontinuation due to adverse effects was less common in the placebo group ( p <0.05). Overall, men receiving terazosin either alone or in combination were more likely to suffer dizziness and men receiving finasteride alone or in combination were more likely to experience erectile dysfunction (ED) or lowered libido. Ejaculatory dysfunction was significantly more common in men receiving combination therapy. Compliance was similar between all four treatment groups, however. Examination of symptom scores revealed that men receiving terazosin alone or in combination with finasteride had improved symptoms compared to both the finasteride and placebo groups ( p <0.001), with respective point reductions of 6.1, 6.2, 3.2, and 2.6 (Fig. 25.1). Peak improvement levels were attained in the terazosinexposed groups by 13 weeks and did not differ significantly between this point and completion of the study. The improvements in symptom score were accompanied by significant increases in Q max ( p <0.001 for terazosin and combination therapy compared to finasteride alone and placebo), which were greatest after 4 weeks. Mean increases in Q max at 52 weeks were 3.2, 2.7, 1.6, and 1.4 ml/s, respectively. Significant reductions in prostatic volume were observed in the finasteride and combination therapy groups (−61 ml and −70 ml, respectively) but no significant change was observed in this value in the other two groups. PSA was also significantly reduced in the finasteride and combination groups ( p <0.001) while increases were noted in men who received terazosin alone or placebo ( p <0.01).20 The results of this study confirm previously documented evidence of the efficacy of terazosin;21,22 but, they are not in agreement with studies indicating that finasteride reduces BPH symptoms and improves Q max.23,24 The VA study suggests that reduction in smooth muscle tone by α-blockers is more likely to reduce symptoms of BPH than androgen suppression using 5α-reductase inhibitors. The role of prostate volume was not assessed in this trial, however. Despite the lack of significant additional benefit with the addition of finasteride to terazosin therapy described in this trial, interactions between the two drugs have been documented.25,26 Rates of apoptosis and proliferation were determined from prostate samples obtained from 76 men who had been treated for BPH with terazosin, finasteride, or a combination of both.25 Both stromal and epithelial rates of apoptosis were significantly higher in

Figure 25.1 VA Cooperative Study: symptom improvement at 1 year according to treatment group. AUA, American Urological Association; Qmax, peak urinary flow.

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Page 341 the combination samples compared to monotherapy samples, although proliferation rates were similar. Upregulation of transforming growth factor (TGF) β1 was observed in the terazosin and combination therapy groups. The cellular relationship between the two drugs remains unclear, however. An additional, retrospective, study of cell proliferation and apoptosis among men treated with doxazosin, terazosin, finasteride, or a combination of finasteride and one of the α-blockers indicated no increase in apoptotic index with addition of finasteride to the other agents.27 A molecular relationship between the two drug classes was described in a comparison of the pharmacokinetic interactions between terazosin and finasteride and between doxazosin and finasteride. In this trial, the maximum plasma concentration and area under the plasma concentration-time curve from 0 to 24 hours of finasteride were significantly greater after coadministration with terazosin.26 The pharmacokinetic profile of terazosin was not altered, however. Whether this relationship is significant in terms of drug efficacy is as yet unknown. Alfuzosin and finasteride ALFIN study The α-blocker alfuzosin is a uroselective preparation that targets the α1-adrenoceptors of the prostate. Animal studies have shown alfuzosin to exert its effect at doses below the threshold of influence on the cardiovascular system.28–30 It does not require titration to its optimum dosage. A 6-month evaluation of the effects of combining 5 mg twice-daily (sustained-release alfuzosin) with 5 mg oncedaily finasteride (the ALFIN study) showed similar effects to the VA study described above.31 Again, the α-blocker was shown to improve symptoms of LUTS secondary to BPH to a greater extent alone or in combination compared to finasteride. The ALFIN study involved 1051 BPH patients aged between 50 and 75 from 11 European countries. Participants had an International Prostate Symptom Score (I-PSS) >7 and Q max of between 5 and 15 ml/s. They underwent a 2-week wash-out period prior to randomization to alfuzosin, finasteride, or a combination of both. Clinical assessment took place at baseline and then after 1, 3, and 6 months of therapy. I-PSS was recorded alongside uroflowmetry, blood pressure, and heart rate during these sessions, while prostate volume, measured using transurethral ultrasound, and PSA level were assessed at baseline and on completion of the study. Adverse events were reported throughout the entire trial. All three patient groups were found to show improvement over the study period (Fig. 25.2). Mean I-PSS fell by 6.3 points in the alfuzosin alone group, 6.1 in the combination group, and 5.2 in the finasteride alone group, but a significantly greater improvement in the alfuzosin and combination groups compared to finasteride was recorded ( p =0.01 and 0.03, respectively). Improvement of at least 50% was observed in 43, 42, and 33% of the men in each group, respectively.

Figure 25.2 ALFIN Study: symptom improvement at 6 months according to treatment group. I-PPS, International Prostate Symptom Score; Qmax, peak urinary flow.

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Page 342 Q max increased by similar degrees at 6 months (alfuzosin 1.8±3.8 ml/s; combination 2.3±4.7 ml/s; finasteride 1.8±4.5 ml/s); however, at 3 months, men in the alfuzosin and combination groups had greater Q max than those in the finasteride alone group. Patients with a baseline Q max of <10 ml/s had a significantly greater Q max at the end of the study period if they were treated with alfuzosin or combination therapy rather than finasteride alone, however ( p =0.05). Prostate volume and PSA level fell significantly in the finasteride and combination therapy groups, but no significant change was observed in men treated with alfuzosin alone. Similar numbers of adverse events were observed in all patient groups; however, sexual dysfunction, in the form of erectile dysfunction (ED) and ejaculatory disorders, was more common among finasteridetreated patients. Levels of vasodilatory events, potentially linked to α-blockade, were similar between all three groups, as was incidence of AUR. This is in accordance with previous reports of both drugs.15,32 The improvements observed with finasteride in this study are higher than those of the VA study, but are significantly lower than those seen with α-blockade by alfuzosin. Patients were not selected or stratified according to prostate size and so the potential effects of this variable on outcome could not be analyzed. A longer-term, but smaller-scale study indicated that the combination of alfuzosin and finasteride brought about greater improvements in I-PSS and urinary flow.33 One hundred and thirty-eight BPH patients with prostates ≥60 ml and I-PSS >13 were treated with alfuzosin, finasteride, or both for 3 years. Improved urinary flow and I-PSS results were observed in 84%, 74%, and 96% of patients, respectively. These findings have yet to be confirmed by larger-scale trials, however. Doxazosin and finasteride PREDICT A large-scale, placebo-controlled study designed to evaluate the potential benefits of combining an αblocker with a 5α-reductase inhibitor was conducted using the α1-selective adrenoceptor antagonist doxazosin in the Prospective European Doxazosin and Combination Therapy (PREDICT) Trial.34 The 1-year trial took place at 90 centers in Europe. Following a 2-week run-in period, 1095 men aged 50–80 with an I-PSS ≥12 and Q max ≥5 ml/s but ≤15 ml/s in a total void of 150 ml or more, were randomized to receive doxazosin alone, finasteride alone, a combination of both drugs, or placebo for 52 weeks. Patients receiving doxazosin underwent a 10-week titration period, while the dose was increased from 1 mg to 8 mg on the basis of treatment response as judged by I-PSS and Q max, as part of their regimen. Participants were assessed at baseline for I-PSS and Q max and then at regular intervals (10, 14, 26, 39, and 52 weeks) throughout the study period. Blood pressure, heart rate, and adverse events were also recorded regularly over the 12-month period, while PSA, electrocardiography, and standard blood tests were performed at baseline and then again on conclusion of the trial. Prostate volume was estimated using DRE. In total, 1007 patients were included in the intention to treat analysis. Mean doxazosin dose was 6.4 mg/day in the monotherapy group and 6.1 mg/day in the combination group. Men who received doxazosin alone or in combination had significantly improved I-PSS results compared to those who received finasteride alone ( p ≤0.0001) or placebo ( p <0.01), for both obstructive and irritative symptoms (Fig. 25.3). Mean I-PSS improvements were −8.3, −8.5, −6.6, and −5.7 points, respectively. No significant difference was observed between the doxazosin and combination groups or between the finasteride and placebo groups. Obstructive but not irritative symptoms improved with finasteride compared to placebo at endpoint ( p <0.05). Again, for Q max, a statistically significant improvement was observed in the doxazosin and combination groups (mean increases of 3.6 ml/s and 3.8 ml/s, respectively) compared to both placebo and finasteride alone (1.4 ml/s and 1.8 ml/s, respectively, both p ≥0.0001). No improvement above placebo was observed with finasteride treatment alone. Discontinuation due to adverse events was similar between groups, however, side-effects differed according to treatment regimen. Participants treated with doxazosin alone or in combination were more likely to report asthenia, dizziness, and hypotension, while patients treated with finasteride and doxazosin in combination were more likely to suffer ED. No significant difference in ED was observed between the monotherapy groups. The PREDICT study demonstrated that, in this patient group, doxazosin more effectively improves symptoms of BPH and urinary flow than finasteride alone or placebo. 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Figure 25.3 PREDICT Study: symptom improvement at 1 year according to treatment group. I-PSS, International Prostate Symptom Score; Qmax, peak urinary flow. MTOPS The results of all three large-scale studies described above suggest that the role of 5α-reductase inhibitors as generalized monotherapy for LUTS may be somewhat limited, a finding at variance with some of the original studies on finasteride,15,16,23,24 An additional, longer-term trial, which progressed in parallel to these studies, has generated important new information on both the clinical potential of 5α-reductase inhibitors as monotherapy and the potential of drug combinations. The Medical Therapy of Prostatic Symptoms (MTOPS) trial, a prospective, randomized, double-blind, multicenter, placebo-controlled trial, was established to determine whether medical therapy can prevent or delay the progression of BPH in the long term.40 Further elucidation of the natural history of BPH, determining baseline factors associated with more rapid disease progression, was a secondary aim of the study. In 18 academic centers across the US a total of 3047 patients were recruited and randomized to receive doxazosin, finasteride, a combination of both, or placebo.41 Mean age of participants was 62.6 years, most were white (82.6%), with 8.8% black and 7.2% Hispanic participants. The inclusion/exclusion criteria allowed men with all prostate sizes to be enrolled, as long as the serum PSA was less than 10 ng/ml. This resulted in a wide distribution of prostate sizes and serum PSA values allowing for stratified analyses of subsets based on these criteria. Disease progression was defined as a worsening of BPH symptoms according to the AUA symptom index (AUASI).42 Progression was deemed to have occurred in the case of one of the following: a 4-point rise in AUASI, confirmed by a second visit within 4 weeks; a 50% increase in creatinine relative to baseline levels; AUR; two or more urinary tract infections (UTIs) within 1 year or a single episode of urosepsis due to bladder outlet obstruction (BOO); socially unacceptable incontinence. The first occurrence of any of the above events indicated BPH progression. Progression as an endpoint represented a novel concept at the time of the initiation of the MTOPS study, although the PLESS study as well as the dutasteride studies later on utilized AUR and surgery as endpoints in their study design.15,17 Entirely novel was the concept of utilizing a threshold to define symptom progression. Based on data from the VA Cooperative study, in which men perceived general improvement in their symptom status once the AUASI improved by more than 3 points, a threshold of 4 points was chosen—to be confirmed within 4 weeks—to indicate global subjective worsening of symptom status.43 To assess the natural history of BPH, Q max, prostate volume, sexual function, and quality of life were regularly recorded with respect to BPH symptoms. Transrectal ultrasound and DRE were used to evaluate prostate volume, the Sexual Function Inventory Questionnaire evaluated sexuality and the Short Form-36 Health Survey instrument recorded quality of life scores. Prostatic biopsies were obtained at baseline and at 5 years (or at primary endpoint) in 37% of study participants who volunteered to take part in a biopsy substudy. Patients were randomized to receive 5 mg finasteride and doxazosin placebo, 5 mg finasteride and doxazosin

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Page 344 titrated to up to 8 mg, titrated doxazosin and finasteride placebo, or two placebo drugs. The results of the trial suggest that the combination of doxazosin and finasteride exerts a clinically relevant, positive effect on rates of disease progression44 (Fig. 25.4). Men who received combination therapy were significantly less likely to experience BPH progression than those receiving either monotherapy or placebo, with risk reduction rates of 39% for doxazosin, 34% for finasteride, and 67% for combination therapy compared to placebo. Overall rates of BPH progression events are shown in Fig. 25.5. Invasive therapy and AUR risk were significantly reduced by finasteride and combination therapy (by 69 and 64%, and by 79 and 67%, respectively), while all treatment regimens (placebo, doxazosin, finasteride, and combination) brought about a significant improvement in AUA symptom score (4.0, 6.0, 5.0, and 7.0, respectively) and Q max (1.4, 2.5, 2.2, and 3.7 ml/s, respectively) at 4 years. AUA symptom score and Q max improved significantly more in the combination therapy group compared to the monotherapy groups, while adverse events were similar to previously reported studies. In addition to indicating the potential benefits of combination therapy, MTOPS provided important data regarding the natural history of untreated BPH and the prediction of BPH patients who will respond most

Figure 25.4 MTOPS Study: risk reduction of BPH clinical progression, BPH-related invasive. surgery, and acute urinary retention in treated patients in comparison to placebo.

Figure 25.5 MTOPS Study: distribution of BPH progression events, all groups. AUR, acute urinary retention; UTI, urinary tract infection; AUA, American Urological Association.

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Page 345 effectively to medical treatment45–47 (Fig. 25.6). While the patients receiving finasteride alone or in combination experienced the expected decrease in prostate volume, patients on placebo or doxazosin alone experienced an increase in prostate volume from a baseline of 34.0 ml by 9.3 (30.3%) (placebo) and from 36.4 ml by 9.9 (31.4%) (doxazosin), respectively.47 Stratified by PSA quartiles, total prostate volume in both placebo and doxazosintreated patients increased from 4.9 ml (24.9%) to 16.2 ml (34.5%) from the lowest to the highest quartile for an annualized growth of 1.1 to 3.6 ml/year. These findings suggest that doxazosin despite its apoptotic effect does not interfere with the natural growth tendency of the prostate gland, and that baseline PSA is a useful predictor of future prostate growth in men with LUTS and BPH.25 Examination of baseline measures and the disease outcomes of 737 patients treated with placebo revealed that PSA, Q max, PVR, and prostate volume at baseline correlated with clinical progression of the disease and the need for BPH-related surgery ( p =0.03 to <0.001).45 Age was linked to clinical progression (p <0.001) and AUA symptom score correlated with need for surgery (p =0.002). Baseline PSA and prostate volume correlated with risk of AUR ( p =0.03–0.003). Risk of progression, BPH-related surgery, and AUR increased alongside levels of serum PSA. In medically treated patients, however, baseline values were variably predictive of BPH outcome.46 In doxazosintreated patients, for example, PSA, Qmax , and prostate volume were predictive of outcome; however, this was not true of patients treated with finasteride alone or combined therapy. The number needed to be treated (NNT) to prevent a case of BPH progression as defined in MTOPS in the overall population was 8.4 for the combination therapy group, and 13.7 and 15.0, respectively, for the doxazosin- and finasteride-treated patients. For those men treated with combination therapy who had a baseline PSA of >4.0 ng/ml, however, the NNT was 4.7, and for those with a prostate volume over 40 ml it was 4.9, suggesting that in fact combination therapy becomes an economically viable option in patients at higher risk for progression (unpublished MTOPS data, personal communication Dr Claus Roehrborn). The link between sexual dysfunction and severity of LUTS was also confirmed by the MTOPS data.48 A correlation was observed between LUTS and five domains of sexual dysfunction (libido, sexual function, ejaculatory function, the patient’s assessment of his sexual problems, and overall satisfaction). In addition, men with larger prostates were more likely to have low libido, low overall sexual functioning, reduced ejaculatory function, and greater sexual problems. Additional combination studies Anticholinergic plus α-blocker The anticholinergic agent tolterodine is used for the treatment of incontinence related to detrusor instability, while

Figure 25.6 MTOPS Study: prediction of future risk of BPH clinical progression, BPH-related invasive surgery, and acute urinary retention from baseline prostate-specific antigen (PSA) measures in placebo-treated patients.

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Page 346 the α-blocker tamsulosin is commonly used for the treatment of BOO. Patients may present with concomitant BOO and detrusor instability. Investigation of the efficacy of a combination of 2 mg tolterodine twice daily and 0.4 mg tamsulosin once daily was performed to determine whether patient quality of life improved as a result.49 Fifty patients took part in the study, and all initially received tamsulosin for 1 week. After this point, the patients were randomized to continue with this regimen or to receive tolterodine in addition to tamsulosin. Baseline urodynamics and quality of life were recorded and these measures were repeated after 3 months of treatment. Quality of life scores were found to increase significantly in patients who received combination therapy ( p =0.0003), while no increase was observed in patients who received tamsulosin alone. In addition, a significant difference in maximum detrusor pressure and unstable contraction pressure was observed in the combination group. Q max and volume at first contraction improved significantly in both groups and no AUR was reported. The results suggest that this combination is a safe and effective treatment option for this patient group. Combined ‘natural’ products The role of plant-derived therapy in the treatment of BPH has been, and still is, considered controversial,50–52 and the combination of products such as Serenoa repens, β-sitosterol, and Pygeum africanum is even more debatable. One trial comparing a combination of cernitin, Serenoa repens, β-sitosterol, and vitamin E to placebo indicated potential benefits for patients receiving the active agents.53 In total, 127 BPH patients with a Q max of 5–15 ml/s took part in the study and were randomized to receive either the combined therapy or placebo for 3 months. AUASI, Q max, PSA, and PVR were assessed at baseline and on conclusion of the trial. Significant reductions in nocturia ( p <0.001) and daytime frequency ( p <0.04) were observed in the active arm of the study compared to the placebo group. Average score on AUASI also improved in this group compared to placebo ( p <0.014). No difference in PSA, Q max, or PVR was observed and no serious side-effects were reported. The combination of phytotherapy with conventional pharmacotherapy has not been fully investigated to date; however, a 3-month trial of tamsulosin, cernitin, or a combination of the two revealed significant improvements in I-PSS in all three groups, but improved Q max and average urinary flow only in the tamsulosin and combination groups.54 Discussion Several large-scale studies have indicated that the combination of an α-blocker with a 5α-reductase inhibitor does not add any clinically significant value to α-blockade alone.6,31,34 However, the larger and longer-term MTOPS study would appear to be at variance with these findings44 (Table 25.1). In this trial, participants were followed up for 4.5 years on average and those who were involved in the pilot phase were followed up for an average of 6 years. This is considerably longer than previous trials of combination therapy for BPH. The VA and PREDICT studies had a duration of 1 year, while the ALFIN study lasted just 6 months. Although earlier trials indicated no benefit over and above α-blockade with the addition of finasteride treatment, the evidence provided by MTOPS has shown that combination therapy may be appropriate for many patients, particularly those with larger glands and higher baseline serum PSA values. This observation is reflected in the recently published AUA Guidelines on the Management of BPH state, on the basis of panel consensus, that the combination of an α-blocker and a 5α-reductase inhibitor may be appropriate in LUTS patients with demonstrable enlargement of the prostate.55 Any reduction in risk of AUR and BPH-related surgery associated with combination therapy described in the MTOPS study should be weighed up against cost and other factors on an individual basis, however.55 The panel stated that those most likely to benefit are men at greatest risk of disease progression, i.e. those with larger prostates and higher PSA levels. Although the best-tested combination to date is doxazosin and finasteride, and the safety of other combinations has not been fully assessed, the panel assumes that any combination of these drug classes would lead to a similar degree of clinical benefit. Additional factors should also be considered in the combination therapy debate. Cost issues are of primary importance, as dual therapy is obviously more expensive than monotherapy alone. It has been suggested that dual therapy need not be continued indefinitely, however, which may have a bearing on associated costs. Baldwin et al. found that BPH patients treated initially with finasteride plus an α-blocker tolerated file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_346.html[09.07.2009 11:54:12]

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discontinuation of combination therapy after 1 year with no compromise in clinical benefit.56 A group of BPH patients ( n =270) were prescribed 2, 4, or 8 mg doxazosin alongside 5 mg finasteride for a period of 3, 6, 9, or 12 months, after which doxazosin was discontinued. Of those who discontinued combination therapy at 12 months, 84% of the

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large-scale combination studies of BPH treatments. Mean baseline n Regimen Symptom Q max % Prostate prostate volume (daily dose) score* % improvement volume % (ml) improvement change 36.2–38.4 305Terazosin 38 26 +1 (10 mg)

310Finasteride 20 15 −17 (5 mg)         309Combination 39 31 –19         305Placebo 16 13 +1 ALFIN31 6 63 41.2 358Alfuzosin 41 19 −0.5 months (10 mg)         344Finasteride 36 18 –11 (5 mg)         349Combination 39 23 –12 PREDICT34 1 year 63 36.3 g 275Doxazosin 49 35 — (<8 mg)         264Finasteride 39 18 — (5 mg)         286Combination 49 37 —         270Placebo 33 10 — MTOPS44 4 years 62 31.0 756Doxazosin 35 24 +18 (4/8 mg)         768Finasteride 30 21 –16 (5 mg)         786Combination 41 35 −13         737Placebo 24 13 +18 *Evaluation tools: for VA, PREDICT, and MTOPS=American Urological Association symptom score; for ALFIN=International Prostate Symptom Score.

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Page 348 2 mg group, 85% of the 4 mg group, and 87% of the 8 mg group experienced no increase in AUA symptom score and reported no desire to resume taking doxazosin 1 month later. Similarly high tolerance levels were reported in patients with BOO and moderately enlarged prostates who discontinued combination therapy after 9 months.57 Other factors, such as the difference in the effects of 5α-reductase inhibitors and α-blockers on PSA levels,58 and the recently discovered relationship between the use of finasteride and a reduction in risk of prostate cancer,59 may also influence the use of combination therapy. It has been suggested that prostate volume influences the outcome of patients treated with finasteride, and that men with larger prostates will benefit more from treatment with 5α-reductase inhibitors.16,17 The VA, ALFIN, and PREDICT studies all included BPH patients with relatively small prostates (36.2–38.4 ml, mean 41.2 ml, and mean 36.3 g, respectively). Men with larger glands may therefore benefit more from combination treatment than those with smaller glands, who might be better treated with an αblocker alone.60 The ongoing subset stratification of the MTOPS data may provide further insight into this area. Conclusions The reduction in frequency of TURP for the treatment of BPH and the rise in use of medical therapy suggest high levels of patient and physician satisfaction with pharmacologic options. However, future advances in available drug preparations may be limited. Dual therapy, involving preparations from different drug classes, may represent a further potential avenue for medical BPH therapy. The efficacy of the α-blockers doxazosin, terazosin, alfuzosin, and tamsulosin and the 5α-reductase inhibitors finasteride and dutasteride has been proven in many large, well-controlled clinical trials. However, the combination of the two drug classes has produced variable clinical results. Until recently, the benefits that might logically be expected from therapy targeting two separate elements of BPH pathology—namely, prostatic enlargement and an increase in smooth muscle tone—had not been described in larger-scale studies. The results of the MTOPS trial, however, indicate that symptomatic improvements in BPH occur to a greater extent in men receiving doxazosin and finasteride in combination compared to either agent alone. Disease progression, as assessed mainly by a four-point rise in the AUASI, was significantly less likely in patients in the combination group, while AUR and BPH surgery were also less common in this group. The strength of the findings has led to the inclusion of recommendations for combination therapy in suitable patients in the AUA BPH management guidelines. Further trials assessing the safety and efficacy of other types of α-blocker and 5α-reductase inhibitor in combination may be expected to follow. The value of different types of combination therapy, involving plant-derived preparations or the use of anticholinergics for example, remains to be determined. References 1. Holtgrewe H L, Bay-Nielsen H, Carlsson P et al. The economics of the management of lower urinary tract symptoms and benign prostatic hyperplasia. In: Denis L, Griffiths K, Khoury S et al. (eds). The fourth international consultation on benign prostatic hyperplasia (BPH), Paris, 2–5 July, 1997. Plymouth, UK: Health Publications, 1998:63–81 2. Baine W, Yu W, Summe J P, Weis K A. Epidemiologic trends in the evaluation and treatment of lower urinary tract symptoms in elderly male Medicare patients from 1991 to 1995. J Urol 1998; 160:816–820 3. McVary K T. Medical therapy for benign prostatic hyperplasia progression. Curr Urol Rep 2002; 3:269– 275 4. Berry S J, Coffey D S, Walsh P C, Ewing L L. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474–479 5. Madsen F A, Bruskewitz R C. Clinical manifestations of benign prostatic hyperplasia. Urol Clin North Am 1995; 22:291–298 6. Lepor H, Williford W O, Barry M J et al. for the Veterans’ Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. The efficacy of terazosin, finasteride or both in benign prostatic hyperplasia. N Engl J Med 1996; 335: 533–539 7. Chapple C R, Baert L, Thind P et al. and The European Tamsulosin Study Group. Tamsulosin 0.4 mg once daily: tolerability in older and younger patients with lower urinary tract symptoms suggestive of benign prostatic obstruction (symptomatic BPH). Eur Urol 1997; 32: 462–470 8. Roehrborn C G for the ALFUS Study Group. Efficacy and safety of once-daily alfuzosin in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a randomised, placebo-controlled trial. Urology 2001; 58:953–959 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_348.html[09.07.2009 11:54:13]

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9. Janknegt R A, Chapple C R. Efficacy and safety of the alpha-1 blocker doxazosin in the treatment of benign prostatic hyperplasia: analysis of 5 studies. Eur Urol 1993; 24: 319–326 10. Kirby R S, Andersen M, Gratzke P et al. A combined analysis of double-blind trials of the efficacy and tolerabil-

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Page 349 ity of doxazosin-gastrointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. BJU Int 2001; 87:192–200 11. Van Kerrebroeck P, Jardin A, van Cangh P, Laval K U. Long-term safety and efficacy of a once-daily formulation of alfuzosin 10 mg in patients with symptomatic benign prostatic hyperplasia: open-label study. Eur Urol 2002; 41: 54–61 12. Marks L S, Partin A W, Dorey F J et al. Long-term effects of finasteride on prostate tissue composition. Urology 1999; 53:574–580 13. Saez C, Gonzalez-Baena A C, Japon M A et al. Regressive changes in finasteride-treated human hyperplastic prostates correlate with an upregulation of TGF-beta receptor expression. Prostate 1998; 37:84–90 14. Feneley M R, Span P N, Schalken J A et al. A prospective randomized trial evaluating tissue effects of finasteride therapy in benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 1999; 2:277–281 15. McConnell J D, Bruskewitz R, Walsh P et al. for the Finasteride Long-term Efficacy and Safety Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998; 338: 557–563 16. Roehrborn C G, Bruskewitz R, Nickel G C et al. Urinary retention in patients with finasteride or placebo over 4 years. Characterization of patients with ultimate outcomes. The PLESS Study Group. Eur Urol 2000; 37: 528–536 17. Roehrborn C G, Boyle P, Nickel J C et al. on behalf of the ARIA3001, ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5 alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002; 60:434–441 18. Boyle P, Gould A L, Roehrborn C G. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48:398– 405 19. Roehrborn C G. Is there a place for combination medical therapy? Curr Opin Urol 2001; 11:17–25 20. Brawer M K, Lin D W, Williford W O et al. Effect of finasteride and/or terazosin on serum PSA: results of VA Cooperative Study #359. Prostate 1999; 39:234–239 21. Lepor H, Auerbach S, Puras-Baez A et al. A randomized, placebo-controlled multicenter study of the efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. J Urol 1992; 148:1467– 1474 22. Brawer M K, Adams G, Epstein H, Terazosin Benign Prostatic Hyperplasia Study Group. Terazosin in the treatment of benign prostatic hyperplasia. Arch Fam Med 1993; 2:929–935 23. Gormley G J, Stoner E, Bruskewitz R C et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992; 327:1185–1191 24. The Finasteride Study Group. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. Prostate 1993; 22:291–299 25. Glassman D T, Chon J K, Borkowski A et al. Combined effect of terazosin and finasteride on apoptosis, cell proliferation and transforming growth factor-beta expression in benign prostatic hyperplasia. Prostate 2001; 46:45–51 26. Vashi V, Chung M, Hilbert J et al. Pharmacokinetic interaction between finasteride and terazosin, but not finasteride and doxazosin. J Clin Pharmacol 1998; 38: 1072–1076 27. Erdogru T, Ciftcioglu M A, Emreoglu I et al. Apoptotic and proliferative index after alpha-1adrenoceptor antagonist and/or finasteride treatment in benign prostatic hyperplasia. Urol Int 2002; 69:287–292 28. Martin D, Jammes D, Angel I. Effects of alfuzosin on urethral and blood pressures in conscious male rats. Life Sci 1995; 57:387–391 29. Rouquier L, Claustre Y, Benavides J. α1-Adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study. Eur J Pharmacol 1994; 261:59–64 30. Martin D J, Lluel P, Guillot E et al. Comparative alpha-1 adrenoceptor subtype selectivity and functional uroselectivity of alpha-1 adrenoceptor antagonists. J Pharmacol Exp Ther 1997; 282:228–235 31. Debruyne F M, Jardin A, Colloi D et al. Sustained release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. European ALFIN Study Group. Eur Urol 1998; 34:169–175 32. Jardin A, Bansadoun H, Delauche-Cavallier M C, Attali P. Alfuzosin for treatment of benign prostatic hyperplasia. Lancet 1991; 337:1457–1461 33. Loran O B, Pushkar’ D I U, Rasner P I. Comparative evaluation of the effectiveness and safety of file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_349.html[09.07.2009 11:54:13]

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combined drug therapy of patients with benign prostatic hyperplasia with finasteride and alfuzozin [in Russian]. Urologiia 2002; Jan-Feb: 19–22 34. Kirby R S, Roehrborn C, Boyle P et al. for the PREDICT Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) Trial. Urology 2003; 61:119–126 35. Christensen M M, Bendix Holme J, Rasmussen P C et al. Doxazosin treatment in patients with prostatic obstruction. A double-blind placebo-controlled study. Scand J Urol Nephrol 1993; 27:39–44

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Page 350 36. Fawzy A, Braun K, Lewis G P et al. Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study. J Urol 1995; 154:105–109 37. Lepor H, Kaplan S A, Klimberg I et al. Doxazosin for benign prostatic hyperplasia: long-term efficacy and safety in hypertensive and normotensive patients. J Urol 1997; 157:525–530 38. Lepor H, Williford W O, Barry M J et al. for the Veterans’ Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. The impact of medical therapy on bother due to symptoms, quality of life and global outcome and factors predicting response, J Urol 1998; 160:1358–1367 39. Roehrborn C G, Boyle P, Bergner D et al. for the PLESS Study Group. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. Urology 1999; 54: 662–669 40. Bautista O M, Kusek J W, Nyberg L M et al. for the MTOPS Research Group. Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial. Control Clin Trial 2003; 24:224–243 41. Kusek J W, Ahrens A, Burrows P K et al. for the MTOPS Research Group. Recruitment for a clinical trial of drug treatment for benign prostatic hyperplasia. Urology 2002; 59:63–67 42. Barry M J, Fowler F J Jr, O’Leary M P et al. and the Measurement Committee of the American Urological Association. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992; 148:1549–1557 43. Jacobsen S J, Guess H A, Panser L et al. A populationbased study of health care-seeking behaviour for the treatment of urinary symptoms: the Olmstead County study of urinary symptoms and health status among men. Arch Fam Med 1993; 2:729–735 44. McConnell J D, Roehrborn C G, Bautista O M et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349:2387–2398 45. McConnell J D, Roehrborn C G, Slawin K M et al. Baseline measures predict the risk of benign prostatic hyperplasia clinical progression in placebo-treated patients. J Urol 2003; 169 (Suppl 4): abstract 1287 46. Kaplan S A, Roehrborn C G, McConnell J D et al. Baseline symptoms, uroflow and post-void residual urine as predictors of BPH clinical progression in the medically treated arms of the MTOPS trial. J Urol 2003; 169 (Suppl 4): abstract 1289 47. Roehrborn C G, McConnell J D, Jacobs S C et al. Baseline prostate volume and serum PSA predict rate of prostate growth: analysis of the MTOPS data. J Urol 2003; 169 (Suppl 4): abstract 1361 48. McVary K, Foley J, Bautista O, Kusek J. Association of lower urinary tract symptoms (LUTS) with sexual function in men participating in a clinical trial of medical therapy for benign prostatic hyperplasia. J Urol 2003; 169 (Suppl 4): abstract 1252 49. Athanasopoulos A, Gyftopoulos K, Giannitsas K et al. Combination treatment with an alpha-blocker plus an anticholinergic for bladder outlet obstruction: a prospective, randomized, controlled study. J Urol 2003; 169: 2253–2256 50. Gerber G S. Phytotherapy for benign prostatic hyperplasia. Curr Urol Rep 2002; 3:285–291 51. Dreikorn K. The role of phytotherapy in treating lower urinary tract symptoms and benign prostatic hyperplasia. World J Urol 2002; 19:426–435 52. Levin R M, Das A K. A scientific basis for the therapeutic effects of Pygeum africanum and Serenoa repens . Urol Res 2000; 28:201–209 53. Preuss H G, Marcusen C, Regan J et al. Randomized trial of a combination of natural products (cernitin, saw palmetto, B-sitosterol, vitamin E) on symptoms of benign prostatic hyperplasia (BPH). Int Urol Nephrol 2001; 33: 217–225 54. T Aoki A, Naito K, Hashimoto O et al. Clinical evaluation of the effect of tamsulosin hydrochloride and cernitin pollen extract on urinary disturbance associated with benign prostatic hyperplasia in a multicentered study [In Japanese]. Hinyokika Kiyo 2002; 48:259–267 55. AUA BPH Guideline Update Panel. The management of BPH, 2003. https://shop.auanet.org/timssnet/products/guidelines/bph_management.cfm 56. Baldwin K C, Ginsberg P C, Roehrborn C G, Harkaway R C. Discontinuation of alpha-blockade after initial treatment with finasteride and doxazosin in men with lower urinary tract symptoms and clinical evidence of benign prostatic hyperplasia. Urology 2001; 58:203–209 57. Baldwin K C, Ginsberg P C, Harkaway R C. Discontinuation of alpha-blockade after initial treatment with finasteride and doxazosin for bladder outlet obstruction. Urol Int 2001; 66:84–88 58. Keetch D W, Andriole G L, Ratliff T L, Catalona W J. Comparison of percent free prostate-specific antigen levels in men with benign prostatic hyperplasia treated with finasteride, terazosin or watchful file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_350.html[09.07.2009 11:54:14]

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waiting. Urology 1997; 50:901–905 59. Thompson I M, Goodman P J, Tangen C M et al. The influence of finasteride on the development of prostate cancer. Published at www.nejm.org June 24, 2003 (doi: 10.1056/NEJMoa030660) 60. Horninger W, Bartsch G. Drug therapy of benign prostatic hyperplasia. Is combination therapy with 5 alpha-reductase inhibitors and alpha-receptor blockers effective? [in German]. Urologe A 2002; 41:442– 446

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Page 351 26 The differential effects of adrenoceptor antagonists on prostate tissue growth N Kyprianou Introduction Benign prostatic hyperplasia (BPH) is the most frequently diagnosed neoplastic disease in the aging male, affecting approximately 85% of all men over 50 years of age. By the ninth decade of life, 50% of all American men require treatment for symptomatic relief of the lower urinary tract symptoms (LUTS) associated with BPH. Clinically, BPH is characterized by prostatic enlargement and the accompanying symptoms of progressive bladder outlet obstruction. Histologically, BPH can present as hyperplasia in both the stromal and glandular components of the gland and arises in the periurethral and transition zones.1 It has been hypothesized that this abnormal proliferation arises because of the ability of the prostate stroma to retain an embryonic growth potential that is ‘reawakened’ in the aging gland.2 Although aging and the presence of a functional testis have become established as major factors causally related to the development of the disease,3,4 the molecular processes involved in the pathogenesis of BPH remain poorly understood. In this chapter we review some recent clinical data5 that may provide additional insight into the pathophysiology of BPH and facilitate the development of more effective pharmacologic therapy. Medical management of BPH: a historical perspective The development of LUTS secondary to prostatic enlargement is thought to be caused by static (mechanical) and dynamic components of urethral restriction. The mechanical component arises from the physical obstruction of urinary outflow caused by urethral constriction, induced by the mass of the enlarged gland. The dynamic component is related to the variations in smooth muscle tone in the fibromuscular stroma, prostate capsule, and bladder neck.6 Treatment modalities therefore aim either to reduce the mechanical obstruction, or to induce relaxation of the periurethral prostatic smooth muscle. A critical level of androgen is required to maintain the benign growth pattern and androgen deprivation results in significant involution of the glandular epithelial com ponent of the prostate,7 without affecting stromal growth. Androgen ablation/deprivation undoubtedly leads to a favorable ‘therapeutic’ response in canine BPH,4 a species where the bulk of the hyperplasia is androgen-dependent epithelial proliferation. In man, however, the maximal therapeutic effect of androgen deprivation appears to be limited by both the substantial stromal component of the proliferation1,8 and by intrinsic resistance of stromal cells to androgen modulation.8 Given that at least 40% of the cellular volume of the enlarged prostate is composed of stromal smooth muscle, it is not surprising that pharmacologic intervention at this level has proved highly successful. In this context, α1-adrenoceptor antagonists (α-blockers) are widely used to produce acute symptomatic relief. The classic belief is that α-blockers reduce the tone of the prostate smooth muscle and thereby inhibit the dynamic component of the obstruction.9,10 The pharmacology of α-blockers is described in detail elsewhere.11 The following represents a summary of the key features. Periurethral smooth muscle tone, and therefore urethral resistance, varies according to the degree of sympathetic nervous system activation of the α1-adrenoceptors in the prostate and prostate capsule.12,13 Therefore, pharmacologic blockade of the α1-adrenoceptors would reduce the actions of noradrenaline (the endogenous neurotransmitter), resulting in tissue relaxation. This provided the impetus for the development of several α1-blockers and has resulted in widespread use of this class of drugs as firstline intervention in BPH. Currently, four native α1-adrenoceptor subtypes—α1A, α1B, α1D, and α1L—have been identified and are known to be located in the prostate.11 The best correlation between prostate tissue contraction and binding with any α1-adrenoceptor recognition site is with the α1A subtype.14,15 Many investigators consider this evidence to be consistent with a primary role of this adrenoceptor subtype in the control of prostate tone and urethral resistance. However, when considering the treatment of BPH symptoms, extraprostatic actions of α1-blockers must also be taken into account11. In particular, α1-adrenoceptors in the bladder and bladder neck,16,17 and spinal cord,18,19 and on efferent pathways19,20 may make an important contribution to the overall improvements in urodynamic

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Page 352 and symptom profiles that are observed shortly after the onset of therapy. Although the immediate and short-term therapeutic benefit of α-blockers is believed to arise from the prostatic and extraprostatic physiologic actions listed above, it has become apparent that in the long term other factors or loci may make an equally important contribution.5 The α-blocker paradox Consistent with their actions as α-blockers on periurethral stromal smooth muscle, the acute clinical benefit of terazosin and doxazosin in BPH is well documented22. In the early days of use in the management of BPH, there was a general expectation that α-blockers might serve as clinical ‘sticking plaster’ in the face of ongoing glandular hyperplasia; tachyphylaxis (tolerance) to the drug action was anticipated. Although this may undoubtedly occur in individual patients, the effects of doxazosin and terazosin in BPH have been maintained (Fig. 26.1), in some cases for up to 7 years,22–24 a period over which the prostate mass would be expected to increase by up to 50%.1 The equivalent long-term data for doxazosin similarly show no overall evidence of tachyphylaxis. On the assumption that the increase in prostate bulk (the static component of obstruction) would result in a corresponding increase in urethra resistance, considerable diminution in benefit might be anticipated over an equivalent time period. Several clinical papers now offer a partial explanation of the well-documented, but unexpected longevity of the

Figure 26.1 Long-term terazosin efficacy data. Data were generated in open-label uncontrolled clinical trials. From 1 month onwards all points were significantly different from baseline and there was no evidence of tachyphylaxis. α-blocker response.5,23,25 These were retrospective, placebo-controlled studies involving a total of 134 BPH patients and were designed to determine the effects of α-blockers on apoptosis and the interrelationship with symptom improvement. Importantly, each patient acted as his own control: LUTS and histochemical parameters were measured at baseline and at one other time point in the study after the patient had been assigned to either placebo or α-blocker. In three other studies, cell proliferation and apoptosis were evaluated in BPH patients, who comprised an untreated control group and two cohorts treated with either terazosin or doxazosin at doses designed to provide symptom relief.26–28 The treatment period varied from 1 week to 3 years. Terazosin was used at 1–10 mg/day and doxazosin at 2–8 mg/day. Proliferation and apoptosis of the stromal and epithelial cell components of the prostate, obtained by initial biopsy or at prostatectomy, were quantified by Ki 67 immunostaining and TUNEL (terminal transferase UTP-end labeling) assay, respectively. Both terazosin and doxazosin induced epithelial and stromal cell apoptosis within the first month of treatment (Fig. 26.2) when compared with the untreated controls ( p <0.05). The marked induction of stromal apoptosis was paralleled by significant decreases in smooth muscle α-actin expression (Fig. 26.3). This loss of prostate smooth muscle cells correlated with the morphologic stromal regression (measured by trichrome staining) and improvement in BPH symptoms. Proliferation was relatively unaffected by both drugs.

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Figure 26.2 Effect of terazosin on prostate apoptosis in patients with BPH. The apoptotic index of glandular epithelial ( ) and stromal ( ) smooth muscle cells in biopsy sections is expressed as mean percentage of TUNEL-positive cells/total number of cells after various periods of terazosin therapy (1–10 mg/day). (Adapted from Chon et al.23)

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Figure 26.3 Effect of terazosin on stromal smooth muscle α-actin expression. The bars represent the quantitative evaluation of smooth muscle α-actin immunoreactivity in prostate sections from BPH patients treated with terazosin (1–10 mg/day). (Adapted from Chon et al.23) The data indicate that there is a significant induction of apoptosis in the prostate epithelium and stroma in response to terazosin and doxazosin (over the normal therapeutic dose range). Compared with the untreated controls, terazosin induced epithelial and stromal cellular apoptosis within the first month of treatment, which correlated with morphologic stromal regression and the improvement in LUTS. There was no effect on cell proliferation. The data indicate that terazosin induced apopto sis in the glandular epithelium and stroma but has no effect on the cellular dynamics of normal (i.e. nonBPH) tissue.22,23 There is an excellent correlation between the degree of apoptosis and improvement of symptoms (Fig. 26.4). One interpretation of these phenomena is that α-blockers can affect abnormal prostate growth such as that observed in BPH and potential prostate carcinoma. This could reflect a direct effect on cellular dynamics or may arise secondary to an action on cellular proliferative factors. As in the case of the vasculature, androgenic and estrogenic factors alter the expression of α1-adrenoceptors in prostate tissue.28,29 Catecholamines have been shown to have proliferative (promitogenic) action in several vascular tissues.30 Should this translate to the prostate, the observed effects could merely reflect the drug-induced attenuation of endogenous catecholamines. A model of the potential intervention points for terazosin is shown in Figure 26.5. The most obvious explanation of the proapoptotic phenomenon is that this is directly related to blockade of α1-adrenoceptor subtypes. A good correlation is known to exist between activity at the α1A subtype and

Figure 26.4 Correlation between induction of apoptosis and improvement in BPH/LUTS. prostate smooth muscle contraction.11 However, prostate tissue contains other α1-adrenoceptor subtypes (α1A and α1B) and it is tempting to speculate that an action at one of these could underpin the cellular effects of the α-block-ers. It is likely that an action additional to blockade of the proliferative effects of endogenous catecholamines, and independent of α-adrenoceptors, is involved.5,30 The clinical evidence for a proapoptotic action of doxazosin and terazosin is supported by cell biology and in vivo animal experiments.31,32 In a mouse prostatic reconstruction model, α-blockers had a file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_353.html[09.07.2009 11:54:16]

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proapoptotic action and reduced oncogene-induced growth hormone without affecting normal cellular growth patterns31. This proapoptotic effect does not appear to be restricted to the mouse, at least in vitro; a similar profile of activity is observed in cancer cell lines33–35 at drug concentrations similar to those found therapeutically.33 The effect was apparent in both hormone-dependent and hormoneindependent cell lines,32,34 and as such could indicate a potential beneficial effect in prostate carcinoma, in addition to prevention of BPH/LUTS. Intriguingly, these actions are not found with tamsulosin.34 Tamsulosin is a sulfonamide that is structurally dissimilar to the quinazoline αadrenoceptor antagonists (Fig. 26.6). This indicates that the proapoptotic actions are not a class effect, and are independent of the α1-adrenoceptor.5,32,34 The effects of terazosin on prostatic apoptosis may also help in the interpretation of clinical data generated by the Veterans’ Affairs study36 and the PREDICT study37 using a combination of finasteride with terazosin and doxazosin, respectively. These studies showed that the combination of finasteride and an α-blocker does not provide any

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Figure 26.5 Representation of some of the major factors controling tissue proliferation and apoptosis. DHT, dihydrotestosterone; EGF, endothelial growth factor; IGF, insulin-like growth factor; KGF, keratinocyte growth factor; TGF-β, transforming growth factor β.

Figure 26.6 Structures of quinazoline (terazosin) and sulfonamide (tamsulosin) αadrenoceptor antagonists. therapeutic benefit within the first 2 years over terazosin alone, at least with respect to symptom improvement. Potentially, doxazosin and terazosin in their own right can affect prostate growth by inducing both epithelial and stromal apoptosis; by comparison, the anti-androgenic effect of finasteride is likely to be restricted to induction only of glandular epithelial apoptosis.38 Thus, it could be argued that the apoptosis-inducing profile of quinazolines provides the molecular basis for the inability of finasteride to enhance the therapeutic effect of doxazosin and/or terazosin therapy in the short to medium term. However, considering the multifactorial pathogenesis, there is logic in the use of therapies that target different cellular components. The combination of a 5α-reductase inhibitor with a quinazoline-type αblocker should potentially combine the clinical benefit resulting from the antigrowth effects of androgen deprivation-induced apoptosis in the epithelium with the apoptosis induced by the quinazolines in the stroma. In the long-term MTOPS study over 7 years such synergy was observed.24 At least with respect to delaying clinical progression, the combination was more effective than either component. Intriguingly, doxazosin alone was found to delay progression only over the first 3 years or so. Thus the long-term data are consistent with the data in the combination studies described above, of 2 years’ duration.36,37 Summary There is now considerable evidence that α-blockers have a proapoptotic effect in prostate tissue. Although such an action may not underlie the short-term therapeutic benefit observed with these agents, it could make an important contribution to the longer-term durability of the response. The proapoptotic effect of doxazosin and terazosin in both stromal and epithelial components could offer an explanation of the inability of finasteride (which has effects on epithelial components) to augment the response of these α-blockers in clinical studies of up to 2 years’ duration.

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Page 355 The finding that tamsulosin does not have these properties raises the possibility that the proapoptotic action is not a class effect, and may be independent of the α1-adrenoceptor. References 1. Oesterling J E. Benign prostatic hyperplasia: a review of its histogenesis and natural history. Prostate Suppl 1996; 6: 67–73 2. McNeal J E. Origin and evolution of benign prostatic enlargement. Invest Urol 1978; 15:340–345 3. Berry S J, Coffey D S, Walsh P C, Ewing L L. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474–479 4. Issacs J T, Coffey D A. Etiology and disease process of benign prostatic hyperplasia. Prostate 1989; 2 (Suppl): 33–50 5. Kyprianou N. Doxazosin and terazosin suppress prostate growth by inducing apoptosis: clinical significance. J Urol 2003; 169:1520–1525 6. Caine M. Alpha-adrenergic mechanisms in dynamics of benign prostatic hypertrophy Urology 1988; 32:16–20 7. McConnell J D. Medical management of benign prostatic hyperplasia with androgen suppression. Prostate Suppl 1990; 3:49–59 8. Peters C A, Walsh P C. The effect of nafarelin acetate, a luteinizing-hormone-releasing hormone agonist on benign prostatic hyperplasia. N Engl J Med 1987; 317:599–604 9. Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in the human prostate, prostate capsule and bladder neck. Br J Urol 1975; 47:193–202 10. Lepor H. Role of long-acting selective alpha-1 blockers in the treatment of benign prostatic hyperplasia. Urol Clin North Am 1990; 17:651–657 11. Andersson K E, Lepor H, Wyllie M G. Prostatic alpha 1-adrenoceptors and uroselectivity. Prostate 1997; 30: 202–215 12. Lepor H, Tang R, Shapiro E. The alpha-adrenoceptor subtype mediating the tension of human prostatic smooth muscle. Prostate 1993; 22:301–307 13. Caine M, Pfau A, Perlberg S. The use of alpha-adrenergic blockers in benign prostatic obstruction. Br J Urol 1976; 48:255–263 14. Marshall I, Burt R P, Andersson P O et al. Human alpha 1c-adrenoceptor, functional characterization in the prostate. Br J Pharmacol 1992; 107:327P 15. Lepor H, Tang R, Meretyk S, Shaprio E. Alpha 1-adrenoceptor subtypes in the human prostate. J Urol 1993; 149: 640–642 16. Perlberg S, Caine M. Adrenergic response of bladder muscle in prostatic contraction. Urology 1982; 20:524–527 17. Yoshimura N, Sasa M, Yoshida O, Takaori S. α1-Adrenergic receptor-mediated excitation from the locus coeruleus of the sacral parasympathetic preganglionic neurone. Life Sci 1990; 47:789–797 18. Ishizuka O, Persson K, Mattiasson A et al. Micturition in conscious rats with and without outlet obstruction: role of spinal α1-adrenoceptors. Br J Pharmacol 1996; 117: 962–966 19. Ramage A G, Wyllie M G. Effects of doxazosin and terazosin on inferior mesenteric nerve activity, spontaneous bladder contraction and blood pressure in anaesthetized cats. Br J Pharmacol 1994; 112:526P 20. Danuser H, Thor K. Inhibition of central sympathetic and somatic outflow to the lower urinary tract of the cat by the α1-adrenergic receptor antagonist prazosin. J Urol 1995; 153:1308–1312 21. Eri L M, Tveter K J. α-Blockade in the treatment of symptomatic benign prostatic hyperplasia. J Urol 1995; 75: 265–270 22. Kyprianou K, Litvak J P, Borkowski A et al. Induction of prostate apoptosis by doxazosin in benign prostatic hyperplasia. J Urol 1998; 159:1810–1815 23. Chon J K, Borkowski A, Partin A W et al. α1-Adrenoceptor antagonists terazosin and doxazosin induce prostatic apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia. J Urol 1999; 166:2002–2005 24. McConnell J D. For the MTOPS steering committee: the long term effects of medical therapy on the progression of BPH: results from the MTOPS trial. J Urol 2002; 167: 265, abstract 1042 25. Lepor H and the Terazosin Research Group. Long-term efficacy and safety of terazosin in patients with benign pro-static hyperplasia. Urology 1995; 45:406–413 26. Kirby R S. Doxazosin in benign prostatic hyperplasia: effects on blood pressure and urinary flow in normotensive and hypertensive men. Urology 1995; 46:182–186 27. Lepor H, Kaplan S A, Klimberg I et al. Doxazosin for benign prostatic hyperplasia; long-term efficacy file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_355.html[09.07.2009 11:54:16]

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and safety in hypertensive and normotensive patients. The Multicenter Study Group. J Urol 1997; 157:525–530 28. Zhang J, Hess M, Hittmair A et al. Human prostatic smooth muscle cells in culture: estradiol enhances expression of smooth muscle cell-specific markers. J Urol 1994; 153:341A 29. Benaim E A, Lin V K, McConnell J D. Quantitation of alpha 1c-adrenergic receptor expression in minute quantities of prostate tissue. J Urol 1995; 153:343A 30. Wyllie M G. Does doxazosin affect prostatic growth? Prostate 1998; 35:152–153

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Page 356 31. Yang G, Timme T L, Park S H et al. Transforming growth factor beta 1 transduced mouse prostate reconstitutions: II. Induction of apoptosis by doxazosin. Prostate 1997; 33: 157–163 32. Kyprianou N, Allen L F, Wyllie M G. Induction of prostate apoptosis by doxazosin; alpha1adrenoceptor-dependent and -independent actions? Br J Pharmacol 1997; 22:283P 33. Kirby R S. Doxazosin in the treatment of obstruction of the lower urinary tract. In: Kirby R S, McConnell J D, Fitzpatrick J M, Roehrborn C G, Boyle P (eds). Textbook of benign prostatic hyperplasia. Oxford: Isis Medical Media 1996:287–293 34. Benning CM, Kyprianou N. Quinazoline-derived alpha1-adrenoceptor antagonists induce prostate cancer via an alpha1-adrenoceptor-indpendent action. Cancer Res 2002; 62:597–602 35. Kyprianou N, Benning CM. Suppression of human prostate cancer cell growth by alpha1-adenoceptor antag-onists, doxazosin and terazosin, via induction of apoptosis. Cancer Res 2000; 60:4550–4555. 36. Lepor H, Williford W O, Barry M J et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans’ Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group [see comments]. N Engl J Med 1996; 335:533–539 37. Kirby RS, Roehrborn C, Boyle P et al. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in the treatment of symptomatic benign prostatic hyperplasia: the prospective European doxazosin and combination therapy (PREDICT) trial. Urology 2003; 61: 119–126. 38. Peters C A, Walsh P C. The effect of nafarelin acetate, a luteinizing-hormone-releasing-hormone agonist on benign prostatic hyperplasia. N Engl J Med 1987; 317:599

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Page 357 27 Terazosin in the treatment of obstruction of the lower urinary tract M Bruwer J M Fitzpatrick Introduction The treatment of the lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) with α-adrenoceptor antagonists (blockers) has evolved considerably since the pioneering clinical work of Marco Caine1 using phenoxybenzamine. Initially, only two types of α-adrenoceptor (α1 and α2) were identified (reviewed in Chapter 5). Phenoxybenzamine has antagonist activity at both α1- and α2adrenoceptors and is therefore a nonselective antagonist. Subsequently, it was found that prostate tissue contraction relied primarily on activation of the α1-adrenoceptor.2 This led to the development and clinical evaluation of the prototype selective α1-adrenoceptor antagonist, prazosin, in an attempt to reduce the side-effects associated with phenoxybenzamine. The proposed mechanism for the efficacy of selective α1-blockade in BPH is via relaxation of prostate smooth muscle. It therefore follows that the magnitude of the clinical response to selective α1-blockade in BPH should be related directly to the proportion of the hyperplasia that is smooth muscle. Shapiro et al.3 evaluated the relationship between the percentage area density of prostate smooth muscle and the clinical response to the selective long-acting α1-antagonist, terazosin. Before starting terazosin therapy, prostate biopsy specimens were obtained from 26 men. The dose of terazosin was titrated to 5 mg, provided that serious adverse events were not observed. The percentage area density of smooth muscle in the biopsy specimens was quantified using double immunoenzymatic staining and color-assisted computer image analysis. A direct relationship between the increase in peak urinary flow rate ( Q max) and the percentage area density of smooth muscle was observed. This correlation strongly supports the hypothesis that a component of the development of bladder outlet obstruction is mediated by an increase in prostate smooth muscle tone. Certainly the classical belief is that α-antagonists act by reducing the tone of the prostate smooth muscle, decreasing urethral resistance, and thereby the dynamic component of the obstruction.4,5 However, increasingly this is being challenged and it is probable that extraprostatic actions of α-antagonists are of considerable importance.6 Although bladder outlet obstruction in aging men is often mediated by prostate smooth muscle proliferation, there is increasing evidence that the severity of urinary symptoms is not exclusively the result of bladder outlet obstruction. The correlation between symptom severity captured by the American Urological Association (AUA) symptom index and Q max is poor7 and, unlike Q max, the density of prostate smooth muscle is not directly correlated with symptom severity.3 These observations suggest that urinary symptoms in the aging male are probably multifactorial. It is also conceivable that symptom improvement in men with prostatism is achieved via nonprostate smooth muscle events mediated by the α1-adrenoceptor. Our understanding of adrenoceptor pharmacology has increased considerably. Four native α1adrenoceptor subtypes have now been identified and are known to be located in the prostate: the α1A, α1B, and α1D subtypes are high-affinity receptors for prazosin; the α1L is a low-affinity receptor. The evolution of this nomenclature has been confusing and has changed over the last few years, as reviewed by Bylund et al.8 The best correlation between prostate tissue contraction and binding with any of the α1-adrenoceptor recognition sites is with the α1A subtype (Fig. 27.1).9,10 On the basis of this and other evidence, many investigators consider that the α1A subtype within the periurethral stroma is the prime determinant of prostatic tone. However, the extraprostatic actions of α-antagonists may make important contributions to the overall urodynamic and symptom score that is observed soon after therapy is initiated.6 Considerably less is known about the role of the prostate α1B and α1D subtypes. However, these could be linked to the effects of terazosin on glandular growth and apoptosis (see Chapter 30), described in more detail below.11 The α-antagonists that have been used clinically in the treatment of LUTS/BPH can be subgrouped according to their selectivity for different receptor subtypes and their pharmacokinetic half-lives. Phenoxybenzamine is a nonselective α-antagonist with equal affinity for α1- and α2-adrenoceptors. Drugs with selectivity for the α1-adreno-ceptor, including prazosin, alfuzosin, indoramin, terazosin, doxazosin, and tamsulosin, were subsequently developed. The primary advantage of these selective α1antagonists is

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Figure 27.1 Correlation plots of the potency of prazosin (1), terazosin (2), indoramin (3), SNAP 1069 (4), 5-methylurapidil (5), SKF104856 (6), and RS 17053 (7) for cloned human and animal (RS 17053) α1A- (a), α1B- (b), and α1D- (c) adrenoceptors versus their potency at inhibiting α1-mediated contraction of the human prostate in vitro. There is a good correlation between functional α1-adrenoceptor affinity (pA2) on human prostate and binding affinity (pKi) for most, but not all, α1-adrenoceptor antagonists at the cloned α1A subtype. (Adapted from references 32 and 49.) that the incidence and severity of adverse events is significantly less than with the nonselective αblocker, phenoxybenzamine. There is no evidence from in vitro or whole-animal experiments that any of the established agents is selective for any one α1-adrenoceptor subtype (Fig. 27.2),6 or possesses any degree of clinical uroselectivity as defined by the α-blocker subcommittee of the International Consultation on BPH.12 As a class, α1-adrenoceptor antagonists have been shown to be safe and effective in the treatment of obstruction-related LUTS.13 Obstructive and irritative symptoms are improved, and changes in urinary flow and residual volume are consistent with a reduction in urethral resistance. Prazosin has been used in this context for several years, but its clinical use is limited by its dosing regimen and the orthostatic hypotension that follows rapid absorption. Terazosin was the first selective α1-antagonist specifically developed to overcome these shortcomings. It has similar affinity for the α1A-, α1B-, and α1Dadrenoceptor subtypes (Fig. 27.2),14 and is therefore considered to have guished from prazosin on the basis of physicochemical dif- a balanced profile. In addition, terazosin can be distinferences that result in a more gradual onset of action and a much longer plasma half-life (16 hours compared with about 3 hours). In this chapter we review the clinical data on terazosin and discuss how the balanced action of terazosin across the three high-affinity α1-adrenoceptor subtypes translates into potential clinical advantages for patient, primary-care physician, and urologist alike.

Figure 27.2 Affinities of doxazosin, terazosin, alfuzosin, tamsulosin, and 5-methylurapidil (5-MU) for the cloned α1A- ( ), α1B- ( ), and a1D-( ) adrenoceptor subtypes. Historic background Terazosin is a potent quinazoline α-adrenoceptor antagonist that is extremely selective for the α1 versus the α2 subtype.2 There is little evidence from isolated-tissue studies or whole-animal experiments that terazosin has higher affinity for any one of the α1-adrenoceptor subtypes.14 The plasma half-life (16 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_358.html[09.07.2009 11:54:18]

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hours) is consistent with once-daily dosing. The contribution of metabolites to the overall profile of terazosin is unknown.

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Page 359 Safety and efficacy in the management of BPH Short-term efficacy At least 11 double-blind placebo-controlled studies in patients with BPH/LUTS have been completed, and a rigorous meta-analysis of the findings has been reported.15 The data from a large (285 patients) representative study16 are shown in Figure 27.3. Statistically significant decreases from baseline were observed for obstructive, irritative, and total symptom scores, for all terazosin groups; the higher doses produced statistically significant improvements over placebo, with up to 70% of patients achieving more than a 30% improvement in symptom scores. Changes in symptoms were mirrored by doserelated improvements in peak and mean urinary flow (Fig. 27.4). The LUTS symptoms associated with BPH were also improved to a statistically significant extent in most of the studies included in the meta-analysis.15 Irrespective of the different symptom scores used in these studies, consistently greater responses were recorded in patients treated with terazosin than in those receiving placebo and, when assessed, the degree of symptom bothersomeness was reduced significantly. The usual effective dose was either 2 mg or 5 mg per day, although additional benefits were observed in some patients with doses up to 10 mg per day. The beneficial effects of terazosin on irritative and obstructive symptoms and urinary flow are seen within the first few weeks of treatment, often before the dose of ter-

Figure 27.3 Percentage of patients experiencing greater than 30% improvement in total symptoms scores ( ) and peak urinary flow ( ) in a randomized double-blind comparison of placebo and terazosin once daily (n=285). azosin has been titrated to its optimum (Fig. 27.4). This has considerable clinical implications, in that patients may be more likely to comply with treatment if they experience an early improvement in symptoms. Systematic reviews of the effectiveness of terazosin in the treatment of LUTS have confirmed that the drug is superior to both placebo and finasteride.15,17,18 In these analyses, terazosin treatment was associated with increases in peak flow of 1.4 ml/s compared to placebo and with an average reduction in symptom score of 2.2 points beyond that observed with placebo. Long-term efficacy Any treatment for LUTS/BPH must achieve a durable clinical response in order to assume a meaningful role in patient management. The durability of the terazosin response has been reported in one openlabel study of almost 500 men over a 4-year period.19 In this study, terazosin was started at 1 mg per day and the dose was titrated upwards at the investigators’ discretion, to a maximum of 20 mg per day. The primary efficacy variables were Q max and Boyarsky symptom score. At the follow-up visits, Q max was significantly higher than baseline; a 30% improvement over the course of the follow-up was observed in 40–59% of patients. Similarly, the irritative, obstructive, and total Boyarsky symptom scores were significantly lower than at baseline at all follow-up intervals (Fig. 27.5); 30% or greater improvement was noted in 62–77% of patients.

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Figure 27.4 Mean change in peak flow rate between baseline and 3 months in terazosintreated patients. The n values indicate the number of patients at each time interval. All data points were significantly different from baseline (p≤0.05).

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Page 360 A similar durability of response was observed in another long-term study involving over 1200 patients in whom the response to terazosin was compared with that of placebo, finasteride (a 5α-reductase inhibitor), and a combination of finasteride plus terazosin (Fig. 27.6).20 In this study, finasteride and placebo were equally effective, producing only marginal improvements in symptoms. By contrast, terazosin and the combination therapy were significantly more effective; terazosin alone reduced the AUA symptom score by 6 units and increased Q max by 3.6 ml/s. Thus, improvements in symptoms and urinary flow were equivalent to those observed in the shorter double-blind studies described above.

Figure 27.5 Mean change in peak flow rate between baseline and 24 months in terazosintreated patients. The n values indicate the number of patients at each time interval All data points were significantly different from baseline (p≤0.05).

Figure 27.6 Group mean symptom problem scores in patients receiving placebo (–), or treated with finasteride (–), terazosin (–), or a combination of terazosin and finasteride (–). These data certainly refute the expectations of earlier years that α-antagonists may only provide temporary benefit in BPH/LUTS. In the face of ongoing glandular proliferation, it was anticipated that tachyphylaxis (tolerance) would occur. However, the long-term data show that the effect of terazosin in BPH is maintained over a 5-year period, over which time the prostatic mass would be expected to increase by up to 50%.21 On the basis that the increased prostatic bulk would result in a corresponding increase in urethral resistance, considerable diminution of benefit could have been expected over this time course. Two clinical studies (described in more detail below) suggest that the unanticipated longevity of the response could be due to induction of apoptosis within the prostate (see Chapter 30).11,22 Safety profile The clinical database for terazosin in the treatment of LUTS/BPH and hypertension extends to more than 3 billion patient days and shows that the drug is well tolerated. In double-blind studies in BPH, overall 15% of terazosin-treated patients discontinued therapy, compared with 9% of placebo recipients (representing only a 6% reduction in compliance compared with placebo). The most frequently reported side-effects in both groups were dizziness, vertigo, headache, and fatigue; cardiovascular events such as postural hypotension were infrequent. Most side-effects were mild in severity and did not warrant file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_360.html[09.07.2009 11:54:19]

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treatment or discontinuation of therapy. Terazosin was equally well tolerated over much longer periods. In the long-term study described above,21 the incidence of adverse events was similar to that observed in the initial double-blind studies. Overall, the side-effect profile of terazosin at doses that are fully effective in providing relief of LUTS/BPH appears to be characteristic of the class.13 Overall clinical profile Effects on blood pressure The role of α1-adrenoceptors in the control of the hemodynamic baseline is of potential clinical consequence to both normotensive and hypertensive BPH patients. Epidemiologic studies have shown that up to 40% of men with BPH have hypertension (controlled or uncontrolled). Although (as described above) there is some consensus that the α1A-adrenoceptor is the prime determinant of prostate tissue contraction, much less is known about the subtype involved in cardiovascular regulation.

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Page 361 Perhaps not surprisingly, as blood pressure is the algebraic summation of many cardiac and vascular processes, the ‘blood pressure receptor subtype’ has not been identified.6 Although there may be differential distributions within the vasculature, all three subtypes (α1A, α1B, and α1D) are ubiquitous.8,23 On this basis it can be assumed that these three subtypes are involved in cardiovascular homeostasis and that effective blood pressure control will therefore occur only with a balanced α1adrenoceptor antagonist, such as terazosin. Equally, a ‘uroselective’ antagonist will not provide effective blood pressure control in the many LUTS/BPH patients who also have hypertension. It is well documented that the changes in blood pressure observed with α1-blockers are highly dependent on the hemodynamic baseline. Terazosin lowers blood pressure when the sympathetic tone is high, for example in BPH/LUTS patients with hypertension (Fig. 27.7),17,24 but has much less effect on resistance vessels in normotensive patients, in whom only clinically insignificant changes in blood pressure are observed (Fig. 27.7).17,24,25 Terazosin has no effect on the hemodynamic baseline, irrespective of whether the BPH/LUTS patients are physiologically normotensive or are stabilized on hypertensive therapy.24,25 Overall, therefore, the potential antihypertensive effect of terazosin could be of considerable advantage to the relatively high proportion (40%) of BPH/LUTS patients who have uncontrolled or poorly controlled hypertension. Similarly, the long-term effects of terazosin in normotensive patients are of little clinical concern,

Figure 27.7 Effect of terazosin on blood pressure in (a) hypertensive and (b) normotensive patients. Data show blood pressure at baseline ( ) and after treatment ( ). (Adapted from reference 17.) although the potential to produce first-dose postural hypotension must always be considered. Tamsulosin does not appear to lower blood pressure consistently or markedly in hypertensive patients.26 This profile is claimed to arise from the intrinsic ‘uroselectivity’ of the drug; however, this claim has been disputed,6 and the ‘uroselectivity’ may simply reflect incomplete α-blockade at the dose used in clinical practice (0.4 mg).27 Cardiovascular risk factors Most of the risk factors for hypertension are common to congestive heart failure and atherosclerosis.28 Particularly relevant are an abnormal lipid profile and abnormal insulin resistance/glucose tolerance. The metabolic effects of terazosin and other antihypertensive agents have been reviewed by Pool.28,29 Terazosin has potentially beneficial actions on several of the risk factors (abnormal lipids, fibrinolysis, platelet aggregation) that could have important implications in the prevention of hypertension, coronary heart disease (CHD), and atherosclerosis.30–32 Extensive studies of almost 17000 hypertensive patients in primary care and community facilities suggest that the blood-pressure-lowering actions of terazosin, coupled with its beneficial effects on associated cardiovascular risk factors, should significantly reduce CHD.30 On the basis of the Framingham model,33 a reduction in the incidence of CHD of approximately 20% would be predicted from these changes in CHD risk factors. However, the recent results from the ALLHAT study,34 and the conclusions of JNC7,35 indicate that terazosin and other α-blockers should not be considered as front-line monotherapy in the treatment of cardiovascular disease. However, bearing in mind that many BPH/LUTS patients have several associated cardiovascular risk factors, these data provide support for the use of terazosin in any holistic approach to the management of the BPH/LUTS patient as a whole. Effects on the urogenital tract file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_361.html[09.07.2009 11:54:19]

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The clinical improvement in BPH/LUTS observed with any α-antagonist depends on a variety of actions within the urogenital tract.6,12 Although actions on prostate smooth muscle undoubtedly contribute to these effects, it is important to remember that there is no direct correlation between changes in urethral resistance and flow rates on the one hand and symptom improvement on the other. Furthermore, it should be remembered that patients usually present because of symptoms and bothersomeness, not because of reduced urinary flow. Thus, the extraprostatic actions of terazosin on the bladder, bladder neck,

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Page 362 spinal cord, and efferent pathways6,36 may be just as important as the changes induced in periurethral prostate smooth muscle tone. Effects on glandular growth Although (as described above) the immediate and shortterm therapeutic benefits of α-antagonists undoubtedly arise from direct and indirect actions on prostate smooth muscle, it is becoming apparent that other factors are important in the long term. In the early days of the use of α-blockers in BPH/LUTS, tachyphylaxis (tolerance) to the drug was expected, and, because of the continued glandular hyperplasia, it was thought that α-antagonists might act only as clinical ‘sticking plasters’, with the effect reducing with time. Clearly, long-term studies with terazosin (Fig. 27.5) show a durability of response beyond the original expectations. The findings of at least two recent clinical studies may offer some insight into this apparently paradoxical longevity of response with terazosin.11,20,37 In one study cell proliferation and apoptosis were evaluated in BPH patients who either received no treatment (control group) or were treated with terazosin at the normal clinical dose range (1–10 mg); the treatment period was between 1 week and 3 years. Compared with the untreated controls, terazosin induced epithelial and stromal cellular apoptosis

Figure 27.8 Effect of terazosin on prostate apoptosis in patients with BPH. The apoptotic index of glandular epithelial ( ) and stromal ( ) smooth muscle cells in biopsy sections is expressed as mean percentage of TUNEL-positive cells/total number of cells after various periods of terazosin therapy (1–10 mg/day). (Adapted from reference 11.) within the first month of treatment (Fig. 27.8), and there was a parallel increase in the expression of smooth muscle α-actin. The loss of prostate smooth muscle cells correlated with morphologic stromal regression and the improvement in LUTS. There was no effect on cell proliferation. The data indicate that terazosin treatment (over the normal dose range) results in a substantial induction of apoptosis in the glandular epithelium and stroma. However, there was no effect on the cellular dynamics of normal (i.e. nonBPH) tissue. One potential interpretation is that terazosin can affect abnormal prostate growth, such as that observed in BPH or prostate carcinoma. Theoretically this could account for the durability of the response to terazosin in long-term studies. The effects of terazosin on prostate apoptosis may also help in the interpretation of the clinical data generated in the Veterans’ Affairs study (Fig. 27.6).20 This study showed that the combination of finasteride and terazosin did not provide any therapeutic benefit over terazosin alone, at least with respect to symptom improvement. Terazosin potentially affects prostate growth by inducing apoptosis in both epithelial and stromal components. Should this be the case, it is perhaps not surprising that finasteride (which affects only epithelial tissue) cannot augment the response to terazosin. However, further clinical evaluation of this hypothesis is required. The overall profile of terazosin and the possibility that the induction of apoptosis is independent of the α1-adrenoceptor and is not a class effect is explored in Chapter 30. Conclusions Terazosin has a balanced pharmacologic action across the three high-affinity receptor subtypes of the α1-adrenoceptor, which is reflected clinically in the drug’s utility in the holistic approach to the management of the patient with BPH/LUTS. At the level of the prostate, the potent action of terazosin on the α1A-adrenoceptor subtype undoubtedly accounts for the rapid changes seen in urinary flow rate file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_362.html[09.07.2009 11:54:20]

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and voiding pressure, secondary to changes in urethral resistance. However, in addition to these prostatic actions, the extraprostatic actions of terazosin on the bladder, bladder neck, and higher centers also contribute to the significant changes in symptoms and bothersomeness. In addition there is increasing evidence that terazosin may have an additional action on apoptosis within prostate tissue. Intriguingly, this action, which could underpin the durability of the clinical benefit seen with terazosin, may not involve an action at adrenoceptors and may not be a class effect.

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Page 363 Terazosin produces clinically beneficial reductions in blood pressure in patients with BPH/LUTS who are also hypertensive, via actions at all three high-affinity α1-adrenoceptor subtypes. However, in patients who are normotensive or whose hypertension is controlled, only minor, clinically insignificant reductions in blood pressure are observed. Terazosin also has beneficial effects on several cardiovascular risk factors (e.g. lipid profiles, glucose metabolism) which, when coupled with the blood-pressure-lowering effect seen in hypertensive BPH patients, could translate into a reduction in CHD risk. In addition to the balanced pharmacologic action across all three high-affinity α1-adrenoceptor subtypes, the physicochemical properties of terazosin offer considerable advantages over most other αantagonists. Terazosin has a long plasma half-life, which makes it suitable for once-daily administration. The relatively slow absorption and gradual onset of action associated with this long plasma half-life underpin the reduced propensity for postural effects and general side-effects. Importantly, the pharmacokinetics are unchanged in the elderly or in patients with renal failure. Terazosin is well tolerated in both old and young patients. Most side-effects are mild or moderate and do not require treatment or discontinuation of therapy. Overall, therefore, terazosin has a desirable clinical profile for the treatment of BPH/LUTS. Any theoretic advantage that could be achieved with a genuinely ‘uroselective’ agent will ultimately have to be weighed against the deficits of such therapy with respect to the treatment of the whole patient. References 1. Caine M, Pfau A, Perlberg S. The use of alpha adrenergic blockers in benign prostatic obstruction. Br J Urol 1976; 48:255–263 2. Lepor H, Gup D I, Bauman M, Shapiro E. Laboratory assessment of terazosin and alpha1-blockade in prostatic hyperplasia. Urology 1988; 32 (Suppl): 21–26 3. Shapiro H, Hartatano V, Lepor H. The response to alpha blockade in benign prostatic hyperplasia is related to the percent density of prostate smooth muscle. Prostate 1992; 21:297–307 4. Caine M, Raz S, Ziegler M. Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol 1975; 27:193–202 5. Lepor H. Role of long-acting selective alpha1-blockers in the treatment of benign prostatic hyperplasia. Urol Clin North Am 1990; 17:651–657 6. Andersson K -E, Lepor H, Wyllie M G. Prostatic alpha1-adrenoceptors and uroselectivity. Prostate 1997; 30: 202–205 7. Barry M J, Cockett A T K, Holtgrewe H L et al. Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of severity of benign prostatic hyperplasia. J Urol 1993; 150:351–358 8. Bylund B D, Eikenberg D C, Hieble J -P et al. International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 1994; 46:121–136 9. Marshall I, Burt R P, Andersson P -O et al. Human alpha1c-adrenoceptor, functional characterisation in the prostate. Br J Pharmacol 1992; 107:327P 10. Lepor H, Tang R, Shapiro E. The alpha-adrenoceptor subtype mediating the tension of human prostatic smooth muscle. Prostate 1993; 22:301–307 11. Chon J K, Borkowski A, Partin A W et al. Alpha1-adrenoceptor antagonists, doxazosin and terazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia. J Urol 1999; 161:2002–2008 12. Jardin A, Andersson K -E, Bono V A et al. Alpha-blockers in the treatment of BPH. In: Denis L, Griffiths K, Khoury S et al. (eds). Proceedings of the fourth international consultation on benign prostatic hyperplasia (BPH). Plymouth: SCI, 1998:599–632 13. Eri L M, Tveter K J. Alpha-blockade in the treatment of symptomatic benign prostatic hyperplasia. J Urol 1995; 154:923–934 14. Kenny B, Naylor A M, Carte A J et al. Effect of alpha1-adrenoceptor antagonists on prostatic pressure and blood pressure in the anaesthetised dog. Urology 1994; 44: 52–57 15. Boyle P, Robertson C, Manski R et al. Meta-analysis of randomized trials of terazosin in the treatment of benign prostatic hyperplasia. Urology 2001; 58:717–722 16. Lepor H, Aurbach S, Puras-Baez A et al. A randomised multi-centre placebo controlled study of the efficacy and safety of terazosin in benign prostatic hyperplasia. J Urol 1992; 148:1467–1474 17. Wilt T J, Howe R W, Rutks I R, MacDonald R. Terazosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2002; CD003851 18. Kaplan S A. Terazosin for treating symptomatic benign prostatic obstruction: a systematic review of efficacy and adverse events. J Urol 2002; 168:1657–1658 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_363.html[09.07.2009 11:54:20]

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19. Lepor H. Long-term efficacy and safety of terazosin in patients with benign prostatic hyperplasia. Terazosin Research Group. Urology 1995; 45:406–413 20. Lepor H, Williford W O, Barry M J et al. The impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response.

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Page 364 Veterans’ Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. J Urol 1998; 160:1358– 1364 21. Oesterling J E. Benign prostatic hyperplasia: a review of its histogenesis and natural history. Prostate Suppl 1996; 6: 67–73 22. Kyprianou N, Litvak J P, Borkowski A et al. Induction of prostate apoptosis by doxazosin in benign prostatic hyperplasia. J Urol 1998; 159:1308–1312 23. Hoffman B B, Hu Z -H. Regulation of responses mediated by alpha1-adrenergic receptors in smooth muscle cultures. Pharmacol Commun 1995; 6:1–3 24. Kirby R S. Terazosin in benign prostatic hyperplasia: effects on blood pressure in normotensive and hypertensive men. Br J Urol 1998; 82:373–379 25. Lowe F C, Olson P J, Padley R J. Effects of terazosin therapy on blood pressure in men with benign prostatic hyperplasia concurrently treated with other antihypertensive medications. Urology 1999; 54:81–85 26. Chapple C R. Tamsulosin. In: Kirby R, McConnell J D, Fitzpatrick J M et al. (eds). Textbook of benign prostatic hyperplasia, 2nd edn. London: Taylor and Francis, 2005 27. Wyllie M G. Alpha1-adrenoceptor selectivity: the North American experience. Urology 1999; 36 (Suppl): 59–63 28. Pool J L. Effects of doxazosin on coronary heart disease risk factors in hypertensive patients. Br J Clin Pract Symp Suppl 1994; 74:8–12 29. Pool J L. Effects of doxazosin on serum lipids. A review of the clinical data and the molecular basis for altered lipid metabolism. Am Heart J 1991; 121:251–260 30. Itskovitz H D. Alpha1-blockade for the treatment of hypertension: a megastudy of terazosin in 2214 clinical practice settings. Clin Ther 1994; 16:490–504 31. Shinori H, Gotoh E, Ito T et al. Long-term therapy with terazosin may improve glucose and lipid metabolism in hypertensives: a multicenter prospective study. Am J Med Sci 1994; 307 (Suppl): 91–95 32. Hernandez R, Angeli-Greaves M, Carvajal A R et al. Terazosin: ex vivo platelet aggregation effects in patients with arterial hypertension. Am J Hypertens 1996; 9: 437–444 33. Levy D, Wilson P W F, Anderson K M, Castelli W P Stratifying patients at risk from coronary heart disease; new insights from the Framingham Heart Study. Am Heart J 1990; 119:712–717 34. Flack J M, Nasser S A. The antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT). Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker versus diuretic. Curr Hypertens Rep 2003; 5:189–191 35. JNC-7. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. May 2003: NIH Publication No 03–5233 36. Ramage A G, Wyllie M G. A comparison of effects of doxazosin and terazosin on the spontaneous sympathetic drive to the bladder and related organs in anaesthetised cats. Eur J Pharmacol 1996; 117:962–966 37. Kyprianou N. Doxazosin and terazosin suppress prostate growth by inducing apoptosis. Clinical significance. J Urol 2003; 169:1520–1525

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Page 365 28 Doxazosin in the treatment of benign prostatic hyperplasia R S Kirby Introduction The treatment with α1-adrenoceptor antagonists of the benign prostatic hyperplasia (BPH) symptom complex associated with obstruction of the lower urinary tract has evolved substantially from the original observations of Caine with phenoxybenzamine. Initially, only two types of α-adrenoceptor (α1 and α2) were identified. Phenoxybenzamine, an antagonist at both α-adrenoceptors, was classified as a nonselective α-adrenoceptor antagonist. Subsequently, the prime determinant of periurethral smooth muscle tone was found to be the α1-adrenoceptor, which led to the clinical evaluation of the first α1selective antagonist, prazosin, in an attempt to improve the side-effect profile of phenoxybenzamine. Understanding has increased further, to an extent where three major subtypes of the α1-adrenoceptor have been cloned and characterized, namely α1A, α1B, and α1D. A fourth receptor subtype, the α1Ladrenoceptor, has also been defined pharmacologically, but neither fully characterized nor cloned.1 The evolution of the nomenclature, which has been confusing and has undergone change over the last few years, is described in a review by Bylund et al.2 As a class, α1-adrenoceptor antagonists are well tolerated and effective in the treatment of obstructionrelated lower urinary tract symptoms.3 Both obstructive and irritative symptoms are improved, and there are changes in urinary flow and residual volume consistent with a reduction in urethral resistance. Prazosin has been used in this context for several years, but its therapeutic potential has been limited owing to the dosing regimen and the sideeffects associated with the rapidity of onset of action. Doxazosin, a selective α1-adrenoceptor antagonist, was developed to overcome these shortcomings. It has similar affinity for all α1-adrenoceptor subtypes and, therefore, can be considered to have a balanced pharmacologic profile.4 In addition, doxazosin can be distinguished from prazosin on the basis of physiochemical differences, which result in a more gradual onset of action and an extended plasma half-life (22 hours), consistent with utility as a once-a-day agent (Fig. 28.1).5,6 Doxazosin has had a wide exposure in BPH and hypertensive patients, and also in the high proportion of patients with concomitant disease.7 This chapter reviews the available data on doxazosin, and analyzes whether the balanced action of doxazosin on α1-adrenoceptor subtypes translates into clinical advantages for patient, primary-care physician, and urologist, alike. α1-Adrenoceptor heterogeneity To understand the clinical profile of doxazosin it is necessary to consider briefly the pathophysiologic roles of α1-adrenoceptor subtypes. A comprehensive review of the literature is not within the scope of this chapter, but the salient features are summarized below. For a more detailed review of the potential role of the different α1-adrenoceptor subtypes throughout the urogenital, cardiovascular, and central nervous system, consult Kirby et al.8 and also Chapter 5 of this book. All three high-affinity α1-adrenoceptor subtypes α1A, α1B, and α1D are present in the prostate. The α1receptor predominates, in both hyperplastic and normal prostate tissue, and its presence is correlated with the prostatic contractile response.9–11 α-Blockers were first thought to relieve the symptoms of BPH by inhibiting the α1A-adrenoceptors of the prostatic smooth muscle. Any associated side-effects were assumed to be mediated via α1-adrenoceptors in the vasculature. However, more

Figure 28.1 Onset of action of doxazosin ( ; mean dose 0.95 mg i.v.) and prazosin ( ●; mean

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dose 1 mg i.v.): effect on standing systolic blood pressure (BP). (From Elliot et al.,5 with permission.)

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Page 366 recent evidence suggests that both the efficacy and tolerability of α-blockers in BPH may have a centrally mediated component.8 The α1D-receptor subtype, for example, is predominant in CNS structures involved with micturition. Side-effects such as asthenia and dizziness may be due to a central rather than a vascular effect. As such, although an α1-adrenoceptor subtype probably cannot preferentially be targeted as a treatment for BPH, reducing activity at the α1B subtype may reduce cardiovascular complications.8 Safety and efficacy of doxazosin in BPH treatment Short-term efficacy A number of double-blind, placebo-controlled clinical studies of doxazosin in patients with BPH have been completed, and reported in the literature.12–19 Patients enrolled in the studies have been men aged between 50 and 80 years with clinical evidence of BPH and maximum flow rates below 15 ml/s. In general, patients receiving treatment with other α1-adrenoceptor antagonists, and patients with urinary tract infections or other serious illnesses, were excluded from these studies. A wash-out phase of at least 1 week was followed by a double-blind treatment period of between 1 and 6 months. Patients were randomized either to doxazosin (at an initial dose of 1 mg/day and increased sequentially according to protocol) or to placebo. Both normotensive and hypertensive patients were included in these studies. Treatment with doxazosin increased both maximum and average urinary flow rates in almost all studies. The changes achieved statistical significance compared with placebo in the majority of patients. Doxazosin also produced a consistently reduced residual urine volume, albeit small and variable, compared with placebo. BPH-associated symptoms were also improved to a statistically significant extent in the majority of studies. Irrespective of the different symptom scores used in these studies, consistently greater responses were recorded in patients treated with doxazosin than in those given placebo. In the studies reported above, the beneficial effects of doxazosin on symptoms and uroflow were seen within the first few weeks of treatment, often before doxazosin had been titrated to the optimum dose (Fig. 28.2). This has important clinical implications, in that patients may be encouraged to continue to comply with treatment if they experience an early improvement in symptoms. Doxazosin has a beneficial effect on symptoms and urinary flow rates, irrespective of the baseline severity of disease. In a pooled analysis of three of the double-blind, placebo-controlled studies reported above, doxazosin was seen to produce a significantly greater improvement compared to placebo in peak urinary flow rate, symptom severity, and symptom bother.20 Stratification by severity of symptoms at baseline demonstrated that the greatest improvement with doxazosin was seen in patients with the most severe symptoms ( p =0.0001); age did not impact on the capacity to benefit from treatment. Thus, it can be concluded that treatment with doxazosin is effective in patients with mild, moderate, and severe BPH, not just those with only mild or moderate symptoms. Pooled analysis also allowed a more in-depth assessment of urodynamic changes with doxazosin versus placebo.21 Doxazosin significantly improved free urinary flow

Figure 28.2 Effect of doxazosin (blue line) versus placebo (pink line) on (a) symptom score and (b) peak uroflow. Asterisks indicate significant differences from placebo (*p<0.005); dagger indicates significant difference from baseline (†p<0.05). (From Fawzy et al.,14 with permission.)

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Page 367 rate versus placebo, and reduced detrusor pressure, leading to a decreased voiding time and increased voided volume. Urethral resistance was also reduced with doxazosin. While the majority of studies have been concluded in men between 50 and 80 years of age, the efficacy and safety of α1-adrenoceptor antagonists has also been investigated in men over the age of 80 years.22 In a study of doxazosin and terazosin, both agents were seen to produce a significant increase in peak urinary flow rate and a significant improvement in American Urological Association (AUA) symptom score. Importantly, doxazosin or terazosin could be introduced for the treatment of BPH in patients who were already receiving antihypertensive treatment. Long-term efficacy The longest double-blind study with doxazosin was conducted by Holme et al.,15 with a duration of 29 weeks. This study demonstrated that efficacy was maintained throughout the treatment period. These double-blind data are supported by data from an open-label extension study of patients who completed three of the doubleblind, placebo-controlled studies listed above.23 A total of 450 men entered the long-term study, and data are available for up to 48 months of follow-up. Results show that doxazosin, over the course of 4 years, produces a clinically and statistically significant increase in maximum and average urinary flow rate (Fig. 28.3), as well as a clinically and statistically significant improvement in total, obstructive, and irritative BPH symptoms (Fig. 28.4). In a further analysis of only those patients with concurrent hypertension and BPH, treatment with doxazosin over 48 months resulted in a sustained improvement in the severity and bothersomeness of BPH symptoms, and an increase in maximum urinary flow rate.24 There was also a significant and sustained reduction in diastolic blood pressure. The efficacy and tolerability of doxazosin in combination with finasteride has also been evaluated in the Prospective European Doxazosin and Combination therapy (PREDICT) trial.25 In this study of 1095 men, doxazosin was effective in improving symptoms and flow and was more effective that finasteride or placebo. Addition of finasteride did not provide further benefit to that observed with doxazosin alone. Therefore, overall the results were similar to combination studies involving other α-blockers.26 The PREDICT study and the Medical Therapy of Prostatic Symptoms (MTOPS)27 study have also provided further evidence of the durability of the response to doxazosin with little evidence of tachyphylaxis. Safety profile The clinical database for doxazosin in the treatment of hypertension extends to more than 3 billion patient days. Data from studies of doxazosin in BPH have shown

Figure 28.3 Maximum urinary flow rates (Qmax) during the 4-year open-label extension study with doxazosin. Decreased patient numbers at successive time points are not because patients withdrew from the study, but primarily because patients were enrolled as they completed each double-blind study, which spanned many months. Asterisks indicate p<0.0001 versus baseline. (From Lepor et al.,23 with permission.)

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Figure 28.4 Effect of doxazosin on obstructive (yellow line), irritative (pink line), and Boyarsky total (blue line) symptom bothersomeness score during the 4-year open-label extension study with doxazosin. Decreased patient numbers at successive time points are not because patients withdrew from the study, but primarily because patients were enrolled as they completed each double-blind study, which spanned many months. Asterisks indicate p<0.0001 versus baseline. (From Lepor et al.,23 with permission.) consistently that the compound is equally well tolerated in patients with this condition and, intriguingly, perhaps is even better tolerated in normotensive than in hypertensive patients. In a pooled analysis of seven double-blind, placebocontrolled studies, doxazosin was well tolerated in normotensive and hypertensive patients with BPH.28 In general, older patients (≥65 years) treated with doxazosin experienced fewer adverse events than younger patients (42% versus 47%), although the difference was not statistically significant. A similar incidence of adverse events was seen in the placebo group (38% compared with 44%). The most commonly reported adverse events in all groups were dizziness, headache, fatigue, and dyspnea. The majority of adverse events were mild and did not require discontinuation of treatment. The good tolerability profile of doxazosin has also been seen with long-term treatment.23 In the 4-year, long-term extension study, almost 90% of adverse events were mild or moderate in severity. The tolerability profile of doxazosin was very similar to that seen in short-term studies, the most frequently reported adverse events being dizziness, headache, and fatigue. Doxazosin was similarly well tolerated by normotensive and hypertensive patients with BPH. The incidence of adverse events with doxazosin did not increase over time. In fact, a reverse Kaplan-Meier plot of patient withdrawals from therapy during long-term treatment illustrates a leveling-off of discontinuations after the first few months. Approximately half of those patients who discontinued therapy with doxazosin due to adverse events did so within the first 9 months of therapy (Fig. 28.5). Treatment of the whole patient Effects on blood pressure control The involvement of α1-adrenoceptor subtypes in cardio vascular control is of prime importance in normotensive and hypertensive patients. Not surprisingly, as blood pressure regulation is the algebraic sum of many cardiac and vascular processes, the ‘blood pressure subtype’ of the α1-adrenoceptor has not been identified. Although there may be differential distributions within the vasculature, and distribution may be species and vessel dependent, all subtypes appear to play a role in the contractile response of vascular tissue.8,9,30 The human α1A-adrenoceptor appears to be the predominant αadrenoceptor subtype in arterial smooth muscle, but this does not mean that it necessarily controls systemic blood pressure and orthostasis. It is more reasonable to assume that cardiovascular homeostasis depends on all subtypes, and effective blood pressure control will be achieved only with a balanced

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Figure 28.5 Reverse Kaplan-Meier plot of discontinuations from long-term doxazosin therapy because of adverse events (upper curve) or inadequate clinical response (lower curve). (From Lepor et al.,23 with permission.) α1-adrenoceptor antagonist. Equally, a prostate-selective antagonist may be incapable of providing effective blood pressure control in BPH patients with associated hypertension. It is well documented that the blood pressure-lowering effects of α1-adrenoceptor antagonists are highly dependent on the hemodynamic baseline. Doxazosin lowers blood pressure when sympathetic drive is high, for example in hypertension. In contrast, doxazosin has less effect on resistance vessel tone in normotensive patients, and clinically insignificant changes in blood pressure are observed (Fig. 28.6).31,32 Interestingly, there is no effect on the hemodynamic baseline, irrespective of whether BPH patients are physiologically normotensive or are stabilized on antihypertensive therapy.31 Hypertension and BPH are often encountered concomitantly in primary care practice. It is important, therefore, that an agent used to treat BPH can be used effectively and safely in patients receiving additional antihypertensive treatment. The Hypertension and BPH Intervention Study (HABIT) evaluated the efficacy and safety of doxazosin in patients with concomitant hypertension and BPH, in a community-based setting.33 There were four groups in the study: patients treated with antihypertensives who were well controlled; patients treated and poorly controlled; untreated, hypertensive patients; and untreated normotensive patients. Treatment with doxazosin was effective in all groups of patients; there was significant improvement in symptom scores as well as

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Figure 28.6 Effect of doxazosin ( ) on the blood pressure of hypertensive and normotensive BPH patients ( , baseline). (From Kirby32 with permission.)

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Page 370 BPH-specific indices of health status ( p <0.0001). A clinically important and beneficial reduction in blood pressure was seen only in patients who had an elevated blood pressure at baseline, and was evident in both younger (45–64 years) and older (≥65 years) patients. The incidence of treatment-related adverse events was similar across all groups, ranging from 30 to 37%. The majority were mild or moderate in severity, the most frequent being dizziness, fatigue, somnolence, and headache. Cardiovascular risk factors Many of the risk factors for hypertension are common to congenital heart failure and atherosclerosis.34 Particularly relevant are an aberrant lipid profile and insulin resistance/glucose intolerance. The effects of doxazosin compared with other quinazolines and other antihypertensive agents have been extensively reviewed by Pool.34,35 Clearly, doxazosin offers a number of benefits in this respect. In the Treatment of Mild Hypertension Study (TOMHS),36 doxazosin, in contrast to other antihypertensive agents, produced sustained reductions over a 48-month period in total and low-density lipoprotein (LDL) cholesterol and triglycerides, and increases in high-density lipoprotein (HDL) cholesterol and HDL: total cholesterol ratios. Although understanding of the effect of α-blockers on serum lipid profile is incomplete, Pool34,35 has identified several in vitro loci that could account for the clinical observations. Increases in LDL-receptor activity and lipoprotein lipase activity, and decreases in intracellular LDL synthesis and cholesterol absorption, have been observed in the presence of these drugs. A single α1-adrenoceptor subtype has not been linked to these effects. Indeed, studies of doxazosin metabolites indicate that a component of the drug’s actions may arise from a direct action on signal transduction, independent of the α1adrenoceptor.37 In the context of cardiovascular risk factors, catecholamines are involved in smooth muscle proliferation in the vasculature via an α1-adrenoceptor mechanism.38,39 α1-Adrenoceptor-antagonist attenuation of a proliferative vascular response could have important implications in the prevention of hypertension, coronary heart disease (CHD), and atherosclerosis. Doxazosin has also been shown to have a favorable effect on other cardiovascular risk factors, including increased fibrinolysis, inhibition of platelet aggregation, attenuation of the adverse hemodynamic and hemostatic effects of smoking, and regression of left ventricular hypertrophy.34,35 Extensive studies of almost 5000 hypertensive patients in general practice show a beneficial effect of doxazosin in significantly reducing CHD.40 On the basis of the Framingham Study equation,41 an approximate 20% reduction in CHD incidence would be predicted to result from these changes in CHD risk factors. In the Hypertension and Lipid Trial (HALT), a study enrolling over 800 patients with hypertension in a clinical practice setting, treatment with doxazosin produced a significant reduction in mean total cholesterol levels, LDL cholesterol, and triglycerides; levels of HDL cholesterol were essentially unchanged. In previously untreated patients, these doxazosin-induced changes in serum lipid profile, together with a significant reduction in blood pressure, resulted in a reduction in mean 5-year coronary disease risk of 15%.42 The effects of doxazosin on predicted coronary disease risk are in contrast to other antihypertensive agents, e.g. β-blockers. In a 5-year comparison of doxazosin and the β-blocker atenolol, doxazosin significantly reduced the predicted 10-year risk of CHD by approximately 12%, whereas atenolol had essentially no effect (0.2% increase). While both agents were effective antihypertensives, and both were well tolerated, only doxazosin had favorable effects on the serum lipid profile.43 More recently, the antihypertensive Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial was completed.44 Although the interpretation of data has created considerable debate, careful analysis confirms that it does not affect the management of BPH patients with doxazosin.45 Thus, the beneficial effects of doxazosin on cardiovascular risk further support the use of a balanced agent in the treatment of the BPH patient as a whole. Sexual function For several years there has been indirect evidence that doxazosin has a positive effect in males with erectile dysfunction (ED). In the 4-year TOMHS study,36,46 a much reduced incidence of ED was reported in the doxazosin group compared with placebo (Fig. 28.7). In contrast, other antihypertensive agents (e.g. diuretics) appeared to increase the incidence. Throughout the duration of the study, erection problems disappeared in 88% of men randomized to doxazosin, compared with 55% of men in all other groups combined. More recently, in an Italian multicenter study in BPH patients, doxazosin was found to improve erectile function, independent of any improvement in LUTS.47 The positive effect is consistent with the welldocumented role of α1-adrenoceptors in the control of corpus cavernosal file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_370.html[09.07.2009 11:54:24]

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Figure 28.7 Treatment of Mild Hypertension Study: incidence of men reporting inability to maintain an erection. (From Neaton et al.,36 with permission.) tone48 and the clinical benefit observed with intracavernosal injection of α1-adrenoceptor antagonists. Although doxazosin may not necessarily represent effective monotherapy for ED per se, there is some suggestion that it could form part of a combination strategy in the management of ED refractory to other agents. In one study of men with moderate to severe ED, oral doxazosin improved the response to intracavernosal alprostadil injection. There was an 18% improvement in International Index of Erectile Function (IIEF) with alprostadil alone, compared with a 52% improvement over 12 weeks with the addition of doxazosin ( p <0.0149). More recently, evidence of synergy with sildenafil has also been reported.50 Overall, given the high degree of co-morbid ED in LUTS,51 the impact of therapy (negative or positive) should be an important component of the decisionmaking process. Other contributing factors to the clinical profile of BPH When considering the urogenital tract it is important to remember the potential contribution from extraprostatic actions to the overall clinical profile of BPH.48 There is no direct correlation between flow rates and urethral resistance and the observed improvement in symptoms. Furthermore, it should be remembered that patients generally present because of symptoms and bothersomeness, not because of a reduced urinary flow. Thus, the extraprostatic actions that have been observed with doxazosin on the bladder,48 spinal cord,52 and efferent pathways53 may be just as important as changes induced in periurethral stromal tone. Several studies have shown that certain α1-adrenoceptor antagonists may regulate prostate growth by inducing apoptosis in the epithelial and stromal cells54 (see also Chapter 5 of this textbook). Over the clinical dose range, within the first month of treatment both doxazosin and terazosin produced a significant induction of apoptosis in prostate biopsies compared to untreated controls. This was paralleled by a loss of prostatic smooth muscle and an improvement in BPH symptomatology.55 This effect, not found with tamsulosin,54,56 is considered to be confined to quinazoline-derived α1antagonists and may indeed be independent of an action on the α1-adrenoceptor.54 Potentially such an action could account for the longterm clinical durability of the response to doxazosin in BPH patients. Doxazosin: the new GITS formulation A new formulation of doxazosin, the doxazosin gastrointestinal therapeutic system (GITS), has been developed to enhance the pharmacokinetic profile of the drug. It employs controlled-release technology to allow more gradual drug delivery with the first dose, and precise, sustained serum levels with longterm, once-daily administration. It is as effective and well tolerated as the standard formulation. For example, in a study of patients with mild hypertension, both doxazosin standard and doxazosin

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Page 372 GITS produced significant reductions in blood pressure compared to placebo ( p <0.001). The most commonly reported side-effects were headaches, dizziness, and asthenia.57 The GITS formulation appears to eliminate the need for doxazosin dose titration in most patients. In a combined analysis of two randomized, double-blind studies in hypertension, approximately 60% of patients achieved goal blood pressure response at the 4mg starting dose.58 The simplified dosing regimen is likely to result in fewer office visits for patients. Studies with doxazosin GITS have also been carried out in patients with BPH.18,19,59 Results have shown that doxazosin GITS provides effective relief from the signs and symptoms of BPH, with an efficacy comparable to that of the standard formulation. In a combined analysis of two double-blind, placebo-controlled studies, a similar increase in urinary flow rate and a similar improvement in symptoms were seen with doxazosin GITS and doxazosin standard (Fig. 28.8). Fewer titration steps were needed with doxazosin GITS, and almost 50% of patients achieved symptom relief at the starting dose of 4 mg/day. Tolerability was also enhanced with doxazosin GITS. In the same combined analysis, the overall incidence of adverse events was similar in doxazosin GITS and placebo groups, and lower than that with standard doxazosin treatment (Table 28.1) Intriguingly, in a ‘gold standard’ double-blind study, the doxazosin GITS (4 mg, 8 mg) was found to be more effective than tamsulosin (0.4 mg, 0.8 mg) in improving LUTS symptoms.60 This could represent the first evidence from a carefully controlled study that α-blockers may have different effects. Conclusions Doxazosin has a balanced pharmacologic action at all subtypes of the α1-adrenoceptor, which is reflected clinically in a beneficial effect on the whole patient. It improves

Figure 28.8 Effect of doxazosin gastrointestinal therapeutic system (GITS) ( ) doxazosin standard ( ●), and placebo ( ●) on (a) total International Prostate Symptom Score (I-PSS) and (b) maximum urinary flow rate. (From Kirby et al.,59 with permission.) Table 28.1 Incidence of adverse events in patients with BPH treated with doxazosin GITS, doxazosin standard, and placebo. (Adapted from Kirby et al.59)   Doxazosin GITS (%) Doxazosin standard (%) Placebo (%) ( n =666) ( n =651) ( n =156) All adverse events 41.1 53.6 39.1 Treatment-related events 16.1 25.3 7.7 Discontinuations due to treatment-related 3.3 4.8 0.6 adverse events GITS, gastrointestinal therapeutic system.

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Page 373 both symptoms and measures of urinary flow in the patient with BPH, as well as producing clinically important blood pressure reductions in BPH patients with hypertension. It is likely that an action on all adrenoceptor subtypes is required to produce this profile. In subjects with physiologic or drug-controlled normotension, only minor, clinically insignificant changes in blood pressure are observed. Doxazosin appears to have a beneficial effect on sev eral risk factors (e.g. lipid profile, glucose metabolism) associated with hypertension, CHD, and atherosclerosis. The α1-adrenoceptor subtype involved has not been identified, and there may be a contribution from receptorindependent events. In addition to these pharmacologic actions, the physiochemical properties of the drug offer considerable advantages. In particular, doxazosin, compared with other α1-adrenoceptor antagonists, has a long plasma half-life consistent with once-daily dosing. The associated gradual onset of action also underpins the reduced propensity for side-effects. Importantly, the pharmacokinetics are unchanged in the elderly and in renal failure. The new GITS formulation extends the established benefits of standard doxazosin therapy. Doxazosin GITS has an efficacy and tolerability profile similar to that of the standard formulation, with the additional advantages of an enhanced pharmacokinetic profile and simplified dosing regimen. Doxazosin is very well tolerated in both old and young patients. Most adverse events are mild or moderate in severity and do not require discontinuation of therapy. There is no suggestion of a deleterious impact on sexual function—in fact, there is evidence of a positive effect of doxazosin on erectile dysfunction. Overall, the balanced action of doxazosin on α1-adrenoceptor subtypes is associated with a highly desirable clinical profile for the BPH patient. Any advantages arising from a genuinely prostate-selective antagonist will ultimately have to be weighed against the deficits of such therapy in the treatment of the whole patient.61 References 1. Kenny B A, Miller A M, Williamson I J et al. Evaluation of the pharmacological selectivity profile of α1 adrenoceptor antagonists at prostatic α1 adrenoceptors: binding, functional and in vivo studies. Br J Pharmacol 1996; 118: 871–878 2. Bylund B D, Eikenberg D C, Hieble J P et al. International Union of Pharmacologic nomenclature of adrenoceptors. Pharmacol Rev 1994; 46:121–136 3. Eri L M, Tveter K L. Alpha-blockade in the treatment of symptomatic benign prostatic hyperplasia. J Urol 1995; 154:923–934 4. Kenny B A, Naylor A M, Carter A J et al. Effect of alpha1 adrenoceptor antagonists on prostatic pressure and blood pressure in the anesthetized dog. Urology 1994; 44:52–57 5. Elliot H L, Meredith P A, Sumner D J et al. A pharmacodynamic and pharmacokinetic assessment of a new alpha-adrenoceptor antagonist, doxazosin (UK-33274) in normotensive subjects. Br J Clin Pharmacol 1982; 13: 699–703 6. Young R A, Brogden R N. Doxazosin: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in mild to moderate hypertension. Drugs 1988; 35:535–541 7. Boyle P, Napalkov P. The epidemiology of benign prostatic hyperplasia and observations on concomitant hypertension. Scand J Urol Nephrol 1995; 168:7–12 8. Kirby R, Andersson K E, Lepor H et al. Alpha-1 adrenoceptor selectivity and the treatment of benign prostatic hyperplasia and lower urinary tract symptoms. Prostate Cancer Prostatic Dis 2000; 3:76–83 9. Forray C, Chiu G, Wetzel J M et al. Effects of novel alpha1-C adrenergic receptor antagonists on the contraction of human prostate smooth muscle. J Urol 1994; 151: 267A (abstract 159) 10. Goetz A S, Lutz M W, Rimele T J et al. Characterization of alpha1 adrenoceptor subtypes in human and canine prostate membranes. J Pharmacol Exp Ther 1994; 271: 1228–1233 11. Ford A P, Daniels D V, Chang D J et al. Pharmacological pleiotropism of the human recombinant alpha1A-adrenoceptor: implications for alpha1-adrenoceptor classification. Br J Pharmacol 1997; 121:1127–1135 12. Chapple C R, Carter P, Christmas T J et al. A three month double-blind study of doxazosin as treatment for benign prostatic bladder outlet obstruction. Br J Urol 1994; 74: 50–56 13. Gillenwater J Y, Conn R L, Chrysant S G et al. Doxazosin for the treatment of benign prostatic hyperplasia in patients with mild to moderate essential hypertension: a double-blind, placebo-controlled, dose-response multicenter study. J Urol 1995; 154:110–115 14. Fawzy A, Braun K, Lewis G P et al. Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study. J Urol 1995; 154:105–110 15. Holme J B, Christensen M M, Rasmussen P C et al. 29 weeks doxazosin treatment in patients with file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_373.html[09.07.2009 11:54:25]

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symptomatic benign prostatic hyperplasia. Scand J Urol Nephrol 1994; 28:77–82 16. Christensen M M, Holme J B, Rasmussen P C et al. Doxazosin treatment in patients with prostatic obstruction.

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Page 374 A double-blind placebo-controlled study. Scand J Urol Nephrol 1993; 27:39–44 17. Mobley D F, Kaplan S, Ice K et al. Effect of doxazosin on the symptoms of benign prostatic hyperplasia: results from three double-blind placebo-controlled studies. Int J Clin Pract 1997; 51:282– 288 18. Andersen M, Dahlstrand C, Høye K. Double-blind trial of the efficacy and tolerability of doxazosin in the gastrointestinal therapeutic system, doxazosin standard, and placebo in patients with benign prostatic hyperplasia. Eur Urol 2000; 38:400–409 19. Gratzke P, Kirby R S. Doxazosin GITS and doxazosin standard in patients with benign prostatic hyperplasia: doubleblind trial of efficacy and tolerability. Fortschr Med 2000; 11:83–92 20. Roehrborn C G, Siegel R L. Safety and efficacy of doxazosin in benign prostatic hyperplasia: a pooled analysis of three, double-blind, placebo-controlled studies. Urology 1996; 48:406–415 21. Abrams P. Urodynamic effects of doxazosin in men with lower urinary tract symptoms and benign prostatic obstruction. Results from three double-blind placebo-controlled studies. Eur Urol 1997; 32:39– 46 22. Kaplan S A, Ikeguchi T E E, Santarosa R P. The treatment of benign prostatic hyperplasia with alpha blockers in men over the age of 80 years. Br J Urol 1997; 80:875–879 23. Lepor H, Kaplan S A, Klimberg I et al. Doxazosin for benign prostatic hyperplasia: long-term efficacy and safety in hypertensive and normotensive patients. J Urol 1997; 157:525–530 24. Fawzy A, Hendry A, Cook E et al. Long-term (4 year) efficacy and tolerability of doxazosin for the treatment of concurrent benign prostatic hyperplasia and hypertension. Int J Urol 1999; 6:346–354 25. Kirby R S, Roehrborn C, Boyle P et al. for the PREDICT study investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) Trial. Urology 2003; 61:119–216 26. Lepor H, Williford W O, Barry M J et al. for the Veterans’ Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. The efficacy of terazosin, finasteride or both in benign prostatic hyperplasia. N Engl J Med 1996; 335: 533–539 27. McConnell J D, the MTOPS steering committee. The impact of medical therapy on the clinical progression of BPH: results of the MTOPS trial. J Urol 2002; 167 (Suppl 4): abstract 1042 28. Kaplan S A, Meade D’Alisera. Tolerability of α-blockade with doxazosin as a therapeutic option for symptomatic benign prostatic hyperplasia in the elderly patient: a pooled analysis of seven double-blind, placebo-controlled studies. J Gerontol 1998; 53A: M201-M206 29. Bylund D B, Regan J W, Faber J E et al. Vascular alpha-adrenoceptors: from the gene to the human. Can J Physiol Pharmacol 1995; 73:533–543 30. Hoffman B B, Hu Z-H. Regulation of responses mediated by alpha1-adrenergic receptors in smooth muscle cultures. Pharmacol Commun 1995; 6:1–3 31. Kaplan S A, Meade-D’Alisera P, Quinones S et al. Doxazosin in physiologically and pharmacologically normotensive men with benign prostatic hyperplasia. Urology 1995; 46:512–517 32. Kirby R. Doxazosin in benign prostatic hyperplasia: effects on blood pressure and urinary flow in normotensive and hypertensive men. Urology 1995; 46:182–186 33. Guthrie R M, Siegel R L for the Hypertension and BPH Intervention Trial (HABIT) Multicenter Study Group. A multicenter, community-based study of doxazosin in the treatment of concomitant hypertension and symptomatic benign prostatic hyperplasia: The Hypertension and BPH Intervention Trial (HABIT). Clin Ther 1999; 21: 1732–1748 34. Pool J L. Effects of doxazosin on coronary heart disease risk factors in the hypertensive patients. Br J Clin Pract Symp Suppl 1994; 74:8–12 35. Pool J L. Effects of doxazosin on serum lipids. A review of the clinical data and molecular basis for altered lipid metabolism. Am Heart J 1991; 121:251–260 36. Neaton J D, Grimm R H, Prineas R J et al. Treatment of Mild Hypertensive Study: final results. J Am Med Assoc 1993; 270:713–724 37. Chait A, Gilmore M, Kawamura M. Inhibition of low density lipoprotein oxidation in vitro by the 6and 7-hydroxy metabolites of doxazosin, an alpha1-adrenergic antihypertensive agent. Am J Hypertens 1994; 7:159–164 38. Jackson C L, Schwartz S M. Pharmacology of smooth muscle cell replication. Hypertension 1992; 20:713–736 39. Hu Z -H, Shi X -Y, Okazaki M, Hoffman B B. Angiotensin II induces transcription and expression of file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_374.html[09.07.2009 11:54:26]

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alpha1-adrenergic receptors in vascular smooth muscle. Am J Physiol 1995; 268: H1006–1014 40. Langdon C G, Packard R S. Doxazosin in hypertension: results of a general practice study in 4809 patients. Br J Clin Pract 1994; 48:293–298 41. Levy D, Wilson P W F, Anderson K M, Castelli W P. Stratifying patients at risk from coronary heart disease; new insights from the Framingham Heart Study. Am Heart J 1990; 119:71–77. 42. Levy D, Walmsley P, Levenstein M for the Hypertension and Lipid Trial Study Group. Principal results of the Hypertension and Lipid Trial (HALT): a multicenter

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Page 375 study of doxazosin in patients with hypertension. Am Heart J 1996; 131:966–973 43. Daae L N W, Westlie L. A 5-year comparison of doxazosin and atenolol in patients with mild-tomoderate hypertension: effects on blood pressure, serum lipids, and coronary heart disease risk. Blood Press 1998; 7:39–45 44. Flack J M, Nasser S A. The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. Curr Hypertens Rep 2003; 5:189–191 45. Kirby R S, Pool J L. Interpretation of the ALLHAT interim analysis and implications for the treatment of patients with BPH. Prostate Cancer Prostatic Dis 2000; 3: 152–156 46. Grimm R H, Grandits G A, Prineas R J et al. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS). Hypertension 1997; 29:8–14 47. De Rose A F, Carmignani G, Corbu C et al. Observational multicentric trial performed with doxazosin: evaluation of sexual effects on patients with diagnosed benign prostatic hyperplasia. Urol Int 2002; 68:95–98 48. Andersson K -E. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993; 45:253–308 49. Kaplan S A, Rodolfo B R, Kohn I J et al. Combination therapy using oral alpha-blockers and intracavernosal injection in men with erectile dysfunction. Urology 1998; 52:739–743 50. De Rose A F, Giglio M, Traverso P et al. Combined oral therapy with sildenafil and doxazosin for the treatment of non-organic erectile dysfunction refractory to sildenafil monotherapy. Int J Impot Res 2002; 14:50–53 51. Frankel S J, Donovan J L, Peters T I et al. Sexual dysfunction in men with lower urinary tract symptoms. J Clin Epidemiol 1998; 51:677–685 52. Ishizuka O, Persson K, Mattiasson A et al. Micturition in conscious rats with and without outlet obstruction: role of spinal alpha1 adrenoceptors. Br J Pharmacol 1996; 117: 962–966 53. Ramage A G, Wyllie M G. Effects of doxazosin and terazosin on inferior mesenteric nerve activity, spontaneous bladder contraction and blood pressure in anaesthetised cats. Br J Pharmacol 1994; 112:526P 54. Kyprianou N. Doxazosin and terazosin suppress prostate growth by inducing apoptosis: clinical significance. J Urol 2003; 169:1520–1525 55. Chon J K, Borkowski A, Partin A W et al. Alpha-1 adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia. J Urol 1999; 161:2002–2008 56. Kyprianou N, Benning C M. Suppression of human prostate cancer cell growth by alpha 1adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis. Cancer Res 2000; 60:4550–4555 57. Os I, Stokke H P. Doxazosin GITS compared with doxazosin standard and placebo in patients with mild hypertension. Blood Press 1999; 8:184–191 58. Os I, Stokke H P for the Doxazosin Investigators’ Study Group. Effects of doxazosin in the gastrointestinal therapeutic system formulation versus doxazosin standard and placebo in mild-tomoderate hypertension. J Cardiovasc Pharmacol 1999; 33:791–797 59. Kirby R S, Andersen M, Gratzke P et al. A combined analysis of double-blind trials of the efficacy and tolerability of doxazosin in the gastrointestinal therapeutic system (GITS), doxazosin standard, and placebo in patients with benign prostatic hyperplasia. BJU Int 2001; 87:192–200 60. Kirby R S. A randomized, double-blind crossover study of tamsulosin and controlled-release doxazosin in patients with benign prostatic hyperplasia. BJU Int 2003; 91: 41–44 61. Roehrborn C G, Schwinn D A. Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol 2004; 171: 1029–1035

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Page 377 29 Alfuzosin A Jurdin Introduction Alfuzosin, a quinazoline derivative, acts as a selective antagonist of α1-adrenoceptor-mediated contraction of bladder neck, proximal urethral, and prostatic smooth muscle. Bladder outlet resistance resulting from benign prostatic hyperplasia (BPH) is consequently reduced. Alfuzosin is approved in Europe for the treatment of symptomatic BPH. Pharmacologic profile of alfuzosin at α1-adrenoceptor subtypes The human prostatic smooth muscle contains high densities of α1-adrenoceptors.1,2 Several α1adrenoceptor subtypes have been identified and their heterogeneity revealed both pharmacologically and by molecular cloning.3,4 The three α1-adrenoceptor subtypes with high affinity for prazosin (grouped under the α1H heading), so far identified, i.e. α1A-, α1B-, and α1D-adrenoceptors, have been cloned (α1a, α1b, and α1d). Another adrenoceptor subtype has been identified and is characterized by a low affinity for prazosin and for that reason entitled α1L.5,7,8 Table 29.1 summarizes the affinity for the three cloned α1-adrenoceptors of the major α1-adrenoceptor antagonists available today. As shown with doxazosin, terazosin, and prazosin, alfuzosin has no distinct selectivity for any of the receptor subtypes. Uroselectivity has been shown to result Table 29.1 Affinity of various α1-adrenoceptor antagonists for the human cloned α1adrenoceptors.   Affinity Compound α1a α1b α1d Alfuzosin 8.20 8.53 8.40 Doxazosin 8.56 8.98 8.78 Prazosin 9.70 9.60 9.50 Tamsulosin 9.70 8.90 9.80 Terazosin 8.16 8.71 8.46 5-ME-Urapidil 8.68 6.76 7.91 Adapted from Forray C et al.6 and Kenny et al.7 from the pharmacodynamic properties of agents without specificity for any particular subtype, however.9 In addition, uroselectivity does not appear to be related to receptor subtype affinity.10 Affinity of alfuzosin for α-adrenoceptors in the human prostate The cranial region of the human prostatic adenoma possesses high affinity [3H]-prazosin binding sites.11,12 These sites display the pharmacologic characteristics of α1-adrenoceptors. As shown in Table 29.2, [3H]-prazosin binding is potently displaced by alfuzosin and phento-lamine, with IC50 values in the low nanomolar range, while the α2-adrenoceptor antagonists idazoxan and yohimbine, and the βadrenoceptor antagonist propranolol, only affect [3H]-prazosin binding with IC50 values in the micromolar range. Thus, alfuzosin shows high affinity for α1-adrenoceptors in the human prostate, which represents the pharmacologic target in BPH. In support of this view, it has been reported that alfuzosin-displaceable [125I]-HEAT (iodo-4-hydroxyphenyl-ethyl-aminomethyltetralone) binding sites, which have the pharmacologic characteristics of α1-adrenoceptors, are exclusively associated with muscular stroma of the prostate and are markedly elevated in sections from prostatic adenomas as compared with nonhypertrophic tissue.13 Table 29.2 Affinity of alfuzosin for α1-adrenoceptors in cranial human prostatic adenoma labeled with 3H-prazosin. Drug IC50* ( μ M) Alfuzosin 0.035±0.008 Phenoxybenzamine 0.038±0.016 Idazoxan 3.5±1.0 Yohimbine 6.0±2.0 Propranolol 37±9 *IC50 values represent drug concentrations producing 50% inhibition of specific 3H-prazosin binding. Values are taken from Pimoule et al.11 and Lefevre-Borg et al.12

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Page 378 As far as α1-adrenoceptor subtypes are concerned, Faure et al.14 have shown that the human prostate expresses at the level of the apex, base, periurethral, and lateral lobe, mRNA transcripts corresponding to α1a-, α1b-, and α1d-adrenoceptors. In addition, these authors have shown that a reconstituted partial sequence (349 amino acids) of the human prostatic α1a-adrenoceptor shares 94% identity with the bovine brain α1a-adrenoceptor, and that this receptor represents the predominant α1-adrenoceptor subtype in this tissue. Functional uroselectivity of alfuzosin Effects on elevated urethral and blood pressure Inhibition of urethral responses to stimulation of hypogastric sympathetic nerves in the cat is considered to represent an animal model of the dynamic sympathetic constriction of urethral smooth muscle, which is regarded as a contributory factor in the obstructive disorders which characterize BPH.15 On the other hand, α1-adrenoceptor antagonist reduction of blood pressure in spontaneous hypertensive rats is accepted as a model to assess antihypertensive drugs acting at receptors physiologically stimulated by an increased sympathetic tone. Thus a relationship between the ability of alfuzosin to inhibit sympathetically mediated increases in urethral tone in the cat and sympathetically mediated hypertension in the spontaneously hypertensive rat can be considered as a relevant way to evaluate the therapeutic margin in BPH with respect to unwanted vascular effects (e.g. orthostatic hypotension).15 Studies conducted in the anesthetized cat and in conscious spontaneously hypertensive rats confirm the α1-antagonist properties of alfuzosin. The compound pro-duces a dose-related as well as a complete and prolonged inhibition of the rise in urethral pressure resulting from postganglionic stimulation of hypogastric sympathetic nerves in the cat. As shown in Table 29.3, alfuzosin decreases the urethral resistance induced by hypogastric nerve stimulation in the cat at doses 11 times lower than those which reduce blood pressure in spontaneously hypertensive rats.15 Effects on normal urethral and arterial blood pressure In recent years, attempts have been made to evaluate, in the same animal, the respective effects of α1adrenoceptor antagonists on prostatic tissue compared to side-effects, most particularly the effects on blood pressure. In the most recently developed model, which allows the simulta-neous measurement of urethral and arterial pressures in conscious male rats,16 a direct estimation of the functional uroselectivity of alfuzosin was performed. At clinically relevant doses (10–30 μg/kg, intravenous route), alfuzosin decreased urethral pressure without noticeable effects on blood pressure (Fig. 29.1). In a comparative investigation, using the same experimental model, the functional uroselectivity of alfuzosin has been shown to be superior to that of other α1-adrenoceptor antagonists.17 These results are further evidence that functional uroselectivity may be achieved in the absence of pharmacologic selectivity for one of the α1-adrenoceptor subtypes. Tissue distribution The role of tissue distribution of α1-adrenoceptor antagonists and its possible effect on functional uroselectivity has been less rigorously examined. However, a direct measurement of plasma and prostate distribution of alfuzosin, related to measurement of its pharmacologic activity on arterial blood pressure and urethral pressure, has brought Table 29.3 Effects of alfuzosin on urethral pressure (UP) in the cat and on mean arterial blood pressure (AP) in the spontaneously hypertensive rat. Compound Dose producing a 50% reduction in Dose producing a 20% reduction in Uroselectivity ratio urethral pressure (ID50 UP) (mg/kg, arterial blood pressure (ID20 AP) (ID20 AP/ID50 id) (mg/kg, UP) Alfuzosin 0.36 4.0 11 Terazosin 0.12 0.42 3.5 Prazosin 0.12 0.13 1 The doses of each compound producing a 50% reduction in urethral pressure (UP50) in anesthetized cats and a 20% reduction in blood pressure (UP20) in spontaneously hypertensive rats are shown. Values are taken from Lefevre-Borg et al.15

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Figure 29.1 Effect of alfuzosin (triangle) compared with vehicle control (circle) on an increase in urethral pressure in the anesthetized cat. Doses of alfuzosin correspond to cumulative i.v. bolus administration of the drug. Increased urethral pressure was elicited by electrical stimulation of sympathetic hypogastric nerves. (From ref. 5 with permission.) new and useful information.18 One hour following oral administration of 10 mg/kg of alfuzosin in rats, plasma and prostate levels, respectively, reached 88.0 ng/ml and 335 ng/ml, leading to a prostate/plasma concentration ratio of 3.8. At 6 hours, the plasma concentration decreased to 20 ng/ml, whereas prostatic tissue concentration was still about nine times higher than plasma concentration. Moreover, in the same study, an index of the antagonistic activity of alfuzosin against phenylephrineinduced urethral contractions was directly correlated with prostatic tissue concentrations. This study, by demonstrating that alfuzosin concentrates in the prostate at levels 4–9-fold above the plasma levels, may thus provide a basis for its preferential activity in the lower urinary tract compared to vascular effects. High prostatic diffusion of alfuzosin has also been observed in orally treated patients.19 Conclusions In conclusion, alfuzosin is a potent selective α1-adrenoceptor antagonist which displays functional uroselectivity in animal models. These pharmacologic properties lend support to the theory that alfuzosin alleviates the dynamic component of urinary obstruction attributable to sympathetic tone in BPH. These pharmacologic properties are likely to underlie the clinical profile of alfuzosin. Pharmacokinetic properties The pharmacokinetics of alfuzosin are linear and nonsaturable. Absorption of the immediate release (IR) formulation of alfuzosin is relatively rapid, with a maximum plasma concentration occurring after a mean of 1.5 hours. Its bioavailability is 64%, with a negligible effect of concomitant administration of food on its absorption. Alfuzosin is approximately 90% protein bound in plasma. It is extensively metabolized by the liver and the metabolites are inactive. Its main route of elimination is fecal. The mean plasma elimination half life of IR alfuzosin is 4.8 hours. Because of this pharmacokinetic profile, the IR of alfuzosin has to be administered three times daily (7.5 mg/day). The slow release (SR) formulation of alfuzosin (5 mg daily), currently available in Europe, has been developed in order to improve compliance with the treatment by reducing the number of daily doses from three to two. The relative bioavailability of this formulation is 15% lower than for the IR formulation of alfuzosin. The time to reach the peak is longer, approximately 3 hours instead of 1.5 hours, confirming that the absorption is delayed as well as its apparent elimination half-life, which is 8 hours. The usual recommended daily dose is 5 mg twice daily, i.e. 10 mg/day. This higher daily dosage compares with the usual daily dose of 7.5 mg for the IR formulation, compensating for the relative loss of bioavailability. A once-daily formulation of alfuzosin is now available and, although the absorption characteristics are

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different from the IR and SR formulations, the metabolism of the drug is similar.20,21 Inactive barrier layers ensure that the active element is released over 20 hours. The dissolution rate is almost constant between 2 and 12 hours and the area under the plasma concentration-time curve is similar over 24 hours to that observed for 2.5 mg thrice-daily and 5 mg twice-daily formulations. The plasma elimination half-life of the prolonged-release 10 mg formulation was 9.1 hours compared to 7 hours for the IR formulation.19 The pharmacokinetic properties of 10 mg alfuzosin oncedaily were not significantly different in patients with renal impairment or in older adults compared to the IR formulation.22,23 The overall pharmacokinetic profile of alfuzosin is not significantly changed in patients with renal insufficiency, in contrast to what is observed in patients with hepatic insufficiency, where dosage modifications appear to be necessary.

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Page 380 Pharmacodynamic effects in humans Urodynamic effects Intravenous alfuzosin significantly reduced high urethral pressure arising from neurologic causes. One hundred and sixty-three patients with neurogenic bladder disease (NBD) and a mean maximal urethral pressure of 108 cmH2O were included in a randomized, double-blind, placebo-controlled study assessing the effect of a single i.v. injection of alfuzosin (0.5, 1, or 2 mg) or placebo. Alfuzosin significantly and dose-dependently decreased urethral pressure, with a mean decrease of 44% for the 2 mg dose.24 A single i.v. test dose of 5 mg alfuzosin had previously been used to determine which patients with spinal cord injury ( n =21) were likely to benefit from alfuzosin therapy. Response was assessed in terms of change in micturition, residual urine, and posterior urethral pressure and diameter.25 Furthermore, in a placebo-controlled study conducted in 66 patients with NBD, this decrease was maintained with oral alfuzosin for 12 weeks and associated with a significant improvement of voiding symptoms (−45%) and residual urine volume (−39%) compared with placebo.26 These actions appear to be correlated with the α1-adrenoceptor antagonism produced by alfuzosin. In patients with BPH, orally administered IR alfuzosin significantly and dose-dependently increased urinary flow rates from the first dose.27 At 90 minutes after a single alfuzosin dose, peak flow rate (PFR) was significantly increased by 23 and 34% with 1.25 and 2.5 mg, respectively, compared with placebo in 93 patients with initial PFR values of less than 15 ml/s. In patients with PFR values of less than 10 ml/s ( n =47), mean increases in PFR with 1.25 or 2.5 mg alfuzosin or placebo were even greater: 26, 55, and 17%, respectively.27 Similar results were observed with SR alfuzosin. At 180 minutes after a single SR alfuzosin dose, PFR was significantly increased by 29 and 36% with 3 and 5 mg doses compared with placebo (+17%) in elderly patients (≥65 years) with initial PFR values of less than 15 ml/s.28 The 30% increase in flow rates, which is the rate of improvement expected with α1-blocker therapy in patients with BPH, is maintained after multiple-dose administration of alfuzosin.28–32 Furthermore, this is of the same order of magnitude as that of prazosin 4 mg per day33,34 and tamsulosin 0.4 mg per day.31 In those patients with an increase in PFR of at least 25% (i.e. 45–50% of patients), the mean increase with alfuzosin is approximately 5 ml/s. Residual urine volume is a parameter reflecting not only the decrease in urinary flow resistance, but also the bladder contractility which may show wide intra-individual variability between serial examinations.35 Alfuzosin has been shown to decrease significantly the volume of residual urine by 38% after 6 months of treatment compared with 9% in placebo recipients.29 A pooled analysis of 11 double-blind, placebo-controlled trials involving 1470 LUTS patients showed that immediate- and sustained-release alfuzosin effectively reduced postvoid residual urine volume.36 Significant differences were observed between patients treated with alfuzosin and those who received placebo. The analysis showed that acute urinary retention (AUR) was more common in men with residual urine greater than 100 ml. Patients receiving alfuzosin were less likely to suffer AUR than those receiving placebo. Several more complex urodynamic assessments have been carried out in patients under alfuzosin treatment. In a 3-month, double-blind, placebo-controlled study performed in 31 patients with urodynamically proven bladder outflow obstruction treated with alfuzosin, there was a significant increase in the volume that produced a strong desire to void, which reflected the increase of bladder capacity.37 A pressure-flow, placebo-controlled study carried out in 52 patients with BPH treated with alfuzosin (7.5 mg/day for 4 weeks followed by a 5–8-week singleblind extension) showed that alfuzosin significantly decreases detrusor pressure compared with placebo (opening pressure, −39%; pressure at maximum flow, −30%; and maximum pressure, −29%; p <0.05 for all parameters). These improvements gradually increased up to 12 weeks.38 It can be concluded that the urodynamic effect of alfuzosin is characterized by a decrease in urethral pressure of about 45%, an increase in flow rate in patients with BPH of 30%, i.e. the expected benefit from α1-blocker therapy in BPH,39 and a beneficial effect on bladder capacity and pressure. Hemodynamic effects At doses used in the treatment of BPH, as would be predicted from the uroselectivity described above, alfuzosin produces only minor changes in blood pressure. After single oral doses of IR alfuzosin (1.25 mg ( n =31) and 2.5 mg ( n =31)) administered to BPH patients, mean supine and standing systolic and diastolic blood pressures were not significantly changed by alfuzosin compared with placebo.29 The effects of SR alfuzosin on supine blood pressure following medium term administration are likewise minimal, as shown in a large placebo-controlled study conducted on 390 patients who received SR file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_380.html[09.07.2009 11:54:29]

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alfuzosin 10 mg per day or placebo for 3 months. The mean reductions in

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Page 381 systolic and diastolic blood pressures did not differ statistically from those observed with placebo in the whole population as well as in the subgroups of normotensive and hypertensive patients.30 Similar results were observed in a large 6-month double-blind study comparing SR alfuzosin (5 mg once daily), and the combination of both: mean changes in blood pressure were comparable in the three treatment groups (Fig. 29.2),32 However, supine blood pressure effects do not entirely represent the potential risk associated with α1blockers, which is mainly related to orthostatic changes in blood pressure, particularly in the elderly and/or hypertensive patients.40 Thus, in order to address this potential risk specifically in patients receiving SR alfuzosin, a combined analysis of two clinical studies conducted with SR alfuzosin (10 mg/day) was performed with special attention to orthostatic blood pressure changes during the first month of treatment.41 Blood pressure was measured at peak plasma concentrations. Asymptomatic orthostatic hypotension (AOH) was defined as a decrease in systolic blood pressure of at least 20 mmHg when standing. The cumulative incidence of AOH was slightly more frequent with alfuzosin than with placebo, but the difference was not

Figure 29.2 Effect of alfuzosin (circle, 0.1 mg/kg; square, 1 mg/kg; triangle, 3 mg/kg) or vehicle control (hollow circle) on an increase in urethral pressure in the anesthetized cat. Doses of alfuzosin correspond to cumulative i.v. bolus administration of the drug. Increased urethral pressure was elicited by electrical stimulation of sympathetic hypogastric nerves. (From ref. 5 with permission.) statistically significant. SR alfuzosin moderately increased the incidence of AOH in elderly and hypertensive patients, during the first month of treatment. This effect was transient and was not associated with an increased incidence of related adverse events (i.e. postural sideeffects) in this subgroup of frail patients. In addition, orthostatic blood pressure changes were assessed in the large ( n =1051 patients) 6-month study comparing SR alfuzosin (5 mg twice daily), finasteride (5 mg once a day (od)) and the combination of both.32 The incidence of AOH was comparable in the three treatment groups, regardless of age or pre-existing hypertension (Fig. 29.3). Therapeutic potential More than 33000 BPH patients have been evaluated in reported European clinical studies assessing the efficacy and/or safety of alfuzosin or the improvement in quality of life after administration of alfuzosin. These studies were conducted with the IR formulation of alfuzosin (7.5 to 10 mg per day given in three divided doses), the SR formulation (SR alfuzosin 5 mg bid), and, more recently, the once-a-day formulation (alfuzosin 10 mg od) for the treatment of symptomatic BPH. Clinical efficacy Jardin et al.29 reported the efficacy of alfuzosin in a large multicenter placebo-controlled study of 518 patients with symptoms of BPH who received either alfuzosin 7.5 or 10 mg/day or placebo for 6 months. file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_381.html[09.07.2009 11:54:29]

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Patients were evaluated using the Boyarsky symptom scoring system, urinary flow rates, and postvoid residual urine volume. Obstructive and irritative symptoms, assessed according to the Boyarsky scale, improved significantly in the alfuzosin group compared with the placebo group ( p =0.004). Fewer patients in the alfuzosin group than in the placebo group dropped out due to lack of efficacy (6.8 vs 14.6%, p =0.0004) and the prevalence of spontaneous acute urine retention (AUR) was lower in the alfuzosin group (0.4% vs 2.6%, p =0.04). By 6 months, mean urinary flow rates had increased ( p <0.05) and residual volume had decreased ( p <0.017) in the alfuzosin group. Clinical improvement with alfuzosin could be maintained for up to 30 months, as observed in noncomparative extensions of the original 6-month study42,43 (Fig. 29.4) In a 3-month placebo-controlled study with the SR formulation of alfuzosin (5 mg bid) in 390 men, patients reported a clinically relevant and statistically significant improvement of their urinary symptoms in comparison with placebo (Fig. 29.5). A clinical improvement in LUTS

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Figure 29.3 Maximum changes in blood pressure (BP) from baseline following a single i.v. injection of alfuzosin of 0.5 ( ), 1 ( ), or 2 ( ) mg in comparison with placebo ( ).

Figure 29.4 Systolic and diastolic blood pressure (BP) in a 3-month study of placebo ( ) vs. slow release (SR) alfuzosin 10 mg/day (_) in 390 patients with BPH: (a) changes from baseline in supine BP; (b) changes in upright minus supine BP (Unpublished data.)

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Page 383 was observed whatever their initial severity, with an overall improvement in total I-PSS score of 30% as a mean.30 The clinical efficacy was observed from the first month. Maximum flow rate increased significantly with SR alfuzosin (+2.4 ml/s, i.e. +29%) compared with placebo (+1.1 ml/s, i.e. +14%, p =0.006). Residual urine was also significantly reduced with SR alfuzosin. In those patients with baseline Q max ≤12 ml/s and I-PSS score ≥13, the total I-PSS score decreased by 6.7 points (36%) (comparison versus placebo: p =0.002) (Table 29.4). The efficacy of the once-daily formulation, administered at a dose of 10 mg per day without initial titration, has been compared to that of the IR formulation (2.5 mg thrice daily) and placebo in a 3month study which

Figure 29.5 Total BPH symptom score improvement with alfuzosin: maintenance of symptomatic efficacy in the long term. Part 1:6-month placebo-controlled study (circle; n=251); part 2:1-year open extension (triangle; n=131); part 3:1-year (additional) open extension (square; n=50). *p<0.05 vs baseline. (Data from refs 29, 42, and 43 with permission.) Table 29.4 Lower urinary tract symptoms (LUTS) and peak urinary flow (Qmax) improvement in patients with baseline Qmax ≤12 ml/s and I-PSS≥13* Parameter SR alfuzosin 10 mg/day Placebo p† I-PSS score‡ n =104 n =110   Baseline 17.8 (3.9) 18.3 (4.1)   Final 11.2 (6.5) 14.4 (6.5)   Change vs baseline −6.7 (−36%) −4.0 (−22%) 0.002 Q max (ml/s)‡ n =91 n =91   Baseline 9.3 (2.1) 8.9 (2.2)   Final 12.5 (5.1) 10.1 (3.8)   Change vs baseline +3.2 (+39%) +1.1 (+16%) 0.0006 % Patients with Q max change >30% 53 26   *Adapted from Buzelin et al.30; †intergroup comparison; ‡mean (SD). SR, slow release.

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Page 384 involved 436 patients: symptomatic improvement with the od formulation was significantly higher than placebo and similar to that of the IR formulation, with I-PSS improvements of 6.9 points in the od group and 6.4 points in the 2.5 mg tid group ( p =0.002 and 0.02 vs placebo, respectively). The bothersomeness of these symptoms, assessed using the quality of life index, was also significantly improved with both formulations compared with placebo (Table 29.5) (the ALFORTI study44). Following treatment with alfuzosin od, Q max (measured at trough plasma levels) also significantly increased in comparison with placebo (mean SD values: +2.3 (3.6) ml/s and +1.6 (3.2) ml/s, respectively; p =0.03), demonstrating the therapeutic coverage over a 24-hour period. In a 9-month, non-blinded extension of this study, the long-term efficacy of 10 mg od alfuzosin was assessed over 12 months.45 In total, 311 of the original 436 patients took part in the extension phase. At the start of the extension phase, mean I-PSS was 10.9 and did not change over the subsequent 9 months, with mean I-PSS 9.3 at endpoint. Significant improvements were observed in patients who had originally received placebo as part of the doubleblind study ( p =0.0001). Peak flow, which was 11.5 ml/s at month 3, remained at its improved rate at month 12 ( p =0.0001 compared to baseline). In addition, the 10 mg od formulation has been compared to 15 mg od over 3 months.46 As in the ALFORTI study, the ALFUS study included a wash-out period of 1 month before treatment with nontitrated alfuzosin or placebo. I-PSS, uroflowmetry, and quality of life were assessed at baseline and then regularly throughout the studies. The men who took part in the trial were aged 50 or over, had a history of LUTS suggestive of BPH, an I-PSS of 13 or greater, a peak flow of 5–12 ml/s, a voided volume of 150 ml or greater, and a PVR volume of 350 ml or less. Patients were stratified in each study according to whether they were <65 or ≥65 and also according to blood pressure (<90 or ≥90 mmHg). The primary efficacy outcome was mean change in I-PSS. The 3-month trial indicated that 15 mg od alfuzosin and 10 mg od both improved I-PSS significantly compared to placebo.46 In the ALFUS study, endpoint I-PSS scores improved from baseline by 3.6 points in the 10 mg od group and 3.4 points in the 15 mg od group ( p =0.001 and 0.004, respectively). As in the ALFORTI study, improvements were observed in the I-PSS filling and voiding subscores. Peak urinary flow increased by 1.7 ml/s (17%, p =0.0004) in the 10 mg od group and by 0.9 ml/s (10%) in the 15 mg od group. Quality of life is now becoming accepted as an important criterion in the evaluation of treatments for BPH.47 Results from a study involving over 7000 outpatients treated with alfuzosin for 3 months in general practice showed quality of life scores to improve by 43% and to correlate significantly with symptom scores.48 These symptomatic and quality of life improvements were maintained in those patients who continued the treatment for 2 years (>4500)49 and 3 years (>3200).50 In this population, the rate of spontaneous AUR and of prostate surgery was low, respectively 0.3% and 3.7%,50 confirming the beneficial effect of alfuzosin on the risk of AUR demonstrated in the medium term.29 In the ALFUS and ALFORTI trials,44,46 quality of life scores were significantly better in the active treatment groups compared to placebo. In the ALFORTI trial, the quality of life index fell by 33%, 30%, and 18% in the Table 29.5 Symptomatic improvement after 3 months of treatment with the once daily formulation of alfuzosin (10 mg od): comparison with immediate release (IR) alfuzosin and placebo.44   Placebo Alfuzozin Alfuzosin p* ( n =154) 10 mg od 2.5 mg tid ( n =143) ( n =150) 1-PSS score Baseline† 17.7 (4.1) 17.3 (3.5) 16.8 (3.7) 0.13 Chaage vs, baseline† −4.9 (5.9) −6.9 (4.9) −6.4 (5.6) 0.005 % of patients with a clearance of at least 50% 26 37 42   Quality of life index Baseline† 3.3 (1.0) 3.3 (1.0) 3.3 (0.9) 0.96 Change vs. baseline† −0.6 (1.2) −0.1 (1.1) −1.1 (1.1) 0.002 *Intergroup comparison; †mean (SD). Data from van Kerrebroeck et al.44

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Page 385 10 mg od, 2.5 mg tid, and placebo groups, respectively44 ( p =0.0008 and 0.005 for the active groups vs placebo, respectively). In the ALFUS study, quality of life index improved by 18% in both active groups compared to 8% with placebo ( p =0.002 vs placebo). The extension of the ALFORTI trial45 saw an improvement from 2.3 at month 3 to 2.1 at endpoint (35% improvement from baseline). The potential additive benefit of combining the α1-blocker alfuzosin and the 5α1-reductase inhibitor finasteride was assessed in a European, randomized doubleblind, multicenter trial which involved 1051 patients with lower urinary tract symptoms associated with BPH.26 Patients ( n =358) received SR alfuzosin 5 mg twice daily without dose titration, finasteride ( n =344) 5 mg once daily, or both drugs ( n =349) for 6 months. Symptomatic improvement was significantly higher from the first month of treatment with SR alfuzosin, alone or in combination; mean changes in I-PSS versus baseline at endpoint were −6.3 and −6.1, respectively, compared with −5.2 with finasteride alone (SR alfuzosin vs finasteride, p =0.01; combination vs finasteride p =0.03). More than 40% of patients who received alfuzosin alone or in combination with finasteride had a 50% reduction of their urinary symptoms (Fig. 29.6). In the overall population, increases in Q max were greater with SR alfuzosin and the combination compared with finasteride alone after 1 month of therapy, but changes at endpoint were similar in the three treatment groups. In those 47% of patients likely to be obstructed (baseline Q max <10 ml/s), however, mean increases in Q max were significantly higher with SR alfuzosin, alone or in combination, whatever the visit. Thus, in this 6-month trial, SR alfuzosin was more effective than finasteride, with no additional benefit in combining both groups. As described above, in symptomatic BPH patients, alfuzosin reduces the residual urine volume and in the medium term the incidence of AUR.29 This beneficial effect on bladder emptying is also confirmed by the low rate of AUR observed in long-term treatment. Moreover, alfuzosin has also been demonstrated to be useful in the management of AUR. Alfuzosin (5 mg bid) administered

Figure 29.6 Maintenance in the long term (up to 6 months) of at least 25% improvement in BPH symptoms (circles, obstructive scores; squares, irritative scores; triangles, total scores) in patients given alfuzosin or placebo.

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Page 386 for 2 consecutive days in patients suffering from AUR secondary to BPH significantly increased the chance of voiding after removal of the catheter in comparison with placebo.51 These results were confirmed at the completion of the study: 22 out of 40 (55%) of patients treated with alfuzosin voided successfully in comparison with 12 out of 41 (29%) who received the placebo.52 Overall, alfuzosin has been found to produce symptomatic improvement in patients suffering from moderate BPH, i.e. a 25% improvement in two-thirds of treated patients and a 50% improvement in one-third, with a favorable impact on quality of life. The increase in flow rate was 30%, and residual urine volume may be decreased by 40%. The relief is prompt, more pronounced than with finasteride, and can be maintained over 3 years. In the medium term, alfuzosin reduced the incidence of AUR and, in long-term treatment, it is associated with a low incidence of AUR and prostate surgery. Side-effects and tolerance Oral IR alfuzosin (7.5–10 mg/day) is generally well tolerat ed in clinical studies of up to 30 months’ duration.29,42,43 The overall incidence of side-effects with alfuzosin appears to be similar to that seen with placebo, and the incidence of postural side-effects potentially related to the pharmacodynamic properties of alfuzosin appears to be lower than that with prazosin (up to 2 mg bid) and similar to that observed with the SR formulation of tamsulosin 0.4 mg od. Reported adverse effects with alfuzosin are usually transitory: the majority occur within the first 4 weeks of treatment and resolve spontaneously after drug withdrawal. Furthermore, both the SR and the od formulations of alfuzosin are at least as well tolerated as the immediate formulation. In the 6-month placebo-controlled study,29 the overall incidence of adverse events was similar in alfuzosin-treated patients (36%) and in the placebo group (36%), with a similar rate of drop-out for adverse events (10 and 9%, respectively). In addition, the number of patients reporting at least one vasodilatation-related adverse effect was also similar in alfuzosin and placebo groups (11 and 10%, respectively). A lower incidence of impotence with alfuzosin (<1%) compared with placebo (3%) may reflect the beneficial effect of α1-adrenoceptor antagonists in this condition (Table 29.6). Alfuzosin appears to be well tolerated in the long term,42,43 which is of particular interest because BPH patients are likely to require long-term treatment. In support of these data were the results of a noncomparative, nonblinded, multicenter postmarketing general Table 29.6 Adverse effects reported by patients with benign prostatic hyperplasia during 6 months’ treatment with alfuzosin 7.5–10 mg/day (n=251) or placebo (n=267). (Adapted from Jardin et al.29) Adverse effect Alfuzosin recipients (%) Placebo recipients (%) Vasodilatory adverse effects Dizziness 7.2 5.2 Headache 6.4 4.9 Postural hypotension 1.9 1.2 Drowsiness 1.6 <1 Tachycardia 1.6 <1 Other adverse effects Skin rash 4.4 5.2 Dry mouth 4.4 2.6 Diarrhea 2.8 <1 Nausea 2.4 <1 Vomiting 1.6 1.9 Asthenia 2.0 3.8 Chest pain 2.0 <1 Hypertension 1.6 2.3 Bad taste <1 3.4 Impotence <1 2.3 practice survey, involving over 13000 evaluable BPH patients who received alfuzosin 2.5 mg three times daily for 3 months. This study showed that the overall discontinuation rate was low (3.7%) and that two-thirds of patients’ withdrawals due to side-effects were caused by vasodilatation-related adverse events: vertigo/dizziness (1.4%), malaise (0.6%), postural hypotension (0.6%), and headache (0.4%). Most of these side-effects occurred during the first week of treatment and in fewer than 0.3% of patients after the first dose.53 As expected, postural sideeffects were more common in the elderly and in patients receiving concomitant antihypertensive treatment. In this survey, which was extended up to file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_386.html[09.07.2009 11:54:32]

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3 years, the incidence of side-effects leading to drug discontinuation was 2.3% and 4.2% during the 1year and 3-year survey, respectively.48–50,53 These figures confirm the good safety profile in longterm administration. Alfuzosin was better tolerated than prazosin in terms of postural symptoms in patients with BPH.33,34 The IR formulation of alfuzosin (2.5 mg tid) was as well tolerated as the marketed formulation of tamsulosin (0.4 mg od) in a 12-week study conducted in BPH.31 Decreases in supine and standing blood pressure were slightly greater in patients receiving alfuzosin than with tamsulosin. However, these changes were not associated with an increased incidence of side-effects, confirming that they were not clinically relevant. The number of

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Page 387 drop-Outs for adverse events was twice as low with alfuzosin than with tamsulosin (4% and 8%, respectively). The incidence of postural hypotension was low, i.e. 1% with alfuzosin and 3% with tamsulosin. The safety profile of SR alfuzosin was specifically addressed in a pooled analysis of two placebocontrolled studies involving 588 patients (292 receiving SR alfuzosin 5 mg twice daily and 296 a placebo).41 Fifty-one per cent of the patients were ≥65 years of age and 43% had associated cardiovascular disease including hypertension and/or were receiving concomitant antihypertensive drugs, SR alfuzosin administered without initial titration was very well tolerated, with an overall incidence of adverse events similar to that of placebo (18.5% and 15.8% of patients, respectively) and an overall incidence of withdrawal from therapy for adverse events lower than that of placebo (3.4% and 5.7%, respectively). Adverse events potentially related to vasodilatation were infrequent with SR alfuzosin (the same incidence as with placebo, i.e. 2.7% of patients) and these adverse events occurred mainly during the first month of alfuzosin treatment. The safety profile of SR alfuzosin was also compared to that of a standard dose of finasteride (5 mg od) and the combination of both drugs.32 The incidence of postural symptoms was not increased in those patients who received alfuzosin (Table 29.7). Conversely, impotence and ejaculatory disorders were significantly more frequent with finasteride, alone or in combination, than with alfu zosin alone. No ejaculatory disorders were reported with alfuzosin monotherapy. The safety profile of the od SR formulation of alfuzosin assessed in the ALFORTI study was also very satisfactory. Alfuzosin od 10 mg was administered without dose titration. No first-day effect was observed. The incidence of adverse events related to vasodilatation was low (dizziness/vertigo 2.8%, headache 1.4%, malaise 1.4%, asymptomatic hypotension 0.7%). No case of syncope was recorded. In addition, no sexual dysfunction was observed.44 An additional 3-month study showed similarly low rates of patient withdrawal and adverse events.46 At least one serious adverse event was experienced by 4.5, 3.4, and 2.9% of the 10 mg, 15 mg, and placebo groups, respectively, with potentially drug-related negative effects reported by 52, 43, and 43% of each group. Dizziness was reported by 7.4% of patients in the active group. Again, clinically relevant blood-pressure or heart-rate changes did not occur. Although supine systolic and diastolic blood pressure fell in the active groups, levels did not differ significantly from the placebo groups (–1.1, 2.3, and 2.7 mmHg and 0.8, 1.5, and 2.1 mmHg, respectively). Orthostatic hypotension rates were also similar between active groups and placebo. Again, ejaculatory disorders did not occur. In a 9-month extension of the 10 mg od formulation of alfuzosin, no specific events occurred that were not observed during the 3-month double-blind phase.45 Discontinuation due to adverse effects occurred in 5.6% Table 29.7 Comparative safety profile of alfuzosin (slow release (SR) 5 mg twice daily), finasteride (5 mg once daily), and the combination of both drugs: incidence of adverse effects.   Alfuzosin Finasteride Combination Intergroup ( n =358) ( n =344) ( n =349) p Vasodilatory events (%) Vertigo/dizziness 1.7 1.2 2.3 NS Headache 1.0 1.2 1.4 NS Postural hypotension/hypotension 0.6 0.9 0.6 NS Malaise 0.3 0.3 0.3 NS Sexual disorders (%) Impotence 2.2 6.7 7.4 <0.002 Ejaculation failure 0.0 1.5 0.9 0.04 Decreased libido 0.6 1.7 2.0 NS Others (%) Somnolence 0.0 0.3 0.6 NS Asthenia/fatigue 1.1 0.6 0.0 NS Myocardial infarction 0.0 0.3 0.3 NS Acute urinary retention 0.6 0.3 0.3 NS Data from Debruyne et al.32

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Page 388 of patients; vasodilatory effects were reported by 4.4% of patients, but were not due to first-day or age effects. Hypertensive patients reported more vasodilatory-related effects. No clinically relevant changes in systolic or diastolic blood pressure occurred (–2.6 and −2.8 mmHg compared to baseline, respectively). Nonclinically relevant orthostatic hypotension affected 2.8% of patients and risk was low in patients with mild and moderate renal impairment. Only 0.6% of patients reported ejaculatory disorders. Apart from the intrinsic functional uroselectivity of alfuzosin, the low incidence of postural events observed with the new formulation of alfuzosin could be related to its pharmacokinetic properties, i.e. delayed peak plasma concentrations due to both a slowing and a prolongation of the rate of release of the active drug. The lack of CNSrelated side-effects such as asthenia or somnolence could also be related to its low brain barrier penetration. Overall, consistent with the good tolerability of the drug, alfuzosin is not associated with impairment of sexual function. Place of alfuzosin in therapy Although it is unlikely that a drug would abolish both the static and dynamic components of BPH as effectively as surgery, pharmacologic approaches to the symptomatic treatment of BPH have attracted increasing interest and have become the mainstay of patient management. α1-Blockers such as alfuzosin54 and 5α-reductase inhibitors55 are now considered first-line therapy for BPH. 5α-Reductase inhibitors can reduce the size of the prostate, but may take months to have such an effect and in the overall study population, the magnitude of benefit is relatively modest.55 The potential benefits of the combination of alfuzosin and finasteride have yet to be demonstrated in the medium term.32 The potential clinical advantage of alfuzosin over some other α1-adrenoceptor antagonists is that it selectively blocks contraction mediated by α1-adrenoceptors in the genitourinary tract compared to its action on receptors in the vasculature. Therefore, as described above, alfuzosin may be effective in BPH at doses that produce minimal adverse effects related to vascular α1 blockade, especially postural symptoms. In addition, the incidence of CNS-related adverse events (i.e. asthenia, somnolence) is not markedly increased with alfuzosin compared to placebo and no deleterious effects on sexual function have been reported. With increased realization of the importance of maintained sexual function in older adults, this factor is likely to be of significant value to BPH patients. Both the SR and IR formulations of alfuzosin offer patient-friendly daily dosings. These are convenient for the normal routine of daily life, as once-a-day and twicea-day regimens are associated with better compliance (73 and 70%, respectively) than are thrice-daily regimens (52%).56 There is new evidence regarding the od formulation, indicating that it is as effective as SR and IR formulations, with fewer vasodilatory effects.44 The beneficial effect of alfuzosin as an adjuvant treatment of AUR is promising, as is the reported low incidence of AUR in patients treated in the medium and long term with alfuzosin. Although the predictive criteria of those patients with BPH who are likely to respond to α1-blockers have not yet been identified, the α1-blocker alfuzosin is a first-line and safe agent in patients with symptomatic BPH. Acknowledgments The author would like to thank S.Arbilla, M.C.Delauche and D.Martin for their fruitful collaboration in the writing of this chapter. References 1. Muramatsu I, Oshita M, Ohmura T et al. Pharmacological characterization of α1-adrenoceptor subtypes in the human prostate: functional and binding studies. Br J Urol 1994; 74:572–578 2. Hieble J P, Caine M, Zalaznik E. In vitro characterization of the α-adrenoceptors in human prostate. Eur J Pharmacol 1985; 107:111–117 3. Michel M C, Büscher R, Kerker J et al. α-Adrenoceptor subtypes affinities of drugs for the treatment of prostatic hypertrophy. Evidence for heterogeneity of chloroethylclonidine-resistant rat renal α1adrenoceptor. Naun Schmied Arch Pharmacol 1993; 348:385–395 4. Price D T, Schwinn D A, Lomasney J W et al. Identification, quantification and localization of mRNA for three distinct alpha1 adrenergic subtypes in human prostate. J Urol 1993; 150:546–551 5. Ford A P D W, Arredondo N F, Blue D R Jr et al. RS-17053 (N-[2-(2Cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α, α-dimethyl-1H-indole-3-ethanamine hydro chloride), a selective α1A-adrenoceptor antagonist, displays low affinity for functional α1-adrenoceptors in human prostate: implications for adrenoceptor classification. Eur J Pharmacol 1996; 49:209–215 6. Forray C, Bard J A, Wetzel J M et al. The alpha1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned alpha1c subtype. Mol Pharmacol 1994; 45: 703–708

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Page 389 7. Kenny B A, Miller A M, Williamson I J R et al. Evaluation of the pharmacological selectivity profile of α1-adrenoceptors: binding, functional and in vivo studies. Br J Pharmacol 1996; 118:871–878 8. Van Der Graaf P H, Deplanne V, Duquenne C et al. The α1A-adrenoceptor is not involved in phenylephrine-mediated contractions of rabbit isolated prostate. Eur Urol 1996; 30/52:51 9. Foray C, Noble S A. Subtype selective α1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia. Expert Opin Invest Drugs 1999; 8:2073–2094 10. Debruyne F M J. Alpha-blockers: are all created equal? Urology 2000; 56 (Suppl 5A): 20–22 11. Pimoule C, Shoemaker H, Jardin A, Langer S Z. Identification and characterization of high affinity [3H]-prazosin binding to the α-adrenoceptor in the human pro-static adenoma. Fund Clin Pharmacol 1988; 3: 446 (abstract) 12. Lefevre-Borg F, O’Connor S E, Schoemaker H et al. Alfuzosin, a selective α1-adrenoceptor antagonist in the lower urinary tract. Br J Pharmacol 1993; 109:1282–1289 13. Benavides J, Peny B, Scatton B. Autoradiographic distribution of alfuzosin sensitive α1-adrenoceptors in normal and hyperplasic human prostate. In: Proceedings of the 22nd congress of the International Society of Urology, Sevilla, Spain, 1991: abstract 487 14. Faure C, Pimoule C, Vallencien G et al. Identification of α1-adrenoceptor subtypes present in the human prostate. Life Sci 1994; 54:1595–1605 15. Lefevre-Borg F, Lechaire J, O’Connor S E. In vivo uroselectivity of alfuzosin compared to prazosin and terazosin. Br J Pharmacol 1992; 106:84P 16. Martin D, Jammes D, Angel I. Effects of alfuzosin on urethral and blood pressures in conscious male rate. Life Sci 1995; 57:387–391 17. Martin D J, Lluel P, Guillot E et al. Comparative α1-adrenoceptor subtype selectivity and functional uroselectivity of α1-adrenoceptor antagonists. J Pharmacol Exp Ther 1997; 282:228–235 18. Martin D J, Lluel P, Pouyet T et al. Relationship between the effects of alfuzosin on rat urethral and blood pressures and its tissue concentrations. Life Sci 1998; 63:169–176 19. Mottet N, Bressolle F, Costa P et al. Orally administered alfuzosin (ALF) has a high prostatic diffusion in benign prostatic hyperplasia tissue (abstract). J Urol 2000; 163 (Suppl 4): 305–306 20. Rauch C, Ahtoy P, Pinquier L et al. Bioequivalence of a new once-a-day controlled-release alfuzosin formulation with the immediate-release alfuzosin [abstract]. Eur J Urol 2000; 37 (Suppl 2) :119 21. Rauch C, Andre F, Thenot J -P et al. Bioequivalence study of a new once-a-day controlled-release alfuzosin formulation with the 5 mg twice daily formulation [abstract]. J Urol 2000; 163 (Suppl): 306 22. Pinquier J L, Fuder H, Amersdorffer J et al. Safety and pharmacokinetics of alfuzosin 10 mg once daily formulation comparatively to standard formulation (2.5 mg tid) in elderly subjects (abstract). Clin Pharmacol Ther 1999; 65: 202 23. Pinquier J L, Rauch-Desanti C, Miller R P et al. Effect of renal impairment on the pharmacokinetics and safety of alfuzosin 10 mg OK formulation (abstract). Clin Pharmacol Ther 2000; 67:111 24. Perrigot M, Delauche-Cavallier M C, Amarenco A et al. Effect of intravenous alfuzosin on urethral pressure in patients with neurogenic bladder disease. Neurol Urodyn 1996; 15:119–131 25. Cramer P, Neveux E, Regnier F et al. Bladder-neck opening test in spiral cord injury patients using a new I.V. alpha-blocking agent, alfuzosin. Paraplegia 1989; 27: 119–124 26. Delauche-Cavallier M C, Richard M, Buzelin J M et al. Alpha-blocker therapy with alfuzosin in neurogenic bladder disease. Neurol Urodyn 1993; 12:24A(abstract) 27. Teillac P, Delauche-Cavallier M C, Attali P and the Dualf Group. Urinary flow assessment after a single oral administration of alfuzosin, a new alpha-blocker, in patients with benign prostatic hypertrophy. Br J Urol 1992; 70:58–64 28. Hansen B J, Nordling J, Mensik H J A et al. and the Alfech study group. Alfuzosin in the treatment of benign prostatic hyperplasia: effects on symptom scores, urinary flowrates and residual volume. A multicentre, double-blind placebo-controlled trial. Scand J Urol Nephrol 1994; (Suppl 157): 169–176 29. Jardin A, Bensadoun H, Delauche-Cavallier M C, Attali and the BPH-ALF Group. Alfuzosin for treatment of benign prostatic hypertrophy. Lancet 1991; 337: 1457–1461 30. Buzelin J M, Roth S, Geffriaud-Ricouard C, DelaucheCavallier M C and the ALGEBI Study Group. Efficacy and safety of sustained-release alfuzosin 5 mg in patients with benign prostatic hyperplasia. Eur Urol 1997; 31: 190–198 31. Buzelin J M, Fonteyne E, Kontturi M et al. Comparison of tamsulosin with alfuzosin in the treatment of patients with lower urinary tract symptoms suggestive of bladder outlet obstruction (symptomatic benign prostatic hyperplasia). Br J Urol 1997; 80:597–605 32. Debruyne F M K, Jardin A, Colloi D et al. SR-alfuzosin, finasteride and the combination of both in the file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_389.html[09.07.2009 11:54:33]

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treatment of benign prostatic hyperplasia. Eur Urol 1998; 34: 169–175 33. Buzelin J M, Hebert M, Blondin P and the PRAZALF Group. Alpha-blocking treatment with alfuzosin in symp-

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Page 390 tomatic benign prostatic hyperplasia: comparative study with prazosin. Br J Urol 1993; 72:922–927 34. Stephenson T P, Jensen R D and the PRANALF Group. A placebo-controlled study of the efficacy and tolerability of alfuzosin and prazosin, for the treatment of benign prostatic hypertrophy (BPH). Proceedings of the 11th Congress of the European Association of Urology, Berlin, Germany, 1994; 25: abstract 48 35. Birsch N E, Hurst G, Doyle P T. Serial residual urine volumes in men with prostatic hypertrophy. Br J Urol 1988; 62:571–575 36. McNeill S A, Hargreave T B, Geffriaud-Ricouard C et al. Postvoid residual urine in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: pooled analysis of eleven controlled studies with alfuzosin. Urology 2001; 57:459–465 37. Ramsay J W A, Scott G I, Whitfield H N. A double-blind controlled trial of a new α1 blocking drug in the treatment of bladder outflow obstruction. Br J Urol 1985; 57: 657–659 38. Martorana G, Gilberti C, Di Silverio F et al. Effects of short-term treatment with α1-blocker alfuzosin on urodynamic pressure/flow parameters in patients with benign prostatic hyperplasia. Eur Urol 1997; 32:47–53 39. Eri L M, Tveter K J. α-Blockade in the treatment of symptomatic benign prostatic hyperplasia. J Urol 1995; 154: 923–934 40. Lipsitz L A. Orthostatic hypotension in the elderly. N Engl J Med 1989; 321:952–956 41. Buzelin J M, Delauche-Cavallier M C, Roth S et al. Clinical uroselectivity: evidence from patients treated with SR alfuzosin for symptomatic benign prostatic obstruction. Br J Urol 1997; 79:898–906 42. Jardin A, Bensadoun H, Delauche-Cavallier M C, Attali P and the BPH-ALF Group. Long term treatment of benign prostatic hypertrophy with alfuzosin: a 12–18 month assessment. Br J Urol 1993; 72:615–620 43. Jardin A, Bensadoun H, Delauche-Cavallier M C et al and the BPHALF Group. Long term treatment of benign prostatic hyperplasia alfuzosin: a 24–30 month survey. Br J Urol 1994; 74:579–584 44. van Kerrebroeck P, Jardin A, Laval KU et al. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur Urol 2000; 37: 306–313 45. van Kerrebroeck P, Jardin A, van Cangh P et al. Long-term safety and efficacy of a once-daily formulation of alfuzosin 10 mg in patients with symptomatic benign prostatic hyperplasia: open label extension study. Eur Urol 2002; 41:54–61 46. Roehrborn G C. Efficacy and safety of once daily alfuzosin in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a randomized placebocontrolled trial. ALFUS Study Group. Urology 2001; 58: 953–959 47. Fowler F J, Barry M J. Quality of life assessment for evaluating benign prostatic hyperplasia treatments. Eur Urol 1993; 24 (Suppl 1): 24–27 48. Lukacs B, Leplège A, Thibault P, Jardin A. Prospective study in men with clinical benign prostatic hyperplasia treated with alfuzosin by general practitioners: 1-year results. Urology 1996; 48:731–740 49. Lukacs B, Comet D, Doublet D et al. Health related quality of life in benign prostatic hyperplasia patients treated for 2 years with alfuzosin. J Epidemiol Bio 1997; 2: 203–211 50. Lukacs B, Grange J C, Comet B, McCarthy C and the BPH group in General Practice. Three year prospective study of 3228 BPH patients treated with alfuzosin in General Practice. Prostate Cancer Prostatic Dis 1998; 5: 276–283 51. McNeill S A, Donat R, Pillai M K et al. Prospective, multicentre randomized, placebo controlled, double-blind study of the effects of alfuzosin on the outcome of trial removal of catheter following acute urinary retention. J Urol 1998; 159: abstract 980 52. McNeill S A, Daruwala P D, Mitchell I D C et al. Sustained-release alfuzosin and trial without catheter after acute urinary retention: a prospective, placebo-controlled trial. BJU Int 1999; 84:622–627 53. Lukacs B, Blondin P, McCarthy C et al. Safety profile of 3 months’ therapy with alfuzosin in 13389 patients suffering from benign prostatic hypertrophy. Eur Urol 1996; 29: 29–35 54. Wilde M J, Fitton A, McTavish D. Alfuzosin: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in benign prostatic hyperplasia. Drugs 1993; 45:410–429 55. Gormley G J, Stonnerr E, Bruskewitz R C et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992; 327:1185–1191 56. Greenberg R N. Overview of patient compliance with medication dosing: a literature review. Clin Ther 1986; 6: 592–599 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_390.html[09.07.2009 11:54:34]

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Page 391 30 Tamsulosin C R Chapple Introduction Introduction to α1-adrenoceptor antagonists α1-Adrenoceptor antagonists were originally developed for the treatment of hypertension. Blockade of postsynaptic α1-adrenoceptors in the blood vessels by these agents results in vasodilatation. As a consequence, the peripheral vascular resistance and blood pressure are reduced. Examples of α1adrenoceptor antagonists that have been developed for and/or are still used for the treatment of hypertension are alfuzosin, doxazosin, prazosin, and terazosin. In 1976, Caine et al. proposed a hypothesis for the use of α1-adrenoceptor antagonists in lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO), also referred to as symptomatic benign prostatic hyperplasia (BPH).1 By inhibiting the effect of noradrenaline—the neurotransmitter of the sympathetic nervous system—at α1-adrenoceptors in the bladder neck, prostatic urethra, and prostate capsule and stroma, α1-adrenoceptor antagonists reduce the dynamic component of BPH.1–3 Today, α1-adrenoceptor antagonists are one of the most widely used medical therapies for this condition.3–5 They improve symptoms and urinary flow quickly (within a few weeks) and have a favorable clinical response in about 70% of patients. Total symptom score is in general improved by 30– 40% and maximum urinary flow rate ( Q max) is increased by 16–25%.3–4 The 5α-reductase inhibitor (5αRI) finasteride is another medical treatment option for LUTS suggestive of BPH accepted by the 4th and 5th International Consultations on BPH.6,7 It reduces the prostatic mass and therefore the mechanical or static component of BPH. Several direct comparative studies between α1-adrenoceptor antagonists and finasteride have been published or presented.8–10 The initial trial demonstrated superior efficacy of α1-adrenoceptor antagonists over finasteride in terms of improvement in BPH symptoms and peak flows. More recently, the MTOPS study has demonstrated greater efficacy for a combination of α1-adrenoceptor antagonist +5αRI, although the extrapolation of these findings to clinical practice still remains the subject of debate11. Comparison of an alternative 5αRI, dutasteride, to α1-adrenoceptor suggests that there are no major therapeutic differences. There is evidence that the efficacy of α1-adrenoceptor antagonists is independent of prostate size at baseline.12 Finasteride in contrast across the whole spectrum of patients has modest efficacy compared with placebo and is most effective in patients with an enlarged prostate (>40 g).6,13 Finally, α1-adrenoceptor antagonists work much faster (within a few weeks) than finasteride (up to 6 months) and, in contrast to 5αRIs are not associated with erectile dysfunction or loss in sexual interest and do not reduce prostate-specific antigen (PSA).14 These facts together will reinforce the use of α1adrenoceptor antagonists as first-choice medical therapy for LUTS suggestive of BPH. The most important drawback of the classical α1-adrenoceptor antagonists remains, however, adverse events attributed to the blood pressure-lowering potential such as dizziness, orthostatic hypotension, and syncope. In addition, in order to reduce the occurrence of the first dose effect (i.e. excessive blood pressure reduction with subsequent symptomatic orthostatic hypotension), they are recommended to be initiated at a low, subtherapeutic dose with gradual titration to the optimal therapeutic dose. Introduction to tamsulosin Tamsulosin hydrochloride (YM-617) has been specifically developed by the Yamanouchi Pharmaceutical Company for the treatment of LUTS suggestive of BPH. The chemical structure of tamsulosin, a methoxybenzenesulfonamide, differs from that of the other clinically available short-acting (alfuzosin and prazosin) and long-acting (doxazosin and terazosin) α1-adrenoceptor antagonists which are quinazoline derivatives.15 This may have consequences for drug-receptor interaction. In the late 1980s and the 1990s, it became clear that part from α1- and α2-adrenoceptors, there exist several subtypes of the α1-adrenoceptor. The International Union of Pharmacology (IUPHAR) has accepted the existence of three α1-adrenoceptor subtypes (with high affinity for prazosin): α1A, α1B, and α1D, (quoted in lower case when referring to the cloned entities).16 Another α1-adrenoceptor subtype has been described pharmacologically, which

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Page 392 is a low-affinity prazosin adrenoceptor, termed α1L.12 Although the molecular identify of this fourth α1adrenoceptor subtype is not fully established, recent evidence suggests that the α1L subtype may represent a particular conformational state of the α1-adrenoceptor.17 It has been demonstrated that the α1A and α1L-adrenoceptor subtypes are the predominant functional α1-adrenoceptors in the human prostate.17–22 Research indicates that α1-adrenoceptors in the human detrusor are of the α1D and to a lesser extent of the α1A subtypes and it has been suggested that inhibition of these subtypes leads to improvement of irritative symptoms by α1-adrenoceptor antagonists.23 It is not complete clear which subtype is involved in blood pressure regulation in humans, since receptor binding and molecular biological techniques do not provide consistent data on this matter.24–26 However, clinical pharmacology studies with doxazosin, terazosin, and tamsulosin suggest that α1B-adrenoceptors are more prominently involved in vasoconstriction than α1-adrenoceptors.27,28 At present, tamsulosin is the only clinically available α1-adrenoceptor antagonist that displays selectivity for α1A- and, to a slightly lesser extent, α1D, over α1B-adrenoceptors.29–31 In addition, tamsulosin has 12 times greater affinity for α1-adrenoceptors in the human prostate than in the aorta in contrast to prazosin which has similar affinity for those in the prostate and aorta.32 This can be referred to as receptor pharmacologic uroselectivity.33 Other available α1-adrenoceptor antagonists (alfuzosin, doxazosin, prazosin, and terazosin) do not display selectivity for any of the α1-adrenoceptor subtypes.29–31 Tamsulosin hydrochloride is available worldwide as a modified-release formulation. Due to the long halflife (about 10–13 hours in elderly subjects), tamsulosin can be classified as a long-acting α1adrenoceptor antagonist that can be taken once daily (after a meal). In Japan it was introduced by Yamanouchi in 1993 under the tradename Harnal®. In Europe it was first introduced in The Netherlands in 1995 and has since been marketed in most countries by Yamanouchi Europe (tradenames Omnic®, Omic®, Omix®, and Flomax®) and/or Boehringer Ingelheim (Alna®, Pradif®, Josir®, or Urolosin®). Tamsulosin is also available in many Latin American countries (Flomax® and Secotex®) and was approved by the FDA in the US in 1997 (Flomax®). Physiologic uroselectivity Physiologically, an α1-adrenoceptor antagonist can be considered uroselective if it inhibits to a lesser extent than other α1-adrenoceptor antagonists the α1-adrenoceptors in the vascular system. Considerable species differences for tissue distribution and functionality of α1-adrenoceptor subtypes exist. Therefore, α1-adrenoceptor antagonists can only be differentiated from a physiologic uroselectivity point of view based on results obtained in human beings. Two such experimental studies have been performed with tamsulosin and a hemodynamically active α1adrenoceptor antagonist to evaluate the inhibition of phenylephrine or cold-induced vasoconstriction.27,28 One placebo-controlled trial compared a single dose of tamsulosin (modifiedrelease formulation) 0.2 mg and doxazosin 1 mg in eight Japanese healthy subjects in a cross-over design.27 The other placebo-controlled trial compared equi-effective single doses of tamsulosin (modified release) 0.4 mg with terazosin 5 mg in ten healthy Caucasian volunteers in a cross-over setting.28 Figure 30.1a shows that the number of patients who had an increase in diastolic blood pressure of 7.6 mmHg after phenylephrine infusion was reduced to a lesser extent in tamsulosin-treated than in terazosin-treated patients. In addition, the inhibition of phenylephrine-induced increases in diastolic blood pressure relative to placebo was less with tamsulosin than terazosin (Fig. 30.1b). There is evidence from in vivo studies in human volunteers that tamsulosin causes less inhibition of vasoconstriction and therefore has lower affinity for vascular α1-adrenoceptors than doxazosin and terazosin.27,28 Clinical uroselectivity Clinical uroselectivity has been defined as ‘desired effects on obstruction and LUTS related to adverse events’ in patients with LUTS suggestive of BPH.33 This implies that the α1-adrenoceptor antagonist should have at least comparable efficacy to other α1-adrenoceptor antagonists with an improved sideeffect profile (i.e. lower potential to induce excessive blood pressure reductions with subsequent dizziness, symptomatic orthostatic hypotension, and syncope). Japanese clinical placebo-controlled data A randomized, double-blind, placebo-controlled, parallelgroup, phase II, dose-ranging study was performed in 270 Japanese patients with LUTS suggestive of BPH, using 0.1, 0.2, or 0.4 mg tamsulosin once daily for 4 weeks, after a 2-week placebo run-in period.34 The Q max for the placebo, 0.2 mg, and 0.4 mg groups improved by 1.4 ml/s (15%), 4.0 ml/s (44%), and 3.6 ml/s (35%), respectively (nonsignificant vs placebo; Table 30.1). With respect to average file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_392.html[09.07.2009 11:54:35]

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urinary flow rate ( Q ave),

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Figure 30.1 (a) Number of responders (increase diastolic blood pressure (DBP) >7.6 mmHg) during treatment with placebo, tamsulosin, or terazosin and (b) percentage inhibition of phenylephrine (PE)-induced increase in diastolic blood pressure during treatment with tamsulosin or terazosin relative to placebo.28 *p<0.05. there were statistically significant differences between 0.2 and 0.4 mg tamsulosin once daily (increases of 26% and 41%, respectively) and placebo (decrease of 4%). In addition, global subjective improvement was similar in the 0.2 mg and the 0.4 mg dosing groups and significantly better in comparison with placebo ( p <0.01). Approximately 80% of patients reported that their condition had (slightly, moderately, or markedly) improved. Tamsulosin was very well tolerated. Neither orthostatic hypotension nor a significant decrease in blood pressure were observed. In conclusion, both 0.2 and 0.4 mg tamsulosin once daily are effective and well-tolerated dosages in the treat ment of Japanese patients with LUTS suggestive of BPH. Tamsulosin 0.2 mg is the recommended dose in Japan. European clinical placebo-controlled data A randomized, double-blind, placebo-controlled, parallel group, phase II dose-ranging study was performed in the UK.35 After a 3-week placebo run-in period, 126 patients with LUTS due to BPH ( Q max <15 ml/s for a voided volume >100 ml; urethral resistance: detrusor pressure (Pdet) at Q max

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( P detQ max)/ Q max2≥0.5) were randomized to placebo or tamsulosin (0.2, 0.4, or 0.6 mg) once daily for 4 weeks. Efficacy was evaluated by free-flow and

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Page 394 Table 30.1 Effect of placebo or tamsulosin on mean free flow Qmax in placebo-controlled studies in Japan, Europe, and the US. First Duration Tamsulosin Placebo p author (weeks) Dose Baseline End- Change Change BaselineChange Grange Value (mg) point (%) (%) Kawabe34 4 0.2 9.1 13.1 4.0 44 9.4 1.4 15 NS     0.4 10.4 14.0 3.6 35       NS Abrams35 4 0.2 9.6 10.7 1.2 13 10.9 −0.1 −1 NS     0.4 9.6 12.1 2.2 23       0.03     0.6 9.1 10.9 1.8 20       NS Abrams37 12 0.4 10.7 12.0 1.4 13 10.4 0.4 4 0.028 Chapple38 12 0.4 10.2 11.8 1.6 16 10.1 0.6 6 0.002 Lepor43 13 0.4 9.5 — 1.8 18 9.8 0.5 5 <0.001     0.8 9.6 — 1.8 19       <0.001 Narayan44 13 0.4 — — 1.5 — — 0.9 — 0.064     0.8 — — 1.8 —       0.007 Lepor46 53 0.4 9.5 — 1.7 18 9.9 0.4 4 —     0.8 9.5 — 2.1 22        

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Page 395 pressure-flow parameters and by a modified Boyarsky symptom score (eight symptoms to be rated from 0 to 5; total score range 0–40). Table 30.1 and Fig. 30.2a show that both the 0.4 and 0.6 mg dose increased mean Q max (2.2 ml/s or 22.6% and 1.8 ml/s or 20.2%, respectively) statistically significantly compared with placebo (−0.1 ml/s or −0.9%, p <0.05). The 0.4 mg dose produced the greatest decrease in mean PdetQ max (−26.6 cmH2O or −28.2%) compared with an increase of 4.9 cmH2O (+5.7%) with placebo (Fig. 30.2b). The decrease in mean total symptom score was comparable for the 0.4 (−4.1 or −28.7%) and 0.6 mg dose (−4.4 or −28.2%) and was superior to the decrease in the placebo group (−2.9 or −17.7%: Table 30.2 and Fig. 30.2c). The difference versus placebo did not reach statistical significance, probably due to the small sample size and the relatively short duration of treatment (4 weeks). The percentage of patients who experienced slight or much improvement in their condition was also greatest in the 0.4 mg group (Fig. 30.2d). It can be concluded that optimal improvement in all efficacy parameters was achieved with the 0.4 mg dose of tamsulosin. This dose was also well tolerated and did not induce statistically significantly greater blood pressure changes during the first 8 hours after the first dose. Therefore, the 0.4 mg dose was further evaluated in phase III clinical trials in Europe. Two multinational, multicenter, double-blind, randomized, placebo-controlled phase III studies were performed in Europe. The Boyarsky symptom score was used to assess the effect on LUTS (nine symptoms, each to be rated from 0 to 3; total score range 0–27).36 Both studies enrolled more than 300 patients with mild-moderate LUTS (total Boyarsky score >6) suggestive of BPH (free flow Q max 4– 12 ml/s for a voided volume ≥120 ml). They were randomized to 12 weeks of treatment with placebo or tamsulosin 0.4 mg once daily in a 1:2 ratio (after a 2-week placebo run-in period).37 As the design, assessments, and results (Tables 30.1. and 30.2) of both studies were

Figure 30.2 Effect of placebo or tamsulosin (0.2, 0.4, or 0.6 mg) once daily on (a) mean free flow Qmax, (b) mean PdetQmax, (c) mean total modified Boyarsky symptom score, and (d) percentage of patients who had slight or much improvement in their condition after 4 weeks of therapy in the phase II dose-ranging study in the UK.35

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Page 396 Table 30.2 Effect of placebo or tamsulosin on mean total symptom score in placebocontrolled studies in Japan, Europe, and the US. First author Duration Tamsulosin Placebo p (symptom score) (weeks) Dose Baseline End- Change Change BaselineChangeChange Value (mg) point (%) (%) Abrams35 4 0.2 16.9 13.6 −3.4 −20 16.7 −2.9 −18 NS (modified   0.4 14.9 10.2 −4.1 −29       NS Boyarsky)   0.6 15.8 10.9 −4.4 −28       NS Abrams37 12 0.4 9.5 6.0 −3.4 −36 9.3 −2.2 −24 0.002 (Boyarsky) Chapple38 12 0.4 9.4 6.1 −3.3 −35 9.4 −2.4 −26 0.002 (Boyarksy) Abrams42 (I-PSS) 12 0.4 17.7 — −8.8 −50 17.4 −4.7 −27 ≤0.01 Lepor43 13 0.4 19.8 — −8.3 −42 19.6 −5.5 −28 <0.001 (I-PSS)   0.8 19.9 — −9.6 −48       <0.001 Narayan44 13 0.4 — — −5.1 — — −3.6 — 0.01 (I-PSS)   0.8 — — −5.8 —       0.01 Lepor46 53 0.4 19.7 — −9.4 −48 19.1 −6.5 −34 —   0.8 20.0 — −9.7 −49          

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Page 397 comparable, a meta-analysis that involved 193 placebo and 381 tamsulosin patients was carried out.38 Tamsulosin increased mean peak flow Q max by 1.6 ml/s (16%). Although there was a considerable placebo-effect (0.6 ml/s or 6%), the difference was statistically significant ( p =0.002: see Table 30.1). The same applied for the percentage of patients with a clinically significant improvement in Q max (defined as an increase from baseline of ≥30%)39:32% of tamsulosin- and 20% of placebo-treated patients ( p =0.003). Mean total Boyarsky symptom score was decreased to a statistically significant extent in the tamsulosin (−3.3 or −35.1%) versus the placebo group (−2.4 or −25.5%, p =0.002). The same applied for the decrease in total voiding ( p =0.008) and filling ( p =0.017) scores. A decrease in total Boyarsky symptom score from baseline ≥25% was considered to be a clinically significant response.40 This was achieved in 66% of patients in the tamsulosin and 49% of patients in the placebo group ( p <0.001). Tamsulosin has a fast onset of action. The increase in mean Q max was already apparent and optimal compared with placebo at the first assessment after 4 weeks of treatment with tamsulosin 0.4 mg (Fig. 30.3a). Although improvements in total Boyarsky symptom score were apparent and significant over placebo at the first assessment at 4 weeks, the symptom score continued to improve for the last 8 weeks of the trial when the effect was (nearly) optimal (Fig. 30.3b). At 4 weeks, about 70% of the total effect seen after 12 weeks was achieved.

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Page 398 Tamsulosin 0.4 mg was very well tolerated. It had minimal effects on blood pressure. In comparison with placebo there were no clinically significant changes in supine or standing systolic or diastolic blood pressure at end-point. Except for the change in standing diastolic blood pressure (−2.5 mmHg), the differences were also not statistically significant (Table 30.3). Approximately 20% of patients were hypertensive. In both the normotensive and hyperTable 30.3 Change in mean systolic and diastolic blood pressure (SBP/DBP) at end-point with placebo or tamsulosin 0.4 mg in metaanalysis of two European phase III placebocontrolled studies: all patients.38   Placebo Tamsulosin ( n =189) ( n =373) Supine SBP (mmHg) Baseline 144.3 143.1 Change −3.5 –3.1 Supine DBP (mmHg) Baseline 85.4 85.4 Change −0.9 −1.6 Standing SBP (mmHg) Hg) Baseline 142.9 141.8 Change −1.7 −3.3 Standing DBP (mmHg) Hg) Baseline 86.4 86.8 Change −0.4 −2.5* *p =0.018 vs placebo. tensive subgroups, tamsulosin 0.4 mg did not affect blood pressure to a clinically significantly greater extent than placebo. The decrease in standing diastolic blood pressure in normotensive patients was statistically significantly greater than in the placebo group but the reduction was minimal (−0.8 mmHg; p =0.049: Table 30.4). In addition, tamsulosin did not induce more adverse events than placebo, be it treatment emergent adverse events (36% vs 32%, p =0.290) or possibly/probably drugrelated adverse events according to the investigator (13% vs 12%, p =0.802). The same applied for the percentage of patients that discontinued due to adverse events (4.5% vs 3.6%). Adverse events commonly attributed to hemodynamically active α1-adrenoceptor antagonists such as dizziness, orthostatic hypotension, and syncope occurred at a comparable incidence in the tamsulosin and placebo groups (Table 30.5). This also applied for other adverse events associated with α1-adrenoceptor antagonists (asthenia, somnolence, rhinitis/nasal congestion). The only adverse event that was reported by significantly more tamsulosin than placebo patients was abnormal ejaculation (4.5% vs 1%, p =0.045). This adverse event was, however, very well tolerated by the patients, because few tamsulosin patients (0.8%) withdrew from the study for this reason.38,41 Other sexual function-related adverse events (impotence and decreased libido) were reported to the same extent in the tamsulosin and placebo groups (Table 30.5).41 Another randomized, double-blind, placebo-controlled phase IV, 12-week study has been performed with Table 30.4 Change in mean systolic and diastolic blood pressure (SBP/DBP) at end-point with placebo or tamsulosin 0.4 mg in meta-analysis of two European phase III placebocontrolled studies: normotensive and hypertensive patients.38   Normotension Hyper tension Placebo Tamsulosin Placebo Tamsulosin ( n =150) ( n =294) ( n =39) ( n =79) Supine SBP (mmHg) Baseline 139.7 137.8 162.2 162.7 Change −2.5 −2.0 −7.2 −7.2 Supine DBP (mmHg) Baseline 81.4 81.1 100.9 101.6 Change +1.0 +0.4 −8.3 −9.1 Standing SBP (mmHg) Baseline 138.7 137.4 159.1 157.9 Change −0.6 −2.5 −5.7 −6.3 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_398.html[09.07.2009 11:54:38]

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Page 399 Table 30.5 Incidence of adverse events (AEs) with placebo or tamsulosin 0.4 mg in the meta-analysis of the two European placebocontrolled phase III studies.38,41 Values are numbers of patients with percentages in parentheses.   Placebo Tamsulosin ( n =193) ( n =381) Any AE 61 (32) 137 (36) Any drug-related* AE 24 (12) 50 (13) Discontinued due to adverse events 7 (3.6) 17 (4.5) Dizziness 6 (3.1) 13 (3.4) Headache 4 (2.1) 8 (2.1) Tachycardia/palpitation 3 (1.6) 5 (1.3) Postural hypotension 1 (0.5) 0 (0) Syncope 1 (0.5) 1 (0.3) Asthenia 2 (1.0) 4 (1.0) Somnolence 2 (1.0) 1 (0.3) Rhinitis (nasal congestion) 1 (0.5) 1 (0.3) Abnormal ejaculation 2 (1.0) 17 (4.5)† Impotence 3 (1.6) 3 (0.8) Libido decreased 0 (0) 4 (1.0) Discontinued due to sexual function-related adverse events 1 (0.5) 3 (0.8) *Possibly or probably drug-related according to the investigator; †p =0.045 vs placebo. tamsulosin 0.4 mg once daily in European patients with LUTS (I-PSS ≥13) suggestive of BPH ( Q max <12 ml/s): ESPIRIT (European Standardized Pressure Flow Investigation Trial).42 In a subset of this trial ( n =193), the effects on pressure-flow parameters were studied in particular. Tamsulosin produced statistically significant decreases in P detQ max (−7.2 cmH2O or −10%) compared with placebo (+2.0 cmH2O or +3%; p =0.038: Table 30.6). Effects on pressure-flow Q max and the Abrams-Griffiths (AG) number ( P detQ max−[2× Q max]) were also significantly improved in the tamsulosin-treated compared with the placebo-treated patients. The AG number was reduced by 10.3 (−19%) on tamsulosin and increased by 1.2 (2%) on placebo ( p =0.014). Clinical improvement in total I-PSS occurred within 1 week with continuing improvement up to 12 weeks (decrease 8.8 or −50% vs −4.7 (−27%) with placebo; p ≤0.01). It can be concluded that tamsulosin 0.4 mg once daily is the optimal dose for European patients with LUTS sugTable 30.6 Effect on pressure-flow parameters and total I-PSS after 12 weeks of therapy with tamsulosin 0.4 mg or placebo in the European ESPRIT study.42   Placebo ( n =54) Tamsulosin ( n =106) PdetQ max (cmH2O) Baseline 68.0 69.2 Change (%) at 12 weeks 2.0 (3%) −7.2 (−10%)* Pressure flow Q max (ml/s) Baseline Change (%) at 12 weeks 6,4 0.4 (6%) 7.1 1.5 (21%)† AG number Baseline 55.2 55.1 Change 1.2 (2%) −10.3 (−19%)‡ Total I-PSS score Baseline 17.4 17.7 Change −4.7 (−27%) −8.8 (−50%)** n =193 instead of 160 for total I-PSS. *p=0.038; †p=0.020; ‡p =0.014; ** p ≤0.01. gestion of BPH. It has a rapid onset of action: Q max is maximally increased at the first assessment after 4 weeks and total symptom score within 1 week. It is extremely well tolerated, even without the need for dose titration. It has no clinically significant effect on blood pressure in normotensive or hypertensive patients and no increased potential to induce symptomatic orthostatic hypotension compared with placebo. Abnormal ejaculation is the only adverse event that occurs to a greater extent than with placebo. US clinical placebo-controlled data Two randomized, double-blind, placebo-controlled phase III short-term (13-week) studies were performed in the US with tamsulosin 0.4 mg or 0.8 mg once daily.43,44 The American Urological file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_399.html[09.07.2009 11:54:38]

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Association (AUA) symptom index, which is identical to the International Prostate Symptom Score (IPSS), was used in these studies to assess the effect on LUTS (seven symptoms, each to be rated from 0 to 5; total score range 0–35).45 In each study, approximately 750 patients with moderate-severe LUTS (total I-PSS ≥13) suggestive of BPH ( Q max 4–15 ml/s) were randomized to one of the three groups after a placebo run-in of 4 weeks. There were four primary efficacy parameters in each study (at endpoint): (a) mean change in total I-PSS, (b) mean change in Q max, (c) number of symptom score responders (decrease total I-PSS ≥25%), and (d) number of Q max responders (increase Q max ≥30%).

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Page 400 In both studies, tamsulosin 0.4 mg and 0.8 mg once daily were statistically significantly superior to placebo (see Tables 30.1 and 30.2, and Fig. 30.4a and b). The only parameter that did not reach but approached statistical significance over placebo in the 0.4 mg group ( p =0.064) was mean Q max (measured at through plasma concentration) in one of the studies.40 Tamsulosin 0.4 mg and 0.8 mg had comparable efficacy in both studies, only the change in total I-PSS at end-point was greater in the 0.8 mg than in the 0.4 mg group ( p =0.020). However, the difference between the two treatment groups was already partly apparent after 1 week of therapy when both the patients in the 0.4 and 0.8 mg groups had received 0.4 mg (Fig. 30.5b). This shows that the greater effect of the 0.8 mg dose with regard to change in total I-PSS at end-point was probably caused by a difference in response between treatment/patient groups and not by a difference in response to tamsulosin dose. Tamsulosin 0.4 mg had a very fast onset of action in both studies. In one of the studies, Q max was measured 4–8 hours after intake of the first dose.43 At that time point, Q max was already significantly and maximally

Figure 30.4 Percentage of (a) Qmax responders and (b) total symptom score responders at end-point in the placebo and tamsulosin groups of two short-term US studies: study 143 and study 2.44 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_400.html[09.07.2009 11:54:39]

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Page 401 increased compared with placebo (Fig. 30.5a). In addition, the difference in improvement in total I-PSS score between tamsulosin and placebo was significant at the first assessment after 1 week (Fig. 30.5b).43,44 The symptom score continued to improve up to 13 weeks when the optimal effect on LUTS was achieved. At week 1, approximately 50% of the total reduction was observed. Tamsulosin 0.4 mg and 0.8 mg had no clinically significant effects on blood pressure, either in normotensive or (controlled or uncontrolled) hypertensive patients. Multiple and rigorous orthostatic stress testing was performed at every visit in both studies. Despite this, the number of patients that developed symptomatic orthostatic hypotension with tamsulosin 0.4 mg or 0.8 mg in both studies was comparable to that with placebo: 1 (0.2%), 2 (0.4%), and 0 (0%), respectively. Other symptoms of orthostatic hypotension reported during the multiple and rigorous orthostatic stress tests (such as dizziness, lightheadedness, and faintness/syncope) were also included in the adverse events listing (Table 30.7). The only adverse event that was reported consistently and significantly more frequently with the 0.4 mg dose in both studies was

Figure 30.5 Effect of tamsulosin (0.4 or 0.8 mg) and placebo on (a) mean Qmax and (b) mean total I-PSS score over time in one of the US short-term studies.43 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_401.html[09.07.2009 11:54:39]

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Page 402 Table 30.7 Incidence of adverse events with placebo, tamsulosin 0.4 mg or tamsulosin 0.8 mg in the two US placebo-controlled, short-term (13-week), phase III studies.39,40 Data in parentheses are percentages.   Study 139 Study 240 Placebo Tamsulosin 0.4 Tamsulosin 0.8 Placebo Tamsulosin Tamulosin ( n =254)mg mg ( n =239)0.4 mg 0.8 mg ( n =254) ( n =248) ( n =248) ( n =244) Any AE 151 (59)165 (65) 180 (73) 181 (76)194 (78) 188 (77) Discontinued due to adverse 22 (9) 18 (7) 31 (13) 20 (8) 22 (9) 30 (12) events Dizziness 13 (5) 25 (10) 28 (11)* 37 (15) 50 (20) 56 (23)* Orthostatic hypotension 0 (0) 1 (0.4) 2 (0.8) 0 (0) 0 (0) 0 (0) Asthenia 5 (2) 12 (5) 13 (5) 22 (9) 27 (11) 29 (12) Headache 46 (18) 48 (19) 45 (18) 53 (22) 49 (20) 59 (24) Rhinitis 14 (6) 31 (12)* 37 (15)* 26 (11) 35 (14) 50 (20)* Abnormal ejaculation 0 (0) 15 (6)* 44 (18)*† 1 (<1) 27 (11)* 45 (18)*† *Significant vs placebo; †significant vs 0.4 mg. abnormal ejaculation (6% and 11%) vs <1% with placebo. The occurrence of this adverse event was dosedependent as it was reported by significantly more patients on 0.8 mg (18%) than 0.4mg in both studies. The reporting of other adverse events such as dizziness, rhinitis/nasal congestion, and somnolence also increased with the higher tamsulosin dose and they were experienced by significantly more patients on tamsulosin 0.8 mg than placebo. Discontinuation due to adverse events occurred in about 8% of patients in both the placebo and tamsulosin 0.4 mg groups and in 12–13% of patients on 0.8 mg.43,44 A total of 418 patients who completed one of the 13-week placebo-controlled US studies43 continued with a 40-week, placebo-controlled extension study in which they remained on the same double-blind medication as in the short-term study.46 The efficacy and good tolerability of tamsulosin (0.4 mg and 0.8 mg) in comparison with placebo was sustained during the 40-week extension phase. Both tamsulosin doses had comparable efficacy (Fig. 30.6). The number of patients that discontinued due to adverse events remained low and comparable in the placebo (6%) and tamsulosin 0.4 mg (5%) groups. A total of 16% of patients on 0.8 mg discontinued due to adverse events. It can be concluded that tamsulosin 0.4 mg is the optimal dose in the treatment in American patients with LUTS suggestive of BPH with a very good safety profile.44 It has a fast onset of action with significant improvements in Q max within 24 hours and a symptomatic score within 1 week. It does not lower blood pressure to a clinically significant extent, even in uncontrolled hypertensives. It has no increased potential for symptomatic orthostatic hypotension compared with placebo, even when administered without dose titration and when exposed to multiple and rigorous orthostatic stress testing. Only abnormal ejaculation occurred consistently and significantly more often with tamsulosin 0.4 mg than placebo. Therefore, 0.4 mg is the recommended tamsulosin dosage in the US. If patients fail to respond after 2–4 weeks, the dose may be increased to 0.8 mg. Long-term open-label extension studies All patients (be it tamsulosin- or placebo-treated) who completed the two European placebo-controlled phase III studies could be enrolled in a long-term extension study with open-label tamsulosin for up to 4 years. In an interim analysis, 355 patients were treated with tamsulosin for up to 3 years.47 The significant improvements in Q max, total Boyarsky symptom score, Q max responders, and symptom score responders observed in the 12-week placebo-controlled studies were sustained for up to 3 years in the patients who remained in the study. The increase in mean Q max from baseline ranged from 0.7 to 1.8 ml/s ( p <0.05) and remained between 11.5 and 12 ml/s throughout the

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Page 403 follow-up period (Fig. 30.7a). Total Boyarsky symptom score was improved from baseline by 3.7 to 4.1 (or −39% to −44%: p <0.001) (Fig. 30.7b). The percentage of patients having a clinically significant response was also sustained: about 30% for Q max and between 70 and 80% for symptom score responders (Fig. 30.8a and b). Tamsulosin also remained very well tolerated. A total of 27% of patients had possibly/probably drug-related adverse events over the entire 3-year period and dizziness and abnormal ejaculation were still the most common side-effects (occurring in ≤6% of patients). Similar results were seen in a meta-analysis of the extension of the placebo-controlled studies and an alfuzosin comparative study (see later) which involved 516 patients followed for up to 3 years.48 In the US, a total of 955 patients received open-label therapy with tamsulosin for up to 2 years49 with sustained efficacy and safety. The range for improvements from baseline were 1.4 to 2.5 ml/s for Q max, −5.9 to −10.4 for total I-PSS, 32–44% for Q max responders, and 58–83% for symptom score responders. A further long-term US trial involved 609 BPH patients treated with tamsulosin for 6 years.50 Participants received a maintenance dose of 0.4 or 0.8 mg/day. The improvements in AUA symptom index

Figure 30.6 Change in (a) mean Qmax and (b) mean total I-PSS score after 53 weeks of treatment with placebo or tamsulosin (0.4 mg or 0.8 mg) once daily in a long-term US study.46

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Page 404 and Q max were maintained throughout the study period, with good levels of tolerance. Orthostatic hypotension was observed in only 1.3% of the group. It can be concluded that the favorable efficacy/safety ratio of tamsulosin is sustained in approximately 1500 patients with LUTS suggestive of BPH receiving openlabel tamsulosin for up to 3 years in Europe or the US. Direct comparative clinical studies vs other α1-adrenoceptor antagonists Three direct comparative clinical studies have been performed.51–53 One was a European phase III, double-blind, randomized, comparative study between alfuzosin (2.5 mg twice daily for 2 weeks and 2.5 mg three times daily for 10 weeks) and tamsulosin (0.4 mg once daily after breakfast throughout). It involved 256 patients with LUTS (total Boyarsky score >6) suggestive of BPH ( Q max 4–12 ml/s). 51 The other single-blind, randomized trial compared terazosin (dose titrated from 1 to 5 mg once daily) and tamsulosin (0.2 mg once daily throughout) for 8 weeks in 98 Korean patients with LUTS (total I-PSS ≥8) suggestive of BPH ( Q max 5–15 ml/s). 52 The results show that tamsulosin had comparable efficacy to both alfuzosin and terazosin. They all increased Q max by 1.6–2.1 ml/s (16–22%:

Figure 30.7 Effect of tamsulosin over time on (a) mean Qmax and (b) mean total Boyarsky symptom score in patients followed for up to 3 years in an extension of the two European

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Page 405 Fig. 30.9a) and reduced total symptom score by 36–40% (Fig. 30.9b). Both tamsulosin and alfuzosin were very well tolerated. The incidence of abnormal ejaculation was also comparable in both groups (one patient with tamsulosin and none with alfuzosin). Terazosin was, however, associated with significantly more drug-related adverse events (37% of patients) than tamsulosin (2% of patients; p =0.001). In particular, dry mouth (16% vs 0%) and dizziness (12% vs 0%) were reported more frequently with terazosin. None of the patients on tamsulosin or terazosin experienced (drug-related) abnormal ejaculation. Alfuzosin and terazosin produces significant decreases in blood pressure compared with baseline whereas this was not the case with tamsulosin (Fig. 30.10). In addition, the blood pressure reductions with alfuzosin were statistically significantly greater than those with tamsulosin, especially in elderly patients.51 A third double-blind, randomized study compared the potential of tamsulosin and terazosin to induce orthostatic hypotension during early morning and nocturnal orthostatic stress testing in 50 normotensive elderly subjects (more than 50% had LUTS).53 Tamsulosin and terazosin were administered for 15 days according to their recommended dosage regimen in daily practice: tamsulosin

Figure 30.8 Effect of tamsulosin over time on (a) Qmax responders and (b) total Boyarsky symptom score responders in patients followed for up to 3 years in an extension of the two

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Page 406 0.4 mg once daily after breakfast without dose titration, terazosin dose titrated from 1 to 5 mg once daily in the evening. The results show that tamsulosin caused significantly less symptomatic orthostatic hypotension (4% of patients) than terazosin (36% of patients; p =0.011: Fig. 30.11). The patient with symptomatic orthostatic hypotension on tamsulosin had pre-study vertigo, which was an exclusion criterion for the study. It can be concluded that α1-adrenoceptor antagonists have similar efficacy in the treatment of LUTS suggestive of BPH. It is their potential to lower blood pressure and produce cardiovascular-related adverse events such as symptomatic orthostatic hypotension that differentiates between α1adrenoceptor antagonists.3,4 Tamsulosin 0.4 mg has the lowest potential to reduce blood pressure and causes less symptomatic orthostatic hypotension than terazosin. This may be clinically important as orthostatic

Figure 30.9 Percentage improvement in (a) total symptom score and (b) Qmaxin two direct comparative clinical trials between tamsulosin and alfuzosin51 or tamsulosin and file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_406.html[09.07.2009 11:54:42]

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Page 407 hypotension and syncope are risk factors for falling. Falls are the sixth largest cause of death in the elderly and the cost of fall-related fractures in the elderly amounts to US $10 billion/year.54 Tamsulosin, furthermore, is easy to use as it does not require dose titration and can be taken once a day. Tolerability in elderly patients and patients with co-morbidity or co-medication Tamsulosin has been repeatedly shown to be well tolerated.51–53,55 A subgroup analysis of younger (<65 years) and older (≥65 years) patients enrolled in the two European phase III placebo-controlled trials38 revealed that tamsulosin 0.4 mg once daily had comparable effects on blood pressure and was as well tolerated in both younger and older patients, compared with placebo.56 In two observational surveys, in which almost 20000 German patients with LUTS suggestive of BPH received tamsulosin 0.4 mg once daily for 4 or 12 weeks, approximately 40–50% of patients had concomitant hypertension, other cardiovascular (CV) diseases, or diabetes.57 It appeared that overall about 95% of patients rated the

Figure 30.10 Effect on blood pressure (BP) in direct comparative clinical study between (a) tamsulosin and alfuzosin51 and (b) tamsulosin and terazosin.52 S, systolic; D, diastolic.

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Figure 30.11 Number of patients with symptomatic orthostatic hypotension during orthostatic stress testing in direct comparative trial between tamsulosin and terazosin.53 global tolerability of tamsulosin as good or very good. Concomitant hypertension, other CV diseases, or diabetes had only a minor effect on global tolerability, which became significant due to the large patient numbers. It was still rated as good or very good in more than 90% and 95% of cases in the two surveys. A multivariate analysis showed that hypertension did not contribute to changes in global tolerability. Diabetes and other CV diseases contributed significantly. This may be due to the reduced quality of life associated with these conditions and the large patient numbers and may therefore not be clinically significant for the majority of these patients. Many patients in these trials also took concomitant CV medication (diuretics, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or calcium antagonists). Global tolerability in these patients remained good to very good in 95% of patients and the CV co-medication did not contribute to changes in global tolerability in a multivariate analysis. Blood pressure changes in patients with comorbidity or co-medication were minimal and comparable to those reported for tamsulosin and placebo in placebocontrolled trials. In patients with co-morbidity or comedication, additional blood pressure reductions were not more than 2 mmHg. This did not significantly contribute to blood pressure changes in a multivariate analysis. In three clinical interaction studies, tamsulosin was administered to the hypertensive patients controlled with the β-blocker atenolol, the ACE inhibitor enalapril, or the calcium antagonist nifedipine. The results confirm that tamsulosin has no clinically significant additional effects on blood pressure or an increased potential to produce orthostatic hypotension in hypertensive patients treated with antihypertensive medication.58 It can be concluded that in such elderly patients and the majority of patients with cardiovascular comorbidity or co-medication, tamsulosin is well tolerated and has minimal effects on blood pressure. Use in patients pretreated with other medical therapy In two large German observational surveys, patients pretreated with other medical therapies, such as phytotherapy, finasteride, or other α1-adrenoceptor antagonists, were asked to rate the global efficacy and tolerability of tamsulosin in comparison with their previous treatment (i.e. worse, similar, better).59 It appeared that relative to patients pretreated with other α1-adrenoceptor antago nists, the global efficacy of tamsulosin was perceived better than that of previous treatment in about 25% of phytotherapy- and 15% of finasteride-pretreated patients (Fig. 30.12a). Relative to previous treatment with phytotherapy, the global tolerability of tamsulosin was perceived better than that of previous treatment in about 25% of other α1-adrenoceptor antagonists and 13% of finasteride pretreated patients (Fig. 30.12b).

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Page 409 Meta-analysis In addition to the two meta-analyses mentioned previously38,41 two systematic reviews of tamsulosin in the treatment of BPH have been performed in recent years.60,61 The latest of these included 14 studies with a total of 4122 participants, mean age 64, with moderate LUTS. Patients were treated with a range of doses of tamsulosin per day. The weighted mean difference (WMD) for mean change in Boyarsky symptom score from baseline showed a 12% improvement with 0.4 mg/day and a 16% improvement with 0.8 mg/day, relative to placebo. Improvements in Q max were 1.1 ml/s for both dosages. Lower doses of tamsulosin (0.2–0.4 mg/day) were found to be as effective as alternative αantagonists. Rates of adverse events, which were generally mild, included dizziness, rhinitis, and abnormal ejaculation. These increased in a dose-dependent manner, with

Figure 30.12 Percentage of patients that perceived (a) the global efficacy and (b) the global tolerability as better than that of previous treatment with β-sitosterol, other file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_409.html[09.07.2009 11:54:43]

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Page 410 discontinuations due to such effects similar to placebo at the 0.2 mg/day dose, but increasing to 16% with 0.8 mg/day. Efficacy increased only slightly with higher doses. Ancillary properties Effect on PSA In contrast to finasteride, which reduces mean PSA plasma levels by 50%, tamsulosin (0.4 or 0.8 mg once daily), in comparison with placebo, had no clinically significant effect on PSA plasma levels, either in the phase III placebo-controlled European54 (Fig. 30.13) or US studies.43,44 Effect on lipids Modest positive effects on lipid plasma levels have been described in hypertensive patients treated with hemodynamically active α1-adrenoceptor antagonists. In one of the US placebo-controlled studies, tamsulosin also reduced serum triglyceride levels by 9% compared with <1% on placebo.44 Summary α1-Adrenoceptor antagonists have superior efficacy over finasteride and phytotherapy (at least in the short term), work independent of prostate size, are not associated with erectile dysfunction, and do not affect PSA plasma levels. Therefore, they are a very good first-choice medical therapy for patients with LUTS suggestive of BPH. The major disadvantages of the classical α1-adrenoceptor antagonists that were originally developed for hypertension (prazosin, doxazosin, terazosin, and alfuzosin) are their blood pressure-lowering potential with subsequent risk of (firstdose) orthostatic hypotension and associated need for dose titration. The reduction of the occurrence of orthostatic hypotension is clinically important because it is one of the risk factors for falling. Falls may lead to major injuries such as fractures and are the sixth leading cause of death in the elderly. Tamsulosin is an α1-adrenoceptor antagonist that displays selectivity for α1A- and α1D-adrenoceptors. In human volunteers, tamsulosin (modified-release formulation) caused less inhibition of experimentally induced vasoconstriction than hemodynamically active α1-adrenoceptor antagonists such as doxazosin and terazosin and it was therefore specifically developed to treat LUTS suggestive of BPH. It is available in Japan, most European countries, many Latin American countries, and the US. The recommended dosage for Caucasian patients is 0.4 mg once daily (after a meal). Tamsulosin 0.4 mg can be administered as its therapeutic dose from the start of therapy with no need for dose titration. As such it has superior efficacy to placebo and is as effective as other α1-adrenoceptor antagonists such as alfuzosin and terazosin. It has, however, a negligible potential for blood pressure lowering compared with other α1-adrenoceptor antagonists such as alfuzosin and terazosin, and induces less symptomatic orthostatic hypotension than terazosin. The only adverse event that was reported consistently and

Figure 30.13 Percentage of patients with specific changes in PSA from baseline on placebo or tamsulosin 0.4 mg once daily in the meta-analysis of the two European phase III placebo-controlled studies.62

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Page 411 significantly more often with tamsulosin 0.4 mg than placebo was abnormal ejaculation. There was no difference in reporting of abnormal ejaculation on tamsulosin, alfuzosin, or terazosin in comparative trials. The very good tolerability and minimal effects on blood pressure of tamsulosin are maintained in elderly patients and the vast majority of patients with cardiovascular co-morbidity and co-medication. The global efficacy of tamsulosin 0.4 mg was perceived better than that of previous treatment with finasteride or phytotherapy. The global tolerability was perceived better than that of previous treatment with other α1-adrenoceptor antagonists or finasteride. Tamsulosin 0.4 mg once daily is therefore a very good firstchoice medical therapy for Caucasian patients with LUTS suggestive of BPH. References 1. Caine M, Pfau A, Perlberg S. The use of alpha-adrenergic blockers in benign prostatic obstruction. Br J Urol 1976; 48:255–263 2. Chapple C R. Medical therapy and quality of life. Eur Urol 1998; 34 (Suppl 12): 10–17 3. Chapple C R. Pharmacotherapy for benign prostatic hyperplasia—the potential for α1-adrenoceptor subtypespecific blockade. Br J Urol 1998; 81 (Suppl 1): 34–47 4. Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of α1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999; 36:1–13 5. McVary K T. Medical therapy for benign prostatic hyperplasia progression. Curr Urol Rep 2002; 3:269– 275 6. Denis L, McConnell J, Yoshida O et al. and The Members of the Committees. 4th International Consultation on BPH. Recommendations of the International Scientific Committee: the evaluation and treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction. In: Denis L, Griffiths K, Khoury S et al. (eds). Proceedings 4th international consultation on benign prostatic hyperplasia (BPH). Paris, 2–5 July, 1997. Plymouth: Plymbridge Distributers, 1998:669–684 7. Focus on lower urinary tract symptoms: nomenclature, diagnosis, and treatment options. Highlights from the 5th international consultation on benign prostatic hyperplasia, June 25–27, 2000, Paris, France. Rev Urol 2001; 3: 139–145 8. Lepor H, Williford W O, Barry M J et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996; 335:533–539 9. Debruyne F M J, Jardin A, Colloi D et al. on behalf of the European ALFIN study group. Sustainedrelease alfuzosin, finasteride and the combination of both in the treat ment of benign prostatic hyperplasia. Eur Urol 1998; 34: 169–175 10. Kirby R S, Roehrborn C, Boyle P et al. for the PREDICT Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) Trial. Urology 2003; 61:119–126 11. McConnell J D, Roehrborn C G, Bautista O M et al. The long-term effect of doxazosin, finasteride, and combination therapy the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349:2387–98 12. Lepor H, Williford W O, Barry M J et al. for the Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. The impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response. J Urol 1998; 160:1358–1367 13. Boyle P, Gould A L, Roehrborn C G. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48:398– 405 14. Brawer M K, Lin D W, Williford W O et al. Effects of finasteride and/or terazosin on serum PSA: results of VA Cooperative Study #359. Prostate 1999; 39:234–239 15. Wilde M I, McTavish D. Tamsulosin. A review of its pharmacological properties and therapeutic potential in the management of symptomatic benign prostatic hyperplasia. Drugs 1996; 52:883–898 16. Bylund D B, Bond R A, Clarke D E et al. Adrenoceptors. In: Gidlestone (ed). The IUPHAR compendium of receptor characterization and classification. London: IUPHAR Media, 1998:58–74 17. Ford A P D W, Daniels D V, Chang D J et al. Pharmacological pleiotropism of the human recombinant α1A-adrenoceptor: implications for α1-adrenoceptor classification. Br J Pharmacol 1997; 121:1127–1135 18. Price D T, Schwinn D A, Lomasney J W et al. Identification, quantification, and localization of mRNA for three distinct alpha1 adrenergic receptor subtypes in human prostate. J Urol 1993; 150:546–551 19. Forray C, Bard J A, Wetzel J M et al. The alpha1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha (1c) file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_411.html[09.07.2009 11:54:44]

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subtype. Mol Pharmacol 1994; 45:703–708 20. Nasu K, Moriyama N, Kawabe K et al. Quantification and distribution of α1-adrenoceptor subtype in RNA’s in human prostate: comparison of benign hypertrophied and non-hypertrophied tissue. Br J Pharmacol 1996; 119: 797–803 21. Ford A P D W, Arrendondo N F, Blue D R Jr et al. RS-17053 (N-[2-(2cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α1-αdimethyl-1 H-indole -3-ethanamine hydro-

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Page 412 chloride), a selective α1A-adrenoceptor antagonist, displays low affinity for functional α1-adrenoceptors in human prostate: implications for receptor classification. Mol Pharmacol 1996; 49:209–215 22. Marshall I, Burt R P, Chapple C R. Noradrenaline contractions of human prostate mediated by α1A(α1C-) adrenoceptor subtype. Br J Pharmacol 1995; 115:781–786 23. Malloy B J, Price D T, Price R R et al. α1-Adrenergic subtypes in human detrusor. J Urol 1998; 160:937–943 24. Hatano A, Takahashi H, Tamaki M et al. Pharmacological evidence of distinct α1-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery. Br J Pharmacol 1994; 113:723–728 25. Faure C, Goutrier C, Langer S Z, Graham D. Quantification of α1-adrenoceptor subtypes in human tissues by competitive RT-PCR analysis. Biochem Biophys Res Com 1995; 213:935–943 26. Rudner X I, Booth J W, Funk B L et al. Subtype specific regulation of human vascular α1-adrenergic receptors by vessel bed and age. Circulation 1999; 100:2336–2343 27. Harada K, Ohmori M, Fujimura A. Comparison of the antagonistic activity of tamsulosin and doxazosin at vascular α1-adrenoceptors in humans. Naunyn Schmiedeberg’s Arch Pharmacol 1996; 354:557–561 28. Schafers R F, Fokuhl B, Wasmuth A et al. Differential vascular α1-adrenoceptor antagonism by tamsulosin and terazosin. Br J Clin Pharmacol 1999; 47:67–74 29. Foglar R, Shibata K, Horie K et al. Use of recombinant α1-adrenoceptors to characterize subtype selectivity of drugs for the treatment of prostatic hypertrophy. Eur J Pharmacol 1995; 288:201–207 30. Michel M C, Grubbel B, Taguchi K et al. Drugs for treatment of benign prostatic hyperplasia: affinity comparison at cloned α1-adrenoceptor subtypes and in human prostate. J Auton Pharmacol 1996; 16:21–28 31. Richardson C D, Donatussi C F, Page S O et al. Pharmacology of tamsulosin: saturation-binding isotherms and competition analysis using cloned α1-adrenergic receptor subtypes. Prostate 1997; 33:55– 59 32. Yamada S, Suzuki M, Tanaka C et al. Comparative study on α1-adrenoceptor antagonist binding in human prostate and aorta. Clin Exp Pharmacol Physiol 1994; 21:405–411 33. Andersson K E. Uroselectivity. In: Cockett A T, Khoury S, Aso Y et al. (eds). Proceedings of the 3rd international consultation on benign prostatic hyperplasia (BPH). Jersey: Scientific Communications International, 1996: 541–542 34. Kawabe K, Ueno A, Takimoto Y et al. and the YM617 Clinical Study Group. Use of an α1-blocker, YM617, in the treatment of benign prostatic hypertrophy. J Urol 1990; 144:908–912 35. Abrams P, Speakman M, Stott M et al. A dose-ranging study of the efficacy and safety of tamsulosin, the first prostate-selective α1A-adrenoceptor antagonist, in patients with benign prostatic obstruction (symptomatic benign prostatic hyperplasia). Br J Urol 1997; 80:587–596 36. Boyarsky S, Jones G, Paulson D F, Prout G R. A new look at bladder neck obstruction by the Food and Drug Administration regulators: guide lines for investigation of benign prostatic hypertrophy. Trans Am Assoc Genitourin Surg 1977; 68:29–31 37. Abrams P, Schulman C C, Vaage S and the European Tamsulosin Study Group. Tamsulosin, a selective α1c-adrenoceptor antagonist: a randomized, controlled trial in patients with benign prostatic ‘obstruction’ (symptomatic BPH). Br J Urol 1995; 76:325–336 38. Chapple C R, Wyndaele J J, Nordling J et al. on behalf of the European Tamsulosin Study Group. Tamsulosin, the first prostate-selective α1A-adrenoceptor antagonist. A meta-analysis of two randomized, placebo-controlled, multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). Eur Urol 1996; 29: 155–167 39. Lepor H, Auerbach S, Puras-Baez et al. A randomized, placebo-controlled multicenter study of the efficacy and safety of terazosin in the treatment of BPH. J Urol 1992; 148:1467–1474 40. Aso Y, Boccon-Gibod L, Da Silva F C et al. Subjective response, objective response, impact on quality of life. In: Cocket A T K, Aso Y, Denis L, Khoury S (eds). Proceedings of the international consultation on benign prostatic hyperplasia (BPH), Paris, 26–27 June. SCI, 1991: 85–90 41. Hofner K for the European Tamsulosin Study Group. Tamsulosin: effect on sexual function in patients with LUTS suggestive of BPO (symptomatic BPH). Eur Urol 1998; 33 (Suppl 1): 129 (abstract 515) 42. Abrams P, Tammela T L, Hellstrom P et al. for the ESPIRIT Group. European pressure-flow investigation of tamsulosin in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO)—ESPRIT study. J Urol 1998; 159 (Suppl 5): 256 (abstract 982) file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_412.html[09.07.2009 11:54:45]

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43. Lepor H for the Tamsulosin Investigator Group. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Urology 1998; 51:892–900 44. Narayan P, Tewari A and Members of United States 93–01 Study Group. A second phase III multicenter placebo controlled study of 2 dosages of modified release tamsulosin in patients with symptoms of benign prostatic hyperplasia. J Urol 1998; 160:1701–1706 45. Barry M J, Fowler F J, O’Leary M P et al. and the Measurement Committee of the American Urological Association. The American Urological Association symp-

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Page 413 tom index for benign prostatic hyperplasia. J Urol 1992; 148:1549–1557 46. Lepor H for the Tamsulosin Investigator Group. Longterm evaluation of tamsulosin in benign prostatic hyperplasia: placebo-controlled, double-blind extension of phase III trial. Urology 1998; 51:901–906 47. Schulman C C, Cortvriend J, Jonas U et al. on behalf of the European Tamsulosin Study Group. Tamsulosin: 3-year long-term efficacy and safety in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction: analysis of a European, multinational, multicenter, openlabeled study. Eur Urol 1999; 36:609–620 48. Schulman C C, Buzelin J-M, Lock T M T W. Tamsulosin: 3-year follow-up of efficacy and safety in 516 patients with LUTS suggestive of BPO. J Urol 1998; 159 (Suppl 5): 256 (abstract 983) 49. Lepor H and the Tamsulosin Investigator Group. Tamsulosin, long-term, open-label, extension study to evaluate response and efficacy. J Urol 1997; 157 (Suppl 4): 331 (abstract 293) 50. Narayan P, Evans C P, Moon T. Long-term safety and efficacy of tamsulosin for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia. J Urol 2003; 170:498–502 51. Buzelin J M, Fonteyne E, Kontturi M et al. for the European Tamsulosin Study Group. Comparison of tamsulosin with alfuzosin in the treatment of patients with lower urinary tract symptoms suggestive of bladder outlet obstruction (symptomatic benign prostatic hyperplasia). Br J Urol 1997; 80:597–605 52. Lee E, Lee C. Clinical comparison of selective and nonselective α1A-adrenoceptor antagonists in benign prostatic hyperplasia: studies on tamsulosin in a fixed dose and terazosin in increasing doses. Br J Urol 1997; 80:606–611 53. De Mey C, Michel M C, McEwen J, Moreland T. A double-blind comparison of terazosin and tamsulosin on their differential effects on ambulatory blood pressure and noc turnal orthostatic stress testing. Eur Urol 1998; 33: 481–488 54. Coffey D S. Controversies in the management of lower urinary tract symptoms: an overview. Br J Urol 1998; 81 (Suppl 1): 1–5 55. Michel M C, Bressel H U, Goepel M, Rubben H. A 6-month large-scale study into the safety of tamsulosin. Br J Clin Pharmacol 2001; 51:609–614 56. Chapple C R, Baert L, Thind P et al. on behalf of the European Tamsulosin Study Group. Tamsulosin 0.4 mg once daily: tolerability in older and younger patients with lower urinary tract symptoms suggestive of benign prostatic obstruction (symptomatic BPH). Eur Urol 1997; 32: 462–470 57. Michel M C, Mehlburger L, Bressel H-U et al. Tamsulosin treatment of 19,365 patients with lower urinary tract symptoms: does co-morbidity alter tolerability? J Urol 1998; 160:784–791 58. Lowe F C. Coadministration of tamsulosin and three antihypertensive agents in patients with benign prostatic hyperplasia: pharmacodynamic effect. Clin Ther 1997; 19: 730–742 59. Michel M C, Bressel H -U, Mehlburger L, Goepel M. Tamsulosin: real life clinical experience in 19 365 patients. Eur Urol 1998; 34 (Suppl 2): 37–45 60. Wilt T J, MacDonald R, Rutks I. Tamsulosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2003; 1: CD002081 61. Wilt T J, MacDonald R, Nelson D. Tamsulosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects. J Urol 2002; 167:177–183 62. Denis L for the European Tamsulosin Study Group. Tamsulosin: effect on PSA levels in 3-month placebo-controlled studies and long-term follow-up of these studies. Eur Urol 1998; 33 (Suppl 1): 130 (abstract 517)

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Page 415 31 Phytotherapeutic agents in the treatment of LUTS and BPH K Dreikorn J M Fitzputrick Introduction The spectrum of synthetic pharmaceutical treatment options for patients presenting with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) has expanded considerably over the last decade and this has been accompanied by an increase in the use of plant-derived therapies.1,2 At the same time, a worldwide decrease in classical operative procedures has been reported, with rates of transurethral resection of the prostate (TURP) and open prostatectomy falling by up to 50% in some countries.3 While there is at least some agreement concerning the scientific rationale and indications for the use of α-adrenoceptor blockers and 5α-reductase inhibitors, the role of phytotherapeutic agents in the treatment of LUTS and BPH has traditionally been less clear and has been continuously debated.4–22 The use of plant extracts is long established in France and Germany, and so products containing extracts of Serenoa repens and Pygeum africanum, among others, have a market share of up to 50% of all preparations used for the treatment of symptomatic BPH. In these countries, plant extracts are prescribable drugs, their costs being totally or partly reimbursed by the heathcare system, in contrast to the UK, for example, where they are neither approved nor reimbursed.23 In the US, plant-derived medications are sold as nonreimbursable nonprescription dietary supplements, mostly in natural health food stores. Some preparations which are available by prescription only in Europe, such as the lipido-sterolic extract of Serenoa repens (LSESr) Permixon®, are not available at all in the US.1 In 2000, US sales of dietary supplements were reported to have reached $17.1 billion,24 and around $1.5 billion are reportedly spent on the self-medication of LUTS.25 According to some US urologists, 50–90% of newly referred patients with LUTS secondary to BPH have already tried or are using some form of alternative or complementary medication at the time of their presentation.13–15,26 The suggestion that ‘natural agents’, commonly supposed to be without sideeffects, might be as efficacious as synthetic and chemical products, seems attractive for patients who prefer such an approach.17,26 We as treating physicians have to face this development. This widespread and increasing patient preference, however, has to be balanced against the need for increased awareness of the importance and necessity to select treatment options on evidence-based rationales.27,28 Origin of plant extracts In Europe alone, more than 100 botanic preparations are available for the treatment of LUTS secondary to BPH.5,6,29 Although extracts from more than 30 different plants are being used for these products, the most popular phytotherapeutic agents originate from the roots, seeds, barks, or fruits of the plants listed in Table 31.1. Table 31.1 Origin of phytotherapeutic agents for the treatment of LUTS secondary to BPH Common term Element utilized Latin term American dwarf palm, saw palmetto Fruit Serenoa repens, Sabal serrulata South African star grass Root Hypoxis rooperi Pine Root Pinus Spruce Root Picea African plum tree Bark Pygeum africanum Stinging nettle Root Urtica dioica Rye Pollen Secale cereale Pumpkin Seeds Cucurbita pepo

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Page 416 Some preparations are produced from a single plant, others contain extracts from two or more sources. The extraction procedures differ from company to company. Therefore, the composition and components of one individual product may be significantly different to those of another manufacturer, even if the product originates from the same plant(s). As a consequence, the results of basic research studies or clinical trials involving a specific product cannot automatically be applied to another preparation. Several active components of plant extracts have been identified (Table 31.2). However, whether these elements Table 31.2 Proposed active constituents of plant extracts. Phytosterols (β-sitosterol) Phyto-estrogens Free fatty acids (lauric and myristic acid) Lectins Flavonoids Plant oils Polysaccharides represent all the most active and important elements of the preparations for the beneficial in vitro and in vivo effects described (Table 31.3) is still not known.6,8–12,29,30 The precise mechanism of action of many products has also yet to be elucidated, although antiestrogenic and proapoptotic effects have been reported for some preparations, alongside inhibition of 5α-reductase activity.31,32 As the extraction methods of products derived from the same source could lead to differing levels of efficacy, bioavailability, and pharmacodynamics, it has been recommended that individual products be evaluated separately.29 In addition, both synthetic and natural products should be subjected to identical analytic, biological, and clinical evaluations. Phytotherapeutic compounds Serenoa repens The extracts from the berries of the American dwarf palm ( Serenoa repens, saw palmetto, Sabal serrulata ) are the most popular plant-based products used in the treatment of symptomatic BPH.4–6,13,16,29 In Germany alone, more than 30 different products contain Serenoa repens,6,29 while numerous similar products are also available in the Table 31.3 Proposed mode of action of plant extracts. Mechanism of action Extract Inhibition of 5α-reductase I and II activity Serenoa repens, Secale cerecale, cactus flower Anti-estrogenic effect Serenoa repens, Pygeum africanum Anti-androgenic effect Serenoa repens, Cucurbita pepo Anti-inflammatory effect Serenoa repens, β-sitosterol, Pygeum africanum, Cucurbita pepo Induction of apoptosis β-Sitosterol, Serenoa repens Interference with prostaglandin metabolism β-Sitosterol, Pygeum africanum Inhibition of phospholipase A2 and 5β-Sitosterol lipoxygenase enzymes Suppression of prostate cell metabolism and Urtica dioica, Serenoa repens growth Inhibition of proliferative growth factors Urtica dioica, Serenoa repens Decrease of sex hormone-binding globulin Urtica dioica Protection/strengthening of detrusor muscle Pygeum africanum Alteration of cholesterol metabolism Pygeum africanum Free radical scavengers/membrane stabilization Pygeum africanum Inhibition of aromatase activity Cactus flower Reduction of prostatic urethral resistance Secale cereale Action on α-adrenergic receptors Secale cereale, Serenoa repens

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Page 417 US. Many of them contain extracts from other plants ( Pygeum africanum, pumpkin seeds, etc.) and minerals, such as zinc. The different extracts contain mainly free and esterified fatty acids, phytosterols, and long-chain alcohols. More recently, free fatty acids have been proposed to be the active components of Serenoa repens extracts, primarily responsible for their beneficial effects on the prostate. On this basis the precise composition could critically influence both biological and clinical activity. The most extensively investigated preparation is Permixon, an n-hexane LSESr and a complex mixture of free fatty acids, phytosterols, aliphatic alcohols, and various polyphrenic compounds.6,29,33 A number of potential mechanisms of action have been attributed to Permixon, including anti-androgenic and antiinflammatory activity, inhibition of cell proliferation, and promotion of apoptosis.31,33–38 The action of Permixon is now considered to be predominantly attributable to uncompetitive 5αreductase type I and type II inhibition, resulting in lower levels of dihydrotestosterone (DHT) formation from testosterone in the prostate.31,39 Although Rhodes et al.,40 in 1993, did not subscribe to this, the theory that Permixon is an effective inhibitor of 5α-reductase type I and type II has been substantiated by in vitro studies by Bayne et al.31,39 In a specially developed clinically relevant model, 5 days’ treatment of co-cultured human prostate cells with 10 μ g/ml Permixon resulted in significant inhibition of 5α-reductase type I and type II; the dose utilized was estimated to correspond to the concentration reached in plasma and prostate at the recommended clinical dose. The hypothesis promulgated is that lauric and myristic acid, which comprise a subfraction of the free fatty acids contained in the preparation, modulate the cell-membrane environment in a way that reduces the activity of the nuclear membrane-bound 5α-reductase.41 The observation that no decrease of prostate-specific antigen (PSA) is observed in vivo42 is explained by the assumption that Permixon, in contrast to finasteride, does not interfere with PSA production and has little or no effect on other androgen-dependent processes which rely on the binding of androgens to their receptor. Subsequent studies also suggested that Permixon specifically decreases cell proliferation and increases the apoptotic index of the prostatic stromal and epithelial cells.38 Studies involving alternative sources of Serenoa repens have suggested that it has anti-estrogenic or anti-inflammatory effects.32,43 Lower levels of DHT and higher levels of testosterone have been identified in the prostates of Permixontreated BPH patients;44 however, superficially at variance with an action as a 5α-reductase inhibitor, no significant effect on serum levels of PSA and prostate volume has been demonstrated in several studies.6,29,33,42 Indeed, the data on several potential mechanisms of action of Serenoa repens are often confusing and contradictory and many of the effects described have only been demonstrated in vitro, often with considerably higher dosages of the extract than are recommended for clinical treatment. The commonly recommended dose of Serenoa repens is 320 mg daily, often divided into two doses. A dose of 160 mg Permixon twice daily seems to be as efficacious as two capsules of 160 mg once daily.45 Aside from occasional gastrointestinal discomforts, no significant side-effects have been reported with the extract, in contrast to most other medical or surgical approaches. The numerous published clinical trials involving Serenoa repens extracts have been critically reviewed by a committee during the 4th (1997) and 5th (2000) International Consultations on BPH,6,29 and in two articles by one of the committee members.15,16 These Consultations recommended that extracts of Serenoa repens produced by different manufacturers be evaluated separately and regarded as discrete entities, due to variance between products associated with different extraction processes and other factors. They also highlighted the need for placebo-controlled trials of such products, as are conducted for traditional synthetic pharmaceuticals. Although it is accepted that uncontrolled trials and comparative trials without placebo controls are of only limited value in the quantification of the clinical efficacy of Serenoa repens in the treatment of LUTS and BPH,6,29 several trials involving the extract have taken place that indicate that significant improvements in LUTS symptomatology occur. However, the results are dependent on the product (and presumably the composition). A recent long-term trial examined the efficacy of twice-daily Permixon (160 mg) in 130 BPH patients over 2 years.46 Prostatic symptoms were assessed using validated instruments such as the International Prostate Symptom Score (I-PSS) and sexual function using the Male Sexual Function (MSF-4) questionnaire. PSA, peak urinary flow ( Q max), and quality of life were also evaluated every 6 months. Significant improvements were observed for I-PSS, Q max, and quality of life, while prostate size fell by 5.9 ml by the end of the study period. MSF-4 scores rose significantly in the second year of treatment and total PSA and hormonal levels did not change. A further, longer-term study of Permixon in men with mild to moderate BPH ( n =26) revealed that file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_417.html[09.07.2009 11:54:47]

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Page 418 administration of 320 mg of the drug decreased mean I-PSS by 8.8±0.18, increased Q max by 4.13±0.51 ml/s on average, and improved quality of life after 5 years, providing further evidence of the long-term efficacy of the drug.47 It has been suggested that a ‘placebo effect’ may contribute to the improvements observed in men receiving some extracts of Serenoa repens . In a study of 50 men with LUTS, who were treated for 6 months with a Serenoa repens preparation, a significant improvement in I-PSS from 19.5 to 12.5 was noted ( p =0.001).48 No significant changes in PSA levels or improvement in Q max, postvoid residual volume (PVR), bladder capacity, or detrusor pressure at peak urinary flow rate were observed, however. The authors accept that this subjective improvement in voiding symptoms that occurred without demonstrable objective change in any of the measure urodynamic parameters may be attributable in part to the placebo effect and conclude that further studies, including placebo-controlled trials, are needed.48 Other studies have suggested that the benefit does not only arise from a placebo effect. A trial excluding patients who had previously responded to placebo medication revealed that, when treated with Permixon, these nonresponders showed significant reductions in both daytime and nocturnal urinary frequency and improvement in Q max. 49 Some data have proven inconclusive.6,16,29 Thus, although it was shown in the 30-day study described above49 that dysuria, daytime frequency, nocturia, and Q max were all significantly improved in Permixon-treated patients compared with baseline values and placebo-treated patients, the study did not show any real perceived clinically relevant benefit of the drug over placebo by the patients or their physicians. When the patients and physicians were asked to assess the global efficacy of the treatment at the end of the trial, the rates of satisfaction were 68% and 47%, respectively, for the placebo group versus 71% and 57%, respectively, for the Serenoa repens -treated patients. The short-term nature of this trial limits the interpretation of the data. In an attempt to quantify the benefit more precisely, double-blind randomized clinical trials have been undertaken on some Serenoa repens -containing products. In a 6-month, double-blind, randomized comparative trial with finasteride in 1098 patients, the efficacy of Permixon was found to be equivalent to that of the 5α-reductase inhibitor50. The decrease in I-PSS was 37% and 39% and the increase in Q max was 2.7 ml/s (25%) and 3.2 ml/s (30%) in the Serenoa repens and finasteride groups, respectively. Greater drug-related side-effects, particularly in terms of lowered libido and increased erectile dysfunction were observed in the finasteride group. Unfortunately, this study did not include a placebo group and the volumes of the prostates were rather small (baseline volumes 43 ml and 44 ml, respectively, for the two groups). As we know today, the effect of finasteride may be limited in small prostates.51 Therefore, in analogy to the VA study,52 the comparison between Serenoa repens and finasteride in this study might simply show equivalency of both agents to placebo, although Hamdy et al. postulated that prostatic volume does not correlate with the efficacy of treatment using either finasteride or phytotherapy.53 Comparison of Serenoa repens to ‘conventional’ therapy is not limited to finasteride, however. A comparison of the α-blocker tamsulosin to Permixon took place over a period of 12 months and involved 811 BPH patients from 11 different countries.54 I-PSS fell by 4.4 in each group and Q max also improved to a similar extent. A second trial, involving alfuzosin and Permixon, also revealed the latter drug to be equally effective for the treatment of urinary symptoms. Sixty-three men with mild to moderate BPH who did not respond to placebo were randomized to receive either 320 mg Permixon daily or 2.5 mg alfuzosin three times a day for 3 weeks.55 Symptom scores improved significantly from baseline with no significant difference between treatment groups. Overall, therefore, Permixon has been shown to produce clinical efficacy equivalent to that observed with both α-blockers and finasteride; this would tend to indicate that the action of Permixon does not arise from a placebo effect alone. Phytosterols/β -sitosterol Although β-sitosterol and various other phytosterols are contained in many plant extracts used for the treatment of symptomatic BPH, some manufacturers presume that β-sitosterol is the major active component and therefore classify their preparation by the content of this element. Most preparations available derive from the species Hypoxis rooperi, Pinus, or Picea. β-Sitosterol is claimed to be both a cyclo-oxygenase and a lipoxygenase inhibitor, interfering with prostaglandin metabolism and thereby exerting anti-inflammatory effects.30 A stimulatory effect on transforming growth factor (TGFβ), which induces apoptosis, and translocation protein kinase Cα has also been discussed.6,56,57 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_418.html[09.07.2009 11:54:48]

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In a German study the β-sitosterol preparation Harzol® was evaluated in a 6-month, double-blind,

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Page 419 placebo-controlled study of 200 patients.56,58 While the placebo group showed only mild improvements, statistically significant improvements were noted for I-PSS, quality of life, Q max, and PVR in the β-sitosterol-treated patients who received 20 mg of the product, three times daily. The I-PSS improved by 2.3 points for placebo and 7.4 for β-sitosterol; Q max increased by 1.1 ml/s for placebo and 5.2 ml/s for the test group. Follow-up observations (up to 18 months) have shown that those patients who continued treatment and even those who stopped the medication maintained their benefit, while placebo-treated patients improved with a similar response once started on β-sitosterol.56 Another preparation, also containing mainly β-sitosterol (Azuprostat®, 65 mg twice daily) was evaluated in a 6-month, randomized, placebo-controlled trial of 177 patients.59 The magnitude of the statistically significant improvement in this study was great: the I-PSS improved by 2.8 in the placebo group compared to 8.2 in the treatment group and Q max increased by 4.4 ml/s and 8.8 ml/s, respectively. The results of both studies with phytosterols, although exciting, await confirmation by other groups. African plum tree Extracts from the bark of the African plum tree (Pygeum africanum) are widely used in France and the US. Almost all basic research and clinical studies have been performed with the product Tadenan®.6,15,16 The chloroform extract contains phytosterols, short-chain (lauric and myristic) and unsaturated long-chain (oleic and linolic) fatty acids. The extract is thought to inhibit fibroblast proliferation and to exert an anti-inflammatory and antiestrogenic effect.6,60,61 Eleven constituents have been identified in the crude extract, including high levels of myristic acid, which is thought to affect membrane fluidity directly and to reduce the contact between propagating free radicals and unsaturated lipid substances, thereby slowing the process of hydrolysis and membrane degradation.61 Moreover, in a rabbit model, the agent is thought to protect the bladder musculature from contractile dysfunction caused by outlet obstruction, improving bladder ultrastructure, bladder compliance, and contractile responses.62–67 According to Levin et al.65 and Hass et al.,61 obstruction induces ischemic muscular membrane damage, which might be caused by lipid peroxidation. High levels of myristic acid found in the Pygeum extract may make the bladder cell membranes less susceptible to lipid peroxidation and thereby exert their protective effect on the bladder. However, in the experimental studies demonstrating this effect, highly supraclinical doses were used. Therefore, the applicability of these findings to clinical BPH remains questionable. Although there are numerous open and short-term placebo-controlled studies suggesting clinical efficacy,68–70 the trials do not meet the guidelines recommended by the International Consultation conferences.6 Breza et al.71 reported a multicenter open-label trial involving 85 patients, treated over 2 months with Tadenan, followed by 1 month without treatment. Improvement in I-PSS was 40%, reduction of nocturia 32%, improvement of quality of life 31%, and increase in Q max 19%, without any reduction of prostate volume. Significantly, the improvements were maintained during the 1-month no-treatment phase. Overall, the data are not conclusive, however, and longer-term data are not available. Stinging nettle Extracts from the roots of the stinging nettle (Urtica dioica) are widely used in Germany. They contain a complex mixture of water- and alcohol-soluble compounds, including lectins, phenols, and sterols.5,6,30 Whether the suggested modes of action, which include inhibition of prostatic growth factor interaction, suppression of prostatic cell metabolism and modulation of the binding of sex hormone-binding globulin, have any relevance in clinical BPH is uncertain. Studies performed more than 10 years ago are inconclusive because of small patient numbers and short trial duration.72,73 In a randomized, placebocontrolled, 3-month study of 41 patients, a liquid preparation showed superiority over placebo, but was not marketed because its taste was not accepted by patients.74 Extracts of stinging nettle are often combined with one or more alternative plant-derived therapy, as discussed later in the chapter. Rye grass pollen extract A product deriving from the pollen of some selected plants growing in southern Sweden is marketed as a registered pharmaceutical (Cernilton®) in some European countries, Japan, Korea, and Argentina. The extract consists of a water- and fat-soluble fraction combined into a tablet or capsule. In vitro studies suggest that pollen extracts exert an effect on α-adrenergic receptors, relax the sphincteric musculature, increase prostatic and serum zinc levels, and 5α-reductase activity.30,75 Moreover, the growth of

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Page 420 immortal cancer cell lines was inhibited and in rats atrophy of the prostatic lobes was observed.76 In a German 3-month, multicenter, double-blind, placebo-controlled study of 103 patients, nocturia and diurnal frequency were significantly reduced by 69 and 66%, respectively, in the treatment group, compared to 37% and 44% in the placebo group.77 A 6-month, doubleblind, placebo-controlled study of 60 patients reported an overall significant symptomatic improvement of 69% in the pollen extract group compared to 29% in the placebo group.78 In a comparative trial of 89 patients over 4 months with a Pygeum africanum extract (Tadenan), the pollen extract showed better results with regard to improvement of irritative and obstructive symptom scores, Q max, and residual urine.75 However, comparison of Cernilton to tamsulosin and a combination of both revealed the combination and tamsulosin alone to be more effective than Cernilton alone.79 Pumpkin seeds Extracts from pumpkin seeds (Cucurbita pepo) are used to treat symptomatic BPH in several countries, such as Germany. The seeds contain a sweet-tasting, oily substance, mainly composed of linolic acid, Δ5 and Δ7 sterols, tocopherol, selenium, magnesium, and carotenoid. The extract is thought to have an anti-androgenic and antiphlogistic action. A randomized, placebo-controlled, double-blind trial of 476 men with BPH showed a significantly greater reduction in I-PSS (−6.8) compared to the placebo group (−5.6) over a period of 12 months. The other parameters ( Q max, quality of life, prostate volume, PVR) did not change in either of the groups, however.80 Cactus flower extracts Cactus flower extract, known as opuntia, is included in the British herbal pharmacopoeia as indicated for prostatic hypertrophy and is a commonly used herbal remedy for BPH in Israel. Aqueous and organic solvent extracts of dried cactus flower powder have been described as having a broad spectrum of activity, including inhibition of both type I and type II 5α-reductase activity and inhibition of aromatase and antioxidant activity.81 The authors postulate that as cactus flower has simultaneous 5α-reductase and aromatase inhibitory activity it possesses a uniquely dual advantage in the treatment of BPH; however, there are no reports of any controlled clinical trials with cactus flower products. Combination products Although there is no scientific evidence showing that the efficacy of phytotherapeutic preparations is enhanced by the combination of extracts from several plants, many companies offer mixtures of plant extracts, claiming that the possible effects demonstrated for extracts from individual plants may be additive in combination products. In a 3-month, randomized, double-blind study of 53 patients given extracts from pumpkin seeds and Serenoa repens, urinary flow rates, micturition time, residual urine, frequency of micturition, and a subjective assessment of the treatment effect were all significantly improved while the changes in the placebo group were not.82 A combination product of Serenoa repens and stinging nettle (Prostagutt® forte) was used in a randomized, placebo-controlled study of 40 patients (6-month doubleblind treatment phase followed by 6 months of open treatment). Greater improvement in both I-PSS and Q max was observed with treatment than with placebo: I-PSS decreased from 18.6 to 11.1 in the treatment group during the 6 months of double-blind treatment, compared to a decrease from 19 to 17.6 ( p =0.002) with placebo. During the open-label extension phase, the initially placebotreated patients decreased in I-PSS from 17.6 to 13.3 and the treatment group continued to improve from 11.1 to 9.8. Q max increased by 2.3 ml/s over the first phase in the verum group and by an additional 1.15 ml/s over the openlabel second 6month phase, while an increase of only 0.45 ml/s was observed in the placebo group over the initial placebo phase with a 2 ml/s increase during the subsequent active treatment phase.83 The same preparation was also compared with finasteride in 489 patients randomized and observed for 48 weeks.84 There was a statistically significant improvement in each group, with a drop in I-PSS from 11.3 to 6.5 for the patients treated with the plant extract, compared with a decrease from 12.6 to 6.9 in finasteride-treated patients. Q max increased by 1.9 ml/s in the plant extract group and 2.7 ml/s in the finasteride group; however, there was no statistical significance between the treatment groups. Prostate volume and PSA decreased in the finasteride group only. The mean baseline prostate volume was 42 ml in the plant extract group versus 44 ml in the finasteride group. Meta-analyses of phytotherapeutic agents If adequate (gold-standard) randomized, placebocontrolled studies are lacking, confirmation of efficacy of file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_420.html[09.07.2009 11:54:49]

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Page 421 a drug is often sought through meta-analysis. There are some potential limitations in this approach, however, as it has been shown that the agreement between meta-analyses and subsequent large clinical trials can be discordant. Meta-analyses have a positive predictive value of 68% and a negative predictive value of 67%.85 This means that up to one-third of meta-analyses may not accurately predict subsequent clinical trial results. Further, when the studies pooled in a meta-analysis are of poor quality, the metaanalysis itself can be compromised and the impact of the conclusions diluted. Overall, however, there is an increasingly widespread use of meta-analyses in the health-care environment. Several meta-analyses involving plant-derived BPH treatments have been published, four on Serenoa repens extracts,86–89 two on β-sitosterols,90,91 one on Pygeum africanum, 92 and two on rye grass pollen (Cernilton).93,94 In general, the meta-analyses support the hypothesis that phytotherapeutic agents are beneficial in the treatment of LUTS in BPH patients. In the original meta-analysis published by Wilt et al.86 on Serenoa repens, 18 randomized studies were included, involving 2939 men with BPH. The mean weighted difference in comparison to placebo was an improvement in symptom score of 1.41 points, an increase in Q max of 1.93 ml/s and a reduction in nocturia episodes of 0.76 per night. A follow-up analysis conducted 4 years later, with an additional three trials and a total of 3139 patients, revealed quantitatively and qualitatively similar results.57 Overall, urinary symptom score fell by 1.41 points (range 0–19), nocturia rates fell by 0.76/night, and Q max increased by 1.86 ml/s. Despite the benefit observed in these analyses, the inclusion of products from 11 different manufacturers obtained by different extraction processes partially compromised the interpretation of the data and thereby potential extrapolation to general clinical use. On the basis of the evidence, it was therefore concluded that Serenoa repens improves urologic symptoms and flow parameters, but that further clinical profiling is needed. In particular, the clinical activity of individual standardized preparations should be determined. It has been emphasized by an expert committee at the ICUD BPH Consultations,6 and even recently by Wilt himself,18 that comparison between various manufacturers’ preparations of the same plant extract is problematic. Data analysis can be hindered because of variations in the extraction processes, absence of precise analytical information on composition, lack of certainty that the same supposedly active component(s) of the extract are included in the final product, and variability in batch preparation. Moreover, only one of the 18 studies included in the first meta-analysis by Wilt et al. fulfilled the three main criteria of being placebo-controlled, utilizing standard symptom score evaluations, and being of at least 3 months’ duration. In an attempt to address some of the issues raised in previous analyses, another meta-analysis on a single Serenoa repens product (Permixon) was published by Boyle et al.87 Eleven placebo-controlled randomized trials and two open-label trials were pooled. Eleven trials had information regarding Q max and nocturia. The additional Permixon effect, beyond that observed on placebo, on Q max was 1.87 ml/s and the additional effect on nocturia was a decrease of 0.55 episodes per night. A further metaanalysis conducted by the same team of all contemporary published data available on Permixon involved a further 1963 men from four randomized studies.89 The additional data allowed examination of the effect of Permixon on I-PSS and revealed that, in addition to improving peak flow (2.28±0.29 above placebo) and nocturia (1.01±0.13 above placebo), the drug caused a significant fall in I-PSS (−4.7±0.41). Such changes are at least as great as those described in equivalent meta-analyses for terazosin95 and finasteride96 (Figure 31.1). Wilt et al.90 also published a review of β-sitosterol studies, including four double-blind trials of 519 men, with a duration of 4–26 weeks. The weighted mean difference (WMD) of β-sitosterol versus placebo was −4.9 points on the I-PSS (35% improvement versus placebo) in two studies. When a study which did not show pure β-sitosterol-β-D-glucoside to be superior to placebo was excluded, the WMD for the Q max was 5.13 ml/s (53% improvement). The authors state that β-sitosterols improve symptom scores by 35%, Q max by 34%, and reduced PVR by 24%. Nevertheless, the necessity of additional studies of sufficient size and duration, with known concentrations of β-sitosterol, is emphasized in order to assess the long-term efficacy of β-sitosterols and their ability to prevent complications from BPH. Three different preparations were used in the four studies, and as it is uncertain whether the doses are comparable, no definite conclusions can be drawn from this review. MacDonald et al.93 published a review of four old studies with the rye pollen extract Cernilton. Two placebo-controlled and two comparative trials involving 444 men were included. None of the studies would have fulfilled the quality criteria of the recommendations of the International Consultation, because of short trial duration, insufficient and incomplete outcome data, and no file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_421.html[09.07.2009 11:54:49]

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Figure 31.1 Comparison of Permixon, terazosin, and finasteride meta-analytical data for peak urinary flow (Qmax) and International Prostate Symptom Score (I-PSS) improvement above placebo. controls in two studies. The conclusion of the review was that Cernilton is well tolerated and modestly improves subjective urologic symptoms. Cernilton was not shown to improve urinary flow compared with placebo. The most important conclusion, however, could be anticipated by looking at the studies included, namely, that randomized, placebo-controlled studies are needed to evaluate the clinical effectiveness and safety of Cernilton and its ability to prevent complications from BPH. After a critical evaluation of the four published metaanalyses available at the time, the expert committee (‘Other Medical Therapies’) of the 5th International Consultation on BPH (Paris, 2000)29 came to the following conclusions: ‘Although there is uniformity in the results of these meta-analyses to suggest clinical efficacy of phytotherapeutic products, it is the opinion of the committee that the hypothesis and claim of phytotherapies to be beneficial in the management of LUTS/BPH can not be confirmed conclusively without large, appropriately randomised clinical trials of adequate duration that meet the GCP Guidelines resp. recommendations of the International Consultation on BPH’. On this basis the more recent analyses by Boyle et al.89 would appear to indicate that, of the products evaluated, only Permixon would come close to satisfying these criteria. Conclusions While there has always been at least basic consensus on the rationale and indications for α-blockers and finasteride in the treatment of LUTS secondary to BPH, there has been much controversy concerning the place and efficacy of plant extracts in these patients. As clinical evidence gathers, at least for some preparations, this picture is slowly changing, however. As evidence of their efficacy, plant-derived agents have been used for many years, especially in some European countries, and their use is increasing in the US, where a 100% rise in the sale of botanic products has been noted since 1994. Moreover, there is an increasing trend of patients and even physicians in many countries to turn away from chemical and synthetic drugs to ‘natural’ preparations and paramedical forms of therapy. Additionally, an increasing number of patients prefer self-medication and treatment, which is supported by the marketing strategies of companies producing such products. On the other hand, the medical profession is increasingly aware of the importance of the need to make treatment selections on the basis of good evidence of benefit: risk from carefully controlled clinical trials.27,28 For novel therapies, potentially this may lead to conflicts when guidelines are established according to the principles of evidence-based medicine.

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Page 423 It is astonishing that, although a tremendous amount of literature concerning the use of phytotherapy in LUTS and BPH exists, many important questions remain at least partially unanswered: • Which are the active components of the preparations? • How do they exert their claimed effects? • What is their bioavailability? • Is there a dose dependency? • How can the products be standardized and compared? The International Consultations on BPH have repeatedly called for phytotherapeutic preparations to be subjected to the same critical evaluations which are applied to the treatment of LUTS and BPH with drugs designed by medicinal chemists, such as α-blockers and 5α-reductase inhibitors.6–8,11,29,97 Ony a few companies have so far taken up this challenge. Reasons for others not having done this might include that the costs of such evaluations would be difficult to recoup because these products are not patentable. Overall, it can reasonably be concluded that phytotherapeutic products are generally well tolerated and, in some countries, less expensive than α-blockers and 5α-reductase inhibitors. Although both objective and subjective clinical improvements have been shown in carefully controlled clinical trials, these evaluations have been restricted to only a few products/brands and have yet to be mirrored with the majority of plant-based preparations. It is pertinent to note that most plant extracts are complex mixtures and a product from one company is, in real terms, unique, as the extraction procedures differ from producer to producer and the exact compositions of the preparations may vary between batches. In the majority of cases they are also only partly chemically defined. Therefore, the products of the different companies may not be comparable with regard to the components contributing to the overall biological and clinical profile, even if the extracts originate from the same plant. As a consequence, meta-analyses containing extracts from different companies are only of limited use in evaluation of the efficacy of plant extracts, even if the products stem from the same species. In addition, it may be assumed that an extract from one type of plant has different mechanisms of action, efficacy, bioavailability, and pharmacodynamics, compared to an extract from another plant species. For this reason, meta-analyses which include studies with products from different companies and different plant species may carry a substantial risk of ‘inborn errors’ if general conclusions are drawn. Further, meta-analytical data from one brand will not be directly translatable to another with a different composition. In conclusion, as long as the components of plant extracts are not chemically defined or standardized for all products, separate scientific studies have to be performed with each extract/mixture in order to assess its individual efficacy. If the principles of evidence-based medicine are applied to the evaluation of the current data on phytotherapeutic agents in the treatment of LUTS and BPH, clear-cut evidence for their efficacy until recently has been difficult to establish- Although there is increasing evidence of efficacy for some products this is not true of all extracts by any means. More proof is needed for other plant-based medications, particularly if the prescription costs are to be reimbursed by the public health care system. If patients buy phytotherapeutic agents because of their preferences for ‘natural’ products as dietary supplements at their own expense they should not be discouraged because they will, at least, enjoy a placebo effect. However, it must be stressed that a sole symptom relief may mask the progression of a disease. Uncontrolled studies with low patient numbers and of short duration, not performed according to accepted standards and guidelines, are of questionable value. Likewise, meta-analyses are only acceptable if the quality of the studies included is assessed and shown to be appropriate. Due to the widely controversial and partly insufficient ‘hard’ data about the efficacy of phytotherapy for the treatment of symptomatic BPH, the International Consultations on BPH were reluctant to recommend phytotherapy as a therapeutic option.98 The same opinion was developed by an expert committee which established the guidelines for the German urologists according to the principles of evidence-based medicine.” More evidence has become available, from gold-standard clinical trials and rigorous metaanalysis,87,89 however, suggesting that a review of the role of phytotherapy in the management of the BPH is required. References 1. Gerber G S. Phytotherapy for benign prostatic hyperplasia. Curr Urol Rep 2002; 3:285–291 2. Vallancien G, Pariente P. Treatment of lower urinary tract symptoms suggestive of benign prostatic file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_423.html[09.07.2009 11:54:50]

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obstruction in real life practice in France. Prostate Cancer Prostatic Dis 2001; 4:124–131

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Page 424 3. Bruskewitz R. Management of symptomatic BPH in the US: who is treated and how? Eur Urol 1999; 36 (Suppl 3) 7–13 4. Dreikorn K, Richter R. Conservative nonhormonal treatment of patients with benign prostatic hyperplasia. N Develop Biosci 1989; 5:109–121 5. Dreikorn K, Schönhöfer P S. Stellenwert von Phytotherapeutika bei der Behandlung der benignen Prostatahyperlasie (BPH). Urologe A 1995; 34:119–129 6. Dreikorn K, Borkowsi A, Braeckman J et al. Other medical therapies. In: Denis L, Griffiths K, Khoury S et al. (eds). Proceedings of the 4th international consultation on benign prostatic hyperplasia (BPH) 1997. Plymouth: Plymbridge Distributors, 1998:633–659 7. Fitzpatrick J M, Dreikorn K, Khoury S et al. The medical management of BPH with agents other than hormones or alpha-blockers. In: Cocket A T K, Aso Y, Chatelain C et al. (eds). Proceedings of the 2nd international consultation on benign prostatic hyperplasia (BPH), Paris 26–27 June 1991 SCI. 1991:195– 199 8. Fitzpatrick J M, Dreikorn K, Khoury S et al. The medical management of BPH with agents other than hormones or alpha-blockers. In: Cocket A T K, Aso Y, Chatelain C et al. (eds). Proceedings of the 2nd international consultation of benign prostatic hyperplasia (BPH), Paris 27–30 June 1993 SCI. 1993:445– 450 9. Fitzpatrick J M, Lynch T H. Phytotherapeutic agents in the management of symptomatic benign prostatic hyperplasia. Urol Clin North Am 1995; 22:407–412 10. Fitzpatrick J M, Lynch T H. Phytotherapeutic agents. In: Kirby R, McConnell J D, Fitzpatrick J M et al. (eds). Textbook of benign prostatic hyperplasia. Oxford: Isis Medical Media, 1996; 331–337 11. Fitzpatrick J M, Braeckman J, Denis L et al. The medical management of BPH with agents other than hormones or alpha-blockers. In: Cockett A T K, Khoury S, Aso Y et al. (eds). Proceedings of the 3rd international consultation on benign prostatic hyperplasia (BPH), Monaco, 26–28 June 1995, SCI, 1996:489–494 12. Fitzpatrick J M. Phytotherapy for treatment of benign prostatic hyperplasia: case not proven. Urology 1998; 53: 462–464 13. Lowe F C, Ku J C. Phytotherapy in treatment of benign prostatic hyperplasia: a critical review. Urology 1996; 48: 12–20 14. Lowe F C, Fagelman E. Phytotherapy in treatment of benign prostatic hyperplasia. Curr Opin Urol 1998; 8: 27–29 15. Lowe F C, Fagelman E. Phytotherapy in the treatment of benign prostatic hyperplasia: an update. Urology 1999; 53: 671–678 16. Lowe F C, Dreikorn K, Borkowski A et al. Review of recent placebo-controlled trials utilizing phytotherapeutic agents for treatment of BPH. Prostate 1998; 37:187–193 17. Marks L S, Tyler V E. Saw palmetto extract: newest (and oldest) treatment alternative for men with symptomatic benign prostatic hyperplasia. Urology 1999; 53:457–461 18. Wilt T J. Phytotherapy. In: Chapple C R, McConnell J D, Tubaro A (eds). Benign prostatic hyperplasia. London: Martin Dunitz, 2000:39–63 19. Dreikorn K. The role of phytotherapy in treating lower urinary tract symptoms and benign prostatic hyperplasia. World J Urol 2002; 19:426–435 20. Preuss H G, Marcusen C, Regan J et al. Randomized trial of a combination of natural products (cernitin, Serenoa repens, β-sitosterol, vitamin E) on symptoms of benign prostatic hyperplasia (BPH). Int Urol Nephrol 2001; 33: 217–225 21. Levin R M, Das A K. A scientific basis for the therapeutic effects of Pygeum africanum and Serenoa repens. Urol Res 2000; 28:201–209 22. Klingler H C. New innovative therapies for benign prostatic hyperplasia: any advance? Curr Opin Urol 2003; 13: 11–15 23. Chapple C R. Introduction and concluding remarks. Eur Urol 1999; 36(Suppl3): 1–6 24. Statement by Joseph A Levitt, Director, Center for Food Safety and Applied Nutrition, Food and Drug Administration, before the Committee on Government Reform, Chairman Dan Burton, US House of Representatives, March 20, 2001. http://www.cfsan.fda.gov/~lrd/st010320.html 25. Kurtzweil P. An FDA guide to dietary supplements. US Food and Drug Administration, 1999. http://vm.cfsan.fda.gov/zdms/dfsupp.html 26. Ernst E. Harmless herbs? A review of the recent literature. Am J Med 1998; 104:170–178 27. Friedland D J, Go A S, Davoren J B et al. Evidence-based medicine: a frame work for clinical practice. Stamford: Appleton & Lange, 1998 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_424.html[09.07.2009 11:54:51]

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28. Speakman M J. Who should be treated and how? Evidence based medicine in symptomatic BPH. Eur Urol 1999; 36 (Suppl 3):40–51 29. Dreikorn K, Lowe F, Braeckman J et al. Other medical therapies. In: Denis L, Griffiths K, Khoury S et al. (eds). Proceedings of the 5th international consultation on benign prostatic hyperplasia (BPH). Plymouth: Plymbridge Distributors, 2001 30. Buck A C. Phytotherapy for the prostate. Br J Urol 1996; 78:325–336 31. Bayne C W, Donelly F, Ross M et al. Serenoa repens (permixon®): a 5-alpha-reductase types I and II inhibitor—

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Page 425 new evidence in a co-culture model of BPH. Prostate 1999; 40:232–241 32. Di Silverio F, D’Eramo G, Lubrano C et al. Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertropy patients. Eur Urol 1992; 21:309– 314 33. Plosker G L, Brogden R N. Serenoa repens (Permixon®): a review of its pharmacology and therapeutic efficacy in benign prostatic hyperplasia. Drugs Aging 1996; 9: 379–395 34. Paubert-Braquet M, Cousse H, Raynaud J P et al. Effect of the lipido-sterolic extract of Serenoa repens (Permixon®) and its major components on basic fibroblast growth factor-induced proliferation of cultures of human prostate biopsies. Eur Urol 1998; 33:340–347 35. Délos S, Iehlé C, Carsol J L et al. Inhibition of human prostatic testosterone metabolism by a lipidosterol extract of Serenoa repens (Permixon®). J Urol 1996; 155 (Suppl): 572A 36. Paubert-Braquet M, Raynaud J P, Braquet G, Cousse G. Permixon® (lipid sterolic extract of Serenoa repens ) and some of its components inhibit b-FGF- and EGF-induced proliferation of human prostate organotypic cell lines. J Urol 1997; 157 (Suppl 4): 138 (abstract 541) 37. Paubert-Braquet M, Cousse H, Raynaud J P et al. Effect of the lipidosterolic extract of Serenoa repens (Permixon®) and its major components on basic fibroblast growth factor-induced proliferation of cultures of human prostatic biopsies. Eur Urol 1998; 33:340–347 38. Vacherot F, Azzouz M, Gil-Diez-de-Medina S et al. Effect of Permixon® on apoptosis and proliferation in the prostate of patients with BPH. J Urol 1999; 161:362 39. Bayne C W, Donelly F, Chapman K et al. A novel coculture model for benign prostatic hyperplasia expressing both isoforms of 5-alpha-reductase. J Clin Endocrinol Metab 1998; 83:206–213 40. Rhodes L, Primka R L, Berman C et al. Comparison of finasteride (Proscar®), a 5-α reductase inhibitor and various commercial plant extracts in in vitro and in vivo 5-α reductase inhibition. Prostate 1993; 22:43–51 41. Habib F K, Ross M, Bayne C W et al. The localisation and expression of 5-alpha-reductase types I and II mRNAs in human hyperplastic prostate and in prostate primary cultures. J Endocrinol 1998; 156:509–517 42. Stauch G, Perles P, Vergult G et al. Comparison of Finasteride (Proscar®) and Serenoa repens (Permixon®) in the inhibition of 5-alpha reductase in healthy male volunteers. Eur Urol 1994; 26:247– 252 43. Breu W, Hagenlocher M, Redl K et al. Antiphlogistische Wirkung eines mit hyperkritischem Kohlendioxid gewonnenen Sabalfucht-Extraktes. In-vitro-Hemmung des Cyclooxygenase- und 5Lipoxygenase-Metabolismus. Drug Res 1992; 42:547–551 44. Di Silverio F, Monti S, Sciarra A et al. Effects of long-term treatment with Serenoa repens (Permixon®) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. Prostate 1998; 37:77–83 45. Stepanov V N, Siniakova L A, Sarrazin B, Raynaud J P. Efficacy and tolerability of the lipidosterolic extract of Serenoa repens (Permixon®) in benign prostatic hyperplasia: a double-blind comparison of two dosage regimens. Adv Ther 1999; 16:231–241 46. Pytel Y A, Lopatkin N, Gorilovsky L et al. Long-term clinical and biological effects of the lipido-sterolic extract of Serenoa repens in patients with symptomatic benign pro static hyperplasia. Adv Ther 2002; 19:297–306 47. Aliaev IuG, Vinarov A Z, Lokshin K L, Spivak L G. Five-year experience in treating patients with prostatic hyperplasia with permixon ( Serenoa repens Pierre Fabre Medicament) [in Russian]. Urologiia 2002; 1:23–25 48. Gerber G S, Zagaja G P, Bales G T et al. Saw palmetto (Serenoa repens) in men with lower urinary tract symptoms: effects on urodynamic parameters and voiding symptoms. Urology 1998; 51:1003–1007 49. Descotes J L, Rambeaud J J, Deschaseaux P, Faure G. Placebo-controlled evaluation of the efficacy and tolerability of Permixon® in benign prostatic hyperplasia after exclusion of placebo responders. Clin Drug Invest 1996; 9: 291–297 50 Carraro J C, Raynaud J P, Koch G et al. Comparision of phytotherapy (Permixon®) with finasteride in the treatment of benign prostatic hyperplasia: a randomized international study of 1.089 patients. Prostate 1996; 29: 231–240 51. Boyde P, Gould A I, Roehrborn G. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomised clinical trials. Urology 1996; 48:398–405 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_425.html[09.07.2009 11:54:51]

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52. Lepor H, Williford W O, Barry M J et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996; 335:533 53. Hamdy F C, Chopin D K, Authié D et al. Prostatic volume does not correlate with efficacy of treatment for mild to moderate benign prostatic hyperplasia using either finasteride or phytotherapy. 4th International consultation on BPH, Paris 1997; abstract 77 54. Debruyne F, Koch G, Boyle P et al. Comparison of a phytotherapeutic agent (Permixon) with an αblocker (tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol 2002; 41:497–507 55. Grasso M, Montesano A, Buonaguidi A et al. Comparative effects of alfuzosin versus Serenoa repens in the treatment of symptomatic benign prostatic hyperplasia. Archiv Españoles Urol 1995; 48:97–103

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Page 426 56. Berges R R, Kassen A, Senge T. Treatment of symptomatic benign prostatic hyperplasia with βsitosterol: an 18-month follow-up. BJU Int 2000; 85:842–843 57. Kassen A, Berges R, Senge T. Effect of beta-sitosterol on transforming growth factor-beta- 1 expression and translo-cation protein kinase C alpha in human prostate stromal cells in vitro. Eur Urol 2000; 37:735–741 58. Berges R R, Windeler J, Trampisch H et al. Randomised, placebo-controlled, double blind clinical trial of betasitosterol in patients with benign prostatic hyperplasia. Lancet 1995; 345:1529–1532 59. Klippel K F, Hiltl D-M, Schipp B. A multicentric, placebocontrolled, double-blind clinical trial of βsitosterol (phytosterol) for the treatment of benign prostatic hyperplasia. Br J Urol 1997; 80:427–432 60. Andro M C, Riffaud J P. Pygeum Africanum extract for the treatment of patients with benign prostatic hyperplasia: review of 25 years of published experience. Curr Therap Res 1995; 56:796–817 61. Hass M A, Nowak D M, Leonova E et al. Identification of components of Prunus africana extract that inhibit lipid peroxidation. Phytomedicine 1999; 6:379–388 62. Levin R M, Hass M A, Bellamy F et al. Effect of oral Tadenan treatment on rabbit bladder structure and function after partial outlet obstruction. J Urol 2002; 167: 2253–2259 63. Levin R M, Riffaud J P, Bellamy F et al. Effects of Tadenan® pretreatment on bladder physiology and biochemistry following partial outlet obstruction. J Urol 1996; 56:2084–2088 64. Levin R M et al. Protective effect of Tadenan® on bladder function secondary to partial outlet obstruction. J Urol 1996; 155:1466–1470 65. Levin R M, Buttyan R, Horan P et al. Changes in contractile response of the rabbit bladder to field stimulation following unilateral iscemia. Protective effect of Tadenan®. J Urol 1997; 157 (Suppl 4): 172 66. Buttyan R et al. Early molecular response to rabbit bladder outlet obstruction. Neurol Urodyn 1992; 11:225–238 67. Chen M W, Levin R M, Horan P et al. Effects of unilateral ischemia on the contractile response of the bladder. Protective effect of Tadenan ( Pygeum africanum extract). Mol Urol 1999; 3:5–10 68. Barlet A, Albrecht J, Aubert A et al. Efficacy of Pygeum africanum extract in the treatment of micturitional disorders due to benign prostatic hyperplasia: evaluation of objective and subjective parameters: a multicentre, placebo-controlled double-blind trial. Wien Klin Wochenschr 1990; 102:667– 673 69. Chatelain C, Autet W, Brackmann F. Comparison of once a twice daily dosage forms of Pygeum africanum extract in patients with benign prostatic hyperplasia: a randomised, double-blind study with long term open label extension. Urology 1999; 54:473–478 70. Yablonsky F, Riffaud J P. Pygeum africanum for the treatment of patients with BPH: a review of 25 years of published experience. Curr Therap Res 1995; 56:796–817 71. Breza J, Dziurny O, Borowka A et al. Efficacy and acceptability of Tadenan ( Pygeum africanum extract) in the treatment of benign prostatic hyperplasia (BPH): a multicentre trial in Central Europe. Curr Med Res Opin 1998; 143: 127–139 72. Dathe G, Schmid H. Phytotherapie der benignen Prostatahyperplasie: Doppelblindstudie mit Extractum Radicis Urticae (ERU). Urologe [B] 1987; 27:233–236 73. Vontobel H P, Herzog R, Rutishauser G H. Ergebnisse einer Doppelblindstudie über die Wirksamkeit von ERU-Kapseln in der konservativen Behandlung der benignen Prostatahyperplasie. Urologe [A] 1985; 24:49–51 74. Engelmann U, Boos G, Kres H. Therapie der benignen Prostatahyperplasie mit Bazoton Liquidum. Urologe [B] 1996; 36:287–291 75. Dutkiewicz S. Usefulness of Cernilton in the treatment of benign prostatic hyperplasia. Int Urol Nephrol 1996; 28: 49–53 76. Habib F K, Ross M, Lewenstein A et al. The identification of a prostate inhibitory substance in a pollen extract. Prostate 1995; 26:133–139 77. Becker H, Ebeling L. Konservative Therapie der benignen Prostatahyperplasie (BPH) mit Cernilton. Urologe [B] 1988; 28:301–306 78. Buck A C, Cox R, Rees R W M et al. Treatment of outflow tract obstructive due to benign prostatic hyperplasia with the pollen extract Cernilton. Br J Urol 1990; 66: 398–404 79. Aoki A, Naito K, Hashimoto O et al. Clinical evaluation of the effect of tamsulosin hydrochloride and cernitin pollen extract on urinary disturbance associated with benign prostatic hyperplasia in a multicentered study [in Japanese]. Hinyokika Kiyo 2002; 48:259–267 80. Bach D. Phytopharmaka. In: Höfner K, Stief C G, Jonas U (eds). Benigne Prostatahyperplasie. Berlin, Heidelberg: Springer, 2000:238–260 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_426.html[09.07.2009 11:54:52]

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81. Jonas A, Rosenblut G, Krapf D et al. Cactus flower extracts may prove beneficial in benign prostatic hyperplasia due to inhibition of 5-alpha-reductase activity, aromatase activity and lipid peroxidation. Urol Res 1998; 26: 265–270 82. Carbin B E, Larsson B, Lindahl O. Treatment of benign prostatic hyperplasia with phytosterols. Br J Urol 1990; 66: 639–641 83. Metzker M, Kieser M, Hölscher U. Wirksamkeit eines Sabal-Urtica-Kombinationspräparates bei der Behandlung

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Page 427 der benignen Prostatahyperplasie (BPH). Urologe [B] 1996; 36:292–300 84. Sökeland J, Albrecht J. Kombination aus Sabal- und Urticaextrakt mit Finasterid bei BPH (Styad.I bis II nach Alken). Urologe [A] 1997; 36:327–333 85. LeLorier J, Grégoire G, Benhaddad A et al. Discrepancies between meta-analyses and subsequent large randomised controlled trials. N Engl J Med 1997; 337:536–542 86. Wilt T J, Ishani A, Stark G et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. J Am Med Assoc 1998; 280:1604–1609 87. Boyle P, Lowe F, Robertson C, Roehrborn C G. Metaanalysis of clinical trials of Permixon® in the treatment of symptomatic benign prostatic hyperplasia. Urology 2000; 55:533–539 88. Wilt T, Ishani A, MacDonald R. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2002; (3): CD001423 89. Boyle P, Robertson C, Lowe F, Roehrborn C G. Metaanalysis of Permixon in treatment of symptomatic benign prostatic hyperplasia: an update [abstract]. J Urol 2003; 169(Suppl 4): 1297 90. Wilt T J, McDonald R, Ishani A. β-sitosterol for the treatment of benign prostatic hyperplasia: systematic review. BJU Int 1999; 83:976–983 91. Wilt T, Ishani A, MacDonald R et al. Beta-sitosterols for benign prostatic hyperplasia. Cochrane Database Syst Rev 2000; (2): CD001043 92. Wilt T, Ishani A, MacDonald R et al. Pygeum africanum for benign prostatic hyperplasia. Cochrane Database Syst Rev 2002; (1): CD001044 93. MacDonald R, Ishani A, Rutks I et al. A systematic review of Cernilton for the treatment of benign prostatic hyperpasia. BJU Int 2000; 85:836–841 94. Wilt T, MacDonald R, Ishani A et al. Cernilton for benign prostatic hyperplasia. Cochrane Database Syst Rev 2000; (2): CD001042 95. Boyle P, Robertson C, Manski R et al. Meta-analysis of randomized trials of terazosin in the treatment of benign prostatic hyperplasia. Urology 2001; 58:717–722 96. Boyle P, Gould L, Roehrborn C G. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48:398–405 97. Roehrborn C G, Boyle P, Nickel J C et al. on behalf of the ARIA3001, ARIA3002, and ARIA3003 study investigators. Efficacy and safety of a dual inhibitor of 5 alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002; 60:434–441 98. Denis L, McConnell J, Yoshida O et al. 4th international consultation of BPH. Recommendations of the international scientific committee: the evaluation and treatment of lower urinary tract syndromes (LUTS) suggestive of benign prostatic obstruction. In: Denis L, Griffiths K, Khoury S et al. (eds). Proceedings of the 4th international consultation of benign prostatic hyperplasia (BPH). Plymouth: Plymbridge Distributors, 1998; 669–984 99. Altwein J, Aumüller G, Berges R et al. Leitlinien der Deutschen Urologen zur Therapie des BPHSyndromes. Urologe [A] 1999; 38:529–536

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Page 429 32 Uroselectivity revisited K-E Andersson M G Wyllie Background The two major components of lower urinary tract symptoms (LUTS)—voiding (obstructive) and storage (irritative) symptoms—associated with benign prostatic hyperplasia (BPH) have traditionally been linked directly or indirectly to pathophysiologic changes in the prostate.1 Voiding symptoms have been attributed to two facets of prostate function: the physical mass of the enlarged gland (the static component) and the tone of the smooth muscle of the prostate stroma (the dynamic component).2 Storage symptoms, however, have been more closely associated with the bladder dysfunction produced secondary to the increased outflow resistance, arising from prostatedependent urethral obstruction. The precise interrelationship between morphologic BPH, bladder outflow obstruction, and profile of symptoms produced is, however, unclear3 and there are several paradoxes. In particular, both voiding and storage symptoms are common in women.3,4 Furthermore, many patients who have undergone prostatectomy to relieve obstruction still experience persistent storage symptoms. Several studies have also now shown that there is little or no correlation between drug-induced changes in flow and symptom improvement5,6. The use of LUTS as a clinical descriptor is a neutral way to describe the symptoms, and makes no assumption about their link to the prostate. On the basis of our knowledge of the control of periurethral, stromal prostate smooth muscle tone (described in Chapter 5) it is logical to assume that prostate α-adrenoceptors should be responsible for at least part of the LUTS associated with BPH (Fig. 32.1). However, the welldocumented beneficial effects of α1-adrenoceptor antagonists on the symptoms of BPH7–11 occur even in the absence of outflow obstruction. This indicates that extraprostatic α1-adrenoceptors may also be fundamentally involved in the pathogenesis of LUTS.10 The lack of correlation between α-antagonist-induced improvements in urine flow and symptom improvement6,12 could also be explained on the basis of an action via extraprostatic α1-adrenoceptors (Fig. 32.1).

Figure 32.1 Sympathetic innervation of the human prostate showing the location of α1 and α2-adrenoceptors.

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Page 430 The extraprostatic α1-adrenoceptors may be located in the bladder, ganglia, and nerves innervating the lower urinary tract and at spinal or supraspinal levels within the central nervous system. Indeed, there is evidence for involvement of α1-adrenoceptors in the spinal control of both sympathetic and somatic (filling), as well as parasympathetic (voiding), efferent activity of the lower urinary tract.10,13 In approximately 10% of patients, the use of α1-adrenoceptor antagonists in common clinical use (alfuzosin, doxazosin, tamsulosin, terazosin) has been limited by side-effects, particularly dizziness, headache, asthenia, nasal congestion, and orthostatic hypotension, that may be attributed to action on nonprostatic α1-adrenoceptors. It is likely that most of the common side-effects are characteristic of a direct action on the vasculature. To circumvent these side-effects, the pharmaceutical industry has attempted to find α1-adrenoceptor antagonists that are selective for the prostate α1-adrenoceptors. The underlying assumption is that these should be ‘uroselective’ agents. It should be noted, however, that the definition of uroselectivity is ambiguous because the criteria were not established at the outset. Not surprisingly, therefore, the term has been used in various contexts which are often confusing and contradictory. In this chapter we attempt to put some degree of definition on the criteria to be used in the definitive designation of a drug as uroselective as it relates to management of the patient with LUTS/BPH. In theory, the selectivity of drugs can be defined using a variety of parameters, including pharmacologic or physiologic uroselectivity, or may be defined from a clinical perspective.9,14 Ultimately, however, only clinical uroselectivity is relevant to patient and physician. Pharmacologic uroselectivity α1 -Adrenoceptors Multiple α1-adrenoceptor subtypes have been identified,15–17 and may offer the opportunity to target the prostate selectively. Receptor cloning and pharmacologic studies of the human prostate have revealed the existence of both high-affinity (α1A, α1B, and α1D) and low-affinity (α1L) receptors for prazosin (see Chapter 5). α1-Adrenoceptors in the prostate Nerves that contain adrenergic, cholinergic, and nonadrenergic, noncholinergic neurotransmitters or mediatorproducing enzymes supply the smooth muscles of the prostate capsule and the trabecular tissue around the ducts.18,19 The adrenergic nerves are considered to be responsible for prostate smooth muscle tone by releasing noradrenaline, which stimulates contraction via α-adrenoceptors.20 Although both α1- and α2-adrenoceptors can be identified in the human prostate, the contractile effects of noradrenaline are mediated primarily by α1-adrenoceptors.10 All three high-affinity α1-adrenoceptor subtypes have been identified in prostate stromal tissue using molecular techniques. The α1a subtype predominates, representing 60–85% of the α1-adrenoceptor population. However, the α1-adrenoceptor subtype responsible for prostatic smooth muscle contraction has not been established unequivocally, although it is likely to be closely related to the α1Aadrenoceptor (see Chapter 5). α1-Adrenoceptors in the urethra Urodynamic studies in humans have suggested that up to about 50% of intraurethral pressure is maintained by stimulation of α-adrenoceptors, as judged from results obtained with α1-adrenoceptor antagonists.21,22 In human male urethral smooth muscle, functional and receptorbinding studies have suggested that the predominating postjunctional α-adrenoceptor is α1.23,24 Using RNase protection assays and in situ hybridization, Nasu et al.25 quantified and studied the distribution of α1-adrenoceptor subtypes in the human proximal urethra. They found (in both males and females) that mRNA for the α1a subtype was predominant; the ratio of mRNA for α1a, α1b, α1d in the male urethra was 100:0:0. Fukasawa et al.26 found that in man the α1L-adrenoreceptor subtype was more prominent in the male urethra than in the prostate. α1-Adrenoceptors in the bladder In detrusor muscle from most species, including humans, β-adrenoceptors, which mediate relaxation, normally dominate over α-adrenoceptors, which mediate contraction; the normal response to noradrenaline is β-adrenoceptor-mediated relaxation. However, this may change in outflow obstruction. Perlberg and Caine27 assessed the response to noradrenaline in the hypertrophic bladder and found that, in strips taken from hypertrophic bladders, noradrenaline caused α-adrenoceptor-mediated contraction in almost one-quarter of patients. This change was also reflected in the symptoms: patients whose bladders responded to noradrenaline by contracting had symptoms of bladder overactivity. This observation suggests that a change in the response to noradrenaline may play a role in producing both obstructive and irritative symptoms. However, Smith and Chapple28 studied α1-adrenoceptor function in file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_430.html[09.07.2009 11:54:54]

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strips from obstructed bladders and found that

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Page 431 only five of 72 strips responded to phenylephrine; these results are not in agreement with the view that α-adrenoceptor stimulation during storage contributes to bladder contraction and thereby to symptoms. Most probably, the balance between β- and α-adrenoceptor functions in the bladder changes in BPH, but it is not known what this really means for the pathophysiology of LUTS, particularly storage symptoms. The predominating postjunctional α-adrenoceptor subtype in the human lower urinary tract seems to be α1; however, the number of α1-adrenoceptors in the detrusor is very low.29 In normal human isolated detrusor muscle, drugs that selectively stimulate isolated α-adrenoceptors, particularly those acting on α1-adrenoceptors, produce a small and variable contractile effect.23 It is not clear which α1adrenoceptor subtype predominates in the detrusor, trigone, and bladder base. Walden et al.30 reported a predominance of α1a-adrenoceptor mRNA in the human bladder dome, trigone and bladder base. This contrasts with the findings of Malloy et al.,31 who found that among the high-affinity receptors for prazosin, only α1a- and α1d-adrenoceptor mRNA was expressed in the human bladder. The total α1-adrenoceptor expression was low (6.3±1.0femtomol/mg), but was highly reproducible. The relationship between the different subtypes was 66% α1d and 34% α1a; α1b was not expressed. This is in contrast to findings in the human prostate.32 The fact that drugs that act selectively on prostate α1-adrenoceptors may have little effect on LUTS could, in theory, be explained if they did not block the α1-adrenoceptors (α1D) of the bladder.33 Considering the doubtful functional importance of the bladder α1-adrenoceptors, this mechanism seems unlikely, but cannot be discounted completely. α1-Adrenoceptors in peripheral and central nervous system structures (Fig. 32.2) In animal experiments, facilitatory α1-adrenoceptors have been identified in ganglia and on cholinergic terminals in the bladder.34–37 An effect of α1-adrenoceptor antagonists at the ganglionic and/or prejunctional level, leading to a decrease in acetylcholine release, is also possible. Descending spinal pathways involved in micturition include noradrenaline-containing projections from the locus coeruleus.38 From the locus coeruleus, the noradrenergic neurones supply sympathetic and parasympathetic nuclei in the lumbosacral spinal cord. Bladder activation through these bulbospinal noradrenergic pathways may well involve excitatory α1-adrenoceptors.39 Thus, in the anesthetized cat, electrical stimulation of the locus coeruleus induced bladder contractions that were antagonized by intrathecal administration of prazosin.39–42 In addition, destruction of noradrenergic cell bodies in the locus coeruleus by microinjection of 6-hydroxydopamine produced a hypoactive bladder, which could be partly reversed by intrathecal injection of prazosin or phentolamine in cats, depressed the external urethral sphincter activity, and reduced reflex firing in pudendal nerve efferent pathways by a presumed central site of action.43 In the conscious cat, however, Downie et al.44 found that the intrathecal prazosin did not alter the micturition reflex. The reasons for these apparently conflicting results are

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Figure 32.2 The micturition reflex. The afferent branch of the micturition reflex runs in the spinal cord via the dorsal root ganglia to the pontine micturition center, which is under voluntary control The efferent branch runs from the pontine micturition center to the sacral micturition center, from which the preganglionic nerves run to the pelvic plexus and then to the bladder to cause contraction. At the same time, the efferent branch inhibits the hypogastric and pudendal nerves, leading to relaxation of the outflow region and the pelvic floor.

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Page 432 unclear, but most of the evidence supports a key central role for central α1-adrenoceptors. In the central nervous system, facilitatory α1-adrenoceptors, tonically active in both the sympathetic and somatic neural control of the lower urinary tract, were identified in the cat.45,46 Intrathecal doxazosin decreased micturition pressure, both in normal rats and in animals with postobstruction bladder hypertrophy.47 The effect was much more pronounced in the animals with hypertrophied/overactive bladders. Doxazosin did not markedly affect the frequency or amplitude of the unstable contractions observed in rats with obstructed bladders. It was suggested that doxazosin may have an action at the level of the spinal cord and ganglia, thereby reducing activity in the parasympathetic nerves to the bladder, and that this effect was more pronounced in rats with bladder hypertrophy than in normal rats.47 Urodynamic studies revealed that spontaneously hypertensive rats (SHRs) have pronounced bladder overactivity.48 These animals also have an increased noradrenergic bladder innervation and an increased voiding frequency.49 Whereas the control rats (Wistar Kyoto rats) have a regular contraction frequency during continuous cystometry, the SHRs show both micturition and nonmicturition contractions. To investigate whether the peripheral adrenergic system was involved in the pathogenesis of the bladder overactivity, SHRs were treated with 6-hydroxydopamine in order to destroy the noradrenergic nerves chemically. Under these conditions, bladder overactivity was maintained (as demonstrated by continuous cystometry).50 Furthermore, α1-adrenoceptor antagonists, injected intraarterially near the bladder, did not abolish the bladder overactivity. On the other hand, when given intrathecally, the same dose of α1-adrenoceptor antagonist normalized micturition. Although the relevance of these findings to man is not known, it is probable that spinal α1-adrenoceptors may contribute to the overall clinical improvement in LUTS seen with α1-adrenoceptor antagonists. The neuronal localization of α1-adrenoceptor subtypes (α1a, α1b, α1d) in the human spinal cord was investigated.51 In situ hybridization studies revealed that α1-adrenoceptor mRNA was present in ventral gray matter only (ventral>dorsal; sacral>lumbar=thoracic>cervical). Signaling cell bodies were detected in anterior horn motor neurones at all levels, in the dorsal nucleus of Clark, and in intermediolateral columns in cervical enlargement, in thoracic and lumbar spinal cord regions, and in the parasympathetic nucleus in the sacral spinal cord. Although all three high-affinity α1-adrenoceptor subtypes were present throughout the human spinal cord, α1d-adrenoceptor mRNA predominated. Whether this has any clinical significance in the treatment of LUTS remains to be established. It is pertinent, however, to note that the distribution of α1-adrenoceptor mRNA subtypes in the rat spinal cord is different from that in humans;52 this should be borne in mind when discussing the clinical relevance of data obtained in rats. Overall, there is good evidence in several species that α1-adrenoceptors at spinal and supraspinal levels can profoundly influence the micturition reflex. The possibility that they may contribute to the overall clinical improvement in LUTS cannot be discounted. α1-Adrenoceptors in the cardiovascular system The involvement of α1-adrenoceptor subtypes in vascular control is of particular relevance to any discussion of uroselectivity. Species- and vessel-dependent α1A-, α1B-, α1D-, and α1L-adrenoceptors all seem to subserve the contractile response in vascular tissue.53–57 On this basis, one could assume that cardiovascular homeostasis depends on all of the different subtypes, albeit to varying extents. Equally, no one α1-adrenoceptor subtype can be considered to be the ‘blood pressure adrenoceptor’. Summary of pharmacologic uroselectivity There is good evidence to suggest that an agent selective for the α1A-adrenoceptor subtype will influence periurethral smooth muscle tone, urethral resistance, and thereby urinary flow. However, there is some degree of uncertainty as to whether the use of α1A-adrenoceptor antagonists would improve symptoms. Indeed, should an extraprostatic action on the other subtypes be required to optimize symptom improvement, an α1A-adrenoceptorselective antagonist may have lower efficacy than existing agents. Equally, a selective action at α1A-adrenoceptors may not necessarily translate into a reduction in cardiovascular side-effects. Thus, although several agents with considerable pharmacologic (α1Aadrenoceptor) ‘uroselectivity’ have been synthesized,58,59 there is no guarantee that this will translate into clinical benefit. Physiologic uroselectivity Obviously the response in the whole animal and, indeed, in man represents an integrated response that is much more complicated than can be predicted from analysis at the pharmacologic or receptor level in isolation. In the whole animal, homeostatic mechanisms tend to counteract many of the effects produced by any drug,

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Page 433 particularly under normal conditions. However, in disease or in situations of abnormal pathophysiology, homeostatic compensation may have occurred to the maximum extent. Thus, the response to the drug under these conditions may be substantially different—either exaggerated or attenuated. In terms of LUTS and in the context of uroselectivity, an agent that decreases outflow resistance without affecting the blood pressure would obviously be of considerable interest. Many groups have reported that α1-adrenoceptor antagonists decrease urethral resistance in animal models.60–66 indeed such animal models are used routinely within the pharmaceutical industry to determine the relative potency and selectivity of α1-adrenoceptor antagonists for prostate function over other parameters such as blood-pressure lowering. The rank order of potency of the effects of various α1-adrenoceptor antagonists on urethral pressure has been defined in several animal models, and has then been related to blood pressure changes in the same animal.11,65 The ratio of these effects could therefore be considered as a potential index of uroselectivity. Although such models may have some predictive value, they also have limitations, and the results may be both species- and assay-dependent.67,68 Thus, results obtained in one animal species may differ from those obtained in another, and it has not been established which animal model is the most predictive of effects in humans. Side-effects that may be dose limiting clinically are not always cardiovascular (or directly related to hemodynamic changes), but may arise from the central nervous system, for example drowsiness and dizziness. Also, because such effects cannot always be studied in animals, animal models may not adequately predict benefit-risk profiles or provide a reliable index of clinical uroselectivity as it would impact on patient management The use of animal models has, however, produced encouraging results. All established agents—alfuzosin, doxazosin, prazosin, tamsulosin, and terazosin—affect urethral pressure in animals over the same dose range that produces vascular effects (see Table 32.1 and Fig. 32.3). The relative lack of uroselectivity seen in whole-animal studies is entirely consistent with the receptor-binding profile of these α1-adrenoceptor antagonists (i.e. the pharmacologic ‘uroselectivity’, as defined by the selectivity for the α1A-adrenoceptor subtype over the other subtypes) (Fig. 32.3). Thus, none of these agents can be considered to demonstrate significant physiologic uroselectivity in the whole animal. Although it is possible to carry out similar evaluations in man,69,70 ultimately we need to define clinical uroselectivity9,71. Clinical uroselectivity A clinically relevant definition of uroselectivity can be made only in relation to man. It is known that Table 32.1 Binding affinities (pKI) for compounds at cloned human α1-adrenoceptors. Compound pKI α1A α1B α1D BMY 7378 6.2±0.10 6.7±0.11 8.2±0.10 Prazosin 9.7±0.20 9.6±0.14 9.5±0.10 Doxazosin 8.5±0.20 9.0±0.20 8.4±0.12 WB 4101 9.3±0.10 8.2±0.16 9.2±0.06 5-Methylurapidil 8.5±0.09 6.8±0.13 7.8±0.09 Tamsulosin 10.3±0.21 9.5±0.17 10.1±0.22 Phentolamine 8.1±0.09 7.1±0.15 7.8±0.03 SNAP 1069 7.8±0.19 7.6±0.18 6.8±0.20 Indoramin 8.3±0.03 8.0±0.12 7.3±0.15 Alfuzosin 8.0±0.20 8.0±0.13 8.5±0.07 Spiperone 7.6±0.12 8.5±0.16 8.1±0.03 Terazosin 8.6±0.22 8.7±0.08 8.3±0.13 Affinities were determined by displacement of 0.2 nM [3H]prazosin from rat-1 fibroblasts stably expressing cloned α1-adrenoceptor subtypes by 12 concentrations of competing drug. Values represent mean ±SEM for three to five separate determinations. Hill slopes for displacement curves were not significantly different from unity. (Data from reference 67 with permission.)

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Page 434 α1-adrenoceptor antagonists have more pronounced effects on blood pressure in hypertensive patients than in normotensive patients. For example, it is well documented that doxazosin and terazosin effectively reduce blood pressure in hypertensive BPH patients but have only relatively modest effects in normotensive men (Fig 32.4).72,73 Assuming that this occurs at doses that affect urinary flow, both drugs could be considered to demonstrate clinical uroselectivity, at least in normotensive BPH patients. Ironically, however, using this definition neither agent would be classified as uroselective in hypertensive BPH patients. The blood pressure-lowering effect is of benefit in the large number of BPH patients who are hypertensive. Thus, in theory, a drug could affect blood pressure in a hypertensive subject before it has any noticeable effects on the urethra (i.e. the drug has no uroselectivity or indeed has vascular selectivity). The same drug may reduce outflow resistance in a normotensive patient but

Figure 32.3 (a) Selectivity profile of doxazosin (Dox), terazosin (Ter), alfuzosin (Alf), tamsulosin (Tam), and 5-methylurapidil (5-MU) for the cloned α1A-, α1B and α1Dadrenoceptor subtypes. 5-MU is the only compound that shows selectivity for the cloned human α1A-adrenoceptor. (b) Selectivity profile of the same compounds in the anesthetized dog. All compounds are equi-active on prostate pressure and blood pressure, except the α1A-selective 5-MU, which is about 30-fold prostate selective.

Figure 32.4 Effect of terazosin on blood pressure in hypertensive and normotensive patients. Data show blood pressure at baseline and after treatment. (Adapted from reference 70.)

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Page 435 without having any effects on blood pressure (i.e. the drug is uroselective in this situation). The situation is complicated further by the fact that pharmacokinetic properties may contribute to apparent differences between drugs in the effects on different organ systems. In the context of managing patients with BPH, it is therefore both obvious and essential to have an allencompassing but precise definition of clinical uroselectivity. This has to take into account the fact that the clinical endpoints of outflow obstruction (as defined urodynamically) and LUTS, and adverse effects may vary independently. Thus, uroselectivity (as for any clinical therapeutic index) may be defined by describing the ratio between the dose required for the desired therapeutic action and the dose that produces side-effects. Such a definition of uroselectivity is the one recommended in 1995 by the Fourth international consultation on benign prostatic hyperplasia: ‘desired effects on obstruction and lower urinary tract symptoms related to adverse effects’.9 It should be noted that clinical uroselectivity defined in this way is not an all-or-nothing phenomenon but is merely a qualitative descriptor. The clinical definition should be borne in mind when considering the profiles described for the α1adrenoceptor antagonists. It is obvious that, although animal studies have greatly increased our understanding of the control of the lower urinary tract, they may be of relatively little value in the prediction of clinical uroselectivity. Conclusions A drug may be uroselective in the sense that it has a preference for the α-adrenoceptors in the prostate, or that in an animal model it can affect the prostate and urethra without affecting blood pressure, for example. There are α1-adrenoceptors in the urethra, trigone, detrusor, spinal cord, supraspinal structures, and peripheral ganglia, the contributions of which to the symptoms of BPH remain unknown, and whose subtypes have not been determined. Thus, such a definition of uroselectivity may not be meaningful from a clinical point of view. A clinically meaningful definition of uroselectivity can be made only with respect to findings in man, and considers desired effects on obstruction and LUTS relative to adverse effects. Clinical uroselectivity can be used as a guideline for selecting drugs for the management of BPH that are costeffective and safe, and which can improve the individual patient’s quality of life. It is possible, however, that the pharmaceutical industry may have exhausted both the pharmacologic and pharmacokinetic options for achieving uroselectivity74. References 1. Abrams P. New words for old; urinary tract symptoms for ‘prostatism’. Br Med J 1994; 308:929–930 2. Caine M. The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol 1986; 136:1–4 3. Shapiro E, Lepo H. Pathophysiology of clinical benign prostatic hyperplasia. Urol Clin North Am 1995; 22:285–290 4. Jollys J V, Jollys J C, Wilson J et al. Does sexual equality extend to urinary symptoms? Neurourol Urodyn 1993; 12: 391–392 5. Lepor H, Machi G. Comparison of the AUA symptom index in unselected males and females between 55 and 79 years of age. Urology 1993; 42:36–40 6. Barry M J, Cockett A T K, Holtgrewe H L et al. Relationship of symptoms of prostatism to commonly used physiological measures of the severity of benign prostatic hyperplasia. J Urol 1993; 150:351–358 7. Eri L M, Tveter K J. α-Blockade in the treatment of symptomatic benign prostatic hyperplasia. J Urol 1995; 154: 923–934 8. Chapple C R. Selective α1-adrenoceptor antagonists in benign prostatic hyperplasia: rationale and clinical experience. Eur Urol 1996; 29:129–144 9. Jardin A, Andersson K -E, Bono V A et al. Alpha-blockers in the treatment of BPH. In: Denis L, Griffiths K, Khoury S et al. (eds). Proceedings of the fourth international consultation on benign prostatic hyperplasia (BPH). Plymouth: SCI, 1998:599–632 10. Andersson K -E, Lepor H, Wyllie M G. Prostatic α1-adrenoceptors and uroselectivity. Prostate 1997; 30: 202–215 11. Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of α1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999; 36:1–13 12. Gerber G S, Contreras BA, Zagaja G P et al. Doxazosin in men with lower urinary tract symptoms: urodynamic evaluation at 15 months. Urology 1997; 50:229–233 13. Andersson K -E. α1-Adrenoceptors and bladder function. Eur Urol 1999; 36 (Suppl 1): 96–102 14. Andersson K -E. The concept of uroselectivity. Eur Urol 1998; 33 (Suppl 2): 7–11 15. Hieble J P, Bylund D B, Clarke D E et al. International Union of Pharmacology. Recommendation for file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_435.html[09.07.2009 11:54:56]

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nomenclature of α1-adrenoceptors: consensus update. Pharmacol Rev 1995; 47:267–270 16. Langer S Z. History and nomenclature of α1-adrenocep-tors. Eur Urol 1999; 36 (Suppl 1): 2–6 17. Zhong M, Minneman K P. α1-Adrenoceptor subtypes. Eur J Pharmacol 1999; 375:261–276

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Page 436 18. Dail W G. Autonomic innervation of male reproductive genitalia. In: Maggi C A (ed). Nervous Control of Urogenital System. London: Harwood Academic Publishers, 1993:69–101 19. Hedlund P, Ekström P, Larsson B et al. Heme oxygenase and NO-synthase in the human prostate— relation to adrenergic, cholinergic and peptide-containing nerves. J Auton Nerv Syst 1997; 63:115–126 20. Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in the human prostate capsule and bladder neck. Br J Urol 1975; 47:193–202 21. Appell R A, England H R, Hussell A R, McGuire E J. The effect of epidural anesthesia on the urethral closure pressure profile in patients with prostatic enlargement. J Urol 1980; 124:410–411 22. Furuya S, Kumamoto Y, Yokoyama E et al. Alpha-adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy. J Urol 1982; 128:836–839 23. Andersson K -E. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993; 45:253–308 24. Hatano A, Takahashi H, Tamaki M et al. Pharmacological evidence of distinct α1-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery. Br J Urol 1994; 113:723–728 25. Nasu K, Moriyama N, Fukasawa R et al. Quantification and distribution of alpha 1-adrenoceptor subtype mRNAs in human proximal urethra. Br J Pharmacol 1998; 123: 1289–1293 26. Fukasawa R, Taniguchi N, Moriyama N et al. The alpha1L-adrenoceptor subtype in the lower urinary tract: a comparison of human urethra and prostate. Br J Urol 1998; 82:733–737 27. Perlberg S, Caine M. Adrenergic response of bladder muscle in prostatic obstruction. Urology 1982; 20:524–537 28. Smith D J, Chapple C R. In vitro response of human bladder smooth muscle in unstable obstructed male bladders: a study of pathophysiological causes. Neurourol Urodyn 1994; 13:414–415 29. Goepel M, Wittmann A, Rübben H, Michel M C. Comparison of adrenoceptor subtype expression in porcine and human bladder and prostate. Urol Res 1997; 25:199–206 30. Walden P, Durkin M, Lepor H et al. Localization of mRNA and receptor binding sites for the α1aadrenoceptor in the rat, monkey and human urinary bladder and prostate. J Urol 1997; 157:1032–1038 31. Malloy B J, Price D T, Price R R et al. Alpha1-adrenergic receptor subtypes in human detrusor. J Urol 1998; 160: 937–943 32. Nasu K, Moriyama N, Kawabe K et al. Quantification and distribution of alpha1-adrenoceptor subtype mRNAs in human prostate: comparison of benign hypertrophied tissue and non-hypertrophied tissue. Br J Pharmacol 1996; 119:797–803 33. Schwinn D A, Price R R. Molecular pharmacology of human α1-adrenergic receptors: unique features of the α1a-subtype. Eur Urol 1999; 36 (Suppl 1): 7–10 34. de Groat W C, Booth A M. Inhibition and facilitation in parasympathetic ganglia. Fed Proc 1980; 39:2290–2996 35. Akasu T, Gallagher J P, Nakamura T et al. Noradrenaline hyperpolarization and depolarization in cat vesical parasympathetic neurones. J Physiol 1985; 361:165–184 36. Keast J R, Kawatani M, de Groat W C. Sympathetic modulation of cholinergic transmission in cat vesical ganglia is mediated by α1- and α2-adrenoceptors. Am J Physiol 1990; 258: R44-R50 37. Somogyi G T, Tanowitz M, de Groat W C. Prejunctional facilitatory α1-adrenoceptors in the rat urinary bladder. Br J Pharmacol 1995; 114:1710–1716 38. de Groat W C, Booth A M, Yoshimura N. Neurophysiology of micturition and its modification in animal models of human disease. In: Maggi C A (ed). London: Harwood Academic Publishers, 1993:227–289 39. Sasa M, Yoshimura N. Locus coeruleus noradrenergic neurons as a micturition center. Microsc Res Tech 1994; 29: 226–230 40. Yoshimura N, Sasa M, Ohno Y et al. Contraction of urinary bladder by central norepinephrine originating in the locus coeruleus. J Urol 1988; 139:423–427 41. Yoshimura N, Sasa M, Yoshida O, Takoaori S. α1-Adrenergic receptor-mediated excitation from the locus coeruleus of the sacral parasympathetic preganglionic neuron. Life Sci 1990; 47:789–797 42. Yoshimura N, Sasa M, Yoshida O, Takaori S. Mediation of micturition reflex by central norepinephrine from locus coeruleus in the cat. J Urol 1990; 143:840–843 43. Gajewski J, Downie J W, Awad S A. Experimental evidence for a central nervous system site of action in the effect of alpha-adrenergic blockers on the external urinary sphincter. J Urol 1984; 132:403– 409 44. Downie J W, Bialik G J, Shefchyk S J et al. Roles for sacral spinal alpha-adrenoceptors in mediating file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_436.html[09.07.2009 11:54:57]

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or modulating bladder and sphincter activity in the cat. Neurourol Urodyn 1991; 10:367–369 45. Danuser H, Thor K. Inhibition of central sympathetic and somatic outflow to the lower urinary tract of the cat by the α1-adrenergic receptor antagonist prazosin. J Urol 1995; 153:1308–1312 46. Ramage A G, Wyllie M G. A comparison of the effects of doxazosin and terazosin on the spontaneous sympathetic drive to the bladder and related organs in anesthetized cats. Eur J Pharmacol 1995; 294:645–650 47. Ishizuka O, Persson K, Mattiasson A et al. Micturition in conscious rats with and without outlet obstruction: role of

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Page 437 spinal α1-adrenoceptors. Br J Pharmacol 1996; 117: 962–966 48. Persson K, Pandita R K, Spitsbergen J M et al. Spinal and peripheral mechanisms contributing to hyperactive voiding in spontaneously hypertensive rats. Am J Physiol 1998; 275: R1366–1373 49. Steers W D, Clemow D B, Persson K et al. The spontaneously hypertensive rat: insight into the pathogenesis of irritative symptoms in benign prostatic hyperplasia and young anxious males. Exp Physiol 1999; 84:137–147 50. Pandita R K, Alm P, Steers W D et al. Hyperactive voiding in spontaneously hypertensive rats is not affected by chemical sympathectomy (abstract). International Bladder Symposium, Washington DC, 4–7 November 1999:1005P 51. Smith M S, Schambra U B, Wilson K H et al. Alpha1-adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding alpha1-adrenergic receptor subtypes at four distinct levels. Brain Res Mol Brain Res 1999; 63:254–261 52. Day H E, Campeau S, Watson S J Jr, Akil H. Distribution of alpha 1a-, alpha 1b- and alpha 1dadrenergic receptor mRNA in the rat-brain and spinal cord. J Chem Neuroanat 1997; 13:115–139 53. Hatano A, Takahashi H, Tamaki M et al. Pharmacological evidence of distinct α1-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery. Br J Urol 1994; 113:723–728 54. Kohno Y, Saito H, Takita M et al. Heterogeneity of α1-adrenoceptor subtypes involved in adrenergic contrac-tions of dog blood vessels. Br J Pharmacol 1994; 112: 1167–1173 55. Kenny B A, Chalmers D H, Philpott P C, Naylor A M. Characterization of an α1D-adrenoceptor mediating the contractile response of rat aorta to noradrenaline. Br J Pharmacol 1995; 115:981–986 56. Muramatsu I, Ohmura T, Hashimoto S, Oshita M. Functional subclassification of vascular α1adrenoceptors. Pharmacol Commun 1995; 6:23–28 57. Vargas H M, Gorman A J. Vascular alpha-1 adrenergic receptor subtypes in the regulation of arterial pressure. Life Sci 1995; 57:2291–2308 58. Williams T J, Blue D R, Daniels D V et al. In vitro alpha 1-adrenoceptor pharmacology of Ro 70–0004 and RS100329; novel alpha 1A-adrenoceptor antagonists. Br J Pharmacol 1999; 127:252–258 59. Lopez FJ, Arias L, Chan R et al. Synthesis, pharmacology and pharmacokinetics of 3-(4-arylpiperazin-1-ylalkyl)uracils as uroselective alpha(1A)-antagonists. Bioorg Med Chem Lett 2003; 2:1873– 1878 60. Imigawa J, Akima M, Saki K. In vivo experiments for the evaluation of α1-adrenoceptor antagonistic effects of SGB-1534 on canine urethra. Eur J Pharmacol 1989; 167: 167–172 61. Shibasaki M, Sudoh K, Inagaki O et al. Effect of optical isomers of YM-12617 on increased intraurethral pressure induced by phenylephrine in anaesthetized dogs. J Autonom Pharmacol 1992; 12:263– 268 62. Breslin D, Fields D W, Chow T C et al. Medical management of benign prostatic hyperplasia: a canine model comparing the in vivo efficacy of alpha-1-adrenergic antagonists in the prostate. J Urol 1993; 149:395–399 63. Lefevre-Borg F, O’Connor S E, Schoemaker H et al. Alfuzosin, a selective α1-adrenoceptor antagonist in the lower urinary tract. Br J Pharmacol 1993; 109:1282–1289 64. Kenny B A, Naylor A M, Carter A J et al. Effect of alphaadrenoceptor antagonists on prostatic pressure and blood pressure in the anaesthetized dog. Urology 1994; 44: 52–57 65. Martin D J, Lluel P, Guillot E et al. Comparative alpha-1 adrenoceptor subtype selectivity and functional uroselectivity of alpha-1 adrenoceptor antagonists. J Pharmacol Exp Ther 1997; 282:228–235 66. Akiyama K, Hora M, Tatemichi S et al. KMD-3213, a uroselective and long-acting alpha (1a)adrenoceptor antagonist, tested in a novel rat model. Pharmacol Exp Ther 1999; 291:81–91 67. Hieble J P, Kolpak D C, McCafferty G P et al. Effects of alpha1-adrenoceptor antagonists on agonist and tiltinduced changes in blood pressure: relationship to uroselectivity. Eur J Pharmacol 1999; 373:51– 62 68. Walsh P C. Benign prostatic hyperplasia. In: Walsh P C, Retik A B, Stamey T E, Vaughan E D Jr (eds). Campbell’s urology, 6th edn. Philadelphia: Saunders, 1992: 1009–1027 69. Sultana S R, Murray K, Craggs M D et al. Alpha1 adrenoceptor antagonist selectivity determined by simultaneous blood pressure and long-term urethral pressure monitoring in men. Br J Clin Pharmacol 1998; 45:192 70. Wyllie M G. Alpha1-adrenoceptor selectivity: the North American experience. Eur Urol 1999; 36 (Suppl 1): 59–63 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_437.html[09.07.2009 11:54:57]

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71. Roehrborn C G. Are all alpha blockers created equal? An update. Urology 2002; 59 (Suppl 2): 3–6 72. Kirby R S. Doxazosin in benign prostatic hyperplasia: effects on blood pressure and urinary flow in normotensive and hypertensive men. Urology 1995; 46:182–186 73. Lepor H and the Terazosin Research Group. Long-term efficacy and safety of terazosin in patients with benign prostatic hyperplasia. Urology 1995; 45:406–413 74. Wyllie M G. Uroselectivity; end of the road? BJU Int 2003; 92:141–142

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Page 439 V Surgical/Interventional Options

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Page 441 33 Surgical interventions for BPH J Shah C G Roehrborn Historical background As men started to live longer, so attention began to focus on the problems of the prostate. The ancient Egyptians used catheters made of silver tubes, reeds, and rolled palm leaves, whilst the ancient Hindu scripts describe catheters made of wood and metal. At the start of the Christian era, more refined methods were described. Surgeons started to use sounds that had ridges approximately an inch behind the tip that could relieve any obstructing tissue when pulled back and forth. These were, of course, blind procedures. However, credit for the first prostatic resection is given to Ambroise Pare in the sixteenth century. He used sounds with sharp cutting edges to pass through the obstruction and into the bladder, and then left an indwelling catheter for a few days. After the catheter was removed, patients voided through the newly bored tunnel. What is unclear is how much control these patients had when they voided. Subsequently, other famous surgeons improved this method. One such example is Leroy d’Etoilles who developed a prostate cutter to amputate and drag through the urethra, the lobes of the prostate, Planned surgical treatment was, however, introduced only just over a century ago. The first complete enucleation was described by Bellfield in the USA and McGill in England, and later by Fuller at the New York Hospital.1,2 In 1901, Sir Peter Freyer, an Irishman, published four cases of total prostatectomy. Although Freyer laid down some fundamental principles (complete removal of the adenomatous tissue, adequate postoperative drainage), it is perhaps incorrect to attribute him with the originality of this approach. He was, however, so successful that he became known as ‘that Galway man so aptly named as ‘pee-freer”. Other methods were described by surgeons of that time, although credit must be given to Millin for describing the retropubic approach in 1945.3,4 One of the most popular methods of prostatectomy is the transurethral route. Hugh Young produced a cold punch that was introduced into the bladder and removed portions of the prostate gland. According to Reed M. Nesbitt, several concepts contributed to the development of this technique: development of the incandescent lamp by Edison in 1879; the development of the cystoscope by Nitze and Lieter in 1887; the development of high-frequency electrical current used to cut prostatic tissue by Hertz in 1888 and DeForest in 1908; and introduction of the fenestrated tube by Hugh Hampton-Young in 1909 that allowed the prostate tissue in the fenestrations to be sheared off.5 After Stern introduced a tungsten wire loop for tissue resection in 1926, McCarthy combined all these concepts later that year to introduce the direct-vision resectoscope with a foroblique lens built by Reinhold Wappler, and a wire loop that allowed both resection and cauterization. Further improvements came after the intro duction of the Hopkins wide-angle lens in the 1970s, and the constant-flow low-pressure resectoscope described by Iglesias et al. in 1975.6 Since the Stern-McCarthy resectoscope, many developments led to the acceptance of transurethral resection of the prostate (TURP) as the gold standard for the surgical management of benign prostatic hyperplasia (BPH). In the past decade, there has been a resurgence of interest in other surgical interventions for BPH leading to trials of lasers, hyperthermia, electrovaporization, and insertion of prostatic stents. Most of the above-mentioned treatments involve heat to destroy prostatic tissue. There are two essential physical principles here: rapid deposition of heat energy causes tissue evaporation, whereas slow deposition of lesser amounts of energy leads to coagulative necrosis and eventual tissue sloughing. Both these methods lead to the same end-point, which is increased size of the prostatic lumen and thus elimination of the obstructive symptoms. Indications By 1962 TURP constituted over 50% of all major operations performed by American urologists and, in 1987, 258000 TURPs were carried out on Medicare patients. By 1986 this number had dropped to 38%. In 1993, only 168000 TURPs were undertaken, representing a 34% reduction.7 TURP still remains second only to cataract surgery on the list of Medicare’s most costly surgical procedures. A 20% sample of Medicare beneficiaries was examined to further specify rates of TURP in the USA. In 1990, the

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Page 442 rates of TURP for all indications were approximately 25, 19, and 13 per 1000 men over the age of 75, 70–74, and 65–69, respectively.8 The age-adjusted rates of TURP during 1991–97 declined further compared to 1984–90, by approximately 50% for whites (14.6/1000 in 1984–90 to 6.72/1000 in 1991– 97) and 40% for black men (11.8/1000 and 6.58/1000 for the same two time periods).9 Both the incidence in the number of prostatectomies undertaken and the relative number of patients treated by TURP compared to open surgery vary greatly between countries, and this is more likely to represent surgeon preference for one procedure over another than actual differences in disease prevalence and case mix (Table 33.1). Most surgical interventions for BPH are carried out for symptoms that are both bothersome and interfere with the patient’s lifestyle. One study noted that over 90% of patients undergoing a TURP had symptoms of bladder outflow obstruction (BOO).10 There are, however, few absolute indications or indications that mandate a surgical approach rather than any of the more conservative management strategies11: • Acute refractory urinary retention (after at least one attempt at removal of the catheter). • Recurrent urinary tract infections. • Recurrent macroscopic hematuria. • Renal insufficiency with upper tract changes. • Significant symptoms that are not responsive to medical therapy. • Bladder calculi. • Large bladder diverticulum formation. • Large postvoid residual urine. Table 33.1 Incidence in number of prostatectomies per 1000 men 55 years of age or older per year, and choice of surgical treatment in various countries.12 Country Incidence % TURP % Open surgery 1988 1990 USA 15 13 97 3 France 14 13 69 31 Belgium 12 14 83 17 Sweden* 11 11 99 1 Denmark† 10 12 97 3 Japan 7 9 70 30 UK** — 7 92 8 *1988 data; †approximately 66% of prostatectomies by general surgeons; **approximately 33% of prostatectomies by general surgeons, data for England only. More recently there has been some success in treating men who have macroscopic hematuria due to BPH with finasteride, a 5α-reductase inhibitor.13 In one study, 94% of patients improved after taking finasteride and 77% experienced no further bleeding.14 In another study, the authors found that the recurrence rate for macroscopic bleeding in men on finasteride after a mean of 23 months was 12%, compared to 77% in control patients.15 Thus the first-line treatment for men with this particular complication of BPH has now changed from TURP to a trial of finasteride. In the USA, the vast majority of patients until recently have undergone surgical treatment either exclusively for symptom relief or for symptoms in combination with other indications (Table 33.2).10 In the UK, approximately 60% of prostatectomies are carried out for reasons other than just symptoms.16 At present, the differential indications for the various surgical treatment modalities are not clearly defined. In general, any patient who has symptoms and/or signs secondary to prostatic obstruction with acceptable surgical and anesthetic risk factors can be considered for TURP, transurethral incision of the prostate (TUIP), transurethral needle ablation of the prostate (TUNA), or open surgery. Historically, patients with prostate glands greater than 100 ml are thought to be better suited to open prostatectomies. The ideal patient for TUNA is considered to be a Table 33.2 Indications for prostatectomy alone and in combination in 3885 patients.10 Indications for surgery Number % Symptoms of prostatism 3522 90.7 Significant residual urine 1336 34.4 Urinary retention, acute 1053 27.1 Recurrent urinary tract infection 479 12.3 Hematuria 465 12.0 Altered urodynamic function 385 9.9 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_442.html[09.07.2009 11:54:59]

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Renal insufficiency Bladder stones Symptoms of prostatism only Prostatism and residual urine Prostatism and acute retention Prostatism and acute retention and residual urine

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176 116 1145 577 372 217

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Page 443 man with obstructive symptoms and a prostate that is less than 60 g, with predominantly lateral lobes. TUIP is usually recommended to men with small prostates of less than 30 g, and no median lobe. Mebust et al. retrospectively reviewed 3885 TURPs and found that 35% produced less than or equal to 10 g of resected tissue, 65% less than or equal to 20 g, and 80% less than or equal to 30 g.10 Thus, based on these criteria, many of the men undergoing TURP could in fact be treated by TUIP. One recommendation for TURP is that the procedure be undertaken if the resection can be completed in less than 60 minutes.17 Anesthetic considerations Open surgical enucleation of the prostate, regardless of which route is employed, is most commonly performed under a general anesthetic. Although TURP can be undertaken using a general anesthetic, most are done using either an epidural or a spinal anesthetic. In one study, 79% of all TURPs were done using a spinal or epidural anesthetic.7 Similarly, in a cooperative study involving 13 institutions, 78% of all TURPs were undertaken with these anesthetic modalities.10 Nielsen et al. found no difference in blood loss between a general and an epidural anesthetic for a TURP.18 McGowan and Smith also noted no difference in blood loss, postoperative complications, or mortality when comparing spinal and general anesthesia.19 The earliest descriptions of TURP under local anesthetic were reported in 1977.20 More recently, two groups have reported their experiences of TURP under local anesthetic.21,22 Birch et al. presented a series of 100 men who underwent a TURP using local anesthetic and intravenous sedation, and found that prostates weighing less than 40 g were more suited to this approach.22 In other studies, the local anesthetic has been administered either by the transurethral or perineal route, or a combination of both, giving a potent analgesic effect.23,24 Many of the newer treatment modalities such as TUIP and transurethral microwave therapy (TUMT) have also been described using local anesthetic, with the majority of patients tolerating the procedure well.17,25–27 The most obvious advantage of undertaking these procedures under local anesthesia is the reduction in hospital stay, which translates to cost reductions. In addition, it has been noted that many of the patients seeking treatment for BPH will have serious co-morbidity. Mebust et al. found that 77% of patients had a significant medical problem, and the most common were pulmonary (14.5%), gastrointestinal (13.2%), myocardial infarction (12.5%), arrhythmia (12.4%), and renal insufficiency (4.5%).10 Therefore, the use of local anesthesia also has benefits for both the patient and today’s health economics. Antibiotic prophylaxis Up to a quarter of patients with BPH have a urinary tract infection, and this figure may be higher in patients with indwelling catheters. There is little doubt that the infection must be treated prior to surgery. The subject of prophylactic antibiotics, however, leads to many questions, such as which antibiotic to use and for how long to continue this postoperatively. One study investigated 4260 patients with sterile urine preoperatively, and found that the rate of bacteriuria decreased from 26% to 9.1% and the rate of clinical septicemia decreased from 4.4% to 0.7% with the use of antibiotic prophylaxis. In addition, the authors found that effective antibiotics for this purpose were quinolones, cephalosporins, co-trimoxazole, and aminoglycosides, given in short courses rather than as single doses.28 According to another study, an effective short course was 24 hours after the operation.29 In patients with BPH who have proven micro-organisms preoperatively, a 3-day prophylaxis with ciprofloxacin significantly eradicated bacteriuria in 83% of patients.30 Hence it is our recommendation that antibiotic prophylaxis be used in all patients undergoing transurethral surgery. Transurethral incision of the prostate (Fig. 33.1) Whether Guthrie introduced TUIP in 1834 or Bottini in 1887, this simple and quick procedure is not new.30,31 The indication for a TUIP is men with a small prostate or the younger man with primary bladder neck obstruction. Nitti et al. reported an incidence of 47% among younger men who have lower urinary tract symptoms.33 The technique is to incise the bladder neck and the prostate from the neck to the verumontanum at the 5 and 7 o’clock positions.34 The aim is to divide the fibers deep enough to penetrate the prostatic tissue down to the prostatic capsule. Care must be taken not to incise too deeply as this would cause extravasation. When appropriate incisions are made, the bladder neck can be seen to spring apart. There are many variations to the above-described technique. Some urologists prefer a single incision at file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_443.html[09.07.2009 11:55:00]

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the 6 o’clock position, or multiple incisions at a variety of locations around the bladder neck. A urethral catheter is usually left for 24 hours.

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Figure 33.1 Transurethral incision of the prostate. One of the most important complications after incision of the bladder neck is retrograde ejaculation. This can be a significant problem in younger men as fertility cannot be guaranteed in this group and occurs in 13–35% of men.35 The incidence is reported to be much lower (approximately 5%) after unilateral incision with effective postoperative symptom control.36 TUIP has been shown to produce an 87% overall improvement in symptoms.36 Another study has demonstrated an increase in urinary flow rate, a reduction in voiding pressure, and a reduction in symptoms following TUIP.37 TUIP was also found to be effective in a prospective study comparing TUIP and TURP in 132 patients over a 2-year period, although the results did not reach statistical significance.38 Riehmann et al. randomized patients to either a TURP or a TUIP and followed them for a mean time of 34 months. The difference in urinary flow rates reached statistical significance only at 3 months and 24 months. In addition, retrograde ejaculation was twice as prevalent in the TURP group than the TUIP group, although the latter group required a nonsignificant higher reoperation rate.35 Finally, in a metaanalysis of the available studies, McConnell et al. noted that the chance of symptom improvement was better with TURP (88%) than with a TUIP (80%).11 Transurethral resection of the prostate Although water was used in the past for transurethral surgery, in 1947 Creevy and Webb pointed out the danger of hemolysis.39 Since that time, nonhemolytic solutions such as 1.5% glycine or mannitol have been used. The patient is placed in the lithotomy position and the urethra is calibrated such that it will easily accommodate the outer sheath of the resectoscope (this is most commonly 28 Fr). Occasionally a meatotomy is required to facilitate this process. The first step in any transurethral surgery is careful inspection of the prostatic urethra, the external sphincter, the bladder neck, the bladder, and the ureteric orifices. It is imperative that the resectionist maintains a threedimensional image of the anatomic relationships between the trigone, the ureteric orifices, the bladder neck, the lateral and median lobe of the prostate, and the verumontanum throughout the entire procedure.

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Page 445 There are various techniques that have been suggested to remove adenomatous tissue systematically and are all based on the principle that the resection should be carried out in a step-wise manner. High-frequency current is used to create a heatinduced zone of vaporization at the area of contact between the loop and the tissue, and the tissue that lifts off is referred to as a ‘chip’. The standard thin loop used for TURP is 0.3 mm. More recently, thick loops that are about four times the width of these standard loops and have the same loop diameter have been employed. In theory, the increased width should produce coagulation and cutting and thus result in less bleeding. However, in one prospective study, the authors found no advantage in using these thicker loops.40 Most of the described techniques suggest initial resection of the ventral tissue between 3 and 9 o’clock so that the anterior tissue will drop down. This will allow the surgeon to resect from the top downward rather than from the floor upward. Whatever method is employed for the resection, cutting open blood vessels cannot be avoided, with resultant bleeding. It is therefore imperative that resection and hemostasis be completed in any one area before moving on to the next. Details of the actual TURP procedure have been described by Nesbitt and others elsewhere.5,41,42 The Nesbitt surgical procedure is divided into three stages: Stage 1 (Fig. 33.2a). The fibers at the bladder neck and those of the immediately adjacent adenoma are resected with short, full-thickness bites circumferentially around the bladder neck. This process may be started at the 12 o’clock position and then carried out on either side until finally the bladder neck tissue between 5 and 7 o’clock is resected in this manner. Following this, the adenoma is resected in quadrants (Fig. 33.2b). Stage 2. The resectoscope is then placed in front of the verumontanum, which marks the distal limit of the resection. The resection again begins at the 12 o’clock position so that the lateral lobe tissue falls into the middle of the prostatic fossa. The upper of the ventral quadrants on both the right and left side are resected first down to the fibers of the surgical capsule. There are a number of features that help to identify this capsule: the orientation of these fibers is circular, and while the nodular tissue of the adenoma tends to be yellow in color, the capsular fibers appear white and glistening. Another feature of the capsule in the lower quadrants is the presence of prostatic calculi that are usually located between the transition zone (that is, the adenomatous part of the gland) and the compressed peripheral zone. In this manner all four quadrants are resected. Caution must be applied to resection at the posterior aspect of the bladder neck, which will lead to undermining the trigone. Stage 3 (Fig. 33.2c). The adenomatous tissue surrounding the verumontanum is located proximal to the external sphincter and is resected last. The prostatic fossa is a biconcave cavity and at this point a sweeping motion is used such that the loop is moved from a lateral to a medial direction as it approaches the sphincter. Once the resection is complete and all the obstructing adenomatous tissue has been removed, there may occasionally be partially obstructing tissue noted at the bladder neck. Kulb et al. have suggested that this tissue be incised to prevent bladder neck contractures, particularly in glands weighing less than 20 g.43 It is not uncommon to have small wings of adenoma attached around the region of the sphincter, and these can only be noted once the resectoscope is pulled into the urethra beyond the verumontanum. These must be trimmed to avoid obstruction. Many modifications have been suggested to improve TURP.44 Among them is the introduction of the constantflow resectoscope that allows continuous resection, clearer vision, use of a monitor to view the operation, and lowpressure conditions within the prostatic fossa that lead to decreased absorption of fluids. Following complete resection, care must be taken to achieve perfect hemostasis within the prostatic fossa, and especially around the bladder neck, where small arterial bleeders are frequently noted. It is virtually impossible to control venous sinus bleeding with the resectoscope. By contrast, arterial bleeders are much easier to control. At this stage, all the chips are evacuated with the Ellik evacuator, after which a second look at the prostatic fossa is mandatory. Once again, hemostasis is perfected. Once the resectoscope is removed, a 22 Fr or 24 Fr three-way Foley catheter is inserted that allows either intermittent or continuous normal saline irrigation. The catheter balloon is usually inflated with 30ml and gentle traction is placed at the bladder neck (not in the prostatic fossa). Some authors have recommended that a significant amount of traction be placed for the first 24 hours after the operation. However, with the ensuing capsular contraction, venous bleeding will usually stop and thus traction is not required. Once the urine is clear, irrigation is stopped, and the catheter may be removed. More recently, a new resection device that replaces the loop electrode has been developed in an file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_445.html[09.07.2009 11:55:01]

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attempt to provide bloodless resection whilst maintaining effective tissue ablation. The Rotoresect system (Karl Storz,

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Figure 33.2 Transurethral resection of the prostate. file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_446.html[09.07.2009 11:55:02]

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Page 447 Tuttlingen, Germany) combines coagulation and vaporization with mechanical tissue ablation using a rotating milling head that is controlled by a foot switch. In pig studies, the system was found to be as effective as TURP, and as bloodless as transurethral electrovaporization of the prostate (TUVP).45 In the study with the longest reported follow-up with Rotoresecect (TURRP) at 4 years, 84 patients with BPH underwent this procedure.46 The authors report the mean duration of catheterization postTURRP at 1.4 days; the peak urinary flow rate improved from 9.7 to 24.2 ml/s, and the residual urine volume reduced from 187.3 to 22.7 ml; the I-PSS improved from 24.0 to 4.1 and the quality of life index decreased from 4.2 to 0.8 at 4 years. During this time, 2/84 patients (2%) required retreatment for treatment failure, and no patients required a blood transfusion. At present, studies are sparse regarding this alteration to the standard TURP technique, but at 4 years, the morbidity, mortality, and effectiveness of TURRP are at least comparable to TURP Intraoperative complications of TURP Bleeding The amount of bleeding is dependent upon the operative time, weight of resected tissue, and the presence of an indwelling catheter. Arterial bleeding is usually easy to spot, both during the operation and afterwards, due to the bright red color of irrigation. It is also relatively easy to control by electrocoagulation. However, venous bleeding is suspected when the irrigation is initially clear and then becomes a dark red color. For this, sustained traction for up to 10 minutes is usually sufficient. One study has recommended optimizing low preoperative hemoglobin as a method of reducing postTURP blood transfusion requirements.47 Extravasation Perforation of the capsule can lead to extravasation of the irrigant, and occurs in 2% of cases. If this complication is suspected, then hemostasis must be secured and the procedure terminated as rapidly as possible. The majority of these patients can be managed by catheter drainage and stopping the operation. In the rare cases where there is extensive extravasation, antibiotics and suprapubic drainage are advised. Transurethral resection syndrome The incidence of transurethral resection (TUR) syndrome is approximately 2% and is caused by a combination of dilutional hyponatremia, glycine-induced ammonia intoxication, and the toxic effect of glycine.10,48 Symptoms suggestive of TUR syndrome include nausea and vomiting, mental confusion, hypertension, bradycardia, and visual disturbances and manifest once the sodium has dropped below 125 mEq. Treatment of this complication involves administration of a diuretic such as frusemide titrated against regular serum sodium levels. Intraoperative erection Intraoperative penile erections can make a TURP difficult or even impossible as the urethra elongates and anatomical landmarks are distorted. The incidence is between 1 and 2.5%, with a preponderance for younger patients.49 There are several options for the management of this complication. These include aspiration of intracavernosal blood, intracavernosal injection of 0.2 mg of phenylephrine, and a penile block with plain 1% lignocaine using 10–20 ml.50 Whatever method is employed, the anesthetist should be informed of the agents administered to the penis. Transurethral electrovaporization of the prostate Bush et al. first described TUVP as a modification of the existing standard TURP causing both vaporization and tissue desiccation in 1993.51 They used a grooved ball that has the advantage of an increased number of leading edges in contact with prostate tissue, which leads to greater efficiency of the vaporization.52 The initial set-up of the patient is similar to the TURP using either a general or regional anesthesia. A continuous-flow resectoscope is used with irrigant fluid and the rollerball is placed in the resectoscope similar to the cutting loop in routine TURP The ball is rolled over the tissue to create the desired cavity. In one in vitro study, TUVP was found to produce greater coagulation depth compared to TURP (2.1 mm vs 0.9 mm, respectively). In addition, the authors found that a 15 to 20 times higher power setting is required for a TUVP compared to a TURP.53 The first report of TUVP was published by Kaplan and Te in 1995, demonstrating efficacy and safety in 25 men with moderate lower urinary tract symptoms.54 All patients had their catheters removed at 24 hours, with the mean time of removal at 14.6 hours. The main advantage of TUVP over TURP is a reduction in bleeding and therefore reduced postoperative irrigation requirements. In a large review of comparative studies of TUVP and TURP, the authors found that the file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_447.html[09.07.2009 11:55:02]

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Page 448 postoperative symptoms, 1-year reoperation rate, and urethral stricture rate were the same in both groups.55 However, operating time was found to be greater for TUVP, presumably due to the time required to achieve good vaporization. In one comparative study, 235 men were randomized to either TURP or TUVP. The authors found no statistically significant difference in operative time, improvement in flow rates, and extent of symptom relief between the two groups. There was also no difference in the complication rates.56 In the prospective randomized study comparing TURP and TUVP with the longest follow-up, the authors found that TUVP was as effective as TURP, and that the initial symptom improvement was maintained during a 5-year period.57 The authors report a 4% urethral stricture rate in both groups, a 3% per year per treatment arm reoperation rate, and a greater rate of impotence in the TUVP arm (17%) compared to the TURP group (11%).57 At present, TUVP appears to be as effective as the gold standard TURP, with most studies operating on prostates of less than 60 ml. Whilst the cost of TUVP may be reduced by the decreased hospital stay, irrigation requirements, and postoperative blood transfusion, the initial additional cost of the rollerball electrode must be borne in mind. Transurethral needle ablation of the prostate For centuries, various substances have been injected locally into the prostate gland to produce necrosis, suppuration, and sepsis that eventually lead to shrinkage. This includes freezing and dehydration by heat treatment. The use of low-level radiofrequency to produce localized necrosis has its roots embedded in the ablation of cardiac nerve bundles. TUNA received Food and Drug Administration (FDA) approval in the USA in 1996. The device consists of a special 22-Fr modified cystoscope, through which two needles are passed under vision into the prostate. The cystoscope can be rotated to direct the needles to the desired area. Low-level radiofrequency energy (approximately 460kHz) generates temperatures of approximately 100 degrees centigrade at the tip of the needles for 4 minutes per lesion. This has two effects: (1) thermal ablation produces coagulative necrosis leading to retraction of tissue and contraction of the capsule; and (2) destruction of α-adrenoceptors within the adenoma and thus permanent blockage of these receptors.58 Microscopic examination of TUNA specimens has shown that the procedure causes an area of necrosis with sharp demarcation from the rest of the tissue. Each lesion can range from 12×7 mm to 18×12 mm.59 The procedure is carried out in the lithotomy position, under general or regional anesthesia, or under local anesthesia with or without additional sedation. The procedure is commenced 1 cm distal to the bladder neck and continued at 1 cm intervals to 1 cm proximal to the verumontanum. The needles have a protective insulation sheath that is retractile to protect the urethra. Postoperatively, patients are given a catheter. The results of TUNA treatments have been summarized by Issa and Oesterling.60 Prostate volumes treated by this method as noted on transrectal ultrasound were 48.1 ml, and the patient most likely to benefit is one with lateral lobe enlargement and a prostate of 60 g or less.61 The mean duration of each procedure was 79 minutes and most procedures were performed on an outpatient basis. At 12 months’ follow-up urinary flow rates had improved by 77% and symptom scores had improved by 58%. The most common complication of TUNA is postoperative urinary retention, with reported rates between 13 and 42%, lasting from 12 to 48 hours. Macroscopic hematuria is reported in 32.3% of patients for up to 48 hours.60 Sexual dysfunction and urethral strictures are uncommon, with rates at approximately 1.5%. Reoperation rates for TUNA have been reported as high as 20% within a 24-month period, and after 5-years’ follow-up one series has reported this figure as high as 25%.62 TUNA has been prospectively compared with the gold standard TURP in the American study.63 After 12 months’ follow-up, symptom scores in the TURP group improved from 23.3 to 8.3, and peak flow rates improved from 8.4 to 20.8 ml/s. In the TUNA group, the symptom score improved from 24.7 to 11.1 and peak flow rates improved from 8.7 to 15.0 ml/s.63 In a more recent study, the authors found that at 18 months’ follow-up, outcomes from TUNA and TURP were comparable. TUNA was found to be safe and effective, with a low morbidity in patients with BPH, and can be undertaken as a day case procedure under local anesthetic.64 However, long-term data to establish the durability of TUNA have yet to be determined. Transurethral microwave therapy TUMT uses computer-regulated microwaves to deliver heat through a catheter to parts of the prostate gland. The file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_448.html[09.07.2009 11:55:03]

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Page 449 tissues closest to the microwave probe are cooled to prevent damage, while the heat is maximized to the area of the transition zone. Temperatures of between 42 and 45 degrees centigrade are reached at the transition zone to produce thermal damage. The procedure can be undertaken in a single 1-hour session as an outpatient procedure with only local anesthesia. Optionally sedation may be administered. At 1 year follow-up, results of TUMT suggest a 67% reduction in symptom score and a 42% increase in peak flow rate.65 The maximum effect is noted 3 months after treatment, with a slight but significant improvement up to 12 months after the procedure. The frequency of urinary retention after TUMT is as high as 40%, and these cases may require catheterization for more than a week.66 Urinary tract infections occur in 18% of patients, irritative voiding symptoms in 37%, and hematuria has been reported in up to 13% of patients after TUMT, with 7.4% of patients having hematuria requiring additional surgical treatment.67 At 1-year, re-treatment rates are consistently reported at approximately 10%, and at 4 years, 11% have been reported to undergo further invasive therapy, and 29%, additional medical therapy.68 The earliest comparative study between TURP ( n =32) and TUMT ( n =37) showed significant and durable improvements at 2 years in both treatment groups, although TURP had a statistically significant advantage. However, retrograde ejaculation was reported in 25% of the TURP group and in none of those treated by TUMT. Additionally, 7.5% of the patients in the TURP arm had urethral strictures, compared to none in the TUMT arm.69 In a more recent study comparing TUMT and TURP, the TUMT method was somewhat refined so that a feedback system based on intraprostatic temperature measurements was used. At 12 months, the authors reported no difference for I-PSS, peak flow rate, or detrusor pressure. This led the authors to suggest that both treatment methods were comparable although, from a simplicity and safety point of view, TUMT was advantageous.67 TUMT seems to be a safe and effective treatment option for patients with BPH. Its place at present can be considered to be between medical and surgical (TURP) interventions. Improvements in symptom scores have been reported at 60% for TUMT compared to 85% after TURP, and improvement in peak flow rates have been reported at 50% with TUMT compared to up to 200% with standard TURP.68 Open prostatectomy Open prostatectomy can be performed by the retropubic or suprapubic routes, and is considered in patients who have conditions that prevent them from being adequately positioned for a TURP, in men with prostate glands greater than 75–100 g, and in men with concomitant bladder conditions, such as diverticulae or calculi. Suprapubic prostatectomy (Fig. 33.3) The open suprapubic or transvesical prostatectomy was the first method applied to the removal of the adenomatous gland, and may still be the most frequently performed open surgery. While it was initially done as a blind procedure with a small suprapubic incision, it is now performed under direct vision, thereby enabling control of bleeding and prevention of bladder neck contractures. The patient is placed supine on the operating table in a slight Trendelenburg position, with the table broken so as to extend the lumbar spine for better access to the pelvis. The suprapubic region is shaved. A Foley catheter is placed in the bladder on the sterile field, and the residual urine is drained. The bladder is then distended with saline solution and the catheter clamped. Either a vertical midline incision or a Pfannenstiel incision may be used to enter the extraperitoneal perivesical space. A selfholding retractor facilitates exposure of the bladder. The bladder may be opened in either a vertical or transverse fashion. Two lateral and one caudally placed midline self-retaining retractor blades are inserted into the bladder to facilitate exposure. At this time, the internal urethral meatus or bladder neck is clearly identified. The catheter is now removed and, using electrocautery, the mucosa over the prostate around the bladder neck is incised circumferentially with a radius of about 1 cm from the center of the urethra. Care is taken to avoid cautery too close to the ureteral orifices. This procedure is complicated if there is a large intravesical lobe present. It is convenient to lift such an intravesical lobe up with an Ellis or Babcock clamp, and continue the incision of the mucosa under this lobe. The index finger of the dominant hand is then inserted into the internal urethral meatus of the bladder neck, and with a forceful motion upward, the anterior commissure is split down to the capsule in the mid prostate. This crack is then continued cranially until it extends into the bladder and connects there with the previously carried out incision of the mucosa. At this time, the self-holding retractor should be removed to facilitate the enucleation under digital control. 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Figure 33.3 Suprapubic prostatectomy.

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Page 451

adenoma (i.e. transition zone) and the surgical capsule (i.e. compressed peripheral zone) must be clearly identified. It is imperative to perform the enucleation at this level. If this is not the case, either adenomatous tissue is left behind, or the surgical capsule or the peripheral zone is perforated, which will make it possible to remove the posterior structures, including the seminal vesicles together with the adenoma. The feeling should be that of having the smooth surgical capsule always lateral or outward and peeling the meat, i.e. the adenomatous tissue, of the surgical capsule as the finger glides around the 12 o’clock position on the right and left side towards the 6 o’clock position. The urethra can be divided at the apex by pinching it between two fingers. If this is not possible, a sharp transection of the urethra is better than a forceful ripping. This can be accomplished with the sharply bent Torek scissors. At this time, the adenomatous tissue can be lifted out of the prostatic fossa and held up with a Babcock clamp or ring forceps. Often, at this stage, the adenomatous tissue is still connected at the bladder neck and blunt or sharp dissection is needed to complete the enucleation of the gland. A large intravesical lobe will require sharp dissection at the level of the bladder neck and great care must be taken not to injure the ureteral orifices or the ureters. Following the removal of the adenomatous tissue, the fossa is carefully palpated to ensure that all adenomatous tissue has been removed. Once this has been accomplished, two figure of eight sutures are placed at the 5 and 7 o’clock positions carefully avoiding the ureteral orifices to control the bleeding that is usually heaviest at these positions. The mucosa just cranial from the bladder neck can be sutured down into the prostatic fossa with an

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Page 452 advantage in efforts to establish a straight plane through which the catheter is inserted into the bladder. This can be done by using 2–0 chromic sutures and sewing the mucosa down into the floor of the prostatic fossa, thus avoiding the ‘step-up’ effect. All bleeders within the prostatic fossa can usually be coagulated with the electrocautery, but occasionally individual suture ligatures are needed. The anterior portion of the bladder neck can be sutured down with 2–0 chromic interrupted stitches to narrow and reconstruct the bladder neck. At this time, a rate stab wound into the bladder and secured with a 26- or 28-Fr suprapubic tube is pulled in through a sepapurse-string suture. Following this, the bladder is closed in two layers in the standard fashion and both catheters are irrigated to assure patency. A single Jackson-Pratt drain is placed in the retropubic space and brought out through a separate stab wound. Wound closure is perfected in the usual fashion. The Foley catheter may be removed as soon as the urine begins to clear, while the suprapubic tube should be clamped after approximately 5 to 7 days. Once the patient is able to void, it may be removed. The pelvic drain is removed when the drainage is less than 75 ml per 24 hours. Retropubic prostatectomy (Fig. 33.4) The principle of retropubic prostatectomy is that the adenomatous tissue is removed through an incision in the

Figure 33.4 Retropubic prostatectomy.

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Page 454 surgical capsule of the prostate rather than through an opening in the bladder. Therefore no incision is made in the bladder, obviating the need for suprapubic catheter drainage in most cases. The incision in the capsule allows for improved exposure and inspection of the prostatic fossa to control bleeding. This is offset by an increased risk of intraoperative problems due to injury and bleeding from the dorsal vein complex of Santorini. The patient is again placed in the supine position on the operating table, and the suprapubic area shaved. A 22-Fr catheter is passed into the bladder. Both a vertical midline incision and a Pfannenstiel incision are acceptable. A self-retaining retractor (Balfour or Bookwalter with bodywall blades) is useful to allow exposure of the anterior surface of the prostate. Ventral veins of the dorsal vein complex are divided between suture ligatures. The fatty tissue overlying the anterior prostate and the puboprostatic ligaments can be bluntly pushed down and lateral, using either a sponge stick or a scraping action of a moist sponge. To reduce bleeding, it is advantageous to place two rows of sutures (2–0 chromic) approximately 5 mm apart in a transverse orientation. These rows of sutures should be overlapping in nature to encompass all veins running on top of the prostate in a cranio-caudal orientation. The lateral sutures can be used for traction purposes. The 30 ml balloon of the catheter is used to identify the junction between the bladder and the prostate and the balloon is deflated. Thereafter, the capsule is incised in a transverse orientation with electrocautery. It is of the greatest importance to carry the incision deep enough to extend through the surgical capsule into the adenoma. It is imperative that at this point the plane between the surgical capsule (i.e. peripheral zone) and the adenomatous tissue (i.e. transition zone) be correctly identified to facilitate enucleation of the adenoma. If needed, curved scissors are used to develop the plane between the capsule and the adenomatous tissue. However, in general, the index finger of the dominant hand is used to enucleate the adenoma and shell it out of the Capsule. As is the case in a suprapubic prostatectomy, sharply bent Torek scissors can be useful to transect the urethra. Furthermore, once the distal aspect of the adenoma is developed, it is possible to lift the adenoma out of the wound with the help of ringed forceps or Babcock clamps, facilitating either blunt or sharp dissection and transection of the adenoma at the bladder neck. Two figure of eight 2–0 chromic sutures are placed at the 5 o’clock position through the bladder neck to control bleeding. Care should be taken to avoid getting too close to the ureteral orifices or the ureters. The mucosa cranial to the bladder neck can be sutured down to the floor of the prostatic capsule with advantage, thus avoiding the ‘step-up’ effect This leads effectively to the retrigonization of the raw area of the bladder neck, making the passage of the catheter and the postoperative course more comfortable, while at the same time being helpful in controling bleeding. All remaining bleeders in the prostatic fossa can be controlled either by electrocautery or by a figure of eight suture ligature. At this time, a number 22- or 24-Fr three-way catheter is inserted through the urethra into the bladder and the balloon is inflated. The transverse incision of the capsule is then closed with appropriate suture material (chromic or vicryl). This may be done in either one or two layers. Care should be taken not to puncture the balloon at this stage, which may be left only partially inflated during this part of the operation. A suprapubic catheter may be placed, however we have not used one in any patient over the last few years. Lastly, a Jackson-Pratt drain is placed in the retropubic space and brought out through a separate stab wound. We usually use continuous irrigation for the first 12–24 hours after surgery, and stop the irrigation the morning after surgery. We have successfully removed the catheter as early as on the second postoperative day, although in some cases it might be advantageous to maintain drainage for several additional days. Treatment outcomes When evaluating surgical treatment modalities, it is important to assess the impact each treatment has on both indirect (peak urinary flow rate and residual urine) and direct outcomes. Direct outcomes affect life or quality of life, and are therefore of greater relevance to the patient.70 Urinary flow rate Among the parameters obtained from flow rate recordings, the peak urinary flow rate ( Q max) is most widely utilized as an outcome parameter of BPH treatment. There are considerable problems associated with the interpretation of the Q max, such as a significant intraindividual variability from recording to recording,71,72 a dependency of Q max on the voided volume, electronic artifacts of most commercial flow rate meters,73 and the fact that Q max does not correlate with symptoms and the bother of lower urinary tract symptoms.74 Figure 33.5 depicts the combined analysis of mean pre- and postoperative Q max, as well as the percentage change from baseline for TURP, TIUP, and open surgery.11

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Page 455 Since the publication of the Agency for Health Care Policy and Research (AHCPR) Guidelines in 1994, very little additional information regarding the outcome of open supra- or retropubic prostatectomy has been published. Consistent with the combined analysis data (Figure 33.5), Mearini et al. reported an increase from 8.2 to 19.7 ml/s in a series of patients treated by suprapubic prostatectomy in Perugia, Italy.75 Wasson et al. published a 3-year follow-up of a prospective, randomized trial comparing watchful waiting with TURP in men with moderate symptoms of BPH.9 In the group of 280 men who underwent TURP, the Q max improved from 11.6±6.4 to 17.8±9.1 ml/s (+54%); of note being the somewhat higher baseline mean Q max resulting from the inclusion criteria of the trial and causing a somewhat lower percentage improvement than reported in retrospective TURP series. Consistent with this contention are the 5-year follow-up data stratified by higher versus lower baseline Q max values.76 Improvement in the former group averaged 8.7 ml/s versus 4.6 ml/s in the latter group. Riehmann et al. randomized prospectively 120 patients with prostates of <20 g resectable weight to TURP ( n =56) and TUIP ( n =61).35 Comparable improvements in peak flow rates were seen for both treatment modalities up to 72 months of follow-up. The multitude of randomized trials of laser treatments, electrovaporization, and minimally invasive therapies for LUTS and BPH using TURP as a control arm provided additional data concerning a variety of outcomes including maximum flow rates, most of which were

Figure 33.5 Combined analysis of pre-( ) and postoperative ( ) peak urinary flow rate (Qmax) and percentage change from baseline for open surgery (OPSU), transurethral incision (TUIP), and transurethral resection (TURP) of the prostate. quite consistent with the meta-analysis done for the AHCPR.69,77–95 Postvoid residual urine The postvoid residual urine volume has severe limitations as an outcome parameter in the evaluation of BPH treatments. It shows significant intraindividual variability,96,97 and only very limited predictive value with regards to treatment outcomes.9 Furthermore, the correlation between residual urine volume and symptoms is practically nonexistent.74 While all treatment modalities are capable of reducing the residual urine volume by more than 50%, a comparison of the various therapies is difficult because of the vastly different baseline mean residual urine volume (Fig. 33.6). In many of the randomized trials using TURP as a control arm, residual urine was used as an outcome parameter and the results found were similar to those from the meta-analysis (Fig. 33.6). Symptom improvement When patients are asked which outcome from treatment for BPH is of greatest significance to them, an overwhelming number of them will rank symptom relief as the most important factor in choosing a treatment. Symptom relief can be measured by counting the number of patients who have either an improvement, no change, or worsening of their symptoms by global subjective assessment following the treatment, or by assessing the magnitude of the

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Figure 33.6 Combined analysis of pre- and postoperative ( ) postvoid residual urine volume (PVR) and percentage change from baseline for open surgery (OPSU), transurethral incision (TUIP), and transurethral resection (TURP) of the prostate.

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Page 456 change in symptoms using pre- and posttreatment symptom score. After TURP, TUIP, and open surgery the patient has a mean probability of symptomatic improvement of over 80% (Fig. 33.7), with open surgery being slightly superior to the endoscopic interventions. However, as there are no direct comparisons available between open surgery and TUIP/TURP, and the other treatment modalities, this could reflect a patient selection bias, such that patients who are more symptomatic at baseline will be treated by open surgery, and will then have a greater probability of perceiving improvement. When expressing the magnitude of the improvement as the drop in symptom severity score normalized to 100%, the interventions achieve a drop of between 73% and 85% from baseline, and all lower the symptom score to about 10% of the total achievable score (this would be about 3.5 points on the 7item, 35-point AUA symptom severity index) (Fig. 33.8). The TURP-treated patients in Wasson’s study experienced a drop in symptom score from 14.6±3.0 to 4.9±4.0 points for a drop of −9.6 points, or from 54% to 18% of the 27-point scale (64% drop).9 In a direct comparison, there were no differences noted between pre- and posttreatment mean symptom scores up to 72 months of follow-up between TURP- and TUIPtreated patients, while in both groups the symptom scores were significantly better at all follow-up visits.35 In a comparison between TUVP and TURP, the noted drop in I-PSS score at 3 years for the TUVP arm was 85% and at 5 years was 78%, and the change in quality of life scores was 80% and 78% at 3- and 5-year follow-up, respectively, for the TUVP group.57 Again, the TURP control arms from laser prostatectomy and minimally invasive therapy intervention provide an excellent frame of reference, suggesting that overall a drop in I-PSS score of >10 points can be expected following standard TURP in the vast majority of patients. Perioperative morbidity The superior symptom improvement effected by surgical treatment of BPH must be balanced with the associated morbidity and mortality. There is an abundance of data available regarding perioperative complications, secondary interventions for bleeding problems (e.g. clot evacuation, surgical reexploration, etc.), the need for blood transfusions, and two specific infectious complications, namely postoperative urinary tract infections and epididymitis. General perioperative complications are those complications listed by the respective authors and are not

Figure 33.7 Combined analysis of probability of experiencing symptomatic improvement following open surgery (OPSU), transurethral incision (TUIP), and transurethral resection (TURP) (90% CI and ) and mean probability indicated by horizontal line and listed on xaxis.)

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Figure 33.8 Combined analysis of magnitude of symptom improvement expressed as drop in symptom score. The upper extent of the boxes indicates the mean pretreatment score expressed as percentage of total possible score, and the lower extent of the box the mean posttreatment score. The numbers in the box indicate the differences between pre- and posttreatment scores, and the numbers in parentheses on the x-axis the percentage drop in symptom score from baseline. OPSU, open surgery; TUIP, transurethral incision of prostate; TURP, transurethral resection of prostate.

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Page 457 grouped by presumed severity. They include wound infection and other wound-related problems, catheter problems, temporary retention, transitory incontinence, pneumonia, urine leakage and fistulae, osteitis pubis, deep venous thrombosis and pulmonary emboli, cardiovascular complications, and other less commonly reported events. Combined analyses are shown in Table 33.3. The mean probability varies from 12% for TUIP to 25% for suprapubic transvesical prostatectomy (OPSS). The mean probability for complications of 15% following TURP may be contrasted with the contemporary series reported by Wasson et al., who reported that 9% of patients suffered from one or another perioperative complication in the first 30 days postoperatively.9 In a contemporary series of 240 suprapubic prostatectomies, Meier et al. reported an overall early complication rate of 19.6%.98 Postoperative complications following TURP are more common in patients with renal insufficiency (25 versus 17%, respectively) and in patients presenting in retention (24 versus 15.7%, respectively) The need for blood transfusion is most likely vastly overestimated in the older literature. The estimates range from 1.1% (TUIP) to 49% (retropubic prostatectomy-OPSR). The reasons for these high transfusion rates are the fact that many series were reported prior to the concern about hepatitis and AIDS virus transmission by blood products. In a contemporary series of 280 patients undergoing TURP at the Veterans’ Administration Medical Centers, the transfusion rate was only 3/280 or 1% and is more likely to reflect current trends, although patients not specifically selected for a randomized trial comparing watchful waiting with TURP are probably more likely to have co-morbidities leading to a slightly higher need for transfusion. Similarly, the transfusion rate for a contemporary series of 240 open prostatectomies was 4.6%, of which only 2.1% were believed to be medically justified.98 More recently, a study comparing TUVP and TURP showed the need for blood transfusion to be significantly lower in the TUVP group (1/115) than the TURP group (9/120).56 In another study comparing TUNA and TURP, none of the TUNA patients required a blood transfusion, with only two of the 26 patients having transient hematuria in the TUNA group.64 Secondary interventions for bleeding have a mean probability ranging from 0.5% (TUIP) to 2.2% (TURP) (Table 33.3) in the literature, and it is not likely that these are significant overestimates. In fact, Meier et al. reported a 2.9% rate for reoperation for clot retention following contemporary open prostatectomy.98 For TUMT, up to 7.4% of patients require additional surgical intervention for bleeding.68 Mearini et al. in a contemporary series of suprapubic prostatectomies, reported a 6% rate of significant hemorrhage and a 26.5% transfusion rate.75 Two specific infectious postoperative complications are the probability for epididymitis and urinary tract infections (UTIs) (Table 33.3). The mean probabilities range from 1.2% (TURP) to 3.6% (OPSS) for epididymitis, and from 2.6% (OPSR) to 15.5% (TURP) for UTIs. The reported incidence of UTIs following TUVP is 6%,57 and following TUMT is between 10 and 13%.68 These data are probably biased by the time of sampling the urine for a culture and whether and for how long patients received perioperative antibiotics. Incontinence Urinary incontinence is defined as the involuntary loss of urine. With regard to surgical treatment for BPH, two types of incontinence are of relevance: total urinary Table 33.3 Combined* analyses for the probability of selected perioperative complications following open enucleation by suprapubic (OPSS) or retropubic (OPSR) prostatectomy, transurethral incision of prostate (TUIP), and transurethral resection of prostate (TURP). Open surgery (OPSU) represents the combined probabilities for OPSS and OPSR. Modality n Bleeding Surgical Epididymitis Urinary tract Perioperative intervention (%)† complications (%)‡ (%)‡ infection (%)‡ morality (%)‡ OPSR 6249 1.7 18.7 (5.7–39.8) 2.5 (0.8– 2,6 (0.1–12.9) 1.8 (0.7–3.8) 5.5) OPSS 3588 12 25.2 (9.5–47.5) 3.6 (0.4– 12.5 (5.0–24.3) 3.8 12.6) OPSU 9538 1.5 21.0 (7.0–42.7) 2.6 (0.4– 13.4 (2.1–31.6) 2.3 (1.0–4.6) 8,2) TUIP 1243 0.5 12.1 (2.2–33.3) 3.0 (0.1– 12.5 (1.6–38.3) 0.5 (0.2–1.5) 16.3) TURP 11693 2.2 15.0 (5.2–30.7) 1.1 (0.1– 15.5 (3.4–38.3) 1.5 (0.5–3.3) 4.5) *The combination was done using the Confidence Profile Method and the software program FAST*PRO (reference 99). †Weighted average. ‡Mean (and 90% CI). file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_457.html[09.07.2009 11:55:08]

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Page 458 incontinence, which indicates the inability of a man to control his urination at all under any conditions, and stress urinary incontinence, which refers to the loss of urine under conditions of stress, e.g. coughing, sneezing, lifting, changing positions, etc. Urge incontinence refers to the involuntary loss of urine associated with the uncontrolable urge to void. Urgency and even urge incontinence are not uncommon in patients with BPH. It represents the clinical symptom of the urodynamic finding of detrusor instability (DI), which is found in about two-thirds of patients prior to surgery for BPH.11 Postsurgical urgency or urge incontinence is rarely reported in the literature and may be due to the irritation from the surgery itself, or from the indwelling catheter associated with the surgery, or it may be a symptom indicating persistent DI after surgery. In reviewing the literature for data on incontinence following surgical treatment for BPH, the authors’ information regarding incontinence was taken at face value. Several potential sources of error may exist. Authors may report incontinence rates at different time points following surgery, and thus some of the reported incontinence may actually only be temporary in nature. On the other hand, it was assumed that if an author reported a certain rate of stress incontinence, but gave no information on total incontinence, the incidence of total incontinence was in fact zero. This assumption is based on the notion that an author who reported incontinence issues at all would certainly report if total incontinence occurred in his patient population. Thus, several partially offsetting biases may affect the subsequent analysis of the literature. Overall, data are available from 18 series of open surgery, nine series of TUIP, and 13 TURP series (Table 33.4). The median probability for stress incontinence ranges from 1.75% for TUIP to 2.59% for OPSS, while for total incontinence it ranges from 0.09% for TUIP to 0.98% for TURP No correlations were noted in the OPSU and TURP studies between the weight of the resected specimen and incontinence rates, the number of patients in each of the studies who were in urinary retention with indwelling catheter prior to treatment, the age of the patients, or any other analyzed variable. Given the nature of the surgical intervention it should not come as a surprise that the differences in the rates of stress incontinence following the various procedures are not significant, while the rate of total incontinence is clearly lower for TUIP than for any of the other modalities, and it is significantly higher for TURP than for any of the other modalities. Stress incontinence is not uncommon in elderly men with or without prostatic diseases, and it is particularly prevalent in nursing home residents. Tinetti et al. found in a 1-year study of 927 men aged 72 and older an incontinence rate (defined as at least one episode of incontinence per week) of 16%.100 In the presented literature review it is impossible to determine the exact percentage of patients who had a similar degree of incontinence prior to the surgical procedure. Wasson et al. reported in the VA cooperative trial that four of 280 men after TURP and four of 276 after watchful waiting had ‘persistent’ incontinence with a relative risk of 0.99 (0.25– 3.90) after 3 years of follow-up.9 Nevertheless, there is little doubt that surgical procedures, and in particular uncontrolled resection of the apical tissue of the prostate, can result in incontinence of differing severity. Total incontinence indeed is a very debilitating complication from surgery. In the absence of any definite contemporary studies of this problem, rates of total incontinence of 0.1% for TUIP, 0.5% for open surgery, and 1.0% for TURP, as shown in Table 33.4 represent best estimates. In addition, to date there are no reports of incontinence after TUMT,65 or after TUNA,64 and one study reports one case of incontinence lasting 6 months after TUVP,56 although another study after 5 years’ follow-up reports no Table 33.4 Combined analyses for the probability of stress and total urinary incontinence following open enucleation by suprapubic (OPSS) or retropubic (OPSR) prostatectomy, transurethral incision of prostate (TUIP), and transurethral resection of prostate (TURP). Open surgery (OPSU) represents the combined probabilities for OPSS and OPSR. Combination was done using the Confidence Profile Method and the software program FAST*PRO.99 Modality n Stress urinary incontinence (mean and 90% Total urinary incontinence (mean and 90% CI) (%) CI) (%) OPSR 5384 1.6 (0.3–4.7) 0.5 (0.3–0.8) OPSS 2329 2.6 (0.5–7.2) 0.3 (0.1–0.8) OPSU 7962 1.9 (0.4–5.2) 0.5 (0.4–0.8) TUIP 1200 1.8 (1.4–2.2) 0.1 (0.02–0.5) TURP 7055 2.2 (1.8–2.5) 1.0 (0.7–1.4)

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Page 459 cases after TUVP.57 However, these should be discussed with the patient. Bladder neck contracture Two complications resulting from surgical treatment of BPH are clearly defined and reported separately in many of the studies in the literature. These are the development of a urethral stricture or of a bladder neck contracture (BNC) following either open or transurethral prostate surgery. While in some cases no treatment might be necessary, many other patients have to undergo either dilatation of the stricture or BNC, or a surgical revision in the form of a visual internal urethrotomy or a BNC resection, which requires anesthesia and must at least be undertaken as a day-sugery procedure. There are 18 studies reporting the incidence of urethral stricture and/or BNC following open surgical enucleation of the prostate. In these studies, 5271 patients were treated by retropubic prostatectomy (OPSR), and 3080 were treated by suprapubic prostatectomy (OPSS). The mean age of the population in these two groups together is 67.8 years, and is 67.7 years and 67.6 years for the subgroups of OPSR and OPSS, respectively. No meaningful conclusion can be drawn from the correlation between the weight of the prostate and the incidence of the complications, since only three of the total of 18 studies report the mean weight, and it ranges from 42 to 51 g in those studies in which it was reported. The mean probability of developing a urethral stricture disease following OPSR is 1.0% (Table 33.5), while for OPSS it is 5.1%. This higher probability results from one study involving 32 patients of which 25% developed urethral stricture disease, and another study involving 179 patients of which 10.06% developed urethral stricture disease.101,102 There is one other study reporting on 309 patients with an incidence of 9.06% of patients who developed urethral stricture disease.103 While two of the studies are rather old and were published in 1970101 and 1976,103 the smallest series stems from 1984 and is carefully reported and documented.102 Overall, open surgical enucleation of the prostate resulted in urethral stricture disease in 181 out of 8634 patients for a mean probability of 2.6% (2.8–9.4%) (Table 33.5). In nine TUIP studies, 21 of 1218 patients developed a urethral stricture for a mean probability of 1.7% (1.2–2.5%). Seventeen studies reported the incidence of urethral stricture disease following TURP These studies totaled 12003 patients with an average age of 67.6 years. A total of 269 patients developed urethral stricture disease for a mean probability of 3.1% (0.5–9.7%). Three studies reported relatively high incidences of 16%,104 16.3%,102 and 13%,105 however they are carefully documented and contemporary. In six studies the average weight of the removed tissue was reported (mean 21.1 g, range 7 to 57 g). There is no correlation between the weight of tissue resected and the incidence of stricture formation. The problem associated with urethral stricture formation following TURP has been recognized early during the use of this procedure. Wares reported on the use of hydrocortisone ointment topically applied to the urethral mucosa in 75 patients of a total number of 173 patients undergoing TURP.106 In the remaining patients no ointment was used. The incidence of stricture postoperatively was 6.0% in the nonhydrocortisone ointment group versus 6.2% in the hydrocortisone ointment group. The author concluded therefore that the topical application of hydrocortisone does not prevent or decrease the incidence of stricture formation.106 The authors do, however, state that prophylactic meatotomy will reduce the incidence of postoperative Table 33.5 Combined analyses for the probabilities of urethral stricture, bladder neck contracture, or either one of the two complications, following open enucleation by suprapubic (OPSS) or retropubic (OPSR) prostatectomy, transurethral incision of prostate (TUIP), and transurethral resection of prostate (TURP). Open surgery (OPSU) represents the combined probabilities for OPSS and OPSR. Combination was done using the Confidence Profile Method and the software program FAST*PRO.99 Modality n Urethral stricture (mean and Bladder neck contracture (mean Combined, (mean and 90% CI) (%) and 90% CI) (%) 90% CI) (%) OPSR 5271 1.0 (0.2–2.7) 1.0 (0.2–3.5) 1.9 (0.3–5.7) OPSS 3080 5.1 (0.5–18.4) 2.9 (0.3–10.5) 7.7 (1.0–24.9) OPSU 8634 2.6 (2.8–9,4) 1.8 (0.2–6.1) 4.3 (0.6–14.1) TUIP 1218 1.7 (1.2–2.5) 0.4 (0.1–1.0) 19 (1.3–2.7) TURP 12003 3.1 (0.5–9.7) 1.7 (1.3–2.1) 3.7 (0.7–10.1)

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Page 460 urethral stricture formation, although no data are reported. Emmet et al. reported on a total of 1036 patients who underwent TURP between 1952 and 1961 at the Mayo Clinic.107 All these men underwent preliminary internal urethrotomy or meatotomy, or both, if calibration up to 30Fr was found to be difficult. This maneuver was found necessary in 24.8% of 2550 consecutive TURPs during this time period. Follow-up data are available on 76% (494/648) patients. Postoperatively, the authors found evidence for urethral stricture in seven of 632 cases (1.2%). The authors concluded that, in order to eliminate the incidence of postoperative stricture, the anterior portion of the urethra must be enlarged by internal urethrotomy or bypassed by performing the TURP through a perineal urethrostomy. Lentz et al. found an incidence of urethral stricture postoperatively of 6.3% (97/1539).108 These strictures were detected at an average of 4.2 months after the TURP. The distribution of the strictures was as follows: meatal strictures 17.5%, postnavicular 23.7%, penile scrotal 11.3%, deep bulbous urethra 32.9%, and multiple 14.4%. The authors found that, during the procedure, residents had a higher incidence of meatal strictures than the teaching staff. The length of the surgical procedure and the amount of tissue removed played no apparent role. In addition, the authors suggested that larger catheters of 26 Fr were associated with a higher incidence of stricture, although this was not significant. The length of catheterization following the procedure did not have any influence on the incidence of strictures and neither did preoperative urinary tract infection predict those patients who would develop a stricture formation. The authors concluded from their analysis, that the important factors were (1) initial calibration of the urethra to determine the anatomic adequacy prior to instrumentation, (2) gentle dilatation of the urethra, (3) the use of perineal urethrostomy in patients who have a stricture noted at the time of initial endoscopy ( n =142), and (4) the size of the urethral catheter used postoperatively (not significant). Lundhus et al. investigated whether the extent of transurethral prostatic resection had an impact on the incidence of stricture formation in a group of men with a median weight of resected prostatic tissue of 7 g (range 1–40 g).109 Four out of 72 patients (5.5%) developed a urethral stricture. Of 68 men with a median resected prostatic weight of 18 g (range 4 to 118 g), eight of 68 men developed a urethral stricture (12%) (not significant).109 Two studies addressed the issue of urethral stricture formation after TURP in a controlled randomized fashion.110,111 Schultz et al. studied stricture formation after TURP in 185 patients. The patients were allocated to either a 2-day urethral catheter dilatation or internal urethrotomy by the Otis method, and at the same time the operation was performed with either an uninsulated metal resectoscope sheath or a polytetrafluoroethylene coded resectoscope sheath. Urethral stricture was defined as an obstruction resulting in a Q max of less than 15 ml/s and not permitting the passage of a 21-Fr cystoscope sheath. The authors found that the frequency of stricture formation was significantly lower after internal urethrotomy (0.4%) than after a 2-day urethral catheter dilatation (16%). The coating of the resectoscope sheath with polytetrafluoroethylene did not alter the incidence of stricture formation significantly (0.8% versus 12%). The incidence of stricture formation was not related to age, duration of preor postoperative catheterization, operating time, and/or the presence of urinary tract infection.110 Hammarsten et al. examined the role of the catheter in a randomized, controlled trial.111 Two hundred and five patients following TURP were randomly assigned to drainage with a suprapubic latex catheter or a transurethrally placed siliconized latex catheter. At 6 to 24 months’ follow-up after the procedure, 17% of the patients in the transurethral group had developed a urethral stricture compared to only 0.4% in the group of patients treated by a suprapubic drainage catheter. This difference was statistically significant at p <0.01. The location of the stricture was equally divided in the TURP group between the external meatus, the fossa navicularis, penilo-scrotal urethra, and the bladder neck, while in the suprapubic group the majority of strictures were located at the bladder neck.111 Wasson et al. reported that at 3 years’ follow-up in a contemporary series of 280 patients following TURP, nine patients (3.2%) had developed a urethral stricture requiring dilatation, a probability almost identical to the calculated mean probability of 3.1% in the older literature.9 Riehman et al. reported that eight of 56 patients (14.3%) initially treated by TURP in their randomized trial had to undergo a transurethral incision or resection of a bladder neck contracture (BNC). This is a considerably higher probability than that estimated from the literature review.35 Mearini et al. found a 2% urethral stricture rate in a contemporary series of over 300 suprapubic prostatectomies.75 BNC following open prostatectomy occurs with a mean probability of 1.0% (OPSR), 2.9% (OPSS), and 1.8% (0.2–6.1%) (OPSU) for both procedures combined (Table 33.5). The previously mentioned report by Beck et al., with a 12.8% incidence of BNC, is mainly responsible for the higher rate following OPSS, while the file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_460.html[09.07.2009 11:55:09]

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Page 461 aforementioned report by Mearini quotes a rate of only 3.5% in a contemporary series.75,101 Of all the reports describing long-term complications following TUIP, only one study reported that two of 646 patients developed a BNC giving a mean probability of only 0.4%.112 Only nine of the studies reporting urethral stricture development following TURP presented data on BNC following the same intervention. The incidence ranges from 0% to 7.1%, with a raw average of 1.4%. Overall, 61 patients of 4152 had this complication for a mean probability of 1.7% (1.3–2.1%). There was no correlation between the amount of tissue resected and the incidence of BNC, although it has been postulated that BNC is more likely to occur after resection of <10 g of tissue. In one report of 388 patients the average weight of resected tissue was 57 g and the incidence of BNC was 0.77%.32 In another report of 84 patients the average weight was 23.5 g and the incidence 7.14%.113 In three studies totaling 52 patients with average resected weights less than 20 g, no patient developed BNC.114–116 These data do not justify the conclusion that there might not be a correlation between amount of tissue resected and the incidence of BNC. Some authors have suggested that a prophylactic bladder neck incision similar to TUIP may reduce the rate of BNC (Table 33.6). Kulb et al. investigated this hypothesis in 114 patients who underwent TURP and bladder neck incision. BNC occurred in only one patient (0.87%), compared to 12 BNCs found in 161 patients who underwent TURP alone.43 The authors found this difference to be statistically significant ( p <0.05). It should be noted that TURP alone resulted in an incidence of 4.7% for BNC (12/253 patients) when all patients were considered, while the incidence was 7.5% in those men with prostates weighing less than 20 g. The additional incision of the bladder neck did not have an impact on the incidence of BNC in those men who had prostates larger than 20 g (Table 33.6). In the VA Cooperative trial, nine of the 280 men (3.2%) undergoing TURP with a mean resection weight of 14 g had to undergo an endoscopic procedure for a BNC at 3 years of follow-up.9 If one assumes that for the patient it is less important what type of complication he develops, but rather that some complications require an active surgical intervention, it is reasonable to combine the numbers for urethral stricture and BNC in one number representing the total number of patients suffering one of these complications that requires surgical intervention. For OPSR a total of Table 33.6 Incidence of bladder neck contracture (BNC) following TURP depending on whether or not simultaneous incision of the bladder neck was performed. The difference in the incidence of BNC in the subgroup of patients with a resected weight of <20 g was statistically significant (p<0.05).43   n BNC n % TURP plus incision All patients 137 1 0.72 <20 g only 114 1 0.9 TURP without incision All patients 253 12 4.7 <20 g only 161 12 7.5 125 of 5271 patients required such an intervention for a mean probability of 1.9%. Following OPSS, 160 of 3080 patients developed such complications for a mean probability of 7.7%. For the entire group of open prostatectomy, 301 out of 8634 men developed these complications for a mean probability of 4.3% (0.6–14.1%). Following TUIP, 23 of 1218 men developed one of these complications for a mean probability of 1.9% (1.3–2.7%), and following TURP, 330 of 12003 men for a mean probability of 3.7% (0.7–10.1%). Given the fact that contemporary surgical series have similar or even higher incidence rates for these long-term complications, it appears unlikely that the mean probabilities listed in Table 33.5 will be significantly improved upon by minor modifications in the surgical technique. Impotence While BPH is a disease of aging men, maintaining or restoring sexual function is of increasing importance to patients suffering from BPH. Excellent estimates regarding the prevalence of erectile dysfunction (ED) are available from the Massachusetts Male Aging Study (MMAS).117,118 Figure 33.9 shows the prevalence of minimal, moderate, and complete ED as reported by over 1200 men between 40 and 70 years of age. The prevalence of any ED increased from 40 to almost 70%, and of moderate to complete ED from 20 to 50% from younger to older men. Incidence rates were calculated from the same population as 12.4/1000 for men 40–49 years old, 29.8/1000 for men 50–59 years old, and 46.4/1000 for those in their sixties.118 It has also been stated that between 20 and 40% of men file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_461.html[09.07.2009 11:55:10]

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presenting for surgical treatment of BPH also suffer from ED. Before discussing the probability of suffering from ED as a result of surgery for BPH one must acknowledge that,

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Page 462 in most of the available literature, the assessment of erectile function was crude at best, and is usually based on a loosely structured and defined physician assessment or interview. Sophisticated means of determining potency status such as standardized questionnaires, nocturnal penile tumescence measurement, and other methods were rarely employed. A total of 24 studies were identified in the literature that reported on potency before and after surgical treatment for BPH in some detail.119–139 Some of the studies include several arms. For example, several authors compared the rate of impotence following TURP or open

Figure 33.9 Prevalence of minimal, moderate, or complete erectile dysfunction in 1290 participants between the ages of 40 and 70 in the MMSA.99 prostatectomy, while others compared the rate of impo tence following general surgical procedures (cholecystectomy or hernia repair) with that after surgery for BPH.126,128,136 Following general surgical procedures, 1.0% of men claimed to convert from potent to impotent (Table 33.7), while following TUIP the rate was 4.6%. Following TURP a rate of 13.6% was noted, while following open surgical procedures, including perineal prostatectomy the rate ranged from 15.6 to 31.5%. Concerning the rate of impotence following TUIP, four of the five available studies ( n =49) reported no new onset of impotence after the procedure, while in one study three of 13 preoperatively potent patients complained of ‘deteriorated sexual performance’.112 The author of this study used a technique of two deep incisions. In a direct comparison of TUIP and TURP in a randomized fashion, all 22 patients who were potent prior to TURP remained potent after surgery, and all 23 patients potent prior to TUIP remained potent as well.35 Wasson et al. found that 19% in the TURP group and 21% in the watchful waiting group reported at 3 years’ follow-up worsening of their sexual performance.9 However, the difference between the two groups was not significant ( p =0.92). Studies of minimally invasive therapies for BPH using TURP as an active control arm continue to suggest that there is a finite risk of suffering from ED as a direct result of the TURP,140 and several possible underlying mechanisms of action have been proposed, ranging from temperature variations induced around the TURP element,141 to capsular perforations adjacent to the neurovascular bundles,142 and damage to the small nerve fibers that is demonstrable histologically.143 Table 33.7 Potency and ejaculatory status before and after and general surgical procedures and various surgical procedures for BPH. Treatment n Mean age Follow-up Before surgery After surgery Retrograde (years) (months) Potent Impotent Potent Impotent ejaculation (%)* n % n % n % n % GENSU 186 66.0 3017493.7 12 6.316897.0 6 3.0 1.0 TUIP 144 63.7 14 6257.9 828 42.1 5995.4 3 44 38.8 TURP 1543 65.1 2498977.5 603 21.573686.4 224 13.6 70.4 OPSR 784 67.4 1454276.2 269 23.844184.4 101 15.6 65.0 OPSS 647 65.5 2255879.2 109 20.844483.6 114 16.4 80.8 PERP 98 n.a. n.a. 5361.0 37 39.0 3668.5 17 31.5 n.a. GENSU, general surgical procedures; TUIP, transurethral incision of prostate; TURP, transurethral resection of prostate; OPSR, retropubic prostatectomy; OPSS, suprapubic prostatectomy; PERP, perineal

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prostatectomy; n.a., not asssessed. *Expressed as a percentage of those previously potent.

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Page 463 In one study comparing TUVP and TURP, the authors reported that five of 29 sexually active men preTUVP became impotent after TUVP. They also reported that none of these men improved after 3 years of follow-up.57 Following TUMT, the rates of ED vary from 0.8 to 5%.65 A study of great significance in the overall context of this particular problem has been conducted by Libman et al.144 In this particular study, the investigators examined 72 married men after a transurethral prostatectomy. Socioeconomic status, personal and demographic variables, symptom check-list, psychological status (brief symptom inventory, BSI), and marital function (Locke Wallace marital adjustment scale, MAS) were assessed. A variety of tests to evaluate sexual functions were also performed. These tests included the sexual history form (SHF), goal for sex therapy scale (GSTS), sexual self-efficacy scale-erectile functioning (SSES), sexual interaction inventory (SII), and additional sexual measures (SHF-A). The authors found that pre- and postsurgery scores correlated highly for all measured parameters except for satisfaction with the current sexual relationship. Men with good presurgical sexual adjustment had a better postsurgery outcome than those with a poor adjustment. In addition, younger men were more likely to retain good sexual capabilities and confidence than older men. However, older men with good couple scores were more likely to remain in the well-functioning range on couple behavior and adjustment after surgery. There was an overall decrease in the frequency of intercourse, reduced variability, and a decrease in sexual desire, erectile capabilities, and selfconfidence, while an increase was noted in the prevalence of retrograde ejaculation.144 Of greatest importance is that the ratings of general couple satisfaction and harmony were not adversely affected by the surgery. This study emphasizes the fact that the effects of prostate surgery may differ greatly, depending on whether the focus is on individual sexual functioning or the sexual relationship within a wellfunctioning adjusted couple. This indicates that these two aspects of sexuality are independent and must be evaluated separately. It is of interest in this regard that one study also demonstrated the impact of a permanent partner on sexual function.139 In this study, 34.4% of all men reporting presurgical impotence had no permanent partner while only 3.9% of those patients who had erectile dysfunction prior to surgical treatment had no permanent partner. This difference between 3.9 and 34.4% was highly significant at a p <0.001 level. Following surgery, the ratio was unchanged (29.3 vs 2.7%). These authors concluded that the risk of postoperative impotence is dependent on the patient’s age as well as the presence or absence of a permanent partner. Retrograde ejaculation Another area of concern is the incidence of retrograde ejaculation (RE) resulting from the destruction of the bladder neck mechanism. The pathophysiology of RE is believed to be a failure of the bladder neck to close during ejaculation, allowing the semen to flow back into the bladder, which in this case is the path of lowest resistance. Under normal circumstances, the bladder neck closes during ejaculation under sympathomimetic influence as a result of the α-adrenergic innervation. It is a well-known and an accepted risk of any surgical procedure performed for BPH that the patient may develop RE. While it appears that some patients are not overly concerned about the possibility of this happening, it is of concern that some patients do not understand the difference between impotence and RE. These patients tend to claim that the surgery left them impotent because they do not have emission during intercourse, although they may be able to have an orgasm. It is the duty of the physician to counsel the patient prior to treatment about the difference between potency and impotency and RE, as well as to inform him about the probability of both of these outcomes occurring. The risk of the development of RE after general surgical procedure is 1%, while for any surgical procedure that involves the bladder neck, the risk is significant, and ranges from 38.8% for TUIP to 80.8% for suprapubic prostatectomy (Table 33.7). In a contemporary randomized study RE was found in 15 of 22 postTURP patients (68%) and in eight of 23 TUIP patients (35%) ( p =0.02),35 This is of concern to both the sexually active man, and the younger man in whom the urologist cannot guarantee fertility. Some urologists therefore perform unilateral incision of the prostate, which may reduce the incidence of RE.36 Following TUNA there have been no reports of RE,64 while after TUVP, rates of RE vary from 48%56 to 72%.57 After TUMT, the rate of RE is in the region of 33%.140 These numbers are comparable to those found in the older literature (Table 33.7). Retreatment rates Treatment failure and the need for retreatment represent some of the most important outcomes from both a file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_463.html[09.07.2009 11:55:11]

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Page 464 patient’s and a healthcare economics point of view. Patients who have undertaken a certain treatment strategy for BPH have in essence invested in this therapy. If the therapy fails to provide long-lasting relief of symptoms, and thus additional treatment becomes necessary, additional costs are invariably incurred. When attempting to calculate treatment failure and retreatment rates, one is faced with several potential sources for bias. To begin with, there are few studies in the literature that report on these outcomes. When comparing the retreatment rates between different treatment strategies, one has to ask whether or not the patient populations at baseline were indeed comparable. For example, it may be assumed that patients selected for a medical therapy could be less symptomatic and thus less likely to fail therapy than those selected for surgical treatment. Moreover, even if retreatment rates are reported, it is not always clear which proportion of the original study population was followed, and whether or not those patients lost to follow-up behaved in a similar way as those for whom follow-up data were available. Lastly, failure to relieve symptoms is not identical to retreatment, and therefore failure rates are not identical to retreatment rates. For example, in medical therapy trials the investigators usually define failure by arbitrarily setting a certain threshold for improvement in symptom score or peak urinary flow rate. However, patients who fail to achieve the said improvement do not necessarily agree with this assessment, and many of them will in fact not undergo retreatment. A retreatment rate can be defined as the fraction of patients who undergo a second surgical procedure. This leads to other interpretational problems. A fraction of patients reported to have undergone a second TURP will in fact have undergone this procedure in an attempt to stage an incidentally found prostate cancer. About 10% of TURP specimens contain prostate cancer, and in an unknown percentage of these the treating physician may elect to undertake a second TURP to document the presence or absence of more cancer in the prostate. Furthermore, some procedures aimed to correct problems such as BNCs may be coded such that a claims data review will not be able to separate them from true retreatments for recurrent or persistent BPH. These latter considerations are less relevant for the patient than they are from a healthcare economics point of view. To the patient it is not so much the precise indication for the anesthesia and surgery, but rather the fact that he has to submit to another surgical procedure that is of considerable importance to him. TUIP retreatment rates Eight reports are available to assess the treatment failure rate and the need for retreatment following TUIP. Helleström et al. compared 13 men with BPH treated with TURP with 11 men with BPH treated by TUIP.114 Patients were estimated to have a prostate gland of less than 30 g in weight. Over a follow-up period of 6 months, none of the men treated by TUIP required retreatment for failure of symptomatic relief. Another study compared 21 men with BPH and prostate glands estimated to be less than 20 g treated by TURP with 17 similar patients treated by TUIP.116 During the follow-up period of 3 months, three of the 17 men who underwent a TUIP required a TURP, and these were deemed as treatment failures. Larsen et al. compared 18 men with BPH and prostates estimated less than 20 g treated by TURP with 19 men treated with TUIP in a randomized trial. Follow-up was available over 12 months.115 None of the men treated with TUIP required retreatment during this period of follow-up. Only one patient in the TUIP group had no improvement in symptoms. This patient underwent a cystoscopy and was found to have a wide-open bladder neck, thereby not requiring further treatment. Nielsen documented a failure rate of three out of 24 men treated with transurethral prostatotomy in a randomized trial compared to 25 men treated by TURP.104 The follow-up was 12 months. Delaere et al. performed TUIP in 32 men with either mechanical or functional bladder outlet obstruction.145 These men were followed over a mean period of 18 months. Three men required retreatment during this time. One problem with this study is that it mixes men with mechanical and functional outlet obstruction. However, the mean age was 60 years and therefore close to the average age of men treated for symptomatic BPH. The exact definition of functional obstruction is difficult to ascertain and the data from this study are included in the retreatment calculation. Katz et al. treated 66 men with BPH and prostates estimated to be less than 15 g in size with TUIP and followed these men for 24 months. During this time, five of 64 men available for follow-up required retreatment.146 Mobb and Moisey treated 94 men with BPH with TUIP and had follow-up data available on 75 men at 60 months.147 During this time, six patients had required retreatment. Edwards et al. treated 700 patients with BPH and had follow-up data from 3 months to 7 years.32 Three hundred and eighty-eight patients were treated by TURP, and 312 patients, with prostates of less than 35 g estimated weight, by TUIP Over the extended follow-up, five of these 312 men required retreatment because of failure of TUIP to relieve file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_464.html[09.07.2009 11:55:11]

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Page 465 symptoms. Orandi has published on several occasions his personal experience with TUIP.38,112,148 He reviewed his experience with TUIP for the treatment of BPH and presented retreatment data in tabular form over a maximum follow-up period of 18 years (total number of procedures 753).148 The data presented allow accurate calculation of the total number of patients at risk for any given time period, the failure rate for the time period extending from 3 to 60 months, and the cumulative failure rate at any given interval. The cumulative failure rate up to 5 years is plotted in Figure 33.10. Up to 5 years no clear decrease in the failure rate is noticeable. However, the highest failure rate occurred within the first year following treatment according to the raw data. The failure rate then remained steady, with only a minor decrease through years 2–5 (failure rates 0.00288, 0.00264, 0.00219, 0.00215). While the data are not shown for the following years, it appears that this failure rate held steady over the next 5 years up to 10 years of follow-up. Based on the available information from Orandi’s series, projected retreatment or cumulative failure rates for 60 months were calculated for all studies for which they were not yet available (R). Using the actual data as well as the projected data, the mean probability for the need of retreatment was 12.9% (90% CI 4.7 to 26.5%) and is indicated as a vertical line in Figure 33.10. If only those studies that actually report 5-year follow-up data are used, the mean retreatment probability is 8.9% (CI 1.2 to 28.1%).32,147,148 While the point estimate is lower than if all actual and projected data are utilized, the CI remains virtually unchanged

Figure 33.10 Actual (p) and projected (r) retreatment rates following transurethral incision of prostate (TUIP). ( , Orandi’s series; all other series). Mean probability and 90% CI are shown as vertical bars and are based on all data. TURP/open surgery retreatment rates Excellent data concerning failure and retreatment rates are available for open surgery (OPSU) and TURP Treatment data have been reported for 44832 patients treated by TURP and 17065 patients treated with open surgery (either suprapubic or retropubic prostatectomy). The individual data points are plotted in Figure 33.11. Roos and Ramsey reported retreatment data on 1855 patients following TURP, 621 patients following suprapubic prostatectomy, and 223 patients following retropubic prostatectomy.149 The data are derived from the Universal Health Insurance System in Manitoba, Canada, and follow-up was available for up to 8 years after the initial procedure. By the end of the follow-up period, 16.8% of the TURP patients had undergone a second prostatectomy, compared to less than 7% of those who initially underwent an open procedure. The TURP patient group required an additional prostatic operation at a constant rate of approximately 2% per year. Roos et al. reported on retreatment rates following TURP and open prostatectomy in Denmark ( n =36703), Oxfordshire, England ( n =5284), and Manitoba, Canada ( n =12090).150 Patients were identified retrospectively through administrative data and followed for up to 8 years. The cumulative probability of undergoing a second prostatectomy, according to the type of initial prostatectomy, was reported for 1, 5, and 8 years. The 8-year probabilities for TURP ranged from 5.0% (Denmark and Oxford region) to 15.5% (Manitoba, Canada). For open prostatectomy, the

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Figure 33.11 Retreatment probabilities following TURP (+) and OPSU ( ). Mean probabilities and 90% CI indicated at 60 months by vertical bars ( , TURP; , OPSU).

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Page 466 8-year retreatment probability ranged from 1.8% (Oxford region) to 4.5% (Denmark). Taylor and Krakauer presented data from a random sample of 3641 Medicare enrolees who underwent prostatectomy in 1985.151 Of these, a subsample of 2617 patients had a diagnosis of BPH and 2449 of these men were treated by TURP (93.6%), while 168 underwent open prostatectomy. The probability of having a repeat prostatectomy after 2 years of follow-up was 4.7% following a TURP and 1.84% following an open prostatectomy. This difference was not statistically significant. Singh et al. reported retreatment rates on 935 patients following TURP and 217 patients following open prostatectomy (198 retropubic and 19 suprapubic prostatectomies).152 Within 1 year of the initial operation, 2.8% in the TURP group required retreatment compared to 0.5% in the open prostatectomy group. Several smaller series are also available to assess retreatment data. Ball and Smith followed 38 patients who underwent TURP for 5 years and documented that two men required retreatment within 5 years of follow-up.153 Aalkjer reported retreatment rates on 110 patients following TURP and compared them with a similar group of patients who underwent dilatation of the prostatic urethra with the Deisting dilator.154 The cumulative probability for retreatment at 5 years was 8.2% in this series, which represents the oldest evidence available. Stephenson et al. studied the outcome of surgery for BPH in Rochester, Minnesota between 1980 and 1987.155 Three hundred and thirty men underwent prostatectomy during this time for BPH and the authors calculated the likelihood of reoperation within 6 years of the initial surgery at 15.1% (95% CI 9.7–20.6). The probability of reoperation at 5 years was 12.9% and therefore the highest reported rate of any of the listed studies. Meyhoff and Nordling reported on 38 men who underwent TURP for BPH and found a retreatment rate of 7.9% at 5-year follow-up.105 There are several other reports in the literature stating a certain rate of retreatment at a certain followup time. However, the quality of the data and the accuracy of follow-up information are inferior to the studies utilized and these studies were therefore not included. In this context, however, it is interesting to observe that in a national survey of all American urologists ( n =2716) the mean percentage of patients who underwent TURP and who had previously undergone a TURP was 8.1%. These data are remarkably similar to those reported by Mebust et al., who found in a cooperative study of 13 participating institutions evaluating 3885 patients that 8% of all patients undergoing TURP had previously undergone a TURP already.10 This number is remarkably similar to the mean probability of 9.7% estimated for the likelihood of undergoing a second prostatectomy within 5 years of follow-up. One important caveat, however, needs to be taken into consideration. Claims data and other administrative data do not necessarily separate those patients who undergo a reoperation because of recurrent or persistent disease from those patients who undergo further surgery to correct a BNC or a urethral stricture. Nevertheless, the main interest for the patient is whether or not he has to undergo repeat surgery and not what the underlying problem actually is. The same is true for those patients who may have undergone reTURP for accurate staging because an incidental prostatic carcinoma was found in the first TURP The majority of the large claims data-based series exclude this patient population, however, and focus the analysis on those patients with histologic BPH. Lu-Yao et al. used a 20% sample of Medicare beneficiaries to calculate reoperation rates in this population between 1984 and 1990.8 The overall risk for a second TURP was 7.2% over the study period, while it was 5.5% when the indication for a second TURP was restricted to BPH only. Age was not a major factor in the reoperation rates as the risk was 5.7% for those over 75 years and 5.4% for those under 75 years of age. Since 1987, the 5-year reoperation rate in this population has essentially remained stable at 5%, and no statistical association with the surgical volume of the urologist was noted.156 The cumulative retreatment probabilities obtained from the literature at 60 months were converted into numbers of patients from the original population that had failed at this time point and used to calculate the mean probability and confidence limits for the need of retreatment. Because of the large number of patients involved in these studies, the confidence limits are rather narrow and the data appear to be stable (TURP: 9.75%; 90% CI 9.36–10.6; OPSU: 2.25%; 90% CI 1.06–4.11) (shown as vertical bars in Figure 33.11). The mean probability estimates and confidence intervals are plotted as vertical lines (mean probability indicated by a horizontal bar) for the three surgical treatment modalities assessed in Figure 33.12. It is apparent that open surgery clearly has the lowest probability of treatment failure and/or need for retreatment within 5 years. In fact it clearly indicates that the probability distributions for the need for retreatment following OPSU versus TURP do not overlap and therefore there is a significant difference between these two treatment modalities in regards to the need of retreatment. The individual data points for TURP and OPSU can be further analyzed. For the TURP retreatment data, the file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_466.html[09.07.2009 11:55:13]

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Page 467 best fit is represented by the formula y =A+B A x (slope (B)=0.138; intercept (A)=1.295), with the correlation coefficient r=0.89. Figure 33.13 demonstrates the linear relation between duration of followup and probability for retreatment and the 95% confidence interval over the entire duration of followup. This analysis clearly demonstrates that the probability for retreatment remains constant throughout at least 8 years of follow-up. This is in contrast to the data available for balloon dilatation, watchful waiting, and TUIP, which demonstrate a very high failure rate in the first year and later a decrease in the failure rate throughout the remainder of the followup, up to 5 years. A similar analysis of the retreatment data for OPSU reveals a somewhat different situation. The correlation coefficient for the linear curve fitting ( y =A+B A x) (slope (B)=0.046; intercept (A)=0.26) is r=0.798. A better fit is obtained using the formula y =A A e bx (slope=0.019; intercept=0.779; e=base of the natural logarithm). The correlation coefficient r=0.827. The data with the best-fit curve are shown in Figure 33.14. It appears that the retreatment probability following open surgery remains very low for the initial 5 years, but that the failure rate increases thereafter at a somewhat faster rate. Theoretically, it seems possible that the retreatment rate for recurrent BPH following open enucleation of the entire adenoma remains very low following the surgery and that it will take several years for recurrent disease to cause obstructive symptoms and require retreatment. At

Figure 33.12 Retreatment probabilities (mean and 90% CI) following transurethral incision of prostate (TUIP), transurethral resection of prostate TURP, and open surgery (OPSU). the same time, it is quite likely that TURPs tend not to be as complete in removing tissue and thus the retreatment rate during the first 5 years is in fact significantly higher than using open surgery. TUVP retreatment rates In one study comparing TURP and TUVP, after 6 months’ follow-up, four patients in the TURP arm ( n =120) and

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Figure 33.13 Reported retreatment rates following transurethral resection of prostate (TURP) up to 8 years of follow-up. Correlation coefficient is 0.89 (y=A+Bx). 95% CI indicated by dotted lines.

Figure 33.14 Reported retreatment rates following open surgery (OPSU) up to 8 years of follow-up. Correlation coefficient is 0.827 (y=AAeex); 95% CI indicated by dotted lines.

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Page 468 one patient in the TUVP arm ( n =115) required retreatment by TURP.56 The authors concluded that early retreatment rates are at least equivalent for TUVP and TURP. In the study with the longest TUVP follow-up period to date, after 5 years, the authors reported a 13% retreatment rate for both TURP and TUVP This is approximately a 3% retreatment rate per arm per year.57 Four patients in the TUVP group subsequently underwent a TURP, and the authors clarified that this was because the operating surgeon had no experience of the vaporization technique. Three patients who initially underwent TUVP had a repeat TUVP The reoperation rate in the first year after TUVP was 3.5% and this higher figure may represent the surgeon’s learning curve with the procedure. TUNA retreatment rates Since TURP remains the gold standard operation for BPH, the outcome of all new treatments must be compared to TURP outcome data. Ramon et al. performed TUNA in 79 patients.58 Nine of these patients were deemed as treatment failures as a result of no improvement in their peak urinary flow rates. In addition, eight patients reported no symptomatic improvement. Steele and Sleep followed their TUNA patients for a 2-year time period, and reported a retreatment rate of 12.7%.157 Another study reported a higher retreatment rate of 20% within the same follow-up period.158 Cimentepe et al. randomized 26 patients to the TUNA arm of their study and 33 patients to be treated with TURP.63 At 18 months’ follow-up, they reported that two patients in the TUNA arm required TURP because of an insufficient therapeutic response (7%), compared to no treatment failures at this time in the TURP arm. They attributed this lower retreatment rate to their strict selection criteria for the study. In the study with the longest follow-up of 5 years after TUNA, Zlotta et al. reported a retreatment rate of 25%.62 TUMT retreatment rates In one study comparing TUMT with TURP, both treatments were found to be durable, although the retreatment rate for TUMT was reported at 10.8% and 15.6% for the TURP group.69 The 1-year retreatment rate for TUMT has been shown to be around the 10% rate by other studies. However, after 3 years 31% of patients who had undergone a TUMT required additional invasive therapy, and 17% required additional medical intervention.65 Blute et al. followed their patients for 4 years after TUMT and showed that 11% of the patients had retreatment in the form of surgery, and 29% required additional medical therapy.159 In another two studies comparing TUMT with TURP, the retreatment rates were 19.8–26% for the TUMT group, and 4.7–12.9% for the TURP group.86,160 Patients in these studies who were given medication were also classed as treatment failures. Of note, the only patients offered retreatment in the TUMT arm were treatment failures. By contrast, those patients offered retreatment in the TURP included, rarely, treatment failures, but mostly surgery for BNCs, meatal stenosis, and urethral strictures. Pooled data from three studies show that the mean rate of retreatment for just treatment failure at least 30 days after initial surgery was 18.7% for patients undergoing TUMT and 12.2% for patients who underwent TURP.69,86,160 One difficulty with comparing retreatment rates in this manner is that inclusion criteria for the studies vary immensely. Hence, it is likely that the retreatment rate will depend on the severity of the disease at the time of inclusion in the study, and the initial choice of treatment. Delayed mortality Perioperative mortality is an important outcome to be considered in the discussion of any major surgical procedure. However, in recent years it has been suggested that there are differences in delayed mortality following TURP and open surgery (for the purpose of this discussion suprapubic and retropubic prostatectomy are considered jointly). The urologic community responded to the challenge before them by attempting to explain the observed differences with patient selection biases. Patients selected for TURP, so the argument goes, differ from those selected for open prostatectomy in regards to their general health status, associated diseases, anesthetic and surgical risks. In short, patients selected for TURP are sicker than those selected for open surgery and have a higher co-morbidity index, and thus are predisposed to a shorter life expectancy independent of the actual surgical procedure. While data regarding co-morbidity are virtually absent in the older literature, most studies addressing the problem of delayed mortality attempt to correct for co-morbidities using a variety of techniques. Roos et al. reported mortality up to 8 years following TURP or open surgery in three geographic areas (Denmark, Oxfordshire, England, and Manitoba, Canada).150 They reported an early postoperative death rate of 2.9% in an analysis of over 40000 patients. The analysis is based on existing computerized databases: the Oxford Record Linkage Study in England, the National Hospital Patient Registry in Denmark, and Provincial claims data in Manitoba. The Manitoba data were file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_468.html[09.07.2009 11:55:14]

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Page 469 Table 33.8 Age-adjusted cumulative risk of death (per 100) after TURP or open surgery (OPSU) according to geographic region.150 Time Denmark Manitoba Oxford TURP (27911)* OPSU (8782) RR TURP (8995) OPSU (3095) RR TURP (2171) OPSU (3113) RR 90 days 2.47 2.67 0.93 1.73 1.57 1.10 4.39 3.21 1.37 1 year 7.55 5.76 1.31 5.97 4.18 1.43 10.32 7.64 1.35 5 years 31.05 25.491.22 25.37 21.141.20 35.42 26.45 1.34 8 years 46.5 39.781.17 39.25 33.531.17 49.49 38.42 1.29 *Numbers in paretheses indicate number of patiens in arm. RR, relative risk. adjusted for claims-based co-morbidity data such as concomitant diagnoses and prior hospitalizations. The ageadjusted cumulative risk of death per 100 patients after TURP or OPSU according to geographic location is presented in Table 33.8. A separate analysis of patients from the University of Manitoba teaching hospital revealed that the relative risk (RR) of dying within 5 years following TURP vs open surgery was 1.45 (95% CI 1.15–1.84) before and after age and co-morbidity adjustment. This finding of a higher RR of dying following TURP remained unchanged when the data were adjusted using a wide variety of risk strata (general health status, age, prior diagnosis of cancer, nursing home resident, on digitalis, high-risk diagnosis, etc.) both from claims data and a separate, concurrent prospective study of anesthetic risk. The size of the prostate gland enucleated during open surgery was not a statistically significant predictor of subsequent survival. An analysis of the causes of death showed that the excess mortality following TURP was mainly due to cardiovascular causes, especially acute myocardial infarction (Table 33.9). Malenka et al. re-evaluated a subset of the patient population that had previously been reported by Roos et al.149,150,161 The purpose was to identify whether differences in case mix unidentified by data previously available explained the increased mortality following TURP. To this end a chart review was performed by six trained abstracters (registered nurses) blinded to the purpose of the study at the Manitoba Health Science Centre, Winnipeg, Canada. The chart review included 485 patients who underwent prostatectomy between 1974 and 1980 (236 OPSU and 249 TURP). The crude RR of dying in the 5 years following TURP/OPSU in this subset was 1.58 (95% CI 1.07–2.33). This relative risk decreased slightly after controling for patient age to a RR of 1.48 (95% CI 1.09–2.01). Further adjustment using co-morbidity data from the chart review, including the Charlson Table 33.9 Multivariate relative risk (RR) of death according to cause after transurethral resection of prostate (TURP) or open surgery (OPSU) (Manitoba data set only).150 Cause of death RR 95% CI All patients ( n =2965) All causes 1.42 1.22–1.65 Cardiovascular 1.51 1.20–1.90 All other 1.51 1.20–1.91 Acute MI 2.50 1.59–1.93 Cerebrovascular accident 1.25 0.73–1.78 Low-risk patients ( n =586) All causes 1.63 0.98–2.73 Cardiovascular 2.92 1.20–7.06 All other 1.06 0.46–2.42 Acute MI 5.50 1.26–24.41 Cerebrovascular accident 0.69 0.12–4.20 CI, confidence interval; MI, myocardial infarction. weighted co-morbidity index and the Karnovsky score, did not change the results signiftcantly.162 Concato et al. conducted a retrospective cohort study at Yale-New Haven Hospital involving 252 men undergoing TURP ( n =126) or open prostatectomy ( n =126) for BPH from 1979 through 1981, and assessed 5-year mortality adjusted for age and severity of co-morbidity at time of surgery.163 Comorbidity was measured by the methods of Kaplan and Feinstein and Charlson et al.162,164 Data were extracted from charts using explicit instructions for abstraction. At least one abstracter was blinded with regard to the procedure. In a sample of 30 records abstracted by two abstracters, an almost perfect concordance was found with respect to co-morbidity scores. At 5 years after surgery, 17.5% (22/126) patients after TURP had died versus 13.5% (17/126) after OPSU The RR of 1.29 TURP/OPSU (95% CI, 0.72–2.31) was not statistically significant, but similar to the unadjusted RR in the originally reported Manitoba data set ( n =1284) (RR file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_469.html[09.07.2009 11:55:14]

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Page 470 Table 33.10 Comparison of treatment groups in regards to Kaplan-Feinstein co-morbidity grade open surgery (OPSU).163 Kaplan-Feinstein grade TURP ( n =126) OPSU ( n =126) Percentage of TURP in Kaplan-Feinstein grade n (%) n (%) None 37 (29) 64 (51)   Intermediate 75 (70) 59 (47) 56 Severe 14 (11) 3 (2) 82 1.27, 95% CI 1.03–1.57). The 5-year mortality rates increased with increasing Kaplan-Feinstein comorbidity grade from 7% (7/101) for grade ‘none’, 18% (24/134) for ‘intermediate’ grade, to 47% (8/17) for ‘severe’ grade (total 16% (39/252)). A comparison of the Kaplan-Feinstein co-morbidity grade revealed a higher proportion of TURP patients having more severe co-morbidity grades (Table 33.10). The point estimate for the RR of dying after TURP/OPSU at 5 years decreases and becomes essentially 1.0 after adjustment for co-morbidity (Table 33.11). A proportional hazard analysis revealed that increasing age was associated with a RR of 1.71 (95% CI 1.08–2.69) and the Kaplan-Feinstein comorbidity grade with a RR of 2.47 (95% CI 1.40–4.34). After taking both these factors into account, the type of surgery did not significantly affect 5-year survival (RR TURP/OPSU 0.91, 95% CI 0.47–1.75, p =0.77). A group of Danish investigators studied survival through linkage of hospital discharge data with mortality data for the entire male population of Denmark (1977–1985).165 For a maximum of 10.5 years (minimum 2 years) 38067 patients were followed, of whom 28991 had a TURP while 9076 had OPSU. After adjustment for age only, the RR for dying after TURP/OPSU within 10.5 years was 1.24 (95% CI 1.20–1.29). After adjusting for age and co-morbidity, the RR after TURP/OPSU was 1.19 (95% CI 1.15– 1.24) for all patients, while it was 1.11 (95% CI 1.03–1.19) for the subgroup of healthiest men. Thus, the additional adjustment for co-morbidity did not significantly change the increased risk of dying following TURP versus OPSU, although the employed indicators of co-morbidity contributed in a multivariate (Cox regression) analysis significantly as predictors of deaths. During the time frame of the study, the fraction of patients treated by TURP changed from 40% (1977–79) to 81% (1983–85). However, this gradual change was not associated with a change in the relative health status of the TURP and OPSU patients. Overall, however, the health status of TURP patients improved over the period of time when diffusion of the new technology of TURP was being completed. The causes of death underlying the higher Table 33.11 Effects of data source and co-morbidity classification on relative risk (RR) for TURP versus open surgery (OPSU).163 Method of grading co-morbidity Mortality rate for entire group (n)* RR (TURP/OPSU)† Discharge diagnoses Charlson sum 0 30/219 (14) 1.20 ≥1 9/33 (27) (0.63–2.26) Medical record review Charlson sum     0–1 27/217 (12) 1.12 ≥1 12/35 (34) (0.57–2.10) Charlson sum 0 17/154 (11)   1 10/63 (16) 1.03 2 7/24 (29) (0.51–2.07) ≥3 5/11 (45)   Kaplan-Feinstein grade None 7/101 (7) 0.97 Intermediate 24/134 (18) (0.51–1.86) Severe 8/17 (47)   *Percentage rate in parenthesees. †Range in parentheses. probability of dying following TURP versus OPSU were different from the previously mentioned studies (Table 33.12). The RR of dying from an acute myocardial infarction after TURP/OPSU was estimated at 1.08 (95% CI 0.99–1.18, p =0.07). The excess risk of death was therefore mainly due to death resulting from respiratory complications, namely chronic obstructive pulmonary disease (COPD) and other respiratory causes. The authors interpreted this as a clue in favor of a selection bias hypothesis in that file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_470.html[09.07.2009 11:55:15]

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vulnerable patients with chronic conditions such as COPD were considered for TURP rather than for OPSU. Taylor and Krakauer analyzed data from a pilot project undertaken by the Health Care Finance Administration (HCFA) and seven peer review organizations and found a co-morbidity adjusted RR of mortality at 2 years following

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Page 471 Table 33.12 Cause of death among 13700 prostatectomy patients who died 1977–87 according to age and surgical approach (RR TURP/OPSU).165 Cause of death 55–64 years 65–74 years 75–99 years Malignancies 0.98 0.97 0.99 Total cardiovascular 0.89 0.96 0.98 Acute MI 0.88 0.96 0.89 Morbus cordis 0.87 0.97 0.99 CVA 1.05 1.09 1.13 Other vascular 0.82 0.91 1.05 Total respiratory 1.44 1.24 1.11 Pneumonia 0.91 0.81 1.03 COPD 1.70 1.59 1.19 Other respiratory 1.29 1.18 1.11 Urologic 0.79 0.81 0.80 Other causes 1.23 1.14 1.12 MI, myocardial infarction; CVA, cardiovascular accident; COPD, chronic obstructive pulmonary disease. TURP/OPSU of 1.68 (95% CI 0.89–3.17).151 However, this increased risk associated with having a TURP was not statistically significant in the analysis controling for other variables associated with mortality. The most important predictors of mortality following prostatectomy were a history of metastasis from cancer (RR 5.74), congestive heart failure (RR 3.56), cancer (RR 3.15), renal insufficiency indicated by elevated blood urea nitrogen (BUN) (RR 2.75), serum albumin <3 mg (RR 2.69), atrial fibrillation (RR 2.33), lung infiltrates (RR 2.22), COPD (RR 2.17), and a history of diabetes (RR 2.04). In the subsample of 2449 TURP patients and 168 OPSU patients with a histologic diagnosis of BPH, the cumulative probability of mortality at 2 years was 14.31% (TURP) and 7.09% (OPSU). Hooten et al. drew from a large database of 2005 men who entered a urologic health screening program a sample of 25 men who underwent TURP and a group of 50 agematched control men with symptoms of prostatism.166 Patients were followed for 6 years. There were four deaths in the 25 TURP patients (16%), while there were five deaths in the 50 control men (10%). While TURP did account for a significant amount of the variability of survival after 5 years of follow-up, a far larger proportion of the variance in survival was explained by other variables such as age, preoperative risk factors, co-morbidity factors, and postoperative urinary disease. The authors concluded that the negative effect of TURP on survival, noticeable after 5 years of follow-up, makes a cause-effect relationship appear speculative only. Sidney et al. assessed the incidence of reoperation and mortality after TURP and open prostatectomy in 8219 men in the Kaiser Permanente Medical Care Program, Northern California Region.167 The vast majority of patients underwent a TURP (7771 to 8219 or 94.5%). Of the open prostatectomies, 211 (49%) were done suprapubically and 138 (31%) retropubically. In 89 (20%) the technique was not known. The age-adjusted RR of dying after TURP/OPSU was most pronounced during the first 5 years postsurgery (RR 1.8, 95% CI 1.3–2.5), and declined to 1.1 (95% CI 0.8–1.6) for deaths occurring after the first 5 years. The authors did not attempt a formal adjustment of co-morbidity in this population. The relative risk ratios for 5-year mortality following TURP/OPSU from those four studies which included some attempt to adjust for co-morbidity were combined using the hierarchic Bayes formula (FAST*PRO). Table 33.13 reflects the RR and 95% CI for the individual studies and the combined RR. The study by Sidney et al. did not attempt co-morbidity adjustment.165 By including the results of this study, the combined RR of dying after TURP/OPSU increases to 1.34 (95% CI 0.98–1.83). By including the study by Meyhoff without age or co-morbidity adjustment the RR of dying after TURP/OPSU increases to 1.4 (95% CI 0.85–2.33).168 More recent studies, conducted to either verify or disprove the excess mortality claims, came to different conclusions. When adjusting only for age, calendar year, and admission type, TURP had a higher mortality rate than open surgery (rate ratio, RR, 1. 20; 95% CI 1.08–1.34) in a series from Australia.169 This study investigated 19598 men who were operated on in Western Australia over a period of 17 years. The RR fell to 1.10 (0.99–1.23) after adjustment for co-morbidity, and to 1.07 (0.95–1.19) when accounting for nonlinearity. The authors concluded that there is at most a small and clinically unimportant excess mortality risk from TURP; any difference could be due to a protective effect of open surgery on the long-term risk of prostate cancer and a lower rate of repeat prostatectomy. Shalev et al. compared mortality due to myocardial infarction between TURP ( n =236) and open surgery ( n =123) patients in a prospective randomized study of 365 patients.170 Although they found that the rate of acute myocardial infarction was greater after prostatectomy (6%) than in the general population file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_471.html[09.07.2009 11:55:15]

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Page 472 Table 33.13 Relative risk (RR) and 95% CI of 5-year mortality following TURP and open surgery for four individual studies and combined analysis. Reference no. Source, adjustments RR and 95% CI 140 Yale-New Haven Hospital 0.91 (0.47–1.76) Co-morbidity (Kaplan-Feinstein), age Chart review data 143 Male Danish population 1.19 (1.15–1.24) Co-morbidity, age Database data 79 Subset from University Hospital 1.45 (1.15–1.83) Co-morbidity Database data 138 Subset from Health 1.48 (1.09–2.01) Science Center, Winnipeg Co-morbidity (Charlson), age Chart review data Combined Hierarchic Bayes 1.26 (0.99–1.59) regardless of approach, the authors found no significant differences between the two cohorts for overall mortality. Cattolica et al. followed a cohort of 4708 patients from 1974 to 1984.171 The RR of mortality for surgery versus no surgery for the total group was 0.88, and the results for each 5-year age group demonstrated a relative risk of 0.77 to 0.95. The authors found no excess mortality for patients undergoing transurethral resection of the prostate compared to age-matched comparison subjects randomly selected from health plan members who did not undergo surgery. A very large database of Scottish patients who had undergone TURP was analyzed and reported by Hargreave et al.172 Among the largest cohort, consisting of 65519 men who underwent prostatectomy between 1968 and June 1989, the RR of late mortality after TURP compared with open prostatectomy was 1.13 (95% CI 1.10–1.16), after controling for age and the presence of a diagnosis of cancer. A more restricted cohort of 18732 men who underwent prostatectomy between 1974 and 1979 allowed adjustment for prior hospitalization with, or concurrent diagnosis of, circulatory and respiratory conditions. In this cohort, the RR of late mortality after TURP as compared with open prostatectomy was 1.15 (95% CI 1.11–1.19) after adjusting for co-morbidity and age. A cohort of ‘healthy patients’ restricted to the 6932 men who underwent prostatectomy from 1974 to 1979, and with no evidence of hospitalization in the previous 5 years or any current diagnosis other than benign hypertrophy of the prostate, showed a RR of 1.14 (95% CI 1.07–1.21). There was no evidence of an increased risk of dying from circulatory disease in general, ischemic heart disease, or acute myocardial infarction after TURP as opposed to open prostatectomy. However, there was an increased risk of dying from respiratory conditions and from cancer, especially of the prostate and bladder. The analysis suggested the possibility that open prostatectomy may have cured some patients with early prostatic cancer, because the late death rate from prostatic cancer was greater in patients who underwent TURP than open prostatectomy. The authors also commented that limitations in the coding of more subtle aspects of the medical condition of the patients that may influence the choice of treatment could mean that the differential mortality after the procedures may reflect preoperative patient selection. In another review of 166 patients over the age of 80 years who underwent TURP, the authors found that 88.5% of the patients were classified as American Society of Anesthesiologists group III or IV. All patients were found to have at least one serious medical condition, and 43 patients died after 60 months’ mean follow-up. When the survival of this group of patients was compared to the expected survival of the age-matched population using the Kaplan-Meier survival curves, the authors found no statistical difference.173 Crowley et al. retrospectively reviewed 1125 patients treated by transurethral prostatectomy and 190 patients treated by nonperineal open prostatectomy for benign disease at one institution from 1978 through 1987. They found no significant differences in survival between the two groups.174 In another study, Hahn et al. compared the morbidity and mortality after TURP ( n =888) and TUMT

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Page 473 ( n =478) after a mean follow-up period of 3.9 years.175 The authors found a higher incidence of acute myocardial infarction than in the general population, especially from 2 years or more after either treatment. The long-term mortality rates were similar for both treatments, and the conclusion reached was that underlying disease, rather than treatment choice played a role in mortality rates.175 The impact of adjusting for age appeared clear in all studies; however, the impact of a co-morbidity adjustment was not noticed by all investigators. All presented studies are based on a retrospective review of either administrative databases or of medical records, or data collected prospectively to answer other research questions. Administrative databases are created and maintained with vastly different purposes in mind and not just retrospective assessment of the risk of dying following certain interventions. Entries in medical records are also not designed to be used for such data analysis. Rather, entries into medical records by surgeons and anesthesiologists reflect the thoughts of the attending physician at the time of entry as to whether or not this patient can or cannot withstand a certain procedure with its associated risk. The assessment of the magnitude of this subjective risk varies from physician to physician. Consequently, the entries may be more or less complete depending on the perceived seriousness of the intervention (bias in favor of reporting co-morbidity in OPSU patients) and opinion among specialists as to the risk involved with the procedure (bias in favor of reporting comorbidity in open-surgery patients). The studies using a detailed review of medical records rather than databases do not come to the same conclusions, but rather differ in their assessment of the adjusted relative risk of dying. Whether this is due to differences in the patient population at the various hospitals, the methods and thoroughness of abstracting, or other unidentified factors is unknown. It is interesting, however, that the type of hospital may have an impact on the risk of dying. Wennberg et al. found no difference in mortality rates between TURP and OPSU in teaching hospitals, and concerns have been raised stating that possibly the surgeons in some of the geographic regions from which patients were analyzed were more or less familiar with one surgery or another.176 Another factor that may have to be taken into account was pointed out by Adell and Grabe.177 In a 7-year follow-up study of 189 men after TURP they found that preoperative treatment with an indwelling catheter inserted for urinary retention was associated with an RR of 2.0 ( p =0.06) of dying in the follow-up period, while age greater than or less than 70 years) was associated with an even greater RR of 3.3 ( p <.001) (Cox proportional hazard multivariate analysis of survival). It appears that most retrospective studies utilizing databases did not capture information on retention and indwelling catheter in an effort to adjust for it. The cumulative probability of dying within 8 years after TURP was clearly higher in the Oxford region (49.49%) than in Manitoba (39.25%).150 Based on the differences in the healthcare systems in both countries during the observation period, it is quite likely that more patients were treated while in retention and wearing an indwelling catheter in England than in Manitoba. Since it is not known to what degree the presence or absence of an indwelling catheter influences survival after OPSU, firm conclusions regarding this variable cannot be drawn. Another important observation is that, while the magnitude of the effect was similar in the various studies, the main cause leading to the increased mortality was vastly different. In the Roos study the excess mortality was due to cardiovascular causes, mainly acute myocardial infarction, while in the Andersen study it was due to respiratory problems. The lack of a consistent difference in specific causes of death among men exposed to TURP and open prostatectomy raises serious questions about the biological plausibility of the finding. It is clear that no retrospective study can match the thoroughness of data collection in a prospective study, and accordingly several investigators have taken the position that the evidence demands the initiation of such a prospective study.151 Faced with the immediate dilemma of explaining the seemingly implausible fact that patients treated with TURP face a greater long-term risk of dying than those treated with open surgery for BPH, investigators have developed an interest in some of the basic pathophysio logic reactions to a TURP. The following discussion will focus on those aspects of TURP that are unique to the procedure itself and that might conceivably explain the observed long-term mortality difference. These aspects are (1) hypothermia occurring during TURP, (2) combination of blood loss and/or circulatory overload due to absorption of irrigation fluid and the effect on cardiovascular performance, (3) hemolysis induced by certain irrigants, (4) other systemic effects induced by the absorption of certain irrigants, (5) metabolic effects exerted by absorbed irrigant, and (6) effects due to arranging patients in a lithotomy position. Hypothermia, during TURP has received little attention in the literature. Allen altered the temperature of the irrigation fluid from 68 to 100 degrees Fahrenheit in 60 patients.178 He documented a progressively lower body file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_473.html[09.07.2009 11:55:16]

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Page 474 temperature in all patients except in those in whom the fluid was kept close to body temperature. In addition, he found that with the use of room-temperature solutions, the temperature drop was linear and time related to 105 minutes. He did not record temperatures beyond this time. Carpenter monitored rectal temperatures in 16 men before and at least 6 hours after TURP. He found that the average patient’s temperature drop continued for 3 hours postoperation, at which point it reached a mean nadir of 96 degrees Fahrenheit (35.6 degrees centigrade).179 In another study, 59 patients underwent TURP using spinal anesthesia and were randomized to receive either isothermic irrigation fluid or fluid at room temperature.180 The authors found that the decrease in body temperature was significantly lower in the room temperature group and suggested the use of isothermic irrigation for TURP. The cardiovascular system is particularly sensitive to hypothermia, and certain ECG changes pathognomonic for hypothermia may occur at 35.6 degrees centigrade, which are known to precede ventricular fibrillation. One study has found that high-risk cardiac patients have a 300% higher risk of perioperative morbid cardiac events when randomized to routine thermal care compared to the same patient population who are randomized to receive more aggressive thermal warming.181 If shivering were to occur to compensate for heat loss, it would increase oxygen consumption significantly, again putting the cardiovascular system at additional risk. However, in most cases the use of either muscle relaxants or a spinal block will abolish the ability to shiver and therefore will aggravate the hypothermia. It is beyond the scope of this discussion to explore the vast body of literature dealing with the issue of fluid absorption during TURP and its impact on (1) hemolysis, (2) cardiovascular changes, (3) TURP syndrome, and (4) mortality. The use of sterilized water has, in most countries, been replaced by the use of isotonic irrigation fluids, thus reducing the risk of hemolysis due to the absorption of hypotonic solutions. The currently utilized irrigation fluids contain sugars such as glycine, sorbitol, or mannitol in varying concentration. The amount of fluid absorbed depends on (1) the experience of the resectionist, (2) the length of time of the resection, (3) the hydrostatic pressure of the irrigation fluid, and (4) the presence or absence of any surgically induced capsular perforation or opened venous sinuses. A modern technique to measure absorption of fluid is to tag it with 1% ethanol and measure the ethanol concentration in the expired breath. Using this method, two investigators found vastly different amounts of fluid absorbed in similar patient popula tions. Hahn studied 70 patients, in whom a mean of 29 g of tissue was resected in an average of 51 minutes (range 20–135 minutes).182 Blood loss averaged 490 ml and fluid absorption averaged 1300 ml (range 200–4300 ml). On the other hand, Hulten et al. described 20 men (duration 42±15 minutes, weight 31±21 g, blood loss 555±483 ml) with an average absorption of only 552±460 ml.168 In another study by the same group, 46 patients underwent TURP and the ethanol method was used to determine the amount of irrigant fluid absorption.183 The authors reported the mean absorption in the 21 patients in whom any ethanol was detected at 2 liters. The two groups, with and without absorption, did not differ significantly in terms of duration of surgery (mean 48 and 47 minutes), resected weight (mean 32.8 and 31.6 g), or blood loss (mean 550 and 483 ml). The impact of the choice of the irrigation fluid on short-term outcome is evident from an old study by Emmett et al.184 After switching from water to a nonhemolytic isotonic irrigation fluid, the mortality following TURP at the Mayo Clinic dropped from about 1.0% to <0.5%. While in most countries isotonic nonhemolytic solutions (mannitol, sorbitol, glycine) are used during TURP, in some institutions sterile water may still be in use. Whether choice of irrigation fluid has a role in the longterm mortality of TURP vs open prostatectomy is unknown, as the available studies have not reported on this factor. In an early study Mebust et al. reported that 90% of patients ( n =30) experienced a decrease in cardiac output by a mean of 17.5% during TURP.185 De-Angelis et al. observed hemodynamic changes occurring in an unpredictable fashion in nine men during TURP.186 Pulmonary capillary wedge pressure increased in four out of nine patients, and was not always indicated by an increase in central venous pressure. Systemic vascular resistance decreased significantly in six out of nine cases. Evans et al. studied hemodynamic changes during routine TURP.187 They noted that heart rate and stroke volume fell progressively over the first 30 minutes of surgery, resulting in a steady-state reduction in cardiac output over time. At the same time, a significant increase in left ventricular afterload was noted. In the authors’ interpretation, these findings demonstrate that hemodynamic responses not detectable by conventional monitoring methodology occur during TURP. In particular, the increased left ventricular afterload indicates increased myocardial workload and oxygen demand, possibly resulting in myocardial ischemia. Overall, these effects may be part of a link to the

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Page 475 increased cardiovascular morbidity and mortality observed following TURP. In this study, the cardiac risk index was assessed using the Goldman classification and a standardized anesthetic technique, including intubation and intermittent positive pressure ventilation, was used. For the actual procedure, intermittent irrigation using 1.5% glycine solution at room temperature delivered through a fast-flow glass set from a reservoir at 60 cm above the pubic symphysis was utilized. Beyond the usual monitoring, total fluid balance was determined by a system of transducers placed under the operating table to give a continuous read-out of the weight of the patient and the operating table (accuracy±50 g at a load of 275 kg). Hemodynamic data were obtained with an esophageal Doppler ultrasound transducer. Mannitol blood pressure and Doppler wave parameters were recorded throughout the procedure in 10 minute intervals. The average age of the ten patients in the study was 68±3.5 years, and the average cardiac risk index was 4.6±1.7. The resected weight averaged 22±2.5 g, the duration of the procedure was 40±2.7 minutes, average blood loss was 203±39 ml, and fluid load averaged 856±492 ml. During the procedure, the heart rate decreased at an average of 8.5±4.5%. The minute distance (MD) (the product of the stroke distance and the heart rate, representing a linear index of cardiac output) decreased by 29±2.6%, and systemic vascular resistance increased by 47±6.4%. No relationship was detected between the magnitude of the hemodynamic changes and either the surgeon, the age of the patients, the resected weight, the length of the operation, estimated blood loss, or the load of irrigation fluid. The authors speculated that among the factors contributing to the unexpected hemodynamic responses during TURP were the irrigation fluid absorption, hemorrhage, the use of anesthetic agents, the absorption of glycine and hyperammonemia, sympathetic responses to the surgery, and the response to heat loss. In a follow-up controlled study the same group of authors compared hemodynamic parameters in 20 men undergoing TURP with eight men undergoing hernia repair and five men who underwent testicular exploration.188 The mean arterial pressure fell in the 13 control patients to 11% below baseline at 2 minutes into surgery (95% CI 5–17%), while in the TURP patients it increased by 16% at the 2 minute recording and remained raised throughout the procedure (95% CI 5–27%). Cardiac output fell by 21% (95% CI 10–32%), and the index of systemic vascular resistance increased by 46.8% (95% CI 28–66%) at the end of the TURP. All observed parameters were statistically different between the controls and the TURP patients (arterial pressure: p <0.05; cardiac output: p <0.005; systemic vascular resistance: p <0.0005). The authors speculated that the observed hemodynamic disturbances may have been due to the rapid central cooling observed during TURP (core temperature fell by a mean of 0.8 (0.6–1.0) degrees centigrade. Considering these sizable hemodynamic effects occurring during TURP, it is of interest to review a study published by Ashton et al.189 The authors obtained ECGs preoperatively and on the first 3 postoperative days in 206 men undergoing TURP. The occurrence of cardiac events was monitored and assessed by measurement of creatinine kinase isoenzymes during the first 3 postoperative days, and by review of the entire clinical course. While 21% of patients developed postoperative ECG changes, mostly involving the T-wave, none had cardiac symptoms or sustained creatinine kinase isoenzyme elevation. The changes were not significantly more common in men known to have coronary disease. The one patient who had a perioperative myocardial infarction had no ECG changes noted. Only one of the 21% of patients who had postoperative ECG changes had a cardiac event in the year after surgery. The low likelihood of a cardiac event in only one of 44 patients followed throughout the 12 months after TURP provided empirical evidence of the limited clinical significance of the ECG changes commonly seen in patients undergoing this procedure. In light of the finding of increased delayed mortality following TURP, this report is of interest in that it documents a high frequency of ECG changes (21%), which not do seem to have any consequences in the year following surgery. Several reports that might possibly shed some light on the puzzling delayed mortality effect examine the effects of one commonly used irrigant, namely glycine. Glycine acts as an inhibitory neurotransmitter in the spinal cord, brainstem, and the CNS.190 Investigators have documented visual aberrations during or following TURP as a result of the absorption of glycine resulting from its specific role as an inhibitory neurotransmitter in the retina.191–193 The same group of investigators also showed significant hemodynamic responses to glycine infusion in dogs. Immediately after infusion, they showed that cardiac output increased and systemic vascular resistance and mean arterial pressure decreased. Later, both cardiac output and mean arterial pressure decreased significantly, while systemic vascular resistance returned to normal. In a similar study conducted in humans, seven healthy volunteers received an intravenous infusion of 1 liter of 2.2%

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Page 476 (isosmotic) glycine over 20 minutes.194 This infusion elicited a significant increase in the plasma vasopressin level by 60% (±13%) above the baseline level. Only in the patient who developed signs of glycine toxicity, however, did the serum cortisol level increase. The results of the study may be interpreted as showing that a glycine solution has water-retaining properties by stimulation of vasopressin secretion, but usually not by increasing the cortisol secretion. The same authors had previously reported that during transurethral prostatic surgery the secretion of vasopressin and cortisol increased once the irrigant solution containing glycine was taken up into the circulation through severed prostatic veins.195,196 However, in the clinical study of TURP in which an increase in the serum cortisol level was reported, glycine absorption was on average 30% greater than the amount of glycine given by intravenous infusion in the experimental study. It is therefore possible that either the 1 liter of infused isomorphic glycine solution was not sufficient to elicit the effect in these healthy volunteers, or that other effects occurring during transurethral prostatectomy caused the stimulation in the cortisol level rather than the infusion of glycine. What remains, however, is the observation that in fact a stress-related hormone, namely cortisol, increases during TURP, whether due to the absorption of irrigant fluid containing glycine or due to other mechanisms. It is evident that a significant increase in the plasma level of such a hormone might have effects on the cardiovascular system, and thus be partially responsible for the observed hemodynamic changes. Glycine has also been reported to be associated with an increased incidence of neurologic symptoms compared with the use of 3% mannitol (or sorbitol).197 While, overall, none of the discussed studies convincingly explain the increased risk of mortality following TURP/OPSU, they do point out some of the unique features associated with transurethral resection versus open surgical enucleation of the prostate. It is apparent that the awareness level has increased and much more attention is paid to these aspects of prostate surgery. There will probably be a number of investigations attempting to address these issues in a scientific and systematic fashion, which may help to explain the retrospective findings. However, in the meantime it is evident that there is a possibility that features unique to TURP, which are not captured in either administrative databases or during chart reviews, may play an important role if there really is an increased risk of long-term mortality following this procedure. Unmeasured co-morbidity among TURP patients, however, still seems the most likely explanation for these findings. Prospective studies may indeed be the only way to settle this question. References 1. Bellfield W. Operations on the enlarged prostate, with a tabulated summary of cases. Am J Med Sci 1890; 100: 439–452 2. Fuller E. Six successful and successive cases of prostatectomy. J Cutan Genito Dis 1895; 13:229 3. Millin T. Retropubic prostatectomy: new extravesical technique. Report on 20 cases. Lancet 1945; 2:693 4. Millin T. Retropubic prostatectomy. J Urol 1948; 59: 267–274 5. Nesbitt R. A history of transurethral prostatectomy. Rev Mex Urol 1975; 35:349–362 6. Iglesias J, Sporer A, Gellman A. New Iglesias resectoscope with continuous irrigation, simulateous suction and low intravesical pressure. J Urol 1975; 114:929–933 7. Holtgrewe H, Mebust W, Dowd J et al. Transurethral prostatectomy: practice aspects of the dominant operation in American urology. J Urol 1989; 141:248–253 8. Lu-Yao G, Barry M, Chang C et al. Transurethral resection of the prostate among medicare beneficiaries in the United States: time trends and outcomes. Prostate patient outcomes reserach team (PORT). Urology 1994; 44: 692–698 9. Wasson J, Reda D, Bruskewitz R et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans’ Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995; 332:75–79 10. Mebust W, Holtgrewe H, Cockett A, Peters P. Transurethral prostatectomy: immediate and postoperative complications: a cooperative study of 13 institutions evaluating 3885 patients. J Urol 1989; 141:243–247 11. McConnell J, Barry M, Bruskewitz R. Benign prostatic hyperplasia: diagnosis and treatment. Agency for Health Care Policy and Research (AHCPR). Clin Pract Guidel Quick Ref Guide 1994; 8:1–17 12. Holtgrewe HL, Ackermann R, Bay-Nielsen H et al. Report from the Committee on the Economics of BPH. In: Cockett AT, Aso Y, Chatelein C, Denis L, Griffith K, Murphy G (eds). Proceedings of the second international consultation on benign prostatic hyperplasia (BPH). Paris: SCI, 1993:345–355 13. Foley S, Bailey D. Microvessel density in prostatic hyperplasia. BJU Int 2000; 85:70–73 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_476.html[09.07.2009 11:55:18]

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14. Kearney M, Bingham J, Bergland R et al. Clinical predictors in the use of finasteride for control of gross haematuria due to benign prostatic hyperplasia. J Urol 2002; 167:2489–2491

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Page 478 47. Ather M, Faruqui N, Abid F. Optimization of low preoperative hemoglobin reduces transfusion requirement in patients undergoing transurethral resection of prostate. J Pak Med Assoc 2003; 53:104– 106 48. Mebust W. Symptoms and urodynamics [editorial]. J Urol 1995; 153:694 49. Van-Arsdelen K, Chen J, Vernon-Smith M. Penile erections complicating transurethral surgery. J Urol 1983; 129: 374–376 50. Stearman F, Nouri M, Coeurdacier P et al. Treatment of intraoperative penile erection with intracavernous phenylephrine. J Urol 1995; 153:1478–1481 51. Bush I, Malters E, Bush J. Transurethral vaporisation of the prostate (TVP): new horizons (abstract). Soc Min Invas Ther 1993; 1993:98 52. Narayan P, Tewari A, Croker B et al. Factors affecting the size and configuration of electrovaporisation lesions in the prostate. Urology 1996; 47:679–688 53. Reich O, Corvin S, Oberneder R et al. In vitro comparison of transurethral vaporization of the prostate (TUVP), resection of the prostate (TURP), and vaporization-resection of the prostate (TUVRP). Urol Res 2002; 30:15–20 54. Kaplan S, Te A. Transurethral electrovaporisation of the prostate (TUVP)—a novel method of treating men with benign prostatic hyperplasia. Urology 1995; 45:566–572 55. Patel A, Fuchs G, Gutierrez-Aceves J et al. Transurethral electrovaporization and vapour resection of the prostate: an appraisal of possible electrosurgical alternatives to regular loop resection. BJU Int 2000; 85:202–210 56. McAllister W, Karim O, Plail R et al. Transurethral electrovaporization of the prostate: is it any better than conventional transurethral resection of the prostate. BJU Int 2003; 91:211–214 57. Hammadeh M, Madaan S, Hines J, Philp T. 5-year outcome of a prospective randomized trial to compare transurethral electrovaporisation of the prostate with standard transurethral resection. Urology 2003; 61: 1166–1171 58. Ramon J, Lynch T, Eardley I et al. Transurethral needle ablation of the prostate for the treatment of benign prostatic hyperplasia: a collaborative multicentre study. BJU Int 1997; 80:128–135 59. Schulman C, Zlotta A. Transurethral needle ablation (TUNA): histopathological, radiological, and clinical studies of a new office procedure for treatment of benign prostatic hyperplasia. Prog Clin Biol Res 1994; 386: 479–486 60. Issa M, Oesterling J. Transurethral needle ablation (TUNA): an overview of radiofrequency thermal therapy for the treatment of benign prostatic hyperplasia. Curr Opin Urol 1996; 6:20–27 61. Naslund M. A cost comparison of TUNA vs TURP J Urol 1997; 157:155 62. Zlotta A, Giannakopoulos X, Maehlum O et al. Long-term evaluation of transurethral needle ablation of the prostate (TUNA) for the treatment of symptomatic benign prostatic hyperplasia (BPH): clinical outcome up to 5 years from 3 centres. Eur Urol 2003; 44:89–93 63. Bruskewitz R, Issa M, Roehrborn C et al. A prospective, randomized 1-year clinical trial comparing transurethral needle ablation to transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia. J Urol 1998; 159:1588–1593 64. Cimentepe E, Unsal A, Saglam R. Randomized clinical trial comparing transurethral needle ablation with transurethral resection of the prostate for the treatment of benign prostatic hyperplasia: results at 18 months. J Endourol 2003; 17:103–107 65. Rosette J D L, D’Ancona F, Debruyne F. Current status of thermotherapy of the prostate. J Urol 1997; 157:430–438 66. de-Wildt M, Wagrell L, Larson T, Eliasson T. Clinical results of microwave thermotherapy for benign prostatic hyperplasia. J Endourol 2000; 14:651–656 67. Wagrell L, Schelin S, Nordling J et al. Feedback microwave thermotherapy versus TURP for clinical BPH—a randomized controlled multicenter study. Urology 2002; 60:292–299 68. Rosette JDL, Laguna P, Gravas S, de-Wildt M. Transurethral microwave thermotherapy: the gold standard for minimally invasive therapies for patients with bengin prostatic hyperplasia? J Endourol 2003; 17: 245–251 69. Dahlstrand C, Walden M, Geirsson G, Pettersson S. Transurethral microwave thermotherapy versus transurethral resection for symptomatic benign prostatic obstruction: a prospective randomized study with 2 year follow-up. BJU Int 1995; 76:614–618 70. Eddy D. Clinical decision making: from theory to practice. Comparing benefits and harms: the balance sheet. J Am Med Assoc 1990; 263:2493–2505 71. Barry M, Girman C, O’Leary M et al. Using repeated measures of symptom score, uroflowmetry and file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_478.html[09.07.2009 11:55:19]

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prostate specific antigen in the clinical management of prostate disease. Benign Prostatic Hyperplasia Treatment Outcomes Study Group. J Urol 1995; 153:99–103 72. Golomb J, Lindner A, Siegel Y, Korczak D. Variability and circadian changes in home uroflowmetry in patients with benign prostatic hyperplasia compared to normal controls. J Urol 1992; 147:1044–1047 73. Grino P, Bruskewitz R, Blaivas J et al. Maximum urinary flow rate by uroflowmetry: automatic or visual interpretation. J Urol 1993; 149:339–341 74. Barry M, Cockett A, Holtgrewe H et al. Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 1993; 150:351–358

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Page 479 75. Mearini E, Marzi M, Mearini L et al. Open prostatectomy in benign prostatic hyperplasia: 10-year experience in Italy. Eur Urol 1998; 34:480–485 76. Flanigan R, Reda D, Wasson J et al. 5-Year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign prostatic hyperplasia: a Department of Veterans’ Affairs Cooperative Study. J Urol 1998; 160:12–16 77. Hammadeh M, Madaan S, Singh M, Philp T. A 3-year follow-up of a prospective randomized trial comparing transurethral electrovaporization of the prostate with standard transurethral prostatectomy. BJU Int 2000; 86: 648–651 78. Donovan J, Peters T, Neal D et al. A randomized trial comparing transurethral resection of the prostate, laser therapy and conservative treatment of men with symptoms associated with benign prostatic enlargement: the CLasP study. J Urol 2000; 164:65–70 79. Talic R, Tiraifi A, El-Faqih S et al. Prospective randomized study of transurethral vaporization resection of the prostate using the thick loop and standard transurethral prostatectomy. Urology 2000; 55:886–890 80. Keoghane S, Lawrence K, Gray A et al. A double blind randomized controlled trial and economic evaluation of transurethral resection vs contact laser vaporization for benign prostatic enlargement: a 3year follow-up. BJU Int 2000; 85:74–78 81. Shingleton W, Terrell F, Renfroe D et al. A randomized prospective study of laser ablation of the prostate versus transurethral resection of the prostate in men with benign prostatic hyperplasia. Urology 1999; 54:1017–1021 82. Erdagi U, Akman R, Sargin S, Yazicioglu A. Transurethral electrovaporization of the prostate versus transurethral resection of the prostate: a prospective randomized study. Arch Ital Urol Androl 1999; 71:125–130 83. Mottet N, Anidjar M, Bourdon O et al. Randomized comparison of transurethral electroresection and holmium: YAG laser vaporization for symptomatic benign prostatic hyperplasia. J Endourol 1999; 13:127–130 84. Tuhkanen K, Heino A, Alaopas M. Hybrid laser treatment compared with transurethral resection of the prostate for symptomatic bladder outlet obstruction caused by a large benign prostate: a prospective, randomized trial with a 6-month follow-up. BJU Int 1999; 84:805–809 85. Carter A, Sells H, Speakman M et al. A prospective randomized controlled trial of hybrid laser treatment or transurethral resection of the prostate, with a 1-year follow-up. BJU Int 1999; 83:254–259 86. D’Ancona F, Francisca E, Witjes W et al. Transurethral resection of the prostate vs high energy thermotherapy of the prostate in patients with benign prostatic hyperplasia: long-term results. BJU Int 1998; 81:259–264 87. Kupeli S, Baltaci S, Soygur T et al. A prospective randomized study of transurethral resection of the prostate and transurethral vaporization of the prostate as a therapeutic alternative in the management of men with BPH. Eur Urol 1998; 34:15–18 88. Gallucci M, Puppo P, Perachino M et al. Transurethral electrovaporization of the prostate vs. transurethral resection. Results of a multicentric, randomized clinical study on 150 patients. Eur Urol 1998; 33:359–364 89. Shokeir A, Al-Sisi H, Farage Y et al. Transurethral prostatectomy: a prospective randomized study of conventional resection and electrovaporization in benign prostatic hyperplasia. BJU Int 1997; 80:570– 574 90. Mostafid A, Harrison N, Thomas P, Fletcher M. A prospective randomized trial of interstitial radiofrequency therapy versus transurethral resection for the treatment of benign prostatic hyperplasia. BJU Int 1997; 80:116–122 91. Sengor F, Kose O, Yucebas E et al. A comparative study of laser ablation and transurethral electroresection for benign prostatic hyperplasia: results of a 6-month followup. BJU Int 1996; 78:398– 400 92. Keoghane S, Cranston D, Lawrence K et al. The Oxford Laser Prostate Trial: a double-blind randomized controlled trial of contact vaporization of the prostate against transurethral resection; preliminary results. BJU Int 1996; 77:382–385 93. Anson K, Nawrocki J, Buckley J et al. A multicenter, randomized, prospective study of endoscopic laser ablation versus transurethral resection of the prostate. Urology 1995; 46:305–310 94. Roehrborn C, Burkhard F, Bruskewitz R et al. The effects of transurethral needle ablation (TUNA) and transurethral resection (TURP) of the prostate on pressure flow urodynamic parameters: analysis of the US randomized study. J Urol 1999; 162:92–97 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_479.html[09.07.2009 11:55:19]

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95. Bruskewitz R, Issa M, Roehrborn C et al. A prospective, randomized 1-year clinical trial comparing transurethral needle ablation to transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia. J Urol 1998; 159:1588–1593 96. Birch N, Hurst G, Doyle P. Serial residual volumes in men with prostatic hypertrophy. BJU Int 1988; 62:571–575 97. Bruskewitz R, Iversen P, Madsen P. Value of postvoid residual urine determination in evaluation of prostatism. Urology 1982; 20:602–604. 98. Meier D, Tarpley J, Imediegwu O et al. The outcome of suprapubic prostatectomy: a contemporary series in the developing world. Urology 1995; 46:40–44 99. Eddy D, Hasselblad V. FAST*PRO. Software for metaanalysis by the confidence profile method. Boston: Academic Press, 1992 100. Tinetti M, Inouye S, Gill T, Doucette J. Shared risk factors for falls, incontinence, and functional dependence. J Am Med Assoc 1995; 723:1348–1353

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Page 481 136. Bolt J, Evans C, Marshall V. Sexual dysfunction after prostatectomy. BJU Int 1986; 58:319–322 137. Libman E, Fichten C. Prostatectomy and sexual function. Urology 1987; 29:467–478 138. Vereecken R. Sexual activity of men presenting with prostatism: effect of prostatectomy. Eur Urol 1989; 16: 328–332 139. Lindner A, Golomb J, Korzcak D et al. Effects of prostatectomy on sexual function. Urology 1991; 38:26–28 140. Francisca E, D’Ancona F, Meuleman E et al. Sexual function following high energy microwave thermotherapy: results of a randomized controlled study comparing transurethral microwave thermotherapy to transurethral prostatic resection. J Urol 1999; 161:486–490 141. Schou J, Holm-Christensen N, Lorentzen CN. Prostatectomy and impotence: can temperature variations around the prostate during TURP explain postprostatectomy impotence? Scand J Urol Nephrol 1996; 179: 123–127 142. Bieri S, Iselin C, Rohner S. Capsular perforation localization and adenoma size as prognostic indicators of erectile dysfunction after transurethral prostatectomy. Scand J Urol Nephrol 1997; 31:545– 548 143. Lefaucheur J, Yiou R, Salomon L et al. Assessment of penile small nerve fiber damage after transurethral resection of the prostate by measurement of penile thermal sensation. J Urol 2000; 164:1416–1419 144. Libman E, Fichten C, Creti L et al. Transurethral prostatectomy: differential effects of age category and presurgery sexual functioning on postprostatectomy sexual adjustment. J Behav Med 1989; 12:469– 485 145. Delaere K, Debruyne F, Moonen W. Extended bladder neck incision for outflow obstruction in male patients. BJU Int 1983; 55:225–228 146. Katz P, Greenstein A, Ratliff J et al. Transurethral incision of the bladder neck and prostate. J Urol 1990; 144: 694–696 147. Mobb G, Moisey C. Long-term follow-up of unilateral bladder neck incision. BJU Int 1988; 62:160– 162 148. Orandi A. Transurethral resection versus transurethral incision of the prostate. Urol Clin North Am 1990; 17: 601–612 149. Roos N, Ramsey E. A population based study of prostatectomy: outcomes associated with differing surgical approaches. J Urol 1987; 137:1184–1188 150. Roos N, Wennberg J, Malenka D et al. Mortality and reoperation after open and transurethral resection of the prostate for benign prostatic hyperplasia. N Engl J Med 1989; 320:1120–1124 151. Taylor Z, Krakauer H. Mortality and re-operation following prostatectomy: outcomes in a medicare population. Urology 1991; 38:27–31 152. Singh M, Tresidder G, Blandy J. The evaluation of transurethral resection for benign enlargement of the prostate. BJU Int 1973; 45:93–102 153. Ball A, Smith P. The long-term effects of prostatectomy: a uroflowmetric analysis. J Urol 1982; 54:538–540 154. Aalkjer V. Transurethral resection/prostatectomy versus dilatation treatment in hypertrophy of the prostate II. Urologia Int 1965; 20:17–22 155. Stephenson W, Chute C, Guess H et al. Incidence and outcome of surgery for benign prostatic hyperplasia among residents of Rochester, Minnesota: 1980–1987. Urology 1991; 38:32–42 156. Wasson J, Bubolz T, Lu-Yao G et al. Transurethral resection of the prostate among Medicare beneficiaries: 1984 to 1997. For the Patient Outcomes Research Team for Prostatic Diseases. J Urol 2000; 164:1212–1215 157. Steele G, Sleep D. Transurethral needle ablation of the prostate: a urodynamic-based study with two-year followup. J Urol 1997; 158:1834–1838 158. Schatzl G, Madersbacher S, Djavan B et al. Two-year results of transurethral resection of the prostate versus four ‘less invasive’ treatment options. Eur Urol 2000; 37: 695–701 159. Blute M, Hanson K, Lynch J, Larson T. United States Prostatron TUMT Study—4 year follow-up and quality of life (abstract 370). J Urol 1996; 155:403A 160. Floratos D, Kiemeney L, Rossi C et al. Long-term followup of a randomized TUMT versus TURP study. J Urol 2001; 165:1533–1538 161. Malenka D, Roos N, Fisher E et al. Further study of the increased mortality following transurethral prostatectomy: a chart-based analysis. J Urol 1990; 144:224–228 162. Charlson M, Pompei P, Ales K, Mackenzie C. A new method of classifying prognostic co-morbidity in file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_481.html[09.07.2009 11:55:20]

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longitudinal studies: development and validation. J Chronic Dis 1987; 40:373–383 163. Concato J, Horwitz R, Feinstein A et al. Problems of comorbidity in mortality after prostatectomy. J Am Med Assoc 1992; 267:1077–1082 164. Kaplan M, Feinstein A. The importance of classifying initial co-morbidity in evaluating the outcome of diabetes mellitus. J Chronic Dis 1974; 27:387–404 165. Andersen T, Bronnum-Hansen H, Sejr T, Roepstorff C. Elevated mortality following transurethral resection of the prostate for benign hypertrophy! But why? Med Care 1990; 28:870–881 166. Hooten M, Finstuen K, Thompson I. Multivariate casecontrol study of survival following resection of the prostate. Urology 1992; 39:111–116 167. Sidney S, Quesenberry C, Sadler M et al. Reoperation and mortality after surgical treatment of benign prostatic

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Page 482 hypertrophy in a large prepaid medical care program. Med Care 1992; 30:117–125 168. Hulten J, Sarma V, Hjertberg H, Palmquist B. Monitoring of irrigating fluid absorption during transurethral prostatectomy. Anaesthesia 1991; 46:349–353 169. Holman C, Wisniewski Z, Semmens J et al. Mortality and prostate cancer risk in 19,598 men after surgery for benign prostatic hyperplasia. BJU Int 1999; 84:37–42 170. Shalev M, Richter S, Kessler O et al. Long-term incidence of acute myocardial infarction after open and transurethral resection of the prostate for benign prostatic hyperplasia. J Urol 1999; 161:491–493 171. Cattolica E, Sidney S, Sadler M. The safety of transurethral prostatectomy: a cohort study of mortality in 9,416 men. J Urol 1997; 158:102–104 172. Hargreave T, Heynes C, Kendrick S et al. Mortality after transurethral and open prostatectomy in Scotland. BJU Int 1966; 77:547–553 173. Matani Y, Mottrie A, Stockle M et al. Transurethral prostatectomy: a long-term follow-up study of 106 patients over 80 years of age. Eur Urol 1996; 30:414–417 174. Crowley A, Horowitz M, Chan E, Macchia R. Transurethral resection of the prostate versus open prostatectomy: long-term mortality comparison. J Urol 1995; 153:695–697 175. Hahn R, Farahmand B, Hallin A et al. Incidence of acute myocardial infarction and cause-specific mortality after transurethral treatments of prostactic hypertrophy. Urology 2000; 55:236–240 176. Wennberg J, Roos N, Sola L et al. Use of claims data systems to evaluate health care outcomes. J Am Med Assoc 1987; 257:933–936 177. Adell L, Grabe M. Long term survival after transurethral resection of the prostate—influence of preoperative bacteriuria and indwelling catheter treatment on late mortality. Scand J Urol Nephrol 1991; 25:9–13 178. Allen T. Body temperature changes during prostatic resection as related to the temperature of the irrigating solution. J Urol 1973; 110:433–435 179. Carpenter A. Hypothermia during transurethral resection. Urology 1984; 23:122–124 180. Pit M, Tegelaar R, Venema P. Isothermic irrigation during transurethral resection of the prostate: effects on perioperative hypothermia, blood loss, resection time and patient satisfaction. BJU Int 1996; 78:99–103 181. Frank S, Fleisher L, Breslow M et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. J Am Med Assoc 1997; 277:1127–1134 182. Hahn R. Blood ammonia concentrations resulting from absorption of the irrigating fluid containing glycine and ethanol during transurethral resection of the prostate. Scand J Urol Nephrol 1991; 25:115– 119 183. Hulten J. How to master absorption during transurethral resection of the prostate: basic measures guided by the ethanol method. BJU Int 2002; 90:244–247 184. Emmet J, Gilbaugh J, McLean P. Fluid absorption during transurethral resection: comparison of mortality and morbidity after irrigation with water and non-hemolytic solutions. J Urol 1969; 101:884– 889 185. Mebust W, Brady T, Valk W. Observations of cardiac output, blood volume, central venous pressure, fluid and electrolyte changes in patients undergoing transurethral prostatectomy. J Urol 1970; 103:632–636 186. De-Angelis J, Chang P, Kaplan J et al. Haemodynamic changes during prostatectomy in cardiac patients. Crit Care Med 1982; 10:38–40 187. Evans J, Singer M, Chapple C et al. Haemodynamic evidence for peroperative cardiac stress during transurethral prostatectomy. Preliminary communication. BJU Int 1991; 67:376–380 188. Evans J, Singer M, Chapple C et al. Haemodynamic evidence for cardiac stress during transurethral prostatectomy. Br Med J 1992; 304:666–671 189. Ashton C, Thomas J, Wray N et al. The frequency and significance of ECG changes after transurethral prostate resection. J Am Ger Soc 1991; 39:575–580 190. Pycock C, Kerwin R. Minireview: the status of glycine as a supraspinal neurotransmitter. Life Sci 1981; 28: 2679–2686 191. Mantha S, Rao S, Singh A et al. Visual evoked potentials and visual acuity after transurethral resection of the prostate. Anaesthesia 1991; 46:491–493 192. Wang J, Creel D, Wong K. Transurethral resection of the prostate, serum glycine levels, and ocular evoked potentials. Anesthesiology 1989; 70:36–41 193. Wang J, Wong K, Creel D et al. Effects of glycine on hemodynamic responses and visual evoked file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_482.html[09.07.2009 11:55:21]

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potentials in the dog. Anesthes Analges 1985; 64:1071–1077 194. Hahn R, Stalberg H, Gustafsson S. Vasopressin and cortisol levels in response to glycine infusion. Scand J Urol Nephrol 1991; 25:121–123 195. Hahn R, Rundgren M. Vasopressin responses during transurethral resection of the prostate. Br J Anaesth 1989; 68:330–336 196. Hahn R. Influence of the fluid balance on the cortisol and glucose responses to transurethral prostatic surgery. Acta Anaesth Scand 1989; 33:638–641 197. Hahn R, Sandfeldt L, Nyman C. Double-blind randomized study of symptoms associated with absorption of glycine 1.5% or mannitol 3% during transurethral resection of the prostate. J Urol 1998; 160:397–401

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Page 483 34 Transurethral laser prostatectomy B S Stein Introduction It has been many years since Malcolm McPhee referred to surgical lasers as ‘machines in search of a disease’, yet in urology this remained true until the recent upsurge in interest generated by the promise of laser treatment of benign prostatic hyperplasia (BPH).1 The development of right-angle-delivery fibers enabled the physician to deliver energy that could be aimed directly at the lateral lobes of the prostate. The new fibers promised something for everybody. For the patient, the word laser’ promised rapid and effective treatment, with no healing time needed and no complications. For the physician, the laser promised a treatment that could be very easily learned, took only about 10 minutes, and produced a satisfied patient. For third-party payers there was the promise of less expensive therapy for the number two surgical procedure under Medicare reimbursement, namely transurethral resection of the prostate (TURP). Enough experience has now been gained with the laser to separate reality from ‘hype’ and to decide, like McPhee, whether the laser is still searching for its niche. Types of lasers Many types of lasers are currently available (Table 34.1). The laser most widely used to treat BPH (albeit not the ideal laser) is the neodymium: yttrium aluminum garnet (Nd: YAG) laser. The holmium: YAG laser has also gained in popularity in recent years. The ideal properties of a Table 34.1 Commercially available lasers. Carbon dioxide Argon KTP Diode Holmium Nd: YAG Excimer Pulsed dye KTP, potassium-titanyl-phosphate. laser used to treat BPH should include the ability to bring about a high degree of vaporization, so that tissue is removed cleanly at the time of treatment. It should also have the ability to coagulate blood vessels as large as those found in the prostatic fossa. The laser should be able to be passed through thin fibers and should not be significantly absorbed by fluids. The laser wavelength should not be associated with posttreatment edema and should allow for the bending of the laser energy by 90 degrees. Types of fibers Four types of fiber systems have been used to treat the prostate, namely bare fibers, right-angled fibers, contact tips, and interstitial fibers. Kandel et al. reported on using the bare fibers to treat the prostate in the canine model.2 They used 100 W and attempted to vaporiz e the gland by dragging the fiber through the prostate. This proved to be slow and ineffective and was abandoned. Shanberg et al. reported on a similar technique, used to perform laser transurethral incision of the prostate.3 They, too, found this to be a slow procedure, and used several fibers per treatment. At about the same time, contact tips were used in an attempt to vaporize prostatic lobes. These initial efforts used sapphire tips to change a coagulating laser into a cutting laser. However, the small size of the tips and the low power that they could tolerate translated into slow treatments of small glands. The ability to deliver higher-power energy at right angles to tissue increased the interest in using Nd: YAG lasers to treat BPH. The initial fibers that were available included the TULIP and the Bard Urolase. The TULIP is composed of a right-angled fiber within a dilating balloon (and guided by transurethral ultrasound). The Urolase fiber is composed of a bare fiber that ends in an open metal cavity with a prism. This system is used under cystoscopic guidance, leading to the term visual laser-assisted prostatectomy (VLAP). Later VLAP fibers included a bare fiber ending in a plastic-enclosed cavity in which the laser energy is bent by air refraction. Both these latter types of VLAP fibers are currently commercially available. Contact tips have also been improved over the years. Each year there are reports from investigators using larger and higher power tips, capable of delivering greater energy, to

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Page 484 allow for vaporization of larger glands. Lastly, or recent interest are interstitial fibers, which are placed transurethrally directly into the prostatic lobes, sparing the urethra from injury. Right-angle fiber physics The VLAP fibers, although all similar in the principle of deflecting the laser beam, have decidedly different properties, making it imperative to understand the physics of the fibers. The two unique properties of these fibers include the angle of deflection and the angle of divergence. Angle of deflection The angle of deflection is the angle at which the beam is bent with respect to the forward direction. The laser energy in all VLAP fibers is delivered through a bare fiber, and is bent at the terminal end to a (more or less) right angle. In order to treat the lateral lobes, the ideal bend of the laser to give the smallest spot size and thus the greatest energy density would be a true 90 degree bend (Fig. 34.1a). However, this is seldom the actual case, as the fiber beam is commonly deflected to more or less than 90 degrees. A bend of less than 90 degrees (Fig. 34.1b) means that greater care should be taken in the bladder neck/orifice area, since the laser is directed slightly forwards. A bend of more than 90 degrees (Fig. 34.1c) means that greater care should be taken near the sphincter area since the laser is directed slightly backwards. Understanding the angle of deflection can help prevent inadvertent injury. Angle of divergence The angle of divergence relates to the spread of the laser beam as it leaves the fiber. If a bare fiber is used, the laser beam spread will be approximately 8 degrees. The various VLAP fibers produce a wide variety of angles of divergence. The greater the angle of divergence, the wider the area of tissue affected by the laser, but the less the power density will be (Fig. 34.2). Von Swol et al. studied the effect of the angle of divergence on the tissue effect.4 They also studied the effect of technique (such as static treatment versus painting) on ultimate tissue effect. In general, the metal cavity (reflective) fibers are of lower power density owing to the wider angle of divergence, while the air-refractive fibers are of higher power density. The differences in power density may be as much as 10-fold at the same power. Since the refractive fibers can tolerate higher power settings than can the reflective fibers, this difference is potentially even greater. In addition,

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Figure 34.1 Right-angled fibers: (a) true 90 degree bend, (b) bend of less than 90 degrees showing forward projection, (c) bend of more than 90 degrees showing retrograde projection. those authors concluded that the difference in tissue necrosis was up to five times higher with the painting technique than with the static treatment technique. It becomes apparent that using refractive fibers can allow for high power density treatment, especially with the painting technique, whereas the reflective fibers allow for lower

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Page 485

Figure 34.2 Angles of divergence: (a) narrow; (b) wide. power density treatment with static techniques. Thus, understanding fiber physics will allow one to choose the ideal fiber for the type of treatment that is desired. Types of treatment The two methods of treating BPH using VLAP fibers are coagulation and vaporization. Coagulative necrosis can be achieved by using low power and long pulse durations; vaporization requires high power settings, and shorter pulse durations. Thus, although 100W for 1s, 50W for 2s, and 25W for 4s all produce 100J, that produced by 25W for 4s will give rise to the greatest depth of penetration since all of the laser energy will be converted into coagulative necrosis. The choice of 100W for 1s will produce the least penetration, since the higher power and shorter pulse duration will result in surface vaporization, with a concomitant decrease in coagulative necrosis. Thus, two treatment potentials are apparent—high power density (using refractive fibers for vaporization) and low power density (using reflective fibers for coagulation)—although both treatments produce some degree of both effects. With coagulative necrosis, temperature changes ranging from 60 to 70ºC are expected, producing coagulative necrosis with little surface vaporization.5 There will be gray-white discoloration of the tissue, with the maximum possible depth of penetration. Tissue ablation requires secondary sloughing of tissue, taking weeks to occur, with early tissue edema. By contrast, with vaporization temperature changes on the surface well in excess of 100ºC can be expected, with immediate tissue ablation. There will be far less depth of penetration, since most of the laser energy is directed to the surface. As a result, there will be less edema postoperatively and less slough, since there is insignificant coagulative necrosis. The actual depth of prostate treated will, however, ultimately be less with this technique. Surgical technique Coagulation treatment As previously described, this treatment is based upon low power and long pulse duration. Thus, the metal reflective fibers would be ideal for this type of treatment. The majority of studies have used between 40 and 60W, although some laboratory studies have suggested that even lower power settings should be used.6 The majority of the investigators have actually increased power settings from 40 to 60W. Pulse durations may vary from 30 to 120s. Currently, the most common combination is 60W for file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_485.html[09.07.2009 11:55:22]

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60s to each of four treatment areas starting just outside the bladder neck. The four areas are at 2, 4, 8, and 10 o’clock and a second treatment at similar locations is undertaken for larger glands. It is advisable to re-check the fibers after the first four-quadrant treatment, since the power delivery may have increased significantly. As this method produces the equivalent of a thermal burn, and produces much tissue edema, prolonged catheter drainage is required, usually for a week or more.7 This treatment can be performed under local anesthesia with pudendal block.8 In recent years, interstitial laser coagulation (ILC) has emerged as an alternative surgical option for BPH. The laser delivery fiber is inserted directly into the prostatic tissue without damage to the urethra while the patient is under local anesthesia with intravenous sedation. Postoperative edema is associated with the procedure, however, severe hemorrhage and intravascular fluid shifts are uncommon. Two interesting papers afford insight into the healing process after VLAP by the coagulation technique. Marks presented seven patients who underwent VLAP and subsequently were studied by serial videoendoscopy.9 He found that in the early weeks after treatment there were

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Page 486 typical findings of coagulative necrosis, i.e. the prostate appeared shaggy, white, and irregular. No patient demonstrated healing in less than 6 weeks. By 3–4 months, some patients had undergone considerable healing, while others still appeared to be actively sloughing tissue. By 3 months, some degree of postprostatectomy defect was noted in all patients; some had a completely clean fossa, while others had residual tissue. Costello et al. studied the histologic changes in the prostate after VLAP in six patients who underwent TURP and one patient who underwent radical prostatectomy, from 24h to 10 months after VLAP.10 Costello et al. found that in the first days after VLAP the findings were similar to those of a thermal burn. As days turned to weeks after treatment, the effect of the VLAP became more pronounced and extensive coagulative necrosis took place. This slough continued until, after 1 month or more, regenerating glandular cells appeared and squamous metaplasia became evident. Ten months after VLAP some denatured tissue remained in a central location. Vaporization treatment This treatment requires higher power density and shorter pulse duration, and is best undertaken with refractive fibers. Power settings of 80–100W are most commonly employed, as is the painting technique. In the painting technique, the median lobe is first treated using tangential laser energy delivery. After vaporization of the median lobe, the fiber is placed just outside the bladder neck (to preserve antegrade ejaculation) and slowly dragged through the lateral lobe to the verumontanum, care being taken to avoid treating beyond this area. The drag rate should be slow enough to ensure adequate vaporization (as determined visually). After four troughs have been created at the 2, 4, 8, and 10 o’clock areas, any remaining untreated tissue is then lasered in the same fashion until the entire prostate has been treated. Owing to the charring and tissue color change, attempts to re-treat areas already vaporized do not result in deeper penetration. Approximately 1000J of laser energy per gram of tissue are delivered in this technique. A catheter will be required, although usually for a shorter period than after coagulation. To the author’s knowledge, this has not been performed under pudendal block, but no doubt could be. Results: Nd:YAG laser Coagulation technique The first paper to appear on the use of VLAP fibers in humans was published in 1992 by Costello et al.11 They described the use of the Lateralase fiber (Trimedyne) in treating four men with outlet obstruction due to BPH, employing 60W for 60s at four quadrants. The initial results were promising, with all four patients showing improvement in flow rates. In addition, one patient underwent VLAP treatment prior to radical prostatectomy for cancer. Histologic examination of the radical prostatectomy specimen revealed a zone of necrosis extending 2.5 cm deep, with an intact capsule. Using an improved fiber, Costello reported on his results with 33 men undergoing VLAP for BPH.12 This study included two patients treated while receiving anticoagulant therapy. The protocol was identical to that in Costello’s first study, except that a second round of treatments was added for men with prostatic lengths greater than 3.0 cm. The procedure was continued until all obvious adenoma had been laser treated. The results of this study are summarized in Table 34.2. The catheter was routinely removed by 48h, and all but seven patients required recatheterization owing to burn edema at the bladder neck. Three patients (9%) failed to void and cystoscopic examination showed no laser effect; these patients underwent TURP The laser was found to be faulty and was blamed for this failure. The first US trial of VLAP was sponsored by C.R. Bard.13 The study was a prospective, randomized trial of TURP versus VLAP A total of 115 patients were randomized, with 59 in the TURP arm and 56 in the laser arm. There were no differences between the two arms in terms of age, prostate size, postvoid residual, or preoperative peak flow rates. American Urological Association (AUA)-6 symptom scores differed statistically, the TURP group having patients with higher preoperative scores (20.8 vs 18.7 for VLAP). Eight of the patients were in urinary retention. This protocol used 40W in four quadrants (3, 6, 9, and 12 o’clock). The pulse durations were 30s at the 6 and 12 o’clock positions, and 60s at the 3 and 9 o’clock positions. A second set of pulses was used for Table 34.2 Results of coagulation using VLAP fibers in 33 men with BPH. Parameter Before treatment After treatment Peak flow rate (ml/s) 8.5 15.2 AUA-SS* 21.5 9.5 *AUA-7 symptom score. Values are means. (From Costello et al.,12 with permission.)

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Page 487 prostate glands over 4 cm in length. Increases in peak flow rates and decreases in postvoid residual and AUA symptom scores were noted in both groups, but were more pronounced in the TURP group (Table 34.3). Six of the 56 patients in the VLAP arm (11%) had a second operation within 6 months. Two had a repeat laser treatment because of laser malfunction, and four underwent TURP owing to unsatisfactory results. Adverse effects were minimal in the laser group (Table 34.4). The largest problem in this group of patients was delayed time to void, but this was not considered to constitute an adverse effect. About one-third or 30% of the men had bouts of urinary retention, requiring repeat catheterization, and 15% experienced irritative symptoms and/or a poor initial flow. Table 34.3 Results of a prospective randomized trial of TURP vs VLAP in 115 patients with BPH.   Peak flow rate (ml/s) AUA-SS* Group Before After† Before After† Laser ( n =56) 8.9 14.2 18.7 9.7 TURP ( n =59) 9.5 16.5 20.8 7.5 *AUA-6 symptom score. †12 months after procedure. Values are means. (From Cowles et al.,13 with permission.) Table 34.4 Adverse effects after VLAP or TURP in 115 patients with BPH. Complication VLAP ( n =56) TURP ( n =59) Impotence 3 (5.4) 2 (3.4) Urinary tract infection 3 (5.4) 1 (1.7) Stenosis/stricture 1 (1.8) 12 (20.4) Clot retention 0 3 (5.1) Transfusion 0 2 (3.4) Post-TURP syndrome 0 2 (3.4) Incontinence 0 2 (3.4) Urinary retention 17 (304) 5 (8.5) Hematuria 9 (16.1) 9 (15.3) Dysuria/pain 10 (17.9) 13 (22.1) Urgency 0 3 (5.1) Dribbling 1 (1.8) 0 Values are numbers of patients, with percentages in parentheses. (From Cowles et al.,13 with permission.) Retrograde ejaculation did not occur in the laser group, but was universal in the TURP group. The 1 year data were examined in a subgroup of this study, of which nine patients underwent laser treatment as described above, and ten underwent TURP (Stein and Zabbo, personal communication). Five of these patients were in retention at the start of this study, of whom two were in the TURP arm and three in the VLAP arm. Both patients in the TURP arm did well, and voided with low postvoid residuals. Of the three patients with retention in the VLAP arm, two failed and required TURP, after which both voided well. As in the entire trial, the patients in the subgroup showed improvements in the AUA symptom scores and peak flow rates after treatment, but such improvements were greater in the TURP arm than in the VLAP arm (Fig. 34.3). Three of the nine laser patients underwent TURP by 1 year. Results from another subset of this multicenter study, arm with 13 patients in the VLAP group and 12 in the TURP arm, have been published by Kabalin et al.14,15 By 6

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Figure 34.3 Results from a subgroup of a randomized trial of TUR ( ; n=10) versus VLAP ( ; n=9) using the Urolase laser: (a) peak flow rates (Qmax); (b) AUA-6 symptom scores (AUA-SS). (Stein and Zabbo, personal communication.)

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Page 488 months the peak flow in the laser group had increased from 8.5 to 20.5 ml/s while the AUA symptom score decreased from 20.9 to 4.6. By contrast, in the TURP arm the peak flow rate increased from 9.0 to 22.9 ml/s and the AUA symptom score decreased from 18.8 to 5.7 (Fig. 34.4). Kabalin et al. also reported on cystoscopic findings on the VLAP patients at 3 months, even though this was not part of the overall protocol: the TURP patients were all found to have open prostatic fossas; the VLAP patients uniformly had residual tissue, with two appearing to have obstructed lobes, despite good uroflow rates and low symptom scores. The only complications in the VLAP arm were in two patients, in whom recent retention necessitated re-catheterization. Later comparisons between ICL and TURP have shown that laser therapy compares favorably to the ‘gold standard’. In one study, 118 BPH patients were randomized to receive ILC, TURP/TUIP, or transurethral microwave thermotherapy (TUMT) and were followed up for 6 months.16 ILC was delivered by a Nd: YAG laser at a wavelength of 1064 nm, applying 20W for 30s, 15W for 30s, 10W for 30s, and 7W for 90s. At the end of the study period, improvements in I-PSS and Q max were observed in all three treatment groups. Mean I-PSS improved from 21.4 and 20.5 to 9.2 in the ILC and TUMT groups and from 21.3 to 6.8 in the TURP group, while peak flow increased from 10.2, 9.1, and 9.6 ml/s to 16.2, 13.2, and 20.6 ml/s, respectively. Complications varied between groups, with urinary tract infection the most common in the ILC group. No bleeding occurred in this group. The results indicate that ILC and TUMT are reasonable alternatives to TURP, and may be particularly suitable for some patients due to the reduced risk of bleeding. Similar results were found in a multicenter trial of 72 BPH patients treated with ILC (20W delivered at a wavelength of 830 nm) or TURP (Table 34.5).17 Median peak flow rate was slightly (2.6 ml/s), but not significantly, better in the TURP group at 2 years while AUA symptom index, problems due to symptom index, and quality of life

Figure 34.4 Results from another subgroup of a randomized trial of TURP ( ; n=12) versus VLAP ( ; n=13) using the Urolase laser: (a) peak flow rates (Qmax); (b) AUA-6 symptom scores (AUA-SS). (From Kabalin et al.,15 with permission.) Table 34.5 Median results following treatment with TURP or ILC. Variable Baseline 24 months TURP ILC TURP ILC Difference between TURP and ( n =35) ( n =35) ILC file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_488.html[09.07.2009 11:55:24]

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Peak flow (ml/s) PvR (ml) AUA symprom index Quality of life Prostate volume (ml) Sexual function score Problems from symprom index score

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9.1 87.5 23.0 11.0 40.0 17.0 19.0

9.2 81.0 24.0 11.0 41.5 18.0 17.0

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16.513.9 44.057.7 7.0 90 2.0 3.0 18.638.4 10.019.5 5.0 4.5

2.6 −13.7 −2.0 −1.0 −19.8 −9.5 0.5

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Page 489 scores improved similarly in each treatment group. Retreatment (TURP) rate for the ILC group was 16% in the following year. Adverse events occurred to a similar degree, although more serious complications were reported in the TURP group. Sexual function was also affected to a greater degree in this group. A review of trials comparing ILC and TURP showed ILC to be a valuable alternative to TURP.18Sixteen trials of 6 months’ or more duration and more than ten subjects in each treatment arm (1488) were included in the study. Eight involved contact lasers, seven noncontract lasers, and four used other techniques. Overall, TURP was associated with slightly more improvement in terms of urinary symptoms (63–77%) and Q max (96–127%) compared to laser techniques (59–68% and 56–119% improvement, respectively). However, fewer blood transfusions and strictures, and shorter hospital stays, were associated with laser therapy. Norris et al. reported on a total of 108 patients treated with the Urolase fiber:19 60W was delivered for 60s to each lateral lobe, as well as to the roof and floor. Further applications were given as needed to blanch the lateral lobes completely. Entry criteria were AUA symptom scores of 15 or more, and peak flow rates of 10 ml/s or less. The uroflow rates improved from 7.5 to 12 ml/s and AUA symptom scores fell from 22.3 to 9.23. The major complication was the need for repeat catheterization, in from 17 to 38% of patients, depending upon which day the catheter was removed, despite the use of 1 mg terazosin postoperatively for 2 weeks in 70 patients. Four of the six patients who presented in retention required a second operation (three TURPs and one repeat laser). Leach et al. reported on a subset of patients treated with a similar 60W protocol, but under local anesthesia as outpatients.8 A total of 46 men underwent VLAP in this fashion, five of whom were treated while on Coumadin. A periprostatic block with a 50/50 mixture of 1% xylocaine and 0.5% bupivacaine was used, as well as Versed i.v. sedation. By 6 months the peak flow rates had improved from 8.1 to 13.0 ml/s and the AUA-6 symptom score had decreased from 21 to 9.4. Only one patient required a second surgical procedure—a bladder neck incision for contracture. Shanberg et al. reported on two sequential series of patients: the first 25 were treated with the above protocol, and the second 25 were treated by multiple pulses over the entire prostate until all pink tissue was ablated.20 The first group was treated with the Urolase or Prolase fiber, while the second group was treated with the Laserscope ADD fiber. All patients were discharged on Toradol and Table 34.6 Results of coagulative VLAP treatment with the Urolase or Prolase fiber (group I) or with the Laserscope ADD fiber (group II) in men with BPH. Group Peak flow rate (ml/s) AUA-SS* Before After Before After I ( n =25) 5.7 13.5 26.5 7.8 II ( n =25) 6.5 14.5 25.6 5.2 *AUA-7 symptom score. Values are means. (From Shanberg et al.,20 with permission.) Hytrin for 10 days. Table 34.6 summarizes these results. No differences between the groups were noted in improvements in AUA symptom scores or uroflow rate improvements. However, there were six failures in the first group and only one failure in the second group; ultimately, three of the 50 patients underwent TURP. Lastly, Malek et al. from the Mayo Clinic have reported on their experience with 47 men treated with VLAP for BPH.21 They used the Urolase fiber in 25 patients, and the Laserscope ADD fiber in 22 patients. They used a protocol identical to that of Norris et al., but reduced the power to 40W for smaller glands. Preoperative values are not given for flow rates or AUA symptom scores, but percentage improvements are given: the AUA symptom score improved by 54 and 78%, and the peak flow improved by 65 and 97% in the Uroloase or Prolase fiber and Laserscope ADD fiber groups, respectively. Urinary retention developed in 26% of patients, taking up to 60 days to resolve. Ten patients were no better after treatment than before, and three of these underwent TURP 6 months after VLAP, with removal of 35–55 g of tissue. Long-term experience with VLAP has shown it to be safe and effective.22 A group of 230 BPH patients who underwent VLAP were followed up for a median of 36 months, with 98 available for evaluation at 5 years. After 6 months, peak flow had increased from 6.7 to 17.9 ml/s, postvoid residual urine had fallen from 159 to 52 ml and AUA symptom score had fallen from 22 to 7.2. These improvements were maintained at 5 years. Irritative symptoms with a duration of 4 weeks or more were reported in 12.2% of patients. Early complications included prostatitis (2.6%), urinary retention (1.4%), and bleeding (0.4%), while late complications included bladder neck contracture (1.4%), urethral stricture (0.9%), and urinary retention file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_489.html[09.07.2009 11:55:25]

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(0.9%). In total, 5.5% of the group required re-operation. The results indicate durable longterm safety and efficacy in most cases.

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Page 490 The combination of laser treatment and minimal TURP may also offer a suitable treatment option for some BPH patients, reducing the morbidity associated with TURP without compromising its efficacy. Corvin et al. investigated the use of combined ILC with limited TURP to determine whether the risks of TURP were reduced by performing ILC directly beforehand.23 In total, 41 patients with bladder outlet obstruction (BOO) took part in the trial, which involved ILC performed using a Nd: YAG laser under visual control followed by TURP. Anesthesiological risk factors in the patients dictated that only a limited resection was carried out of the bladder neck or prostate. Average operation time was 35 minutes, and 5±3 g of tissue was resected. No major complications and no TUR syndrome occurred. Blood loss and irrigation fluid uptake were minimal (−1.7±1.1 g/dl hemoglobin, 9±32 ml, respectively) and blood transfusion was not required in any case. The authors suggest that this may offer an alternative to conventional TURP, especially suitable for high-risk patients. In summary, the coagulation technique is simple and rapid; it has several disadvantages, however. The patients have a prolonged time to void and their initial voiding is often associated with a poor stream and severe irritative complaints that may take months to resolve. The improvements in symptom scores and flow rates are, in most comparative studies, poorer than those seen in the TURP arm. In addition, re-operation rates in the first year approximate 5–10%. For patients presenting in retention, the need for a second operation (usually TURP) is even greater, making this VLAP technique a poor choice for these patients. Recent results observed with ILC, however, suggest efficacy approaching that of TURP, with fewer adverse effects.17 Vaporization techniques Early published experience with the vaporization technique includes that of Narayan et al.,24 who treated 61 men with BPH. Entrance criteria included an AUA symptom score of more than 8 and a peak flow rate of less than 15 ml/s or patients in retention. The size of the glands ranged from 20 to 97 g. A refractive fiber and power settings of 60–80W were used, the technique employed being as described earlier. A total of 32000–225000J was delivered. The catheter was removed on day 2 in 43 and on days 3–7 in 18 patients; only five patients required recatheterization. Two of the 61 patients required a TURP for residual adenoma. All 12 patients in retention voided well. Urinary tract infection was the only significant complication, seen in 4.9% of patients. Results are summarized in Table 34.7. The experience of the present author and colleagues with this technique has been identical; they have also used Hytrin lead-in (l–5 mg/day) for 3 weeks before and 3 weeks after laser treatment. This may help the patient over the initial period of edema and, in the author’s experience, has reduced the need for recatheterization. Narayan et al. randomized 64 men to either laser prostatectomy using the vaporization (termed evaporation in this chapter) technique or the coagulation technique, using the Nd: YAG laser and the right-angled fiber.25 The improvements in the AUA symptom scores were the same in both groups, including the data at 12 months (see Table 34.8). However, the peak flow rates were higher in the vaporization group, both at 1 month and at 12 months. Complication rates were very different between the two groups. In the coagulation group five (15.6%) of the patients required a second operation within the first year, while none in the vaporization group did. In addition, eight patients (25%) in the coagulation group developed retention after having their Foley removed and required recatheterization, versus only two (6.25%) in the vaporization group. Both techniques were associated with significant postoperative irritative complaints, 39% in the coagulation group and 32% in the vaporization group (not a statistically significant difference). The authors concluded that the vaporization technique is superior due to its lower complication rate, while allowing that both were successful in providing patient relief. A comparison of TURP, contact laser prostatectomy, and electrovaporization of the prostate in 141 BPH patients showed similar subjective improvements between all three techniques.26 A Nd: YAG laser was used to carry out the laser prostatectomy while electrovaporization was performed using a Vaportrode element and glycine for irrigation. The I-PSS, BPH impact index, and symptom Table 34.7 Results of the vaporization procedure in 61 men with BPH. Parameter Assessment Pre treatment 3 months 6 months 12 months Peak flow rate (ml/s) 9.3 15.5 13.2 24.6 AUA-SS* 27.5 8.0 6.6 8.0 *AUA-7 symptom score. Values are means. (From Narayan et al.,24 with permission.)

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Page 491 Table 34.8 Results of coagulation technique vs vaporization technique.21   Peak flow AUA symptom score Coagulation Vaporization Coagulation Vaporization Baseline 7.0 6.4 22.1 22.4 1 month 12.0 17.0 9.8 9.9 12 months 16.9 19.9 5.2 5.3 problem index were performed at baseline, then 1 week, 6 weeks, and 3, 6, and 12 months after the procedures. Associated morbidity differed between groups, however, with more bleeding and perforation observed in patients who underwent TURP However, pain and hematuria levels were lower and greater retention was observed in the laser group, although incontinence was less common in these men. Quality of life scores were better in the laser group after 1 week; however, no significant difference was observed at subsequent assessments. Examination of the urodynamic effects of each of the techniques 6 months after their performance also revealed similar results between the groups.27 Peak urinary flow, detrusor contractility, and Schafer obstruction grade were determined at baseline and again after 6 months. Detrusor contractility did not change in any group, while similar increases in peak flow (by a factor of 2.4 for TURP and electrovaporization, and 2.5 for laser prostatectomy) and obstruction grade (−0.3) were observed in all groups. Two patients in the laser group suffered obstruction, however. Similar improvements in detrusor stability, effective capacity, and postvoid residual volume were found in all groups. Results: high-power KTP laser The potassium-titanyl-phosphate (KTP) laser is now becoming available in higher-power settings, and as such is capable of vaporizing the prostate. Malek et al. studied a prototype of a 60W KTP laser for BPH.28 They used the right-angled fiber and vaporized tissue including the median lobe. The laser resection was taken down to the level of the capsular fibers. Bleeding was coagulated with the same laser wavelength. All patients had Foley catheters left indwelling until the morning after their procedure. At that time the catheters were removed, and uroflow measurements were obtained. The mean peak flow rate for the ten patients treated with this technique increased from 8 ml/s preoperatively to 19.4 ml/s at 24 hours. None of the patients complained of hematuria, dysuria, or incontinence. Only three patients had reached the 3-month follow-up at the time of the publication, but all were pleased with their results. Shingleton et al. used either 20W or 40W of KTP laser before using the 60W Nd: YAG laser in an attempt to improve the patients’ voiding.29 They studied 38 patients with 20W of KTP and 12 patients with 40W of KTP laser, vaporizing the fossa as the initial treatment. Following this, craters in the prostatic lobe were produced using the Nd: YAG at 60W. Both of these treatments used the right-angled fiber. When the prostatic volume was <30 ml, the KTP laser was used to perform bladder neck incisions at the 5 and 7 o’clock positions. All patients had Foley catheters placed, however no length of catheterization nor need for catheter re-insertion is mentioned in the paper. Their conclusions were that the patients treated with the higher power of KTP laser had more rapid and sustained improvements in voiding symptoms, but identical uroflow results. A 3-year follow-up of 100 patients treated with TURP or laser prostatectomy (KTP at 36W followed by Nd: YAG at 60W) was conducted. A line of craters was created by lasing each for 1–2 minutes, after which a slow drag technique was used to connect the craters and remove further tissue. AUA symptom score was found to fall from 22 to 9.9 in the laser group and from 21.2 to 7.7 in the TURP group at the end of the study period.30 Peak urinary flow increased from 8.2 to 12.3 ml/s and from 7.3 to 12.8 ml/s, respectively, indicating that the initial positive results observed with laser prostatectomy are durable and remain similar to those seen with TURP. A pilot study recently revealed that the KTP/532 laser may be used at a strength of 80 W during photoselective vaporization of the prostate (PVP) to safely and effectively reduce symptoms of BPH.31 A 6 F side-firing fiber was used to deliver the laser energy, after which PVP was performed in ten BPH patients. No urinary retention or other major complications were reported, although mild dysuria was observed in two patients and mild hematuria in one patient. After 1 year, AUA symptom score fell from mean 23.2±4.7 to 2.6±0.5 points while peak flow increased

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Page 492 from mean 10.3±1.4 to 30.7±5.8 ml/s. Postvoid residual volume decreased significantly and overall prostate volume fell by 27% on average. The laser was active for 19.8 minutes on average during each procedure. The results of this study indicate that the 80W StarPulse KTP/532 laser offers a more rapid, but equally effective option compared to the 60W continuous wave laser; however, further large-scale trials are needed to confirm the results. Results: holmium laser Higher-power holmium lasers are also becoming available. They are now capable of producing 60–80W of power, and this can be used to both vaporize and incise the prostate. The techniques reported to date largely come from the work of Gilling et al. from New Zealand. They use a bare fiber and cut the prostate in slices, with about half of the tissue being vaporized and the other half needing to be removed from the bladder. The major technical problems encountered to date have included a longer operative time than other forms of laser prostatectomy and the need to extract large fragments of the prostate from the bladder by cutting them into smaller pieces. Gilling et al. reported on the use of a transurethral tissue morcellator which may solve the problem of removing the larger tissue fragments.32 Mackey et al. reported on the results of holmium laser prostatectomy performed on 967 men with BPH treated in either the UK or New Zealand.33 The technique included enucleating the prostate to the level of the surgical capsule and removing the remaining pieces. A catheter was left indwelling for one night. The results showed that the mean duration of catheterization was 1.5 days, with a range of 1–21 days. Two patients required a blood transfusion and two required recatheterization for bleeding. Postoperative irritative symptoms were similar to those encountered following TURP, and much less than are usually seen after laser prostatectomy with the Nd:YAG laser. Results are shown in Table 34.9. In the authors’ experience, any size prostate can be treated with the holmium Table 34.9 Results using the high-power holmium laser.25   Number Q max AUA score Preoperative 967 8.8 20.6 1 month postoperative 967 19.3 9.2 6 months postoperative 323 22.3 4.8 laser, even those glands greater than 100 g. In addition anticoagulated patients can be treated as well. Gilling et al. also reported on a series of 44 men randomized to holmium or Nd:YAG laser prostatectomy.34 They found that although the results relative to AUA symptom score and peak flow rates were the same at 1 year, there were fewer perioperative complications with the holmium laser. Catheterization times were shorter and recatheterization rates were lower. Immediate postoperative dysuria was greater in the Nd:YAG laser group. Holmium laser enucleation of the prostate (HoLEP) has developed from holmium laser prostatectomy in recent years and involves the use of the incisional and hemostatic properties of the particular laser wavelength.35 The procedure begins with a bladder neck incision, which is followed by enucleation of the median lobe and the lateral lobes. After this, transurethral morcellation takes place. Irrigation following the procedure is often unnecessary and catheterization time is minimal (<24 hours). HoLEP combined with mechanical morcellation has been shown to be an effective surgical technique for the treatment of BPH in men with both larger and smaller glands.36 Enucleation was performed using a high-powered 80 W holmium laser and transurethral mechanical morcellator. According to Hurle et al., the median lobe is enucleated following incisions at the 5 and 7 o’clock positions, connected by a transverse incision continuing under the lobe towards the bladder neck, after which point the lobe is floated into the bladder. The left and right lobes may be floated into the bladder after extension of the 5 o’clock incision along the left lateral wall, followed by a downward incision. The transurethral morcellator may then be used to resect the floating tissue. One month following the procedure, significant improvements in I-PSS, quality of life, and peak flow were observed in 155 patients and these scores continued to improve over the next few months. No significant difference was observed in men with prostates larger or smaller than 50 ml. A recent comparison of transurethral HoLEP to open prostatectomy showed that the holmium laser was similarly effective at removing large prostatic adenomas, but that such an approach was associated with far less perioperative morbidity than the open procedure.37 A group of 120 BPH patients with urodynamic obstruction and prostates larger than 100 g were randomized to receive either HoLEP or transvesical open enucleation. Baseline AUA symptom score and urodynamic assessment were performed and patients were re-assessed after 1, 3, and 6 months. Peak flow, postvoid residual volume, and AUA file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_492.html[09.07.2009 11:55:26]

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Page 493 symptom score improved to a similar extent in both patient groups. Differences were observed in periand postoperative factors, however, with the laser procedure being longer in duration but associated with significantly lower levels of bleeding, shorter catheterization time and hospital stay. Adverse events were also less common in this group and none of the patients required blood transfusions, in contrast to eight patients in the open surgery group. The combination of HoLEP with electrocautery resection may offer an additional option, negating the need for devices such as a morcellator.38 The ‘mushroom technique’ involves enucleating the median lobe of the prostate along the surgical capsule, although it remains attached at the bladder neck by a narrow pedicle, allowing the lobe to be electroresected, after which point the base of the pedicle may be lasered. The left and right lobes are resected through the creation of a lateral convex line, with the tissue enucleated until a small pedicle prevents the release of the lobe into the bladder. A resection loop may then be used to fragment the devascularized tissue. Drainage may then be performed. Examination of this bloodless technique, which was performed in 156 BPH patients, showed it to be safe and effective at relieving obstruction. The average I-PSS fell from 20 to 3 at 6 months and did not change significantly at 1 and 2 years, while median peak flow increased from 8 to 20 ml/s. Postvoid residual urine volume fell and remained low at 6, 12, and 24 months and detrusor pressure at peak flow also fell significantly. Conclusions Laser prostatectomy continues to undergo refinement. Newer lasers or higher-power versions of current lasers will modify the treatment and further improve results. TURP took approximately 40 years to become the gold standard, and the laser is improving at a more rapid rate. Further evolution of this technology will continue to improve results. References 1. McPhee M S, Mador D, Tulip J, Lakey W H. Surgical lasers: machines in search of a disease? Mod Med Can 1982; 37:1445–1449 2. Kandel L B, Harrison L H, McCullough D L et al. Transurethral laser prostatectomy in the canine model. Lasers Surg Med 1992; 12:33–42 3. Shanberg A M, Tansey L A, Baghdassarian R. The use of Nd:YAG in prostatectomy. Poster 331, American Urological Association, Atlanta, May 1985 4. Von Swol C F P, Verdassdork R M, Van Vliet R J et al. Side-firing devices for laser prostatectomy. World J Urol 1995; 13:88 5. Stein B S, Kendall A R. Lasers in urology. 1. Laser physics and safety. Urology 1984; 23:405–410 6. Orihuela E, Motamedi M, Pow-Sang M et al. Low-power laser radiation for the treatment of benign prostatic hyperplasia: initial clinical experience. J Endourol 1994; 8: 301–304 7. Stein B S (personal experience) 8. Leach G E, Sirls L, Ganabathi K et al. Outpatient visual laser-assisted prostatectomy under local anesthesia. Urology 1994; 43:149 9. Marks L S. Serial endoscopy following visual laser ablation of prostate (VLAP). Urology 1993; 42:66– 71 10. Costello A J, Bolton D M, Ellis D, Crowe H. Histopathological changes in human prostatic adenoma following neodymium:YAG laser ablation therapy. J Urol 1994; 152:1526–1529 11. Costello A J, Johnson D E, Bolton DM. Nd:YAG laser ablation of the prostate as a treatment for benign prostatic hypertrophy. Lasers Surg Med 1992; 12:121–124 12. Costello A J, Schaffer B S, Crowe H R. Second-generation delivery systems for laser prostatic ablation. Urology 1994; 43:262–266 13. Cowles R S, Kabalin J N, Childs S et al. A prospective randomized comparison of transurethral resection to visual laser ablation of the prostate for the treatment of benign prostatic hyperplasia. Urology 1995; 46:155–160 14. Kabalin J N. Laser prostatectomy performed with a right angle firing neodymium:YAG laser fibre at 40 watts power setting. J Urol 1993; 150:95–99 15. Kabalin J N, Gill H S, Bite G, Wolfe V. Comparative study of laser versus electrocautery prostatic resection: 18-month follow up with complete urodynamic assessment. J Urol 1995; 153:94–98 16. Norby B, Nielsen H V, Frimodt-Moller P C. Transurethral interstitial laser coagulation of the prostate and transurethral microwave thermotherapy vs transurethral resection or incision of the prostate: results of a randomized, controlled study in patients with symptomatic benign prostatic hyperplasia. BJU Int 2002; 90:853–862 17. Kursh E D, Concepcion R, Chan S et al. Interstitial laser coagulation versus transurethral prostate file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_493.html[09.07.2009 11:55:27]

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resection for treating benign prostatic obstruction: a randomized trial with 2-year follow-up. Urology 2003; 61:573–578 18. Hoffman R M, MacDonald R, Slaton J W, Wilt T J. Laser prostatectomy versus transurethral resection for treating

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Page 494 benign prostatic obstruction: a systematic review. J Urol 2003; 169:210–215 19. Norris J P, Norris D M, Lee R D, Rubenstein M A. Visual laser ablation of the prostate: clinical experience in 108 patients. J Urol 1993; 150:1612–1614 20. Shanberg A M, Lee I S, Tansey L A, Sawyer D E. Extensive neodymium-YAG photoirradiation of the prostate in men with obstructive prostatism. Urology 1994; 43:467–471 21. Malek R S, Barrett D M, Dilworth J P. Visual laser ablation of the prostate: a preliminary report. Mayo Foundation for Medical Education and Research 1995; 70:28 22. Segnor F, Gurdal M, Tekin A et al. Neodymium:YAG visual laser ablation of the prostate: 7 years of experience with 230 patients. J Urol 2002; 167:184–187 23. Corvin S, Schneede P, Siakavara et al. Interstitial laser coagulation combined with minimal transurethral resection of the prostate for the treatment of benign prostatic hyperplasia. J Endourol 2002; 16:387–390 24. Narayan P, Leidich R, Fournier G et al. Transurethral evaporation of prostate (TUEP) with Nd:YAG laser using a contact free beam technique: results in 61 patients with benign prostatic hyperplasia. Urology 1994; 43:813–820 25. Narayan P, Tewari A, Aboseif S et al. A randomized study comparing visual laser ablation and transurethral evaporation of prostate in the management of benign prostatic hyperplasia. J Urol 1995; 154:2083–2088 26. van Melick H H, van Venrooij G E, Eckhardt M D, Boon T A. A randomized controlled trial comparing transurethral resection of the prostate, contact laser prostatectomy and electrovaporization in men with benign prostatic hyperplasia: analysis of subjective changes, morbidity and mortality. J Urol 2003; 169: 1411–1416 27. van Melick H H, van Venrooij G E, Eckhardt M D, Boon T A. A randomized controlled trial comparing transurethral resection of the prostate, contact laser prostatectomy and electrovaporization in men with benign prostatic hyperplasia: urodynamic effects. J Urol 2002; 168:1058–1062 28. Malek R S, Barrett D M, Kuntzman R S. High-power potassium-titanyl-phosphate (KTP/532) laser vaporization prostatectomy: 24 hours later. Urology 1998; 51: 254–256 29. Shingleton W B, Terrell F, Renfroe L et al. Low-power vs high-power KTP laser: improved method of laser ablation of prostate. J Endourol 1999; 13:49–52 30. Shingleton W B, Farabaugh P, May W. Three-year followup of laser prostatectomy versus transurethral resection of the prostate in men with benign prostatic hyperplasia. Urology 2002; 60:305– 308 31. Hai M A, Malek R S. Photoselective vaporization of the prostate: initial experience with a new 80 W KTP laser for the treatment of benign prostatic hyperplasia. J Endourol 2003; 17:93–96 32. Gilling P J, Fracs, Kennet K et al. Holmium laser enucleation of the prostate (HoLEP) combined with transurethral tissue morcellation: an update on the early clinical experience.J Endourol 1998; 12:457– 459 33. Mackey M J, Chilton C P, Gilling P J et al. The results of holmium laser resection of the prostate. Br J Urol 1998; 81:518–519 34. Gilling P J, Cass C B, Malcolm A et al. Holmium laser resection of the prostate versus neodymium:yttrium-aluminum-garnet visual laser ablation of the prostate: a randomized prospective comparison of two techniques for laser prostatectomy. Urology 1998; 51:573–577 35. Tan A H, Gilling P J. Holmium laser prostatectomy: current techniques. Urology 2002; 60:152–156 36. Hurle R, Vavassori I, Piccinelli A et al. Holmium laser enucleation of the prostate combined with mechanical morcellation in 155 patients with benign prostatic hyperplasia. Urology 2002; 60:449–453 37. Kuntz R M, Lehrich K. Transurethral holmium laser enucleation versus transvesical open enucleation for prostate adenoma greater than 100 gm: a randomized prospective trial of 120 patients. J Urol 2002; 168:1465–1469 38. Hochreiter W W, Thalmann G N, Burkhard F C, Studer UE. Holmium laser enucleation of the prostate combined with electrocautery resection: the mushroom technique. J Urol 2002; 168:1470–1474

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Page 495 35 Transurethral needle ablation (TUNA) for treatment of benign prostatic hyperplasia C C Schulman A R Zlotta Introduction The need for simpler, less morbid, and alternative surgical therapies to transurethral resection of the prostate (TURP) has logically led to the emergence of minimally invasive therapies. Patients are usually eager to choose a treatment which will relieve their symptoms without significant side-effects. Medical therapy is becoming the first-line approach since most men want to avoid anesthesia, postprocedure catherization, hospitalization, and a prolonged convalescence. Since not all patients will subjectively experience symptomatic improvement with medical therapy and others are reluctant to take medications for a long period of time, minimally invasive therapies (among which thermal treatments play an important role) have gathered much interest over the last decade. All thermal treatments, whatever the form of energy they use, aim to achieve sufficient therapeutic temperatures (above 60ºC) in order to produce a necrosis of the prostatic tissue. It is now 10 years since the first evaluation of transurethral needle ablation of the prostate (TUNA) as a therapy for treatment of symptoms associated with benign prostatic hyperplasia (BPH). Low-level radiofrequency (RF) energy is delivered directly into the prostate, producing reproducible and localized controlled necrotic lesions.1–4 Because of the precision of RF delivery and the lesion created, this type of energy has logically been evaluated for the treatment of hypertrophic benign prostatic tissue.5

Figure 35.1 Tip of first-generation TUNA catheter with adjustable shields. The first edition of this textbook on BPH appeared at a time when clinical results obtained with this minimally invasive technique for BPH therapy were only preliminary. Several thousands of patients have now been treated worldwide. The treatment is FDA approved and reimbursed in numerous states in the USA and in various countries worldwide, from Europe to Asia. TUNA therapy is given to patients with symptomatic BPH. Part of the interest about TUNA is due to the fact that this procedure has been demonstrated to be safe and effective, and it can be performed in an outpatient setting without the need for spinal or general anesthesia. The TUNA system: radiofrequency energy principles The TUNA system consists of a special TUNA catheter which is connected to a low-level RF generator.5 Two independent needles are deployed within the prostatic tissue and the base of these needles may be covered by a protective teflon shield (Fig. 35.1). The generator produces a monopolar 460–490 kHz RF signal. This type of low-level RF allows greater penetration and a more uniform temperature distribution than do microwaves (300–3000 MHz).5 The current passes through the prostatic tissue in the direction of a grounding pad placed on the sacrum of the patient. Prostate cells resist the passage of the electrical current and, as a result, ionic or molecular agitation is produced and the collision of particles in accordance with the frequency of the generated wave of energy results in a central, periurethral hot core. The nature of the RF signal is such that it can only be applied into the tissue through direct contact and it has limited distance dissipation, which reinforces the safety of this wavelength (heat generated is directly proportional to 1/radius4). If the power is too high, it will cause rapid desiccation of the tissue and a rise in impedance and prevent the effects of the RF energy.5 The dimensions of the thermal lesion will correspond to the geometry of the active needles, to the time period during which the hot core is maintained and to tissue impedance.5–9 The tissular effects of RF and size of the lesions are extremely localized and very much dependent on the heat loss due to convection, i.e. vascularity.5 Indeed, RF is file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_495.html[09.07.2009 11:55:28]

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Page 496 extremely vulnerable to vascular flow and has virtually no effect on vessels larger than 2–3 mm in diameter.8 Animal and human ex vivo studies Prior to human treatment, Goldwasser et al.10 demonstrated that 1 cm necrotic lesions could be created in the dog prostate using the TUNA system with no resultant damage to the rectum, bladder base, or distal prostatic urethra. Similar lesions were observed in an ex vivo human prostate study by the same authors.11 Human pathologic studies: lesion extent Preliminary studies have assessed the tolerance, safety, and the extent of the lesions produced by TUNA. Patients have been treated with TUNA prior to a scheduled retropubic prostatectomy.5,6 Between 3 and 5 minutes of treatment per lesion were performed. Macroscopic examination of the surgical specimens recovered from 1 day to 3 months after TUNA demonstrated localized controlled necrotic lesions with sharp delineation with the untreated areas, maximal in size at 7 days post-treatment.5,6 The maximum lesion size ranged from 10×7 to 20×10 mm2. Specific immunohistochemical staining showed destruction of all tissue components. Absence of staining for prostate-specific antigen (PSA), smooth muscle actin, neural tissue, α-adrenergic and nitrinergic receptors was evident in the ablation area.5,6,9 On analyimens recovered 1–46 days after TUNA, no positively sis of histologic sections from 10 open prostatectomy specstained nerve cells (using S100 antibodies) were noted in the treated areas.6 Issa et al.9 reported that the nitric oxide synthase (NOS) receptors seemed to be the most vulnerable to thermal damage, whereas thermal damage to α-adrenergic receptors was more pronounced 1–2 weeks later.9 Temperatures achieved at the core of the lesion are close to 95–100ºC.7 Recently, using new catheters and fully automatic generators (Precision™ Plus), lesions can be produced in 3 minutes because of the permanent balance between power delivered and temperature in the tissue itself. The TUNA catheter and generators The TUNA catheter design has evolved over the last few years. However, the basic principles remain the same. The TUNA catheter is a specially designed cystoscopic instrument, plastic moulded and connected to the RF generator (Fig. 35.2). Two needles, which diverge with an angle of 40º between them, emerge perpendicularily to the bulletshaped catheter tip (Fig. 35.1). The specificities of this catheter and needle are the two protective Teflon shields that can be deployed independently in order to cover a certain amount of needle, thus protecting this area from thermal ablation. The flexible needles and covering shields can be advanced and retracted by moving calibrated controls on the catheter handle. Thermosensors at the end of the shield and on the tip of the catheter monitor prostatic and urethral temperatures during TUNA. An optical path within the catheter allows the introduction of a 0-degree fiber optic viewing system in order to position the catheter accurately within the prostate under

Figure 35.2 Precision™ Plus catheter and generator. RF, radiofrequency.

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Page 497 guidance similar to that used in a simple cystoscopic procedure. The design of TUNA catheters has been constantly envolving. The most recent version is the Precision Plus.12 In contrast to the previous versions of TUNA catheters, part of the device is now reusable. Optics have been improved, as they use usual 30º fiberoptics. The needles are now visible when they enter the prostatic tissue, which was not the case previously (Fig. 35.3). The procedure resembles any endoscopic therapy because the lesion can be introduced very accurately under direct vision. The generators which deliver RF energy are fully automatic, constantly adapting the power to the impedance of the tissue, thus preventing any ‘charring’ of the tissues and enabling smooth and very rapid constant rises in temperature (Fig. 35.2) Temperatures above 100ºC are obtained in 60 seconds and maintained for 3 minutes duration. Studies have demonstrated lesions of similar size whether treatment was given during 3 or 4 minutes.12 A major feature of TUNA: the preservation of the prostatic urethra The preservation of the prostatic urethra is a major feature of the TUNA treatment. Indeed, destruction of the urethral mucosa can be the source of significant postoperative voiding symptoms, as well as increasing the retention rate after thermal treatments. Clear differences in the distribution of nerve endings within the prostate are usually observed.6,9 A higher density of innervation in the connective stromal parts of the prostate has been demonstrated, just under the prostatic urethral mucosa, under the capsule, and around the prostatic hypertrophic nodules. A limited number of nerve endings are seen in the glandular areas of the prostate. Overall, the nerve density of the adenomatous gland is clearly decreased. Therefore, since very few nerve endings are present in the deepest part of the transition zone, the rapid destruction of the submucosal nerve endings with the preservation of those located 2–3 mm beneath the urothelium may serve to explain the absence of even moderate discomfort experienced by patients during the TUNA treatment without spinal or general anesthesia. Preoperative evaluation Transrectal ultrasound and cystoscopy are helpful prior to TUNA therapy. Transrectal ultrasound, in addition to its role in diagnosis and evaluation of BPH, is used to plan

Figure 35.3 Endoscopic view of the needle placements with the ProVu catheter. Needles are now visible at endoscopy. Note that no part of the needle is uncovered.

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Figure 35.4 TUNA lesion on microscopic examination (arrows). Note the clear delineation with untreated prostate (H and E×40). the needle deployment extent. Indeed, as anatomo-pathologic studies have demonstrated that lesions may extend up to 6 mm beyond the deployed needle (Fig. 35.4), measurements of the transverse diameter of the prostate (in the base, mid-prostate, and apex) are mandatory in order to avoid necrosis of undesired areas. TUNA treatment13–17 (Figs. 35.5–35.7) Most urologists perform the procedure as a minimally invasive therapy. TUNA treatment is performed like a usual cystoscopy with 2% intraurethral local xylocaine anesthesia, which can be supplemented with intravenous sedation if necessary. We leave a penile clamp for 10 minutes. Similarly to the procedure for simple prostate biopsies, we use a periprostatic anesthesia under ultrasound

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Figure 35.5 TUNA procedure: (1) advancement of TUNA catheter into prostatic urethra.

Figure 35.6 TUNA procedure: (2) TUNA catheter is positioned 1 cm under the bladder neck for treatment of the first lesion. The shaft of the catheter is rotated toward the lateral lobe and needles are deployed.

Figure 35.7 TUNA procedure: (3) four lesions have been completed. control (lidocaine-marcaine mixture). In our experience and in many other centers, no general or spinal anesthesia is required for TUNA treatment and it can be performed as an outpatient procedure. The TUNA catheter is advanced and positioned in the prostate using direct fiber-optic vision (Fig. 35.5). The length of the needle deployed within the prostate is calculated on the basis of the ultrasound measurement of the prostate. Therefore the needle should not be deployed more than 5–6 mm less than half the diameter of the prostate. At the same time, shields are deployed inside the prostate, thus protecting the prostatic urothelium (Fig. 35.3). file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_498.html[09.07.2009 11:55:30]

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When both needles are adequately positioned in the prostate, RF energy is delivered for 3 minutes per lesion using the Precision system. The number of lesions depends on the size of the prostate. One pair of lesions (because there are two needles) is usually performed per 20 g of prostate. Of note, bladder emptying is sometimes necessary after several lesions have been performed as irrigation is used. Depending on how much irrigant has been introduced in the bladder, the bladder should be emptied periodically to prevent overdistension. Patients very rarely complain about pain due to heat, but often note urgency or desire to void. This usually occurs where the first lesion is performed close to the bladder neck. For lesions created deep in the mid portions of the transition zone of the prostate, patients almost never note any discomfort at all. After the procedure, hyperhemic areas where needles were introduced are often visible endoscopically. No catheter is left in situ at the end of the procedure. Once patients have voided, they are allowed to return home with a few days of anti-inflammatory agents associated with antibiotics. Clinical results Several prospective studies including randomized studies comparing TUNA and transurethral resection of the prostate have demonstrated the efficacy of the TUNA procedure in terms of improvement in subjective and objective parameters. The major common problem with all new minimally invasive therapies for BPH has been the lack of long-term data concerning efficacy, re-intervention rates, and side-effects, but results are now available for TUNA with follow-up of >5 years. Early published results in 20 patients with a 6-month follow-up showed that TUNA was a promising, anesthesia-free alternative treatment, with clear improvements in peak flow rate and in both international prostate symptom

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Page 499 score and quality of life at 6-month follow-up.18 The initial US clinical trial on 12 patients confirmed a 70% improvement in both peak flow rate and quality of life, with maximum detrusor pressure and detrusor opening pressure decreasing significantly.19 Since these early results, numerous groups have reported long-term data with follow-up up to 5 and 6 years (Table 35.1).12,20,28 The 12-month results of a prospective multicenter American study including 130 patients demonstrated that the American Urological Association (AUA) symptom score decreased from 23.7 to 11.9 points, whereas the peak flow rate improved from 8.7 ml/s at baseline to 14.6 ml/s at 1 year.22 The majority of patients had an improvement in both AUA symptom index and flow rate. For instance, approximately 50% of patients at 6 and 12 months experienced an improvement of 4 ml/s or more, 30% experienced improvements of 6 ml/s or more, while 20% had increases of more than 8 ml/s (Table 35.1). In the University of Florida experience, in 45 patients following TUNA treatment the International Prostate Symptom Score (I-PSS) decreased from a mean of 20.9 at baseline to 9.9 at 1 year and the peak flow rate improved from a baseline mean of 8.3 to 14.9 at 1 year.29 Of the two patients in whom the procedure failed, one required a bladder neck incision at 3 months and the other a transurethral resection of the prostate (TURP). The prospective multicenter collaborative study including 76 patients from seven different centers in Europe and Israel demonstrated that TUNA produced significant improvements in the I-PSS, urinary flow rate, and quality of life at 1-year follow-up.23 A large-scale prospective randomized American study has compared TUNA with TURP for treatment of BPH.24 Fifty-six men were treated with TURP and 65 were treated with TUNA. In this trial, in terms of AUA symptom score and quality of life, TUNA was equal to TURP In terms of adverse events, TUNA was much superior to TURP In terms of peak urinary flow rate and postvoid residual volume (PVR), TURP was superior to TUNA, with peak urinary flow rates at 12 months of 20.8 ml in the TURP group against 15.0 ml in the TUNA group Table 35.1 Recent TUNA clinical results. Study group No of patients at Follow-up Symptom Peak flow follow-up (months) score rate (ml/s) Baseline Post- Baseline PostTUNA TUNA Issa19 (US pilot study) 12 6 25.6 9.8 7.8 13.5 Bruskewitz et al.24 (US randomized study) 65 12 24.7 11.1 8.7 15 Roehrborn et al.22 (US Prospective 93/130 12 23.7 11.9 8.7 14.6 multicenter study) Steel and Sleep20 38/60 24 22.4 9.5 6.6 11.0 Campo et al.21 72/120 12 20.8 6.2 8.2 15.9   42/120 18 20.8 6.7 8.2 14.1 Rosario et al.25 58/71 12 23.0 10.6 9.0 11.3 Ramon et al.23 (European multicenter study 60/76 12 22.0 7.5 8.7 11.6 Giannakopoulos al.27 50 12 −22.4 9.1 7.6 16.8 Chandrasekar et al.33 76 84 19.1 11.9 7.5 9.6 Bergamaschi et al.26 (Nonrandomised 36 12 16.7 5.1 12.9 16.1 prospective study TUNA vs TURP) Kahn et al.29 45 12 15.4 9.9 8.3 14.9 Zlotta et al.32 131/188 60 20.9 8.7 8.6 12.1 Hill et al.30 58/111 36 24.0 14.0 9.2 14.0   131/188 60 24.0 11.0 9.2 11.7

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Page 500 (both groups had mean pretreatment uroflow values of 8.8 ml/s, Fig. 35.8). A randomized trail compared TUNA with TURP with 18-month follow-up data in 59 patients. Improvements in Q max, PVR, I-PSS, and quality of life score were statistically significant for both groups at 18 months’ follow-up. The increase in the mean Q max of the TURP group was higher than that observed in the TUNA group, whereas no significant differences were found in the two groups regarding improvements in I-PSS and quality of life scores. A nonrandomized prospective study in Italy comparing TUNA with TURP26 has shown results similar to the American study. Most series confirm that 70–80% of the patients are objectively and subjectively improved (Table 35.1). Steele and Sleep20 showed, in 47 patients included prospectively, that TUNA produced sustained subjective and objective improvements, which included 2-year follow-up with pressure-flow studies. With an 18-month follow-up, Campo et al.21 reported similar findings. At 3-year follow-up, the improvement in flow was maintained as compared to 1-year follow-up.28 It seems that the type and selection of patients are important since TUNA appears to be very effective in patients with mild to moderate obstruction,21 while it has been shown that in patients with more severe obstruction results after TUNA may be less satisfactory.25 When pressure-flow studies are analyzed, several reports have shown that maximum detrusor pressure and detrusor opening pressure decreased significantly after TUNA (Table 35.2). Following TUNA, the number of patients with complete removal of obstruction, by urodynamic criteria, may vary, but seems to average 50%.21,25,26 Five-year data are available from a three-center study on the long-term evaluation of TUNA of the prostate. One hundred and eighty-eight consecutive patients with symptomatic BPH were treated using older versions of TUNA catheters. As shown in Table 35.1, TUNA was found to be effective and provided good long-term clinical improvements at 5-year follow-up with data available in 131/188 patients and 41 others who required additional treatment following the original TUNA procedure.32 Seven-year results from 152 patients enroled in a prospective study comparing TUNA and TURP also found that improvements observed were sustained over time.33 TUNA treatment for patients in retention Several studies have demonstrated that TUNA is effective in relieving patients in urinary retention due to BPH and seems particularly suitable for treating higher-risk surgical patients.34 On analysis of 38 patients in urinary retention with a poor surgical risk who were treated with TUNA, nearly 80% resumed voiding, with a mean of 8.7 days after the procedure. Complications were minimal and none of the patients developed any further retention during follow-up. In a comparable group of patients, Millard et al. reported a 75% (17/20) success rate after TUNA.31,35

Figure 35.8 Evolution in symptom score (SS), quality of life (QL), and uroflow (Qmax) in the prospective randomized US study comparing transurethral needle ablation (TUNA) vs transurethral resection of the prostate (TURP).24 pretx, pretreatment; FU, follow-up.

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Mean detrusor pressure (cmH2O)/maximum flow rate Baseline Post-TUNA 6 91.8 70.9

Issa19 (US pilot 9 study) Steele and Sleep20 41/60 1 92.4 77.0   34/60 6 92.4 54.8   29/60 12 92.4 72.9   12/60 24 92.4 58.9 Campo et al.21 86/120 6 85.3 61.3   72/120 12 85.3 63.7   42/120 18 85.3 67.8 Rosario et al.25 70/71 3 97.0 79.0   45/71 12 97.0 82.0 Millard et al.31 11/20 6 70.7 59.9 Roehrborn et al.42 121 6 78.7 64.5 Therefore, TUNA seems to be particularly suitable for treating patients in urinary retention who are at greater risk during surgery. TUNA treatment for patients with nonbacterial prostatitis In a very limited number of patients and with a very short follow-up period, Chiang et al.36 suggested that TUNA could be used to improve patients with nonbacterial prostatitis. Lee et al.37 investigated the role of TUNA in chronic nonbacterial prostatitis in 42 patients. All patients had high leukocyte counts in expressed prostatic secretions (EPS). Mean symptom and satisfaction scores improved significantly 3 months after TUNA and 71% had normal EPS within 3 months of TUNA. The effects of TUNA on symptoms of chronic pelvic pain syndrome were evaluated in Finland in a prospective study with a sham therapy arm.38 TUNA relieved symptoms for at least 12 months but, due to small numbers, the results failed to be statistically significant. In contrast, another randomized and sham-controlled study failed to demonstrate a benefit for the treatment of chronic pelvic pain syndrome (category III prostatitis),39 In 39 patients, in whom all previous therapies had failed, Giannakopoulos et al. demonstrated that over 80% had an improvement in quality of life and prostatic symptom score which was sustained at 3 years. Adverse events with TUNA Adverse events, if any, usually occur early in the postoperative course. Indeed, most series have pointed out the very low rate of late adverse events. As demonstrated in the randomized US study comparing TUNA with TURP, TUNA is associated with far fewer adverse events than endoscopic resection (Fig 35.9). From morbidity reports: • A urinary retention observed in 13.3–41.6% of cases.7,14,17,22,24,29 Most series report rates around this retention is transient (1–3 days) in the majority of patients and rarely lasts more than 1 week. It is usually easily treated by suprapubic tube or by urethral catheterization for a few days. Some centers have also used intermittent catheterization for a few days. • Mild hematuria is noted in most patients for 2 days, but never requires any transfusion. Patients with significant coagulopathy may eventually experience more pronounced hematuria and should be counseled preoperatively. Rosario et al. reported no problem with bleeding in patients on warfarin at the time of the TUNA.25 • Irritative voiding symptoms, dysuria, and increase urinary frequency may develop a few days after treatment and are usually treated with antiinflammatory agents.

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Figure 35.9 Comparison of adverse events in the prospective randomized US study comparing transurethral needle ablation (TUNA) vs transurethral resection of the prostate (TURP).24 Erectile dysfunction, retrograde ejaculation, incontinence of any type, urinary infection, and need for postoperative catheterization are indicated as percentages in both arms of the randomized study. • Urinary infection and epididymitis are very rare (<1%). • Sexual dysfunction is minimal. Whereas most series found no retrograde ejaculation nor impotence at all after TUNA, the prospective multicenter US trial found less than 1% and 2% of retrograde ejaculation and impotence, respectively.22 • Urethral strictures have been described in less than 1% of the cases.18,20,21,22,24 • No urinary incontinence has ever been reported. Reoperation rate Reoperation rates appear to be low, as reported to date. Steele and Sleep noted a 12.7% reoperation rate in 47 patients followed at 2 years.20 Out of 45 patients at 1 year, Kahn et al. reported that two men underwent additional surgical procedures and were considered to be failures.29 According to Zlotta et al.,12 11.1% of patients treated by TUNA in their series have been operated for absence of clinical improvement with a 5-year follow-up. In the multicenter collaborative study in Europe and Israel, out of 76 patients there were nine failures (11.8%) as assessed by the Q max, eight of whom reported no symptomatic improvement and only five of whom reported no improvement in quality of life.23 Obviously, longer follow-up data are still needed to evaluate the exact reoperation rate over a long-term follow-up period. Long-term effects and retreatment rates The lack of long-term data on re-intervention rates has always been a drawback for the widespread use of minimally invasive therapies for BPH. In the three-center study with a follow-up of 5 years, in 188 patients, medical therapy was given to 12 patients (6.4%), a second TUNA was performed in seven patients (3.7%), and surgery was indicated in 22 (11.1%).32 Overall, 23.3% of patients (less than a quarter) required additional treatment at 5 years’ follow-up following the original TUNA procedure. In 152 patients, Chaudasekai et al. found a failure rate of 3.9% in the first year, 2.6% in the second year, 2.65 in the third, fourth and fifth years, and no failures at 6 and 7 years.33 In the TURP group, 1.3% required re-resection at 2 years. The cumulative failure rate during the 7-year follow-up was 19.7%. Indications and limitations of TUNA treatment Patients with very large prostate glands (over 100 g) or with a large median lobe or isolated bladder neck hypertrophy are not the best candidates for TUNA treatment, but may be treated. As noted by Naslund,13 the ideal patient for the TUNA procedure is a man with obstructive BPH who has a prostate gland of 60 g or less with predominantly lateral

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Page 503 lobe enlargement. For large glands, the same author reported his limited experience with prostates up to 140 g. Successful treatment could be achieved provided that treatment was performed at 1-cm intervals in each lateral lobe (therefore up to seven treatments per lobe were necessary in some cases). For median lobes, treatments have already been performed both by manipulating the TUNA catheter so that the needles point out inferiorly, taking care to measure the height of the median tissue to be treated, and entering the mid portion of the median lobe. TUNA for patients with large prostates and median lobes Although initially TUNA was not designed to treat large prostates and median lobes, a report from Canada demonstrated that this therapy is feasible and effective. In 10 patients with bilobar hyperplasia, but without large median lobes (prostate size 7 g), all but two patients were significantly improved at 1year follow-up.40 Possible mechanisms of action of transurethral needle ablation of the prostate on BPH symptoms Analysis of histologic sections from 10 open prostatectomy specimens recovered after TUNA has clearly demonstrated that severe thermal damage was caused by TUNA to the intraprostatic nerve fibers in treated area.6,9 The nitric oxide synthase (NOS) receptors seemed to be the most vulnerable to thermal damage following the TUNA treatment, as was evident by the complete lack of immunohistochemical staining within the first few hours after TUNA.9 Possible impairment of the α-receptor fraction and/or sensory nerves could explain the clinical effects of TUNA. Furthermore, the distribution of the intraprostatic nerves may explain the excellent tolerance of this procedure under local anesthesia only. Tissue ablation from necrosis probably accounts for some of the clinical improvements observed after TUNA as well. Several groups have demonstrated the absence of a significant decrease in prostate size after TUNA.5,14,17,18,19,24 There is little evidence of prostatic cavitation on transrectal ultrasound after TUNA (Fig. 35.10). Follow-up cystoscopy after the TUNA procedure shows scarring or prostatic defects, or lateral lobe retraction in fewer than half of the patients. In many cases, no specific prostate defects are noted.6,13 The combination of the destruction of intraprostatic nerves with a moderate decrease in the transition zone volume of the prostate may possibly explain in part the observed clinical efficacy of TUNA. New data regard-

Figure 35.10 Transrectal ultrasonography after TUNA (2 weeks). Note the hypoechoic lesion (white arrow). ing the lesions produced have been reported for the new Precision catheters.12 Costs Comparisons of cost estimates of TUNA versus TURP have been addressed in two different studies: one from the United States and another from the United Kingdom. In a study by Naslund and Stitcher, the cost estimate for TUNA reached $3378 while in Maryland in 1995 TURP averaged $5767.41 Most of the costs with TURP were related to the hospital stay, while on the other hand, the disposable catheter was responsible for a major part of the TUNA costs. However, hospital charges are sometimes difficult to file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_503.html[09.07.2009 11:55:32]

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obtain and to analyze. Without referring to long-term complications, TUNA appears to be less costly than TURP. In a published economic evaluation of TUNA versus TURP and drug therapy by Quintiles Medical Technology Consultancy in the UK, analyzing reimbursement and price from a purchaser’s perspective when comparing TUNA versus TURP, total management costs for patients reached £970.38 for TUNA versus £1372 for TURP. However, logically, the longer the hospital stay for TURP, the higher the price associated with it. Indeed, from a provider’s perspective, if a 3-day stay for TURP costs £1220, it may reach £1594 for 5 days for TURP. Again, most of the costs with TUNA came from the disposable catheter, while most of the costs associated with TURP came from the hospital stay. The second study

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Page 504 performed in the UK compared the costs of various drug therapies including prazosin, terazosin, alfuzosin, tamsulosin, and finasteride (data not shown). For the TUNA procedure, the study provided a direct comparison assuming that both treatment modalities are equally effective, but ignoring drug treatment failure and reoperation rates. With an annual average cost of TUNA of £800, after 2 years, most medical treatments reached a higher cost than the price for TUNA. Again, this should be considered from the perspective that no reoperation rates have been taken into account and that the effectiveness of the treatment was not evaluated. In conclusion, at the present time, it appears that TUNA is more cost effective than TURP and drugs. However, we must wait for the long-term results (especially the reoperation rates) in order to draw definitive conclusions on the final cost estimates of the transurethral needle ablation of the prostate. Conclusions Transurethral needle ablation of the prostate, a relatively new, minimally invasive treatment modality for BPH, approved by the FDA for treatment in the United States, has undergone extensive evaluation by numerous investigators worldwide. The results to date indicate that needle ablation is safe and effective for relieving symptoms in patients with BPH and the effect has been demonstrated to be durable for at least 5 years. TUNA clearly might fill the gap between medical and surgical therapies for BPH. As with all other minimally invasive therapies, it is important not to take into account end results only, but also to consider the advantages of such therapies which may not necessarily reach the same efficacy as TURP There is a place for such therapies, because not all patients need an operation and many patients do not want one. Since this procedure can be performed in the typical office setting and adverse events are negligible, it does not have to be equivalent to TURP to find an important role as secondary therapy for medical failures or primary therapy for symptomatic BPH. TUNA seems to be both patient- and operator-friendly, since it is an outpatient procedure, does not require anesthesia and provides a clear symptomatic and objective improvement in BPH symptoms in the majority of cases. In addition, TUNA is much less morbid than TURP and could be performed at a lower cost (if reoperation rates remain low in the long term). Finally, for elderly patients with a high surgical risk, especially for urinary retention, TUNA could become the treatment of choice. Nevertheless, additional investigations with longer follow-up data are needed to address the important issues of extended durability (5–10 years) and biophysiologic mechanism of action, in order to establish this therapy definitively in the urologist’s armamentarium. If the newer, less invasive treatment modalities provide stable, long-term results at competitive costs, they will be tempting alternatives to prostate resections and may also challenge medical therapy. As always, time will tell… References 1. Calkins H, Langberg J, Sousa J et al. Radiofrequency catheter ablation of accessory atrioventricular connections in 250 patients. Circulation 1992; 85:1337–1346 2. Rossi S, Di Stasi M, Buscarini E et al. Percutaneous radiofrequency interstitial thermal ablation in the treatment of small hepatocellular carcinoma. Cancer J Sci Am 1995; 1:73–81 3. Zlotta A R, Kiss R, De Decker R, Schulman C C. MXT mammary tumor treatment with a high temperature radiofrequency ablation device. Int J Oncol 1995; 7: 863–869 4. Lord S M, Barnsley L, Wahis B J et al. Percutaneous radiofrequency neurotomy for chronic cervical zygapophyseal-joint pain. N Eng J Med 1996; 336:1721–1726 5. Schulman C C, Zlotta A R, Rasor J S et al. Transurethral needle ablation (TUNA): safety, feasibility and tolerance of a new office procedure for treatment of benign prostatic hyperplasia. Eur Urol 1993; 24:415 6. Zlotta A R, Raviv G, Peny M O et al. Possible mechanisms of action of transurethral needle ablation of the prostate on benign prostatic hyperplasia symptoms: a neurohistochemical study. J Urol 1997; 157:894–899 7. Schulman C C, Zlotta A R. Transurethral needle ablation of the prostate (TUNA): pathological, radiological and clinical study of a new office procedure for treatment of benign prostatic hyperplasia using low-level radiofrequency energy. Semin Urol 1994; 13:205 8. Organ L W. Electrophysiologic principles of radiofrequency lesion making. Appl Neurophysiol 1976; 39:69–76 9. Issa M M, Wojno K J, Oesterling J E et al. Histopathologic and biochemical study of the prostate following transurethral needle ablation (TUNA): insight into the mechanism of improvement in BPH symptoms. J Endourol 1996; 10:109 10. Goldwasser B, Ramon J, Engelberg S et al. Transurethral needle ablation (TUNA) of the prostate using low-level radiofrequency energy: an animal experimental study. Eur Urol 1993; 24:400 11. Ramon J, Goldwasser B, Stenfeld B et al. Needle ablation using radiofrequency current as a file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_504.html[09.07.2009 11:55:33]

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Page 505 prostatic hyperplasia: experimental results in ex vivo human prostate. Eur Urol 1993; 24:406–410 12. Zlotta A R, Vanden Bossche M, Petin M et al. Analysis of intraprostatic lesions induced by a new generation of TUNA generator and catheter: an histological study using NADPH. J Endourol 2001; 15 (Suppl): A90 (abstract C5-P6) 13. Naslund M J. Transurethral needle ablation of the prostate. Urology 1997; 50:167–172 14. Schulman C C, Zlotta A R. Transurethral needle ablation of the prostate: a new treatment of benign prostatic hyperplasia using interstitial low-level radiofrequency energy. Curr Opin Urol 1995; 5:35 15. Heaton J P W. Radiofrequency thermal ablation of the prostate: the TUNA technique. Tech Urol 1995; 1:3 16. Dixon C M. Transurethral needle ablation for the treatment of benign prostatic hyperplasia. Urol Clin North Am 1995; 22:441 17. Issa M M, Oesterling J E. Transurethral needle ablation (TUNA™): an overview of radiofrequency thermal therapy for the treatment of benign prostatic hyperplasia. Curr Opin Urol 1996; 6:20–27 18. Schulman C C, Zlotta A R. Transurethral needle ablation of the prostate for treatment of benign prostatic hyperplasia: early clinical experience. Urology 1995; 45:8 19. Issa M M. Transurethral needle ablation of the prostate: report of initial United States clinical trial. J Urol 1996; 156:413–419 20. Steele G S, Sleep D J. Transurethral needle ablation of the prostate: a urodynamic based study with 2-year follow-up. J Urol 1997; 158:1834–1838 21. Campo B, Bergamaschi F, Corrada P, Ordesi G. Transurethral needle ablation (TUNA) of the prostate: a clinical and urodynamic evaluation. Urology 1997; 49: 847–850 22. Roehrborn C G, Issa M M, Bruskewitz R C et al. Transurethral needle ablation for benign prostatic hyperplasia: 12-month results of a prospective, multicenter US study. Urology 1998; 51:415–421 23. Ramon J, Lynch T H, Eardley I et al. Transurethral needle ablation of the prostate for the treatment of benign prostatic hyperplasia: a collaborative multicentre study. Br J Urol 1997; 80:128–135 24. Bruskewitz R, Issa M M, Roehrborn C G et al. A prospective, randomized 1-year clinical trial comparing transurethral needle ablation to transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia. J Urol 1998; 159:1588–1594 25. Rosario D J, Woo H, Potts K L et al. Safety and efficacy of transurethral needle ablation of the prostate for symptomatic outlet obstruction. Br J Urol 1997; 80:579–586 26. Bergamaschi F, Campo B, Ordesi G, Torelli T. Prospective non-randomized study of TUNA® vs TURP for patients with BPH demonstrating moderately high detrusor pressures and elevated symptom score. Eur Urol 1996; 30 (Suppl): A984 27. Giannakopoulos X, Grammeniatis E, Gartzios A, Pappas G. Transurethral needle ablation (TUNA®) of the prostate: preliminary results using the new generation TUNA® III catheter on patients with symptomatic BPH controlled by a series of 50 patients using the TUNA® II device. Eur Urol 1996; 30 (Suppl): A986 28. Virdi J, Pandit A, Sriram R. Transurethral needle ablation of the prostate (TUNA®). A prospective study, three year follow-up. Eur Urol 1998; 33 (Suppl): A9 29. Kahn S A, Alphonse P, Tewari A, Narayan P. An open study on the efficacy and safety of transurethral needle ablation of the prostate in treating symptomatic benign prostatic hyperplasia: the University of Florida experience. J Urol 1998; 160:1695–1700 30. Hill B, Belville W, Arbor A et al. Five year results of prospective randomized trial comparing transurethral needle ablation (TUNA) to TURP for treatment of symptomatic BPH. J Urol 2003; 167:294 (abstract 1161) 31. Millard R J, Harewood L M, Tamaddou K. A study of the efficacy and safety of transurethral needle ablation (TUNA) for benign prostatic hyperplasia. Neurol Urodyn 1996; 15:916–929 32. Zlotta A R, Giannakopoulos X, Maehlum O et al. Long-term evaluation of transurethral needle ablation of the prostate (TUNA) for treatment of symptomatic benign prostatic hyperplasia: clinical outcome up to five years from three centers. Eur Urol 2003; 44:89–93 33. Chandrasekar P, Virdi J S, Kapasi F. Transurethral needle ablation of the prostate (TUNA) in the treatment of benign prostatic hyperplasia: a prospective, randomised study, long term results. J Urol 2003; 169:468 (abstract 1754) 34. Zlotta A R, Peny M -O, Matos C, Schulman C C. Transurethral needle ablation of the prostate: clinical experience in patients in urinary retention. Br J Urol 1996; 77:391 35. Harewood L, Cleeve L K, O’Connel H E et al. Transurethral needle ablation of the prostate (TUNA): file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_505.html[09.07.2009 11:55:33]

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clinical results and ultrasound, endoscopic, and histologic findings in pilot study of patients in urinary retention. J Endourol 1995; 9:407–412 36. Chiang P H, Tsai E M, Chiang C P. Pilot study of transurethral needle ablation (TUNA) in treatment of nonbacterial prostatitis. J Endourol 1997; 11:367–370 37. Lee K C, Jung P B, Park H S et al. Transurethral needle ablation for chronic nonbacterial prostatis. BJU Int 2002; 89:226–229

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Page 506 38. Altomaa S, Ala-Opas N. The effect of transurethral needle ablation on symptoms of chronic pelvic pain syndrome—a pilot study. Scand J Urol Nephrol 2001; 35: 127–131 39. Leskinen M J, Kreponen A, Lukkarinen O, Tammela T L. Transurethral needle ablation for the treatment of chronic pelvic pain syndrome (category III prostatitis): a randomized, sham-controlled study. Urology 2002; 60: 300–304 40. Sulivan L O, Paterson R F, Gleave M E et al. Early experience with transurethral needle ablation of large prostates. Cancer J Urol 1999; 6:688 41. Naslund M, Stitcher M F. A cost comparison of TUNA vs TURP. J Urol 1997; 157: A610 42. Roehrborn C G, Buskhard F C, Bruskewitz R C et al. The effects of transurethral needle ablation and resection of the prostate on pressure flow urodynamic parameters: analysis of the United States randomized study. J Urol 1999; 162:92–97 43. Minardi D, Garofalo F, Yehia et al. Pressure-flow studies in men with benign prostatic hypertrophy before and after treatment with transurethral needle ablation. Urol Int 2001; 66:89–93 44. Giannakopoulos X, Entezari K, Schulman C et al. Transurethral needle ablation for chronic non bacterial prostatitis: a 3-year follow-up study. Eur Urol 2004; 2 (Suppl 3): 205 (abstract 808)

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Page 507 36 Interstitial laser therapy for benign prostatic hyperplasia T McNicholas Introduction Laser techniques for benign prostatic hyperplasia (BPH) have emerged as the main challenge to the ‘gold standard’ of TURP. This article reviews the interstitial methods of applying laser energy for BPH treatment. Primarily this means the use of laser light as a means of transferring energy into the prostate where it will have either a thermal or a photochemical effect. Reports of the therapeutic use of heat date back to ancient Egypt (circa 1700 BC).1 When tissue is heated to a temperature range of 41–45ºC there is some degree of selectivity of the effect on normal and malignant tissues, with the latter being somewhat more sensitive. Above 50ºC (and probably above 45ºC) this selectivity is lost, with an equal thermal effect and irreversible cellular damage occurring in normal and malignant tissue. At temperatures at or above 60ºC coagulation necrosis occurs with sloughing or reabsorption of necrotic tissue later. At 100ºC vaporization occurs with acute disruption of tissue due to steam formation. Higher temperatures are associated with tissue burning and carbonization and a degree of immediate surface tissue removal may be seen endoscopically. Currently, research effort is being devoted to the destruction of BPH by three laser techniques. Two are predominantly thermal and the third invokes a photochemical process. All are delivered to the target tissues by the same fiber-optic mechanisms: • Photodynamic therapy (PDT) by endoscopic and interstitial methods; • Endoscopic laser coagulation (ELC); • Interstitial laser coagulation (ILC). Photodynamic therapy PDT involves the use of lasers to produce pure light wavelengths chosen to activate previously administered photosensitizing agents to cause cell injury by a nonthermal mechanism. Ideally, the photosensitizing drug is taken up or retained to a greater degree by the target tissue than by other tissues. The precise mechanism by which cells are killed is unclear, but probably involves the liberation of oxygen radicals and toxic effects on small blood vessels.2 PDT research has largely been directed at malignant disease, but attention has since turned to BPH.3 However, it is clearly much too early to predict whether there will be any role for PDT in BPH, although experiments are approaching clinical application. Endoscopic laser coagulation The neodynium: yttrium aluminum garnet (Nd:YAG) laser beam can be directed at high intensity at the bulging prostatic adenoma under direct vision to perform Visual laser ablation of the prostate’ (VLAP) by three methods: • Bare fiber method; • Transurethral endoscopic fiber with a specialized ‘tip’; • Transurethral endoscopic fiber with various beam deflecting devices alone or contained within a transurethral balloon. The development of right-angle beam delivery devices4 and laser balloon devices5 has both increased the efficiency of laser transmission into the prostate and improved transurethral access to all areas of the prostate, and greatly extended the role of endoscopic laser coagulation for BPH. Certainly the current devices improve maneuverability of the beam within the prostatic urethra and reduce the risk of tissue debris becoming stuck to the fiber, although generally the operator must still keep the laser ‘window’ free from adherent debris. High total energies can be more readily and easily applied by these devices than by bare fiber methods. The laser energy is applied to the walls of the prostatic cavity either by a continuous passage of the beam over the surface or by firing the laser at 40–60W for 30–60s at a series of points (usually 5–10 mm apart) so that the laser coagulative effects at each spot will overlap. Laser prostatectomy by these methods appears safe and quick and has gained general acceptance as an alternative, relatively nonmorbid treatment option for men with bladder outlet obstruction (BOO) due to BPH. However problems remain: • Apical tissue is relatively spared in order to avoid sphincteric injury and may cause a degree of residual obstruction.

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Page 508 • There is often a slow response, during which time there are considerable obstructive symptoms and it may take up to 3 months or more for full benefit to occur. • VLAP appeals to the urologist as the application of laser effect appears to be under endoscopic control, but once within the prostate the process is largely invisible. • These laser processes are less predictable in terms of tissue effect compared to TURP • Once laser light strikes the prostatic urethral lining it will undergo variable degrees of reflection, absorption, scattering, and transmission, with the result that the process is relatively uncontrolled. • Symptoms of bladder irritability are often severe and may relate to the prolonged presence of necrotic prostatic tissue within the prostatic urethra in contact with the urinary stream. • Large adenomas are more difficult to treat by VLAP and the response is slower and less complete. However, since a mass of adenoma within the prostate can be seen endoscopically, imaged ultrasonically, and reached by a needle, ‘interstitial’ therapy, i.e. the insertion of the chosen laser energy delivery source directly into the tissue to be treated, offers the possibility of controlled deep tissue heating and has been shown to significantly reduce symptoms of BPH.6,7 Temperatures well above 45ºC are achievable, allowing short treatment durations and local’ ized tissue destruction whilst preserving the prostatic urethral lumen. Intraprostatic necrotic tissue is separated from the urinary stream and is resorbed by the normal process of tissue repair. For these reasons, the use of interstitially delivered laser energy via a small-caliber fiber placed into the target tissue has attracted attention. Interstitial laser coagulation of the prostate Rather than endoscopically shining light at the prostate and accepting energy and efficiency losses by reflection and into the irrigant, it may be more efficient to stick a fiber into the prostatic tissue target and heat it up directly, thereby obviating any energy loss. ILC is the interstitial application of laser energy, endoscopically or percutaneously, using a ‘bare’ or modified fiber to achieve tissue coagulation by a thermal process. The advantage of the interstitial laser technique is that only relatively low-power Nd: YAG or diode laser light (2–10W) is needed to cause localized coagulative necrosis of prostate since all the laser energy is available for scattering and absorption and little is lost by reflection or transmission. This energy is easily placed into the tissue either transurethrally, transrectally, or percutaneously, through a small, relatively atraumatic fiber. Several groups have subsequently investigated whether sources of laser light can be placed within the prostate gland to cause precise, controlled necrosis of a size that might be useful for the treatment of BPH. Initial work involved the transrectal or transperineal approach, but most interest now focuses on the transurethral approach to ILC, with the fiber system chosen being delivered to the prostatic urethra through a cytoscope and then being inserted through the prostatic urethral mucosal wall into the adenoma (Fig. 36.1). Essentially, the laser energy can be introduced into prostatic tissue by the following method: • A simple bare fiber. This is cheap and easily repairable, but the fiber cladding may not resist the very high intraprostatic temperatures that may develop, leading to the cladding burning and damaging the fiber and leading to breakage of the silica glass fiber itself within the prostate. The fiber and tissue heating effects are readily visible by transrectal ultrasound (TRUS). • A more complex fiber with a distal ‘diffuser tip’ attached. This acts to diffuse the emitted laser light over a relatively large surface area, to prevent excessive heat build-up on the tip surface. There is a mechanical ‘weak point’ at the junction of the fiber and diffusor tip that may be prone to failure. The fiber may be inserted into the prostate within a protective outer plastic sheath and is ultrasound visible, but as yet no real-time ultrasound-visible tissue heating changes have been described. Diffusor fibers have been made by several laser device manufacturers, but many of the recent study data available relate to the Indigo system (Indigo, Palo Alto, California, USA), which appears robust and can penetrate the prostatic adenoma transurethrally. • A compromise between these two basic fiber types is a bare fiber within a cannula, through which saline flows to protect the cannula, the cladding, and the fiber, similar in size to the diffusor tip fiber. Current experiments show characteristic ultrasound-visible changes during prostatic heating, although different in nature to those that develop during bare fiber ILC.

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Figure 36.1 Diagrammatic representation of transurethral interstitial laser therapy. Experimental background Nd:YAG laser light was suggested for the purpose of creating focal areas of tissue coagulation within a solid organ.8 Since that time Bown et al. have explored this possibility and interest has spread widely. Nd:YAG laser light distributed in the tissue causes a predominantly thermal effect. When delivered by a fine transmitting fiber inserted within the tissue the Nd:YAG laser energy results in a well-demarcated cytotoxic effect, as shown in previous experimental studies performed on animal liver and gut.9,10 Matthewson et al.9 placed single bare fibers in the rat liver and described areas of coagulation surrounding the fiber of approximately 15 mm diameter. Subsequent studies in larger animals, particularly the dog, have con firmed that single bare fibers can cause homogeneous areas of necrosis in the canine pancreas and liver varying from 8 to 12mm in maximum diameter, and rather larger lesions could be created using multiple fibers.11 This same group12 has implanted fibers in rats bearing a transplantable fibrosarcoma and treated cohorts of rats with varying combinations of power and exposure times, with a range of effects on the target tumors. These figures were all produced using a very similar amount of energy, 675–1500J. This makes the concept of the delivery of a ‘dose’ of laser energy causing a predictable amount of thermal necrosis an attractive proposition. The reasons why similar results should be obtained in different organs in different animals is not entirely clear. The thermal and optical properties of the prostate, pancreas, and liver differ

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Page 510 with regard to optical density (color) and therefore light penetration. They also have different thermal diffusion and blood flow characteristics, all of which in theory should alter the tissue response to lowpower laser irradiation and alter energy absorbed per unit volume of tissue. It may be that if charring occurs at the fiber tip, and some small amount was seen in all these studies, then this area always acts as a point heat source, rather than a light source, with thermal diffusion away from that point into the surrounding tissue in all tissues at a similar rate. Hashimoto et al.13 described what appears to have been the first reported clinical application of Bown’s suggested technique. They inserted a quartz glass fiber, the end of which was altered to give a hemispherical shape to give diffuse emission of light. Under ultrasonic imaging, tumors of the liver were identified, their volume calculated, and the fiber was inserted into the center of the identified tumor. Using a continuous wave YAG laser at a power of 15W they administered energy according to a protocol of 1000 J/ml of tumor. A pronounced fall in tumor markers followed treatment. On ultrasound scanning the characteristic low-echo areas of tumor were gradually replaced by high echoes, presumably related to local gas formation. Similar appearances have been seen in other tissues.14 If the resulting thermal effect was readily visible in the prostate on ultrasound, this raises the possibility that energy deposition could be adjusted according to the anatomic configuration of the prostate and of the adenoma within the gland, allowing that laser energy could be applied more effectively and safely, whilst directed under constant ultrasonic guidance (either transrectal or transurethral ultrasound). Similar hyperechoic changes were seen in the canine and human prostate by McNicholas et al.15 using a simple bare fiber and were thought likely to aid in control of the heating process. However, they were not seen by Muschter et al.,16 who used a complex fiber with a larger caliber ‘diffusor tip’, and this may be due to the different tissue temperatures achieved by these two devices. ILC of the prostate: canine studies Initial experimental studies17–19 showed that large or small volume lesions could be produced in the canine prostate which healed with fibrocystic degeneration with no significant sequelae. McNicholas et al.18–20 implanted 150–400 mm fibers within the substance of elderly male beagle prostates. Nd:YAG laser energy was transmitted through the fiber(s) using longer exposures (200– 1500s) and lower powers (1–5W) than used in routine endoscopic laser therapy. Well-defined areas of coagulative necrosis were created without extensive tissue charring or damage to the fiber. For an energy dose of 1000J, a lesion ±1 cm in diameter resulted at 4 days. There appeared to be a threshold of approximately 650–700J, below which tissue necrosis was negligible. Treatments were well tolerated. At 6 weeks following treatment, healing was by fibrosis surrounding an area of cystic degeneration. With a multiple-fiber system, larger lesions could be made, destroying most of the canine prostate. Time would be a major limitation if a single-fiber system was being used to create a large volume effect and if it had to be replaced and repositioned in different parts of the target tissue, each part then being given its thermal treatment. However, an effective multifiber system immediately overcomes at least part of the problem by allowing the simultaneous treatment of a much larger volume of tissue within the ‘acceptable’ treatment time. In practice, however, clinical studies have shown that single-fiber systems can readily create large volume necrosis within the human prostate by making a number of punctures sequentially within a reasonable time span, as discussed below.21 Littrup et al.17 have described the ablation of canine prostate in a similar manner to that described above, but using higher powers of between 15 and 60W for 5s, giving total energy doses of between 75 and 300J. They also compared the effects of percutaneous injection of absolute ethanol or Nd:YAG laser ‘hyperthermia’ via a fiber, with both inserted under TRUS guidance. They showed the procedure was feasible under ultrasound control in dogs and their results are very similar to those described by McNicholas et al.,18–20 the tissue effects being much better controlled when produced by the laser than by ethanol. Hoopes et al.22 used a prototype saline-cooled fiber in the canine prostate and showed fiber preservation, ultrasound-visible changes during treatment that correlated with the pathologic changes seen acutely and later, and high tissue temperatures localized to the zones of ultrasound-visible change. These studies suggest that with low-power or mediumrange Nd:YAG laser energy it was possible to make reproducible areas of thermal necrosis in the normal canine prostate that healed with time with little harm to the animal. Various stages of the process and the lesions themselves could be seen with ultrasound. Feasibility studies to assess the application of canine results to man However, there are enormous differences between the soft, glandular canine prostate and the complex, vascular file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_510.html[09.07.2009 11:55:36]

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Page 511 human gland which is more resistant to heating. The limitations of this standard dog prostate model are such that it is not wise to extrapolate from canine results to the human. Further experiments and the application to the more challenging human prostate have been described.15,23 McNicholas et al.15 concluded that, in man, 0.15–0.4 mm diameter bare fibers and carrying needles inserted transurethrally or transrectally into the prostate were seen on ultrasound and could be accurately placed and that the heating process itself had characteristic ultrasound appearances, thereby allowing the operator to titrate the treatment against the tumor (or adenoma) volume, adding to the margin of safety. Therapeutically useful temperatures were generated within the male prostate that would be expected to lead to significant tissue death. Coagulative necrosis could be produced immediately and was more extensive at 1 week. On follow-up of patients distinct changes were visible within the target area on TRUS at 6 weeks to 3 months. The mixed pattern of hyperechogenic changes and hypoechogenic small cystic spaces has not been reported for any other heating modality and did suggest a distinct physical effect of the laser energy on a significant volume of human prostatic tissue. Similarly encouraging preliminary results were reported by Muschter et al.16 using higher powers transmitted via larger (1.6–1.7 mm diameter) specialized interstitial fibers that were inserted via a percutaneous transperineal approach. Current clinical experience Subsequently Muschter et al.24 described the results of several diffusor tip fibers in 172 men treated by the transperineal or the transurethral interstitial approach. American Urological Association (AUA) symptom scores fell from 25.1 to 5.7 and peak flow rates rose from 5.8 to 16.2 ml/s at 6 months. Orovan et al.25 reported 16 men treated transurethrally with a power of 7W for 10 minutes for each lateral lobe and for 5 minutes for the median lobe, and found AUA-7 scores fell from 16.3 to 5.8 and flow rates increased from 8.8 to 11.9 ml/s at 3 months within minimal side-effects. The authors commented that there were less irritative symptoms than seen with other laser procedures and shorter periods of catheterization’. Arai et al.26 reported on 61 men with up to 6 months’ follow-up, then on 76 men with 44 reaching 12 months’ follow-up.27 AUA-7 scores fell from 18.9 to 7.7 (59%) and flow rates increased from 6.7 to 10.0 ml/s (49%) at 3 months. Prostatic volume fell from 37.1 to 31.6 ml (15%) at 3 months, although volume increased immediately after ILC to 44.8 ml (21%), presumably due to edema. There was no reported erectile dysfunction (ED), 16 had a reduced volume of ejaculate, two had retrograde ejaculation, and 53% claimed an improved sex life. All were catheterized for 2–3 days then 25 (41%) developed acute retention or a significant increase in postvoid residual (PVR) and were managed by ISC or indwelling catheter for a mean of 12 days (range: 2–28 days), which they felt was ‘unacceptable’, although irritative voiding symptoms such as urgency and pain were not significant. Fifteen (25%) had mild hematuria for 5 days or more. Ultrasound changes were not described. With longer follow-up and larger numbers, I-PSS changed from 20.4 to 7.4 and flow rates increased from 7.4 to 11.1 ml/s. Results appeared better with more punctures and when more energy was given.27 Further research by the same team revealed that, among 173 BPH patients treated with TURP, microwave therapy, needle ablation, or ILC, patient satisfaction was highest among the ILC and TURP patients.28 Sexual dysfunction, in terms of ejaculatory function and volume, was lowest in the ILC group, although ED and libido did not change significantly in any group. German experience with the MBB (MBB, Munich, Germany) Nd: YAG laser and diffusor tip fiber inserted transurethrally or transperineally has the advantage of including detailed pressure-flow studies and adequate follow-up.29 Fortyseven of 59 relatively unfit men had reached 12 months’ follow-up, at which point ‘a significant improvement in all voiding parameters including symptom scores was observed’. Detrusor pressure fell from 90 to 42 cmH2O). They found a distinct correlation with the number of laser fiber punctures and concluded ILC was ‘an effective and safe method of treatment’. Comparison of ILC to TURP has shown it to compare respectably to the ‘gold standard’ in terms of symptom reduction and to have fewer adverse effects.30,31 The combination of ILC with minimal TURP has also shown positive results. Our experience has been with a transurethrally delivered saline-cooled interstitial laser fiber in 25 patients with symptomatic BPH. The mean age was 69 years (range: 61–77 years) and mean prostatic volume was 40 ml (range: 24–72 ml). Mean total energy given was 11400J (range: 5560–17600J) at powers of 5–10W over a mean laser exposure time of 22 minutes (range: 6.5–45 minutes). Postoperative bladder drainage in the first ten men was by an 8Fr suprapubic catheter, after which catheters were dispensed with and the patients were taught intermittent clean self-catheterization (ICSC). Patients were discharged home on the first postoperative day to be reviewed 1 week posttreatment to allow removal

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Page 512 Table 36.1 Pre- and postoperative features of 25 men undergoing transurethral interstitial laser coagulation with a saline-cooled fiber. Preoperative Postoperative (3 months) AUA Q max RV AUA Qmax RV 22 9.5 116 5.4 13.8 88 (18–29) (6.7–14.7) (35–500) (3–9) (8.3–18.5) (0–281) Values are means, with ranges in parentheses. of the suprapubic catheter or for general review. Patients were then reviewed at 4 weeks, 3, 6, and 12 months, with measurement of symptom score, flow rate, and residual volume. Intraprostatic changes were monitored by TRUS. Eight patients managed to void satisfactorily a few days following the treatment and the suprapubic catheter was removed on postoperative day 7. Five patients showed slower improvement and the suprapubic or urethral catheter needed to remain in situ for 3 weeks. Twelve patients had their bladder drained with a fine urethral catheter, which was removed on postoperative day 1. The patients commenced using self-catheterization if necessary, with an average of 3 days of ICSC being required. The preoperative mean AUA-7 score of 22 (range: 18–29) fell to 5.4 and the mean peak flow rate increased from 9.5 to 13.8 ml/s at 3 months (Table 36.1). Most of the patients tolerated the treatment very well and the majority required only mild oral analgesia in the immediate postoperative days. One patient developed severe dysuria in the immediate postoperative period and required transurethral resection. The preresection TRUS indicated a large volume of necrosis in the site of coagulation, which was confirmed endoscopically and by histologic examination of the removed prostatic tissue. However, no other patient had these symptoms despite ultrasound evidence of similar or greater tissue destruction. Most of the patients noticed improvement in their symptoms as well as their flow rate on the fourth week posttreatment. Complications were otherwise minor. As with most laser reports, there were no major effects on ejaculation in these studies. TRUS during treatment showed the cannula in situ and the thermal changes within the adenoma as heating developed (Figs. 36.2 and 36.3). TRUS on the fourth week posttreatment showed a zone of mixed hyper- and hypodense echoes corresponding to the site of coagulation. By the sixth week, cystic changes appeared in the center of the treated zone surrounded by a rim of hyperdense tissue, and by the third month posttreatment these characteristic changes became very distinct with the cystic changes becoming larger in size and sometimes extend-

Figure 36.2 TRUS during treatment showing the cannula in situ.

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Figure 36.3 TRUS during treatment showing the thermal changes (white areas) within the adenoma as heating develops. ing along the complete length of the adenoma (Figs. 36.4 and 36.5). Positioning of the process is crucial. Further work should develop devices to allow safe and even more accurate fiber insertion and treatment control. Long-term follow-up of ILC patients has shown that improvements in I-PSS and quality of life are maintained.29,30,34 For this method to be successful it is necessary to have a laser capable of reliably producing low power in a stable manner. The Nd: YAG laser technology used is widely

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Figure 36.4 TRUS (transverse view) 3 months posttreatment: the characteristic changes become very distinct, with the cystic changes becoming larger in size within the adenoma.

Figure 36.5 TRUS (longitudinal view) cystic changes extending along the complete length of the adenoma. available and becoming cheaper. With the availability of multiple fiber couplers the standard Nd: YAG laser can be used both for ‘traditional’ high-power applications and for multiple-fiber low-power interstitial uses by a range of different specialties, so long as that particular laser will produce a stable output at the lower end of its power range. Alternatively, smaller, cheaper Nd: YAG lasers are now available. At the low powers used in this study there is little need for complex electrical or cooling arrangements and the lasers are more likely to be truly portable. Relatively small, tough, and viable ‘diode’ lasers producing coagulative wavelength light are already available. We found the effect of the Diomed 805 nm wavelength diode laser in the human prostate in vivo to be identical to that of the Nd: YAG laser, Our experiments with the Cytocare Diolase 950 nm diode laser for VLAP showed very similar effects and long-term results when compared to the Nd: YAG laser35 and the interstitial effects are also likely to be similar. This also appears to be the case in data reported for the Indigo diffusor tip fiber and diode laser, which generates 830 nm light.36,37 The system senses temperatures at the fiber tip and adjusts the power output to maintain a temperature of 100ºC throughout the treatment cycle, while avoiding tissue carbonization. One small study has reported on 25 men treated with this laser and fiber system.38 The results showed a mean symptom score improvement from 20.6 to 9.4 at 1 month and 6.9 at 3 months. The peak flow rate ( Q max) increased from 9.1 to 14.1 and then to 20.3 ml/s. Temperatures reached and power levels required varied according to the site of puncture, with apically placed lesions requiring less energy to achieve and maintain target temperature. Presumably the tissue cooling mechanisms are less effective at the prostatic apex. Daehlin and Hedlund incorporated pressure-flow measurements in a 26-man subset of 49 men treated, and followed them for 1 year.39 They showed ‘substantial effects on symptoms and moderate to small effects on urodynamic variables’, 15% required retreatment in 1 year; the I-PSS fell from 22 to 11 and the Q max rose from 7.7 to 9 ml/s. They found the greatest efficacy in

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men with larger prostates and/or moderate or equivocal bladder outlet obstruction and challenged the notion that ILC was any less painful than other options as 72% reported perineal pain for approximately 2 weeks. An interim report by Greenberger and Steiner described a ‘safe and effective’ therapy, associated with the Indigo system, with AUA-SS falling from 20.2 to 9.8 in 25 men.40 Although the studies described above were all directed at the treatment of BPH, Amin et al.41 treated an area of recurrent or residual prostatic adenocarcinoma in this manner after the failure of initial radiotherapy. Discussion Higher-power methods of destruction of focal liver lesions have been described which involve a much shorter exposure period, but this does not necessarily confer any advantage and may cause more marked tissue disruption due to the rapid tissue heating and steam formation. Godlewski et al.42 described a laser interstitial method using a 5 mm diameter probe to carry a fiber to the target tissue (liver), but using a much higher power (80W) for a shorter period (10s), i.e. similar to the parameters used in traditional endoscopic practice. They produced 12–18 mm diameter lesions in pig liver, with marked central cavitation and charring. Despite the much higher

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Page 514 powers used the temperatures measured at 1 cm from the laser source were very similar to those found in the lowpower studies of Bown’s group. While 5-s treatment times seem immediately attractive compared to the 600–1500-s exposures of the lowerpower method, it is our impression that a slower treatment will give greater opportunity to adjust the fiber(s) position(s), particularly if the laser effect is seen to extend into an undesirable area. In addition, multiple-fiber systems available now and in the foreseeable future cannot cope with the high powers quoted17,42 and, indeed, clinical Nd: YAG lasers that will produce enough laser power to ‘split’ to give 60W down a 4-fiber system are not available. The ‘slow cooking’ method may allow observation of the evolution of the lesion, with readjustment of the position of the fiber(s) if necessary. It is not yet clear whether either method differs in terms of patient sensation, although the liver and pancreatic lesions created in clinical practice according to the same overall method as described here were performed under light sedation alone43 and prostatic needle insertion (and biopsy) is performed as part of urologic practice with minimal or no sedation. It appears that transurethral prostatic heating by VLAP can be tolerated under local prostatic block,44 and the same may be true for ILC. But what exactly is happening within the tissue? There are two ways by which laser light of a coagulating wavelength may have a thermal effect. The first is optical penetrance of the tissue, with the light being absorbed by the cells with concomitant thermal damage. The second is that light is absorbed around the fiber by blood and this coagulates and forms a char, which then absorbs the laser light, from which point there is thermal diffusion through the tissue with the laser fiber acting as a point heat source. Which method of heating occurs probably depends on the trauma of insertion at the fiber and the color of the tissue under treatment. In dark tissue, such as the liver which contains a lot of pigment and blood, the latter method most probably applies, whereas in a paler structure such as the pancreas, and possibly the prostate, optical penetrance may play a greater role since the prostate, in vitro at least, has been shown to be relatively ‘transparent’ to laser wavelengths.45 It is difficult, however, to be sure what is the percentage mixture of these methods. The reason for the interest in the optical penetrance is that if tissue light scattering and absorption coefficients are know, then calculations relating to light penetrance and hence the amount of tissue effected can be performed, which would allow the planned delivery of a dose of laser energy adequate to heat a known tissue volume. These calculations only have significance if charring (or significant bleeding) does not occur. There is much debate as to whether charring is essential to the process of ILC or not. This is important because it impacts onto the design and complexity of the fiber systems required. If charring is to be avoided then a fiber with a large emitting surface is needed to reduce the power density so as to diffuse the Nd: YAG laser light into the tissues.16,23,46 This should avoid raising the temperature of the body fluids adjacent to the fiber surface to the level that would cause carbonization (whereupon laser light distribution falls sharply, since the light is now intensely absorbed by the adjacent charred tissue acting as a’black body’, rather than being highly scattered into the surrounding tissues). Bown et al. were not impressed by the apparent advantages of more complex fiber systems. Sapphire tips are more complicated to use and are more traumatic to insert due to their larger size. Van Eeden et al.47 showed that the diameter of necrosis that can be produced in liver around a sapphire-tipped probe is less than that around a bare fiber for the equivalent laser powers and exposure times. Karanov et al.,48 using transplanted tumor in mice, have found that the extent of coagulation necrosis created by 1200J delivered by a sapphire tip ‘contact’ system was significantly less than that resulting from the same energy by external beam irradiation or a bare fiber interstitial method. Nolsoe et al.46 measured the size of lesions created by Nd: YAG light passed through either a simple ‘bare’ fiber system or a larger caliber fiber with a ‘diffusor tip’, but were unable to show any statistically significant advantage for the larger fiber. It would seem sensible to use simple yet robust fiber systems which should be minimally disruptive to the tissues through which they must pass. Furthermore, it may even be the case that charring or carbonization is essential to achieving a larger volume effect. We observed some charring was in all our animal and human studies, even at very low powers. We suspect that it is inevitable and may be beneficial in achieving larger volume lesions. If so, then the charred zone, however small, having absorbed light energy then acts as a heat transmitter. If this is a substantial contribution to the total thermal effect then it raises the possibility that the laser light itself, and certainly the wavelength, is not crucial to the process and it would suggest that the same thermal process could be produced by other nonlaser heating methods. Such an approach has been used with a diathermy heating probe, which vaporizes saline irrigated through it. The use of laser file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_514.html[09.07.2009 11:55:38]

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Page 515 fibers will remain a very elegant and minimally invasive method of applying the original energy. The ILC method produces much higher temperatures than are usually seen in conventional hyperthermia, but this does not seem to be a problem either in animal or clinical prostate studies or in the clinical studies reported by our collaborators in gastroenterology,11 as long as the energy is appropriately and precisely directed to where the necrotic effect is intended. Certainly in the liver and pancreatic studies, even when there was evidence on ultrasound of microvaporization and therefore high temperatures, this was not associated with patient discomfort. Although high, the temperatures generated are very localized. If the operator can see (ultrasonically) or predict the site of the end of the fiber he can assess where the region of high temperature will be. This does not detract from the need to develop sensitive thermometry methods to improve ILC. A combination of TRUS and thermometry may enhance the safe and effective use of interstitial laser hyperthermia. Conclusions Controlled tissue coagulation can be produced by lowpower laser light transmitted by fine fibers inserted interstitially by the percutaneous transperineal, transrectal, and endoscopic routes to destroy moderate BPH safely. Clinical studies have shown: • ILC can be applied accurately and safely under transrectal ultrasound (TRUS) control or by endoscopic methods alone. • Therapeutically useful temperatures in a significant volume may be achieved in the more challenging human prostate. • Significant tissue changes can be created and these are visible on TRUS. • Overall symptomatic changes are similar to other laser methods. • There are minor to moderate changes in flow rate and urodynamic parameters. • The technique is safe for high-risk patients. • Catheterization for approximately 2 weeks afterwards may be expected. • There is no evidence that the early postoperative problems of dysuria and obstruction are any less problematic for ILC. • It is possible to make laser prostatectomy more controlled and therefore more predictable by exploiting the ultrasound visibility of ILC. • The ‘slow cooking’ method allows repositioning of the fiber during treatment as and when necessary to achieve total coagulation of the target without extensive tissue disruption. Higher powers result in the explosive production of super-heated steam. • It has yet to be determined which fiber method is best for ILC and whether there is any significant difference between them. The diffusor tip fibers do not appear to give rise to ultrasound-visible thermal changes, possibly an important means of controling energy deposition and heating, but factory-prepared diffusor fibers may be easiest to use in clinical practice. References 1. Brested J H. The Edwin Smith surgical papyrus, 1st edn. Chicago: University of Chicago Press, 1930 2. Star W, Marijnissen H, van der Berg-Blok A et al. Destruction of rat mammary tumour and normal tissue microcirculation by haematoporphyrin derivative photoradiation observed in vivo in sandwich observation chambers. Cancer Res 1986; 46:2532–2540 3. Selman S, Keck R. The effect of transurethral light on the canine prostate after sensitization with the photosensitiser tin (II) etiopurpurin dichloride: a pilot study. J Urol 1994; 152:2129–2132 4. Costella A J, Johnson D E, Bolton D M. Nd:YAG laser ablation of the prostate as a treatment for benign prostatic hypertrophy. Lasers Surg Med 1992; 12:121–124 5. Assimos D G, McCullough D L, Woodruff R D et al. Canine transurethral laser induced prostatectomy. J Endourol 1991; 5:145–149 6. Aho T F, Gilling P J. Laser therapy for benign prostatic hyperplasia: a review of recent developments. Curr Opin Urol 2003; 13:39–44 7. Larson T R. Rationale and assessment of minimally invasive approaches to benign prostatic hyperplasia therapy. Urology 2002; 59 (2 Suppl 1): 12–16 8. Bown S G. Phototherapy of tumours. World J Surg 1983; 7:700–709 9. Matthewson K, Coleridge-Smith P, O’Sullivan J et al. Biological effects of intrahepatic Nd:YAG laser photocoagulation in the rat. Gastroenterology 1987; 93:550–557 10. Barr H, Tralau C J, MacRobert A J et al. PDT in the normal rat colon with phthalocyanines sensitization. Br J Cancer 1987; 56:111–118 11. Steger A, Bown S, Clark C. Interstitial laser hyperthermia—studies in the normal liver. Br J Surg 1988; 75:598 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_515.html[09.07.2009 11:55:38]

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Page 516 12. Matthewson K, Barr H, Tralau C et al. Low power interstitial Nd: YAG laser photocoagulation: studies in a transplantable fibrosarcoma. Br J Surg 1989; 76:378–381 13. Hashimoto D, Yabe K, Uedera Y. Ultrasonic guided lasers and spheric lasers. In: Riemann J, Ell C (eds). Lasers in gastroenterology (international experiences and trends). Stuttgart: Georg Thieme Verlag, 1989:134–138 14. Steger A, Shorvon P, Walmsley K et al. Ultrasound features of low power interstitial laser hyperthermia. Clin Radiol 1992; 46:88–93 15. McNicholas T, Pope A, Timoney A et al. Hyperthermia of the prostate by interstitial laser coagulation. J Urol 1992; 147:345A 16. Muschter R, Hofstetter A, Hessel S et al. Hi-tech of the prostate: interstitial laser coagulation of benign prostatic hyperplasia. In: Anderson R (ed). SPIE; 1992. San Jose: SPIE the International Society for Optical Engineering 1992:25–34 17. Littrup P, Lee F, Borlaza G et al. Percutaneous ablation of canine prostate using transrectal ultrasound guidance, absolute ethanol and Nd: YAG laser. Invest Radiol 1988; 23:734–739 18. McNicholas T, Steger A, Charig C et al. Interstitial Yag laser coagulation of the prostate. Lasers Med Sci 1988; 3: abstract 446 19. McNicholas T, Steger A, Bown S. Interstitial laser coagulation of the prostate: an experimental study. Br J Urol 1993; 77:439–444 20. McNicholas T, Steger A, Bown S et al. Interstitial laser coagulation of the prostate: experimental studies. In: Watson G (ed). Proceedings of the international society for optical engineering SPIE’s biomedical optics, 1991. Los Angeles: SPIE Optical Engineering Press, 1991:30–35 21. McNicholas T, Hoopes J, Williams J et al. Interstitial laser coagulation (ILC) of the canine prostate with ultrasound and thermal monitoring. In: SIU meeting, September 1994, Sydney. Abstract 319 22. Hoopes J, Williams J, Harris R et al. Interstitial laser coagulation (ILC) of the canine prostate with ultrasound and thermal monitoring. J Urol 1994; 151:334A (abstract 425) 23. Muschter R, Hofstetter A, Hessel S et al. Interstitial laser prostatectomy—experimental and first clinical results. J Urol 1992; 147:346A 24. Muschter R, Zellner M, Hessel S et al. Lasers and benign prostatic hyperplasia—experimental and clinical results to compare different application systems. J Urol 1994; 230A 25. Orovan W, Whelan J. Neodymium YAG laser treatment of BPH using interstitial thermometry: a transurethral approach. J Urol 1994; 151:230A (abstract 212) 26. Arai Y, Ishitoya H, Okubo K et al. Transurethral interstitial laser coagulation for BPH: treatment outcome and quality of life. Br J Urol 1996; 78:93–98 27. Arai Y, Okubo T, Maekawa S et al. Interstitial laser coagulation for management of benign prostatic hyperplasia: a Japanese experience. J Urol 1998; 159:1961–1965 28. Arai Y, Aoki Y, Okubo K et al. Impact of interventional therapy for benign prostatic hyperplasia on quality of life and sexual function: a prospective study J Urol 2000; 164: 1206–1211 29. Krautschik A W, Kohrmann K U, Henkel T O et al. Interstitial laser coagulation in benign prostatic hyperplasia: a critical evaluation after 2 years of follow-up. Urol Int 1999; 62:76–80 30. Kursh E D, Concepcion R, Chan S et al. Interstitial laser coagulation versus transurethral prostate resection for treating benign prostatic obstruction: a randomized trial with 2-year follow-up. Urology 2003; 61:573–578 31. Norby B, Nielsen H V, Frimodt-Moller P C. Transurethral interstitial laser coagulation of the prostate and transurethral microwave thermotherapy vs transurethral resection or incision of the prostate: results of a randomized controlled study in patients with symptomatic benign prostatic hyperplasia. BJU Int 2002; 90:853–862 32. Reich O, Schneede P, Corvin S et al. Combination of interstitial laser coagulation and transurethral resection of the prostate: ex vivo evaluations: Urology 2003; 61: 1172–1176 33. Corvin S, Schneede P, Siakavara E et al. Interstitial laser coagulation combined with minimal transurethral resection of the prostate for the treatment of benign prostatic hyperplasia. J Endourol 2002; 16:387–390 34. Kochakarn W, Nilsakulwat R, Roongruangsilp U, Muangman V. Interstitial laser coagulation for the treatment of benign prostatic hyperplasia: a 3-year follow-up of 30 cases. J Med Assoc Thai 2001; 84:1126–1130 35. Alsudani M, Aslam M, Akbar M et al. A comparison of diode and Nd YAG laser therapy for symptomatic benign prostatic hyperplasia (BPH). J Urol 1995; 153:416A 36. Costello A J, Agarwal D K, Crowe H R, Lynch W J. Evaluation of interstitial diode laser therapy for file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_516.html[09.07.2009 11:55:39]

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treatment of benign prostatic hyperplasia. Tech Urol 1999; 5: 202–206 37. Matsuta Y, Ichioka K, Terada N et al. Interstitial laser coagulation for benign prostatic hyperplasia: clinical results of the indigo diode laser system [abstract, article in Japanese]. Hinyokika Kiyo 2003; 49:195–200 38. de la Rosette J, Muschter R, Lopez M et al. Interstitial laser coagulation in the treatment of benign prostatic hyperplasia using a diode-laser system with temperature feedback. Br J Urol 1997; 80:433–438 39. Daehlin L, Hedlund H. Interstitial laser coagulation in patients with lower urinary tract symptoms from benign

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Page 517 prostatic obstruction: treatment under sedoanalgesia with pressure-flow evaluation. BJU Int 1999; 84:628–636 40. Greenberger M, Steiner M S. The University of Tennessee experience with the Indigo 830e laser device for the minimally invasive treatment of benign prostatic hyperplasia: interim analysis. World Urol 1998; 16:386–391 41. Amin Z, Lees W, Bown S. Technical note: interstitial laser photocoagulation for the treatment of prostatic cancer. Br J Radiol 1993; 66:1044–1047 42. Godlewski G, Sambuc P, Eledjam J et al. A new device for inducing deep localized vaporization in liver with the NdYAG laser. Lasers Med Sci 1988; 3:111–117 43. Steger A, Lees W, Walmsley K et al. Interstitial laser hyperthermia: a new approach to local destruction of tumours. Br Med J 1989; 299:362–365 44. Leach G, Sirls L, Ganabathi K et al. Outpatient visual laser assisted prostatectomy under local anesthesia. Urology 1994; 43:149–153 45. Pantelides M, Whitehurst C, Moore J et al. Photodynamic therapy for localised prostate cancer: light penetration in the human prostate gland. J Urol 1990; 143:398–401 46. Nolsoe C, Torp-Pedersen S, Holm H et al. Ultrasonically guided interstitial Nd-YAG laser diffuser tip hyperthermia: an in vitro study. Scand J Urol Nephrol 1991; 137 (Suppl): 119–124 47. Van Eeden J, Steger A, Bown S. Fibre tip considerations for low power laser interstitial hyperthermia. Lasers Med Sci 1988; 3: A336 48. Karanov S, Karaivanova M, Getov H et al. External benign sapphire tip contact and interstitial NdYAG laser therapy at 1064 μm on a transplanted adenocarcinoma in mice: a comparative study. Laser Med Sci 1992; 7: 483–486

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Page 519 37 Transurethral microwave thermotherapy S St Clair Carter A Tubaro History In the 1980s the phenomenal success of extracorporeal lithotripsy for the treatment of urinary stones inspired many urologists to believe that a similar minimally invasive treatment could be found to treat benign prostatic hyperplasia (BPH). Earlier work had shown that heat could be used to preferentially kill malignant tissue, leaving normal tissues intact.1 Yerulshami et al. originally suggested heating the prostate for the treatment of cancer.2 A group of enthusiasts soon realized that heat could also be used to destroy BPH tissue and also believed that microwave energy was the best method of delivering heat to the prostate. Initially the treatments were of low temperature and given in fractions from a transrectal applicator.3 Symptomatic improvements were seen but little objective improvement could be demonstrated. Improvements in microwave antenna technology allowed the development of urethral microwave delivery devices.4 At the same time, Devonec et al. proposed the concept of urethral cooling in order to preserve the prostatic urethra while providing deeper heating in the adenoma and this was termed ‘transurethral microwave thermotherapy’ (TUMT).5,6 With growing confidence more energy was applied and over the next 10 years more heat was used in shorter time periods, with increasing objective benefit.7,8 The ability to treat the symptoms and physiologic obstruction of BPH on an outpatient basis was established, but the outcome in any individual patient remains unpredictable.8 The story of TUMT has challenged our scientific knowledge to find the mechanism of action and employ the technique to best effect. Over 300 papers have been published in the last 12 years but, as yet, the technique has failed to gain the confidence of the urological community in many parts of the world. However, unlike many other minimally invasive treatments developed within the last two decades, TUMT remains in the panoply of acceptable clinical treatments.9,10 Technical details of TUMT Transurethral microwave thermotherapy is defined by the delivery of microwaves from an intraurethral antenna with the intention of achieving temperatures greater than 45 degrees centigrade in the prostate. Two frequencies of microwave energy are commonly used (916 and 1296 MHz). A number of different designs of antenna have been developed to produce a field of heating to match the shape and volume of the prostate.11 Despite arguments as to which is the best design, little difference in clinical outcome is seen with either differing frequency or antenna.12 One of the original concepts for TUMT that differentiated it from simple microwave therapy was the technique of cooling the catheter containing the antenna at the same time as producing irradiative heating to the adenoma. The summative effect produced differential heating within the prostate (Fig. 37.1).5 The greatest temperature is therefore delivered deep within the prostate, with urethral mucosal preservation. The structure of the TUMT catheter is complex, designed to accommodate the microwave antenna as well as a number of channels

Figure 37.1 Transurethral microwave thermotherapy concept: the x-axis represents the distance from the antenna in the urethra; the y-axis represents the temperature. The

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combination of deep radiative heating and superficial conductive cooling leads to an asymmetrical temperature profile, with steep ascending slope and progressive descending slope. Because of the cell toxicity threshold, periurethral tissue is preserved as long as the temperatue stays below the therapeutic threshold. Tissue coagulation (dark area) is obtained as soon as the ascending slope crosses therapeutic threshold and is maintained until the descending slope crosses it.

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Page 520 for the circulation of coolant, fiberoptic thermosensors, and a simple channel for the inflation of the retaining balloon. A number of modifications of the cooling system have been made in an attempt to provide differential cooling of the lateral wall of the prostate and posterior margin.11,13 In the initial phase of development of TUMT there was considerable concern that temperatures within the prostate and urethra might damage the rectum and lead to the development of a recto-urethral fistula. In order to avoid such a catastrophic situation, temperature control systems were developed to regulate the rectal wall and the urethral surface temperature.5 Fiberoptic thermosensors, unaffected by the microwave field, are placed in the catheter and on a rectal probe, primarily as safety controls. Using the basic concepts of microwave irradiation and conductive cooling, various programs were developed to play with the pattern of heating, cooling, and duration of treatment. Several generations of controling software have been developed; broadly these can be described as low energy (LE-TUMT), high energy (HE-TUMT), short, or long treatments. While there has been intense commercial competition, most of the data within these classes are remarkably consistent. The response to microwave heating The temperature achieved in the prostate has been studied in a number of different ways. In the original studies performed by Devonec and Carter et al. the temperatures were measured by the placement of several intraprostatic thermosensors.5,6,14 Others have tried real-time techniques to measure the temperature in a diffuse volume of the prostate, although no technique yet seems to give a clear indication of the thermal dose.9 Most recently a system by which a thermosensor is deployed from the side of the catheter, to measure temperature in real time during the therapy, has been developed.15 The continuous temperature-measurement system allows the operator to identify patients in whom an exaggerated vascular response may lead to inadequate heating and require greater energy input.16 Experimental and clinical studies initially indicated that the therapeutic level to achieve a cell kill is 45 degrees centigrade for 45 minutes.5,17 Higher temperatures need to be achieved at the center of the microwave field in order to create a larger lesion by thermal diffusion, although the heat may need to be applied for less time.15,18 Within the zone of therapeutic heating there is an intense hemorrhagic infarction leading to coagulation necrosis. The edges of this zone are clearly defined and represent a very specific heat dose (calculated from maximum temperature and exposure time), as shown in Fig. 37.2. After a few days an inflammatory response at the edge of the lesion starts to attack the coagulation necrosis and reduces the volume of whole gland. The thermotherapy lesion typically extends about 32 mm across and the inner surface of the lesion in cooled thermotherapy is about 1.5 cm from the lumen.12 Studies with magnetic resonance imaging (MRI) delineate the extent of the tissue destruction clearly and can be used to study the efficacy of the treatment; however, they do not as yet offer a routine real-time feedback system with which to control the therapy.19,20 Clinical outcome is dependent on the temperature achieved within the prostate, duration of heating, and volume of adenoma heated.14

Figure 37.2 (a) Coagulative necrosis 1 week after TUMT in a transverse section of a large adenoma. (b) A photomicrograph of the margin of the thermal injury with the normal tissue on the left and coagulative necrosis on the right, demonstrating the sharp delineation of the thermal lesion.

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Page 521 Indications for TUMT The original intention was for TUMT to be used to treat men with symptomatic BPH with evidence of bladder outflow obstruction either on the basis of flow rate or of comprehensive urodynamic studies.6 The treatment was seen as an alternative to surgical intervention. More recently, the indications have broadened to include those with LUTS but without objective evidence of obstruction and the treatment is now often seen as an alternative to pharmacotherapy.21,22 Several studies have looked at the possibility of using this technique for the relief of acute retention or sustained retention.23–25 A few studies have suggested that TUMT can be used for chronic prostatitis and claim some success.26,27 Other studies have proposed that it might be used for prostatic cancer in combination with other treatments, although generally the presence of cancer is regarded as a contraindication for routine treatment.28 The contraindications for TUMT are few and are mainly based on theoretical risks.6 One such consideration is the possible interactions of the microwave field with metallic implants such as metallic hip prostheses or cardiac pacemakers. However, there are anecdotal accounts of treatments being undertaken safely in both circumstances. Previous surgery to surrounding organs such as the rectum is thought to represent an absolute contraindication because of the fear that unpredictable heating will occur, causing extraprostatic tissue damage. Treatment is also contraindicated where the prostate or bladder neck has been damaged because the positioning balloon might be displaced distally and the heat affect the external sphincter or urethra. Certain configurations of the prostate are regarded as unsuitable for treatment by TUMT. These include a predominant middle lobe enlargement protruding into the bladder, which will not be heated by the antenna, and very small prostates where the heating of the rectum will be excessive and the thermal dose to the prostate reduced in order to preserve the rectal wall from damage. Clinical results The initial clinical experience with TUMT was reported as unrandomized clinical trials.6,29,30 It was some years before conclusive data from well-designed clinical trials became available. It is of note that in the very early series relatively low-energy protocols were used and then abandoned, not because of a lack of evidence of symptomatic improvement but because the urological community required data to show objective improvement before accepting TUMT as a legitimate treatment. At the time of the first studies many of the instruments, such as the I-PSS or pressure-flow algorithms that are now commonly used to measure clinical response in BPH, had not been developed or validated. It is interesting to speculate whether some of the earlier very-low-energy treatment protocols, which gave good symptomatic benefit with minimal morbidity, might have survived as an alternative to pharmacotherapy if tested today. Sham studies At the outset of the investigations into TUMT it was important to demonstrate that the heating effect was greater than a placebo or sham treatment. A number of studies were performed as part of the licensing procedure for different devices as shown in Fig. 37.3.31–35 Significant placebo effects were seen and only one study was unable to show that there was benefit from heating.36 Typically there was a 20–30% improvement in symptom score in the sham group and the improvement was 60–80% in the TUMT group. Flow rates improved by about 10–20% for sham patients and 40–50% in the treatment arm. Some criticism can be directed at such studies because of the intrinsic difficulty in blinding the patient to the treatment arm. It is now felt that there is sufficient evidence of clinical efficacy of TUMT so that there is no need to undertake these studies in the proof of a new treatment program or device. Comparison with pharmacologic therapies It is surprising, given the dominance of the pharmacologic treatment of lower urinary tract symptoms (LUTS) today, that few comparisons have been made between TUMT and medical therapy. Djavan et al. have investigated the use of α-blocking agents as adjuvant and neoadjuvant treatments to TUMT.37 The findings of this study suggest a different mechanism of action for the two treatments. At 2 months the outcome of patients treated with adjuvant tamsulosin and TUMT versus TUMT alone was different in that there was an earlier symptomatic improvement with the addition of α-blockade. However, at 3 months the outcome was similar in terms of symptom score, quality of life, and maximal flow rate. In a further study the same authors made a direct randomized comparison between α-blocking therapy and TUMT over a period of 6 months.38 In this important study, the patients were randomized between TUMT using a low-energy protocol and terazocin in doses titrated to give maximum symptomatic benefit. The study showed that within the first 2 weeks symptomatic and objective outcome was

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Figure 37.3 A graphical display of the results of randomized controlled studies of TUMT versus sham treatment and drug therapy. The graph represents pIdicated otherwise) versus percentage change in urinary peak flow rate. The numbers for each series refer to the numbers of months of follow-up.31–36,38 inferior with TUMT as a result of the significant recovery phase for thermotherapy, but by 6 weeks the outcome was similar or better for TUMT-treated patients. At 6 months there is a significantly better outcome in terms of symptom scores, quality of life, and peak flow rate for TUMT (Figs. 37.2 and 37.3). Quality of life had improved by 1.7 points (45%) for the terazocin-treated group and 2.6 points (67%) for TUMT-treated patients. The number of treatment failures due to lack of treatment efficacy or adverse events was significantly higher in the terazocin arm (17%) than in the TUMT arm (2%). In a subsequent publication the 18-month data from this study showed a continued benefit in favor of the TUMT group, with 41% treatment failure for terazocin therapy and 6% for TUMT.39 It seems that TUMT has short-term disadvantages but long-term advantages over α-blocking therapy for LUTS. Comparison with TURP At the outset of the TUMT experience in the late 1980s the predominant treatment for LUTS from benign prostatic enlargement was transurethral resection of the prostate (TURP). As a result, the aspiration for TUMT was for the results to be similar in terms of symptom reduction and also to have a significant impact on the urodynamic measures of voiding function. A number of randomized studies between TURP and TUMT have now been published and the data for percentage change of flow rate against symptoms is given in Fig. 37.4.40–43 One other study, which only has 6 months of data, has shown no significant improvement in TUMT and a significant improvement in all measures for TURP.44 All other studies show a similar improvement in symptoms for TUMT and TURP, but a greater improvement in flow rate for TURP. Pressure-flow studies were measured before and after in three studies and showed that for HE-TUMT there was a 31–34% reduction in detrusor pressure at peak flow (PdetQ max) as opposed to 40–46% for TURP.41,43 A series of LE-TUMT did not show any difference in PdetQ max.40 Prostate volume in LE-TUMT is unchanged, but a 16–30% change is seen in HE-TUMT as compared to 49–51% for TURP. Retention studies Many centers have undertaken treatment of sustained acute urinary retention by TUMT during the last decade, but there are few reports in the peer-reviewed literature. The first study using LE-TUMT by Van-Cauwelaert in 1993 described a 91% success rate in enabling patients to void after episodes of retention which would otherwise have been treated by TURP.45 High-energy TUMT was used by Djavan et al. in 31 patients with a 94% success rate,23 and more recently Schelin reported a series of 24

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Figure 37.4 A graphical display of the results of randomized controlled studies of TUMT versus sham treatment and drug therapy. The graph represents percentage change in symptom score (I-PSS or AUA, unless indicated otherwise) versus percentage change in urinary peak flow rate. The numbers for each series refer to the numbers of months of follow-up.38,40–43 patients with an 80% success rate using the feedback thermotherapy device.25 Some doubt has been expressed as to the long-term durability of the treatment by Floratos et al., suggesting that the retreatment rate might be as high as 25% in the first year.24 Most authors suggest that TUMT should only be reserved for patients at high risk for conventional surgery. Morbidity Transurethral microwave thermotherapy is a minimally invasive treatment; although it is not free of morbidity either during or after treatment, serious complications are very rare. The procedure is performed as an outpatient office procedure, usually without the use of significant sedative drugs. It is important not to lose sight of the fact that there is no need for a hospital stay as compared to the 4-day stay conventionally seen with TURP. The principal problems during treatment are the pain and discomfort of catheterization with a significantly sized treatment applicator (20Fr), pain from the heating, and bladder spasms. High-energy treatments are less well tolerated than lowenergy protocols. Tsai et al. reported that burning sensation was the most frequent complaint (38.5%), followed by urethral discomfort (29.2%), and urgency (9.2%),46 Occasional patients (3.1%) have to interrupt TUMT because of intolerable pain, and as many as 6% cannot complete the treatment.47 In the past some have suggested that routine sedation is required, but most authors now believe that local topical anesthesia alone is sufficient and that only occasional patients require sedo-analgesia.49 Recent developments of shorter treatments have made the procedure more tolerable.49 The main issue for posttreatment morbidity is the duration of catheterization following the procedure. Most agree that for HE-TUMT protocols, some period with catheter drainage is essential to avoid a high proportion of patients returning to the hospital after discharge in acute retention. Previously for LETUMT catheterization, rates were between 12 and 36%.33,34 Catheterization times seem to vary with design of the applicator, with some devices having times as short as 1 day and others as long as 16 days.22 In a summary of treatment morbidity, de la Rosette et al. have calculated that the mean catheterization time for TURP is 3.6 days, and 13.7 days for TUMT.8 Some groups use suprapubic catheters to check on the efficacy of voiding before removing the drainage system completely. Others have used a temporary stent with some benefit, although this does not seem to have gained wide acceptance.50,51 A major feature of the recovery from TUMT is the presence of urgency of micturition following treatment,

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Page 524 which can last up to a few weeks. Wagrell et al. have shown that this is greater in TUMT than in TURP patients, and reported that 37% of TUMT patients experienced this.43 Occasionally the urgency may be sufficiently severe to give urge incontinence. Urinary tract infection is seen to have a similar rate to TURP.8 Infection is often the result of the catheter and is seldom important, although occasionally there is epididymitis which seems to be increased in those who have treatment rather than sham catheterization.35 Sexual function is affected in a proportion of patients, with between 0 and 44% experiencing retrograde ejaculation and 0.8–11% impotence.52 Generally the risks to sexual function are greater with higherenergy programs, particularly those that create a cavity in the prostate, but the results are substantially better than with TURP.53 Hematuria and mild urethral discomfort are almost universal.8,22 More serious complications include occasional urethral strictures and, very rarely, major urethral damage from inadvertent heat injury after distal displacement of the treatment applicator. Clinical utility Response rates The clinical results of thermotherapy treatments have been dogged by the lack of a consistent response. The unpredictable nature of the treatment presumably results from variations in heating consequent on local vascular thermoregulation as well as a variable ability of an individual to repair the thermal injury. Greater heating has a more consistent response, with a greater likelihood of producing a cavity within the urethra and a urodynamically useful response.14,54 The definition of response rates is difficult. A common method, used in TUMT studies, is to call patients who have a 50% increase in peak flow rate and a 50% decrease in symptom score a success. Figures for TUMT response rates defined this way are in the region of 30%.55,56 More recently, Wagrell et al. have quoted a success rate of 88% for TURP as compared to 82% for feedback thermotherapy using slightly different criteria for success.43 There has been considerable speculation in the literature as to how to select patients for a successful response. Larson et al. made the point that it is impossible to select for a successful outcome on symptoms alone.35 Others have suggested a better response is obtained in men with larger prostates, higher prostate-specific antigen (PSA), and more obstruction as defined by low flow rates and urodynamic patterns, particularly the constrictive type.8,55,57 An alternative way of looking at the outcome of TUMT is to look at the frequency of requiring another treatment or intervention for symptomatic failure or to manage a complication. The failure rate is similar for TURP and TUMT, but the nature of the failure is different. Reintervention within 30 days of treatment for TUMTs is rare, but is needed in about 7% of patients undergoing TURP.8 The predominant cause for failure in TURP (12.9%) is due to the development of a stricture of the urethra or bladder neck, whereas for TUMT (19.8%) it is due to a failure to improve symptoms.42 The failure rate for the newer technique of feedback thermotherapy was 5% at 1 year for TUMT, which was the same as for TURP (6%) in a randomized trial.43 Durability of response Long-term follow-up studies of TUMT are now available. Initial studies of LE-TUMT suggested success rates at 4 years of up to 60%, but other more recent studies have shown 67% requiring retreatment at 5 years.58 Other lowenergy devices have even lower long-term success rates of just 15.5%.46 The durability of response of another device has been reported by Miller et al.59 Twenty-nine per cent of men had sought other treatments within 5 years, however another third of the study patients had been lost to follow-up or died. Of those who were followed and had had no further treatment, 82% felt that they had a significant improvement in symptoms. The symptoms and quality of life scores, and flow rate parameters, had not changed over 5 years in the survivors. These data suggest that an initial good response bodes well for long-term success. Long-term data for newer therapies are not available and as yet there are no 5-year follow-up data for HETUMT, but the early signs are that the durability will be greater.42 It is reasonable to note that the long-term success rate of pharmacologic therapy is poor. In direct comparison with TUMT, Djavan et al. showed 41% of patients on α-blocker therapy had sought alternative treatment at 18 months as opposed to 5.9% of those undergoing TUMT.40 Cost effectiveness A number of groups have looked at the cost effectiveness of TUMT in comparison to other therapies, based on the data obtained from randomized studies of TUMT against other therapies and nonrandomized comparisons of established series.60–62 These studies have been set in both nationalized healthcare systems and also in the US health economy. All studies have suggested that TUMT is a costeffective alternative to TURP. One study has studied the

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Page 525 cost effectiveness in terms of cost per ‘quality adjusted life years’, or QALY, and compared this to previous data for medical treatments of illnesses as diverse as chronic bronchitis and schizophrenia and found the cost similar.61 Medical management of LUTS has been calculated to be similar to TURP, and thus by extrapolation TUMT should work out to be of a similar or lower cost in the long term.63 The issues of cost and reimbursement for TUMT have been a major factor in determining the uptake of TUMT into clinical practice in each country. Within Europe the financial benefits generally have been more difficult to prove and have not acted as a spur for urologists and institutions to invest in this technique, which is expensive to establish as a routine service. Conclusions Transurethral microwave thermotherapy represents a brave attempt by doctors and engineers to provide a treatment that is better overall than the current established, highly effective procedures. The information available shows that TUMT is an effective treatment with minimal morbidity. It could be argued that TUMT is the most mature of the ‘minimally invasive therapies’ for BPH, and even the gold standard as suggested by de la Rosette et al.8 The understanding of TUMT continues to grow and there are several new developments which may prove fruitful. However, during the history of TUMT the other established treatments have improved; newer and better pharmaceutic agents are available and endoscopic surgery and anesthesia continue to improve. The continuous improvement in instrumentation for TURP has led to a steady decline in morbidity associated with conventional endoscopic treatment, making it still harder to beat as the definitive solution for LUTS from BPH. We have to wait to see whether TUMT can still challenge these new standard therapies. References 1. Caveliere R, Ciocatto E, Giovanella B et al. Selective heat sensitivity of cancer cells. Cancer 1967:20:1351 2. Yerushalmi A, Servadio C, Leib Z et al. Local hyperthermia for treatment of carcinoma of the prostate: a preliminary report. Prostate 1982; 3:623–630 3. Yerushalmi A, Fishelovitz Y, Singer D et al. Localized deep microwave hyperthermia in the treatment of poor operative risk patients with benign prostatic hyperplasia. J Urol 1985; 133:873–876 4. Baert L, Ameye F, Willemen P et al. Transurethral microwave hyperthermia for benign prostatic hyperplasia: preliminary clinical and pathological results. J Urol 1990; 144:1383–1387 5. Devonec M, Berger N, Perrin P. Transurethral microwave heating of the prostate—or from hyperthermia to thermotherapy. J Endourol 1991; 5:129–135 6. Carter S, Patel A, Royer P et al. Single-session transurethral microwave thermotherapy (TUMT) for the treatment of benign prostatic hypertrophy. J Endourol 1991; 5:137–144 7. Laguna M P, Muschter R, Debruyne F M. Microwave thermotherapy: historical overview. J Endourol 2000; 14: 603–609 8. de la Rosette J J, Laguna M P, Gravas S, de Wildt M J. Transurethral microwave thermotherapy: the gold standard for minimally invasive therapies for patients with benign prostatic hyperplasia. J Endourol 2003; 17: 245–251 9. Debruyne F, Djavan B, de la Rosette J J et al. Interventional therapy for benign prostatic hyperplasia. In: Chatelain C, Denis L, Foo K T et al. (eds). Benign prostatic hyperplasia. Jersey: Scientific Consultation International, 2000:397–420 10. de la Rosette J J, Alivizatos G, Madersbacher S et al. EAU Guidelines on benign prostatic hyperplasia (BPH). Euro Urol 2001; 40:256–263 11. Bolmsjo M, Wagrell L, Hallin A et al. The heat is on—but how? A comparison of TUMT devices. BJU Int 1996; 78: 564–572 12. Larson B, Bostwick D G, Corica A, Larson T. Histological changes of minimally invasive procedures for the treatment of benign prostatic hyperplasia and prostate cancer; clinical implications. J Urol 2003; 170:12–19 13. Larson T R, Blute M L, Tri J L, Whitlock S V. Contrasting heating patterns and efficiency of the Prostatron and Targis microwave antennae for thermal treatment of benign prostatic hyperplasia. Urology 1998; 51:908–915 14. Carter S, Tubaro A. Relation between intraprostatic temperature and clinical outcome in microwave thermotherapy. J Endourol 2000; 14:617–625 15. Wagrell L, Schelin S, Bolmsjo M, Brudin L. Intraprostatic temperature monitoring during transurethral microwave thermotherapy for the treatment of benign prostatic hyperplasia. J Urol 1998; 159:1583– 1587 16. Bolmsjo M, Sturesson C, Wagrell L et al. Optimizing transurethral microwave thermotherapy: a file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_525.html[09.07.2009 11:55:43]

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model for studying power, blood flow, temperature variations and tissue destruction. Br J Urol 1998; 81:811–816 17. Larson T R, Bostwick D G, Corica A. Temperature-correlated histopathologic changes following microwave thermoablation of obstructive tissue in patients with benign prostatic hyperplasia. Urology 1996; 47:463–469

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Page 526 18. Bischof J, Bhowmick P, Coad J et al. Heat sensitivity of human prostatic tissue implications for thermotherapy. J Urol 2003; 169:287 (A) 19. Tazaki H, Deguchi N, Baba S et al. Magnetic resonance imaging following microwave thermotherapy, laser ablation and transurethral resection in patients with BPH. Urologe 1995; 34:105–109 20. Osman Y M, Larson T R, El Diasty T, Ghoneim M A. Correlation between central zone perfusion defects on gadolinium-enhanced MRI and intraprostatic temperatures during transurethral microwave thermotherapy. J Endourol 2000; 14:761–766 21. Hofner K. Transurethral microwave thermotherapy In: Chapple C, McConnell J D, Tubaro A (eds). Benign prostatic hyperplasia. London: Martin Dunitz, 2000:117–145 22. Djavan B, Seitz C, Marberger M. Heat versus drugs in the treatment of benign prostatic hyperplasia. BJU Int 2003; 91:131–137 23. Djavan B, Seitz C, Ghawidel K et al. High-energy transurethral microwave thermotherapy in patients with acute urinary retention due to benign prostatic hyperplasia. Urology 1999; 54:18–22 24. Floratos D L, Sonke G S, Francisca E A et al. High energy transurethral microwave thermotherapy for the treatment of patients in urinary retention. J Urol 2000; 163: 1457–1460 25. Schelin S. Microwave thermotherapy in patients with benign prostatic hyperplasia and chronic urinary retention. Eur Urol 2001; 39:400–404 26. Zeitlin S I. Heat therapy in the treatment of prostatitis. Urology 2002; 60 (Suppl 6): 38–40 27. Nickel J C, Sorensen R. Transurethral microwave thermotherapy for nonbacterial prostatitis: a randomized double-blind sham controlled study using new prostatitis specific assessment questionnaires. J Urol 1996; 155: 1950–1954 28. Khair A A, Pacelli A, Iczkowski K A et al. Does transurethral microwave thermotherapy have a different effect on prostate cancer than on benign or hyperplastic tissue? Urology 1999; 54:67–72 29. Blute M L, Tomera K M, Hellerstein D K et al. Transurethral microwave thermotherapy for prostatism: early Mayo Foundation experience. Mayo Clin Proc 1992; 67:417–421 30. Kirby R S, Williams G, Witherow R et al. The prostatron transurethral microwave device in the treatment of bladder outflow obstruction due to benign prostatic hyperplasia. Br J Urol 1993; 72:190– 194 31. Ogden C W, Reddy P, Johnson H et al. Sham versus transurethral microwave thermotherapy in patients with symptoms of benign prostatic bladder outflow obstruction. Lancet 1993; 341:14–17 32. de la Rosette J J, Froeling F M, Debruyne F M. Clinical results with microwave thermotherapy of benign prostatic hyperplasia. Eur Urol 1993; 23 (Suppl 1): 68–71 33. Blute M L, Patterson D E, Segura J W et al. Transurethral microwave thermotherapy v sham treatment: doubleblind randomized study. J Endourol 1996; 10:565–573 34. de Wildt M J, Hubregtse M, Ogden C et al. A 12-month study of the placebo effect in transurethral microwave thermotherapy. Br J Urol 1996; 77:221–227 35. Larson T R, Blute M L, Bruskewitz R C et al. A high-efficiency microwave thermoablation system for the treatment of benign prostatic hyperplasia: results of a randomized, sham-controlled, prospective, double-blind, multicenter clinical trial. Urology 1998; 51:731–742 36. Nawrocki J D, Bell T J, Lawrence W T, Ward J P. A randomized controlled trial of transurethral microwave thermotherapy. Br J Urol 1997; 79:389–393 37. Djavan B, Shariat S, Fakhari M et al. Neoadjuvant and adjuvant alpha-blockade improves early results of highenergy transurethral microwave thermotherapy for lower urinary tract symptoms of benign prostatic hyperplasia: a randomized, prospective clinical trial. Urology 1999; 53: 251–259 38. Djavan B, Roehrborn C G, Shariat S et al. Prospective randomized comparison of high energy transurethral microwave thermotherapy versus alpha-blocker treatment of patients with benign prostatic hyperplasia. J Urol 1999; 161:139–143 39. Djavan B, Seitz C, Roehrborn C G et al. Targeted transurethral microwave thermotherapy versus alphablockade in benign prostatic hyperplasia: outcomes at 18 months. Urology 2001; 57:66–70 40. Dahlstrand C, Geirsson G, Fall M, Pettersson S. Transurethral microwave thermotherapy versus transurethral resection for benign prostatic hyperplasia: preliminary results of a randomized study. Eur Urol 1993; 23:292–298 41. d’Ancona F C, Francisca E A, Witjes W P et al. Transurethral resection of the prostate vs high-energy thermotherapy of the prostate in patients with benign prostatic hyperplasia: long-term results. Br J Urol 1998; 81: 259–264 42. Floratos D L, Kiemeney L A, Rossi C et al. Long-term followup of randomized transurethral microwave ther-motherapy versus transurethral prostatic resection study. J Urol 2001; 165:1533–1538 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_526.html[09.07.2009 11:55:44]

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43. Wagrell L, Schelin S, Nordling J et al. Feedback microwave thermotherapy versus TURP for clinical BPH—a randomized controlled multicenter study. Urology 2002; 60:292–299 44. Ahmed M, Bell T, Lawrence W T et al. Transurethral microwave thermotherapy (Prostatron version 2.5) compared with transurethral resection of the prostate for the

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Page 527 treatment of benign prostatic hyperplasia: a randomized, controlled, parallel study. Br J Urol 1997; 79:181–185 45. Van-Cauwelaert R R, Castillo O C, Aquirre C A et al. Transurethral microwave thermotherapy for the treatment of benign prostatic hyperplasia: preliminary experience. Eur Urol 1993; 23:282–284 46. Tsai Y S, Lin J S, Tong Y C et al. Transurethral microwave thermotherapy for symptomatic benign prostatic hyperplasia: short-term experience with Prostcare. Urol Int 2000; 65:89–94 47. Cormio L, Bloem F, Laduc R, Debruyne FM. Pain sensation in transurethral microwave thermotherapy for benign prostatic hyperplasia: the rationale for prophylactic sedation. Eur Urol 1994; 25:36–39 48. Djavan B, Shariat S, Schafer B, Marberger M. Tolerability of high energy transurethral microwave thermotherapy with topical urethral anesthesia: results of a prospective, randomized, single-blinded clinical trial. J Urol 1998; 160: 772–776 49. Tomera K M, Tomera F M, Clark W R. Initial and superior experience with 30 minute TUMT. Techniques Urol 2000; 6:276–277 50. Djavan B, Ghawidel K, Basharkhah A et al. Temporary intraurethral prostatic bridge-catheter compared with neoadjuvant and adjuvant alpha-blockade to improve early results of high-energy transurethral microwave thermotherapy. Urology 1999; 54:73–80 51. Dahlstrand C, Grundtman S, Pettersson S. High-energy transurethral microwave thermotherapy for large severely obstructing prostates and the use of biodegradable stents to avoid catheterization after treatment. Br J Urol 1997; 79:907–909 52. Francisca EA, d’Ancona RC, Meuleman EJ et al. Sexual function following high energy microwave thermotherapy: results of a randomized controlled study comparing transurethral microwave thermotherapy to transurethral prostatic resection. J Urol 1999; 161:486–490 53. Wagrell L, Schelin S, Nordling J et al. Prostalund microwave feedback treatment compared with TURP for treatment of BPH; a prospective randomised multicentre study with 24 months follow up. J Urol 2003; 169:466A 54. Hoffmann A L, Laguna M P, de la Rosette J J, Wijkstra H. Quantification of prostate shrinkage after microwave thermotherapy: a comparison of calculated cell-kill versus 3D transrectal ultrasound planimetry. Eur Urol 2003; 43: 181–187 55. Tubaro A, Carter S S, de la Rosette J et al. The prediction of clinical outcome from transurethral microwave thermotherapy by pressure-flow analysis: a European multicenter study. J Urol 1995; 153:1526–1530 56. Tubaro A, d’Ancona F C. Case selection for high-energy transurethral microwave thermotherapy. World J Urol 1998; 16:124–130 57. Djavan B, Bursa B, Basharkhah A et al. Pretreatment prostate-specific antigen as an outcome predictor of targeted transurethral microwave thermotherapy. Urology 2000; 55:51–57 58. Ohigashi T, Baba S, Ohki T et al. Long-term effects of transurethral microwave thermotherapy. Int J Urol 2002; 9:141–145 59. Miller P D, Kastner C, Ramsey E W, Parsons K. Cooled thermotherapy for the treatment of benign prostatic hyperplasia: durability of results obtained with the Targis System. Urology 2003; 61:1160–1164 60. Manyak M J, Ackerman S J, Blute M L et al. Cost effectiveness of treatment for benign prostatic hyperplasia: an economic model for comparison of medical, minimally invasive, and surgical therapy. J Endourol 2002; 16:51–56 61. Blute M, Ackerman S J, Rein A L et al. Cost effectiveness of microwave thermotherapy in patients with benign prostatic hyperplasia: part II—results. Urology 2000; 56: 981–987 62. Walden M, Acosta S, Carlsson P et al. A cost-effectiveness analysis of transurethral resection of the prostate and transurethral microwave thermotherapy for treatment of benign prostatic hyperplasia: twoyear follow-up. Scand J Urol Nephrol 1998; 32:204–210 63. Chirokos T, Sanford E. Cost consequences of surveillance, medical managment or surgery for benign prostatic hyperplasia. J Urol 1996; 155:1311–1316

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Page 529 38 Temporary stents J Nordling Introduction The insertion of a stent to relieve infravesical obstruction due to benign prostatic hyperplasia (BPH) was first described in 1980 by Fabian (Prostacoil or Urocoil).1,2 Almost 10 years later, Nissenkorn3 reported on a silicone stent (intraurethral catheter, IUC), Nordling et al.4 on a gold-plated coil (Prostakath), and Williams et al.5 on a stent of woven stainless steel (Urolume). Subsequent development in this area has increased rapidly. Stents have been described as temporary (removable) or permanent (incorporated into the tissue, epithelialized), but the distinction between the two groups is becoming less clear, as the temporary stents might be left in situ for several years, and often patients die with the stent in situ. The internal diameters of the stents differ, however, and permanent stents have the advantage that cystoscopy can be easily carried out through the stent, although this is also possible through the second generation of temporary stents. This chapter deals with temporary stents, which have been divided into first- and second-generation stents (Table 38.1). First-generation temporary stents Urospiral The initial stent was introduced by Fabian1 (Fig. 38.1). This device is a coil of stainless steel. It consists of three parts. The body lies in the prostatic urethra and protrudes 10–15 mm into the bladder. The length of the body ranges from 45 to 75 mm to fit the length of the sphincteric urethra. The neck is 20 mm long and should be positioned in the sphincteric urethra; the head is 2 mm long, and lies in the bulbous urethra distal to the sphincter. Before insertion of the stent, prostatic urethral length is measured either endoscopically or by either abdominal or rectal Table 38.1 Temporary stents. First generation Second generation Urospiral Memokath Prostakath   Intraurethral catheter   ultrasound. It is the author’s experience, that these methods give quite different results. Endoscopic length is often quite short, partly because measurement is normally to the verumontanum and not to the apex, which may be 1–2 cm further distal in the urethra. Using the rigid endo scope, the straight distance from the bladder neck is also measured, whereas the prostatic urethra is normally curved, at least posteriorly where the stent preferably should be positioned. The Urospiral is inserted under endoscopic guidance using a special grasping forceps. A 7-Fr ureteral catheter used as a guidewire considerably facilitates insertion. Insertion is performed under sedoanalgesia or using urethral gel containing local analgesic. Insertion through a cystoscope sheath,6 guided by fluoroscopy,7 or by rectal ultrasound,8 has been described. Occasionally, insertion is not possible because of a urethral stricture. Symptomatic outcome A success rate of about 70% is reported within the first year after insertion (Table 38.2), but only sparse information exists on symptom scores. Guazzoni et al.17 reported postinsertion mean Boyarsky symptom scores of 11.1 (3 months), 13.2 (6 months), and 13.5 (12 months) in 20 patients, all of whom were in urinary retention before stent insertion. Effect on obstruction An increase in peak urinary flow rate is reported, although actual figures are scarce, especially before stent insertion,

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Figure 38.1 Urospiral

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Page 530 Table 38.2 Results of studies using the Urospiral Reference No. of patients Age (years) Follow-up Success rate Complications (median (range)) (months) (%) (number) Fabian1 2 (75–79) 5–12 100   Fabian2 48 80 (53–92) ≤30 88   Langkopf et al.9 15   ≤3 45   Fabricus et al.10 15   ≤12 30 Migration (6) Rohl et al.11 11 75.4 (63–93) ≤12 45 Incontinence (6) Flier and Seppelt12 49 (62–93) ≤24 70 Dislocation (5) Too short (6) Encrustation (1) Schops and Kierfeld13 7   ? 100   Langmeyer and Ferwerda14 11 77 (62–91) ≤7 90 Encrustation (1) Roth and Rathert15 8 ? ≤12 25   Garbit et al.16 26 (61–94) ≤24 80   Guazzoni et al.7 20 85 (78–92) 6 95 Incontinence (1) Parker et al.6 36 75 (50–98) 1–18 67 Pain/dysuria (2) Migration (2) Encrustation (2) as a majority of patients were in retention. A peak flow rate of about 10–15 ml/s up to 1 year after insertion has been reported.6,7,18 No data exist on pressure-flow evaluation. Complications The most common complications are bacteriuria, migration, encrustation, incontinence, and urethral stricture (Table 38.2). Bacteriuria is normally not a serious problem and many patients become clear of infection with time.2 The longest reported follow-up with the Urospiral in most reports is 24 months. Possible complications after this time are unknown. Prostakath This device is shaped like the Urospiral but is covered with gold to prevent encrustation19. A special detachable catheter makes insertion much easier and not too different from inserting an indwelling catheter (Fig. 38.2). A 7-Fr ureteral catheter is recommended as a guidewire during insertion and is also provided with the stent. The stent is most easily inserted under ultrasonic guidance (Fig. 38.3).4 The Prostakath comes in lengths from 35 to 95 mm and also has an outer diameter of 21Fr (Fig. 38.4). Insertion is performed as an outpatient procedure using a urethral gel with local analgesic.

Figure 38.2 Prostakath mounted on an insertion catheter. Symptomatic outcome The success rate of about 70% is very much like that of the Urospiral (Table 38.3), but the reported follow-up time is much longer (up to 5 years). Thomas et al.23 demonstrated a much better outcome in patients with acute retention (success rate 89%) than in patients with chronic retention (success rate 30%) in a study with up to 4 years’ follow-up. In a small controlled study24 a modified Madsen-Iversen score decreased from 8 to 5, 4 months after insertion of the Prostakath; in the control group, the symptom score decreased from 8.5 to 7. After transurethral prostatectomy, symptom scores decreased considerably in both groups, to 2 and 3, respectively. Since 1987, the author has personally treated 318 patients with the Prostakath. Voiding symptoms are outlined in Table 38.4. As can be seen, most of these quite elderly patients

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Figure 38.3 (a) Abdominal ultrasound scan of the prostate. Prostatic urethral length 4.1 cm. (b) Prostakath: 55 mm long body is seen in place.

Figure 38.4 Prostakath after removal of the insertion catheter. have no, or only minor, voiding symptoms with the stent in situ. The most bothersome symptoms are persistent frequency and urgency in 15–30% of all patients. Within this long observation period, the stent was removed in 150 patients, while 48 patients died with a functioning stent. Reasons for stent removal are outlined in Table 38.5. Effect on obstruction Two papers report on pressure-flow studies with the Prostakath.24,25 They only include a small number of patients, but the first is randomized and controlled and patients in both groups ultimately had a transurethral prostatectomy (TURP). In the latter,25 eight patients were evaluated at a median of 61 days after stent insertion and detrusor pressure at this time was 46 cmH2O (median) or in the middle of the equivocal area. In the first study,24 detrusor pressure at peak flow rate decreased from 74 cmH2O before stent insertion to 60 cmH2O 4 months after stent insertion, which is in the obstructed area. In the observation group, detrusor pressure increased slightly during 4 months’ observation. After TURP, all patients became unobstructed. This observation confirms that the relief of obstruction seen immediately after stent insertion with an increase in peak flow rate from a mean of 7.9 to 22.3 ml/s deteriorates with time.22 Complications As for the Urospiral, the most common complications with the Prostakath are encrustation,22,26 migration,22,23 incontinence,22 and urethral stricture. Although in 318 patients the author found chronic bacteriuria in 53 and intermittent bacteriuria in 27, this never represented a significant clinical problem. Patients with irritative symptoms due to bacteriuria were normally well treated on long-term, low-dose antiobiotics. All patients received prophylactic antibiotics before stent insertion. One death due to sepsis after stent removal in an 89-year-old man prompted the use of intravenous antibiotics before any stent manipulation. This death was one of two major complications seen during the 8 years of study. The other case was that of an 84-year-old man who had his stent removed after 2 years owing to recurrence of obstructive symptoms. The head of the stent was buried in mucosa, which is often seen and normally represents a mucosal hyperplasia. At removal (by grasping the neck with a hook), 2–3 cm of the urethra was stripped in the whole circumference. At the last follow-up the patient had an indwelling catheter, but the final outcome remained to be seen. Encrustations have not been a major problem, although they may sometimes be fairly severe and become more so after extended follow-up. The stones are very soft and fracture easily. Intraurethral catheter The intraurethral catheter (IUC) was introduced at the same time as the Prostakath.3 The device is a double Malecot 16-Fr polyurethane catheter available in 25–80 mm lengths at 5 mm intervals (Fig. 38.5). It is inserted under local anesthesia with gel, either cystoscopically or using a special insertion

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tube. The IUC lies in the

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Page 532 Table 38.3 Results of studies using the Prostakath. Reference No. of Age (years) (median Follow-up Success patients (range)) (months) rate (%) Yachia et al.20 26 (59–86) <12 77 Harrison and de 30 80 (65–93) ? 55 Souza21          

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Complications (number) Incontinence retention Urethral stricture (1)

Failure in patient with chronic retention Nordling et al.22 150 76 (40–95) 8.2 (0–40) 66 Calcification (21)           Incontinence (25)           Migration (42) Table 38.4 Voiding symptoms in 318 patients after insertion of the Prostakath. Symptom Incidence (number) None Moderate Severe Stress incontinence 244 20 17 Urge 155 79 46 (incontinence) Frequency 162 63 45 Nocturia 205 (0–1 times/night) 61 (2–3 times/night) 12 (>3 times/night) Emptying problems 259 15 8 Urethral bleeding 271 9 2 Local discomfort 262 13 7 Table 38.5 Reasons for removal of Prostakath stent in 150 of 318 patients. Reason for removal No. of patients Planned prostatectomy Incontinence Retention Local discomfort Irritative voiding symptoms No symptomatic improvement Stent migration Not stent related (e.g. stroke) Urethral bleeding Infection

29 17 35 9 17 12 16 14 1 0

Figure 38.5 Intraurethral catheter.

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Page 533 posterior urethra with one of the expansions in the bladder and the second just above the external sphincter (Fig. 38.6). A nonabsorbable nylon suture is connected to the distal end of the catheter and remains within the urethra. This makes removal of the stent very easy if necessary. Symptomatic outcome Success rate is of the same order as with the coils (Table 38.6). Effects on symptom scores are not reported, mainly because the patients were mainly elderly, fragile men with urinary retention. Effect on obstruction Patients previously in retention are normally able to void freely with the device in the correct position. Complications Migration and encrustation are the main complications (Table 38.6).

Figure 38.6 Correct positioning of the intraurethral catheter stent. Second-generation stents The two available second-generation stents are both made of nickel-titanium, a metal increasingly used in medicine. The metal has an intrinsic memory, expands when heated (at a preselected temperature) and becomes flaccid and increasingly bendable when cooled. Memokath The Memokath is an intraprostatic coiled spiral stent made of a nickel-titanium alloy thread, 0.65 mm thick. It has an outer diameter of 22 Fr and an inner diameter of 18Fr. The material exists in two states at different temperatures. When heated to 45–50 degrees centigrade the coil returns to its original shape, expanding the lower five turns conically to a maximum diameter of 11 mm (Fig. 38.7). When the coil is cooled using water at a temperature of 5–10 degrees centigrade, it becomes extremely pliable and may be easily removed. Due to its thermoplastic properties, the Memokath is capable of ‘remembering’ its shape and its use has been associated with significant success rates in selected patients.29–38 The stent is positioned endoscopically using a 14–16-Fr flexible cystoscope in the prostatic urethra with the tip at the bladder neck and the expandable section at the apex above the external sphincter. The stent should not protrude into the bladder, thus minimizing the risk of encrustation (Fig. 38.8). The length of the prostatic urethra must be determined before implantation of the stent, which comes in lengths of 40, 50, 60, and 70 mm. The cystoscope is passed through the insertion catheter and the stent, so that it projects 2–3 mm beyond the tip of the stent. The urethra is lubricated with local anesthetic gel and the stent is inserted under direct vision. The tip is positioned at the bladder neck and the distal part of the stent is flushed with water at 55 degrees centigrade. This dilates the distal part of the stent, thereby releasing it from the sheath. The sheath and the flexible cystoscope can then be gently retracted. Table 38.6 Results of studies using the Nissenkorn intraurethral catheter. Reference No. of Age (years) (median Follow-up Success rate Complications patients (range)) (months) (%) (%) Nissenkorn27 73 74 (54–100) 6–16 74 Migration (5)           Obstruction (2) file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_533.html[09.07.2009 11:55:47]

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  Sassine and Schulman28  

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  up to 24

 

 

 

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  Stone (1) 85 Migration (9)  

Stone (1)

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Figure 38.7 Memokath: (a) during insertion; (b) after flushing with 50-degree-centigrade water.

Figure 38.8 Correct positioning of the Memokath stent. If the stent is to be removed, cold irrigation fluid is used. This makes the stent soft, bendable, and as easy to extract as a long thread. Effect on symptoms Poulsen et al.39 reported a success rate of 83% with a median follow-up of 3 months (range 0.2–9 months). Similarly, Booth et al.40 reported a success rate of 80%, and in 57 patients treated in 1995 the success rate with 12 months’ follow-up was 93%.41 In a long-term follow’up study of 211 men fitted with Memokath stents, a mean improvement in the International Prostate Symptom Score (I-PSS) of 12.1 points was recorded in the first 3 months. This score then changed little over the following 7 years.38 Over this period, 24% of patients had their stents removed. Reasons included the renewed possibility of performing TURP, worsening symptoms, or stent migration. Overall, the men were more likely to die than the stent was to fail. The author has treated 64 patients with the Memokath, with an observation time of up to 3 years. A total of 24 stents have been removed, but only ten because of stent problems: in five patients removal was due to urinary retention, in three it was due to urinary incontinence, in one it was due to local discomfort, and one patient experienced stent migration. Patients’ symptoms are outlined in Table 38.7. Seven patients received no further treatment after stent removal; seven had another type of stent inserted, three received an indwelling catheter, and only seven went on to prostatectomy. It must be remembered that stents are mostly used in patients who are too old or frail for surgery,29 so the patient population is not comparable to a normal prostatectomy population. This should be taken into consideration with rates of stent failure or the recurrence of urinary symptoms. Regarding the frailty of many Memokath recipients, a reduced risk of methicillin-resistant Staphylococcus aureus (MRSA) infection, which is associated with suprapubic catheterization, has been identified with use of this stent.30 MRSA colonization poses a severe risk to frail or immunocompromised individuals, so a reduction in this risk factor could be of significant benefit. In patients with spinal injuries and detrusor-sphincter dyssnergia, reductions in residual urine volumes, preoperative hydronephrosis, and autonomic dysreflexia have been reported.31 Ease of placement and removal were also observed and 79% of patients experienced successful stent function. The author concluded that patients with spinal injuries who are unsure as to their preferred method of bladder file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_534.html[09.07.2009 11:55:48]

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management, those likely to use intermittent selfcatheterization at some point in the future, and those undergoing fertility treatment are particularly suitable for Memokath stents.

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Page 535 Table 38.7 Voiding symptoms in 64 patients after insertion of the Memokath. Symptom Incidence (number); None Moderate Severe Stress incontinence 49 1 1 Urge 17 15 10 (incontinence) Frequency 28 14 10 Nocturia 36 (0–1 times/night) 15 (2–3 times/night) 1 (>3 times/night) Emptying problems 49 2 1 Urethral bleeding 49 2 1 Local discomfort 52 0 1 Effect on obstruction Peak flow rate has been reported to increase following Memokath placement. One study documented an increase from a mean of 8 to 16 ml/s immediately after insertion,39 although this tended to decrease after some months. No data are available on pressure-flow studies. Complications Stent migration has been found in 13% of patients over an 8-year period.38 This is a better migration rate than with the first-generation stents. Encrustation and stone formation seem to be reduced as well, affecting only 25 of patients in this long-term study. Of 24 stents removed by the author, 12 were without macroscopic encrustation, three had minor, three slight, and three severe encrustation. Of 42 evaluable patients, 13 had persistent bacteriuria causing no clinical problems; in four, urinary infection was cured with antibiotics. In order to avoid such complications, it has been recommended that the length of the stent be slightly overestimated, as the stent requires a longer path than a flexible cystoscope to reach the bladder neck; that UTIs be cleared before stenting; that detrusor function be confirmed; and that patients and carers be appropriately informed about how and why the procedure is being performed.38 Prostacoil This stent is also made of nickel-titanium and is wound on a delivery catheter. At insertion it has an outer caliber of 17Fr, and after release it takes on a wavy form, with an alternating caliber of 24–3 30Fr. The stent is, like the Urocoil and the Prostakath, composed of three sections (Fig. 38.9). The intraprostatic section is made in 40, 50, 60, 70, and 80 mm lengths, while the intrabulbar section

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Figure 38.9 Prostacoil: (a) intraprostatic section; (b) intrabulbar section; (c) helican transsphincteric section. has a length of 10 mm. The two parts are connected by a helical trans-sphincteric section. The Prostacoil is provided on a delivery catheter and inserted under fluoroscopy (Fig. 38.10). The patient is catheterized at least 24 hours previously with a 20-Fr Foley catheter. After removal of the catheter, a retrograde urethrogram is performed and the position of the external

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Page 536

Figure 38.10 Radiograph of the Prostacoil in situ. sphincter is marked with an external radio-opaque marker. The distance from the bladder neck to the external sphincter is measured using an open-tip measuring catheter. The tip of the stent is designed to protrude 5–10 mm into the bladder, so a stent of appropriate length is chosen. A guidewire is threaded through the measuring catheter, which is then removed, and the guidewire is used for insertion of the stent. When the stent is in place, the lock on the introducing catheter is released, first the distal and then the proximal part. A new endoscopic device for delivering the Prostacoil is currently being tested. The Prostacoil may be removed either by using a 12-Fr Foley bag catheter inserted through the stent or by grasping the distal end of the stent and pulling it out through the endoscope. Effect on symptoms A success rate of 88% was reported by Yachia et al.42 in 65 patients with a mean follow-up of 16 months (range 3–28 months). In 11 patients refusing surgery, the Prostacoil was used for long-term treatment.43 With a follow-up of 2–28 months the I-PSS decreased from 28 to 9. Effect on obstruction Patients unable to void before stent insertion voided freely afterwards. In the above-mentioned 11 patients, maximum urinary flow rate increased from 4.2 ml/s to 21.3 ml/s. Complications Migration has been reported in only one patient and obstructing stone formation in six patients.43 Patients with sterile urine remained sterile and, in 26 of 32 patients, a previous infection cleared within 2 months. Stents for short-term use The introduction of BPH treatments producing necrosis of the prostatic tissue without tissue removal has initiated the development of stents for use until tissue edema has disappeared and debridement of the necrotic prostatic tissue is complete. Self-retaining intraurethral catheter (Trestle) The Trestle catheter consists of two tubes with an outer diameter of 22Fr and connected by wires. The upper tube, 75 mm in length, is positioned in the prostatic urethra, the threads in the sphincter area and the lower tube in the bulbous urethra. It is inserted under guidance of rectal ultrasound. file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_536.html[09.07.2009 11:55:49]

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The Trestle catheter has been used in 43 patients after transurethral microwave therapy (TUMT).44 Stent insertion was possible in 42 patients, but had to be changed in six patients due to clot retention. All stents were removed after 1 month. The Madsen score decreased from 13.7 to 4.6, while the maximum flow rate increased from 8.1 ml/s to 14.6 ml/s at 1 month. The catheter was employed in 54 patients in a separate study.45 Barnes stent This is a single Malecot stent very much like the IUC, but without the expansion inside the bladder. It is 75 mm long, 16 Fr in outer diameter and made of polyurethane. It is inserted by means of a curved introducer, dislodged into the bladder and pulled back in place under endoscopic control. It has been used in 80 patients after endoscopic laser ablation of the prostate.46 Fifty-nine patients voided immediately. In 55 patients, the maximum I-PSS fell from 25 to 8 and the maximum flow rate increased from 8.5 ml/s to 16 ml/s. The stent migrated in five patients, requiring suprapubic drainage, and in three caused no voiding problems. At 8–12 weeks all stents were removed.

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Page 537 Biodegradable stents Biodegradable materials are based on polymers. Biodegradable stents are made of polymers of glycolic acid and lactic acid. Degradation time for a self-reinforced polyglycolic acid (SR-PGA) stent is 3–4 weeks and for a self-reinforced poly-DL-lactic acid (SR-PLA 96) stent about 3–4 months. The SR-PGA stent has been used in 22 patients after visual laser ablation of the prostate.47 Four patients experienced late retention due to early degradation of the stent. The Danish prostatic symptom score (DAN-PSS-1) decreased from 16.4 to 3.0 at 6 months. The maximum flow rate increased from 6.9 ml/s to 14.1 ml/s. The procedure was repeated in 27 patients in a randomized study with the same results.48 The SR-PLA stent was used in 22 patients after visual laser ablation of the prostate in a randomized study.49 Eighteen patients voided freely. At 6 months fragments of the stent were still present in 20 of 22 patients and two patients had stone formation. Although further investigation of the benefits of biodegradable stents is needed, additional promising results have been reported recently. Discussion Long-term indwelling catheters are simple to use, but are associated with significant complications,50,51 besides the considerable embarrassment and bother associated with such a device. Prostatectomy is by far the best treatment for a patient facing the need to carry an indwelling catheter because of infravesical prostatic obstruction. If the patient for some reason is unfit for surgery, several alternatives are possible, such as thermotherapy, clean intermittent self-catherization, permanent stents, or temporary stents. Temporary stents allow normal voiding for many months. They are easy to insert, even as an outpatient procedure, and are normally easy to remove, especially the second-generation nickel-titanium stents. First-generation temporary stents carry a considerable risk of complications in the form of encrustation inside and outside the stent, and stent migration. The latter complication seems to be much less of a problem with the second-generation stents. Very few data exist on symptom scores, but it seems that these patients at longer follow-up are still fairly symptomatic.17 In this context it must be remembered that a majority of these patients are old and frail—a population often suffering from lower urinary tract symptoms that are due to causes other than infravesical obstruction. Longterm follow-up of patients fitted with the Memokath, however, showed significant improvements in I-PSS that were maintained over a period of 8 years.38 The effect on infravesical obstruction has been poorly described. Pressure-flow studies involving one type of temorary stent (the Prostakath) showed patients to be clearly obstructed 4 months after stent insertion. Stent insertion initiates an edematous reaction in the urethral mucosa. Even in the large calibrated permanent stents this may become obstructive; in the temporary stents with their smaller diameter it is much more likely. It seems that the ability to void freely immediately after insertion of a temporary stent is followed by increasing mucosal obstruction, leaving the patient able to void but with the problem of a moderate to severe infravesical obstruction. First-generation temporary stents protruding into the bulbous urethra (Prostacoil, Prostakath) carry the risk of developing urethral strictures (Table 38.3) and many (30%) of these patients have some degree of urinary incontinence. A bioabsorbable stent that disintegrates within a few weeks to months has been described.52 This stent might be particularly useful after laser prostatectomy or in other conditions where very short-term relief of infravesical obstruction is needed. Although promising, these stents are still under development.53–55 Second-generation stents, such as the Memokath, have proved to be simple to insert and remove under local anesthetic and may, in fact, be considered permanent in frail patients as such individuals are often more likely to die with the stent in place than to require the insertion of another.38 In patients with spinal injuries, high success rates have been reported.31 The cost of stenting will have a strong influence on its acceptability and use. It is traditionally accepted that temporary stenting is far more expensive than use of an indwelling catheter. However, investigation of the cost implications of the Memokath revealed that use of the temporary stent was only slightly more costly than an indwelling catheter.29,32The initial cost of placement of a catheter may be low; however, the cost of dealing with associated complications and ongoing care by the district nursing service (DNS), or similar, adds to the cost considerably. In 1 year, for example, 10115 visits were made by the DNS to only 607 patients. Conclusions First-generation temporary stents are indicated only as an alternative for an indwelling catheter for short-term relief of prostatic obstruction, for example, in patients waiting file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_537.html[09.07.2009 11:55:50]

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Page 538 for surgery, after laser prostatectomy, or as a treatment for a longer period in patients unfit for surgery. Second-generation temporary stents seem to have fewer complications, with the indications being the same as for the first-generation stents. Although recent studies have shown positive results with second-generation temporary stents, in terms of I-PSS and complication rates, further long-term studies of their effect on lower urinary tract symptoms and infravesical obstruction are needed. References 1. Fabian K M. Der intraprostatische spirale ‘Partielle Katheter’ (Urologische spiral). Urologe A 1980; 19: 236–238 2. Fabian K M. Der intraprostatische ‘Partielle Katheter’ (Urologische spirale) II. Urologe A 1984; 23:229–233 3. Nissenkorn I. Experience with a new self retaining intraurethral catheter in patients with urinary retention: a preliminary report. J Urol 1989; 142:92–94 4. Nordling J, Holm H H, Klarskov P et al. The intraprostatic spiral: a new device for insertion with the patient under local anaesthesia and with ultrasonic guidance with 3 months follow up. J Urol 1989; 142:756–758 5. Williams G, Jager R, McLoughlin L. Use of stents for treating obstruction of the urinary outflow in patients unfit for surgery. Br Med J 1989; 298:1429–1431 6. Parker C J, Birch B R P, Connelly A et al. The porges urospiral: a reversible endoprostatic prosthetic stent. World J Urol 1991; 9:22–25 7. Guazzoni G, Montorsi F, Columbo R et al. Long term experience with the prostatic spiral for urinary retention due to benign prostatic hyperplasia. Scand J Urol Nephrol 1991; 25:21–24 8. Billiet I, Matterlaer J, Van Brien P. Use of transrectal longitudinal sonography in the placement of a prostatic coil. Eur Urol 1990; 17:76–78 9. Langkopf B, Oehlmann U, Geshe R, Rebmann U. Erste Erfahrungen mit einer harnrohren Endothese bein Blasenhalsadenom. Z Urol Nephrol 1991; 74:793–800 10. Fabricus P G, Matz M, Zefinich H. Die endourethral Spirale—eine Alternativ zum Dauerkatheter? Z Arztl Fortbild (Jena) 1983; 77:482–483 11. Rohl H F, Bauhe H P, Andersen O P. Den urologiske Spiral. Et Endoprostatik Kateter. Ugeskr Laeger 1987; 149:2076–2077 12. Flier G, Seppelt U. Erfahrungen mit der urologischen Spiral. Urologe (B) 1987; 27:308–309 13. Schops W, Kierfeld G. Die urologische Spirale und ihr klinischer Stellenwert. Urologe (B) 1987; 27:308–309 14. Langemeyer T N M, Ferwerda W H H. De prostaat Spiral als Alternatief voor een Verblijtscatheter. Ned Tijdschr Geneeskd 1987; 131:2022–2025 15. Roth S T, Rathert P. La ‘spirale urologique’. Une possibilite therapeutique dans le traitement du carcinoma prostatique. J Urol (Paris) 1988; 94:261–263 16. Garbit J L, Blitz M, Bomel J et al. La prothese endo-prostatique spirale de Fabian. J Urol (Paris) 1988; 94: 265–267 17. Guazzoni G, Montorsi F, Bergamaschi F et al. Prostatic spiral versus prostatic urolume Wallstent for urinary retention due to benign prostatic hyperplasia. Eur Urol 1993; 24:332–336 18. Conart P as cited in Smith P H. Other non-medical therapies (excluding lasers) in the treatment of BPH. In: Cockette A T K, Khoury S, Aso Y et al. (eds). Proceedings of the 2nd international consultation on benign prostatic hyperplasia (BPH). Jersey: SCI 1993:470–471 19. Holmes S A V, Miller P D, Crocker P R, Kirby R. Encrustation of intraprostatic stents—a comparative study. Br J Urol 1992; 69:383–387 20. Yachia D, Lask D, Rabinson S. Self retaining intraurethral stent: an alternative to long-tern indwelling catheters or surgery in the treatment of prostatism. Am J Roentgenol 1990; 154:111–113 21. Harrison N W, de Souza J V. Prostatic stenting for outflow obstruction. Br J Urol 1990; 65:192–196 22. Nordling J, Ovesen H, Poulsen A L. The intraprostatic spiral: clinical results in 150 consecutive patients. J Urol 1992; 147:645–647 23. Thomas P J, Britton J P, Harrison N W. The prostakath stent: four years experience. Br J Urol 1993; 71:430–432 24. Nielsen K K, Kromann-Andersen B, Poulsen A L et al. Subjective and objective evaluation of patients with prostatism and infravesical obstruction treated with both intraprostatic spiral and transurethral prostatectomy. Neurourol Urodyn 1994; 13:13–19 25. Nielsen K K, Kromann-Andersen B, Nordling J. Relationship between detrusor pressure and urinary flow rate in males with an intraurethral prostatic spiral. Br J Urol 1989; 64:275–279 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_538.html[09.07.2009 11:55:50]

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26. Rosenkilde P, Pedersen J F, Meyhoff H H. Late complications of prostakath treatment for benign prostatic hypertrophy. Br J Urol 1991; 68:387–389 27. Nissenkorn I. Prostatic stents. J Endourol 1991; 5:79–82 28. Sassine A M, Schulman C C. Intraurethral catheter in high-risk patients with urinary retention. 3 years experience. Eur Urol 1994; 25:131–134 29. Booth C M, Chaudry A A, Lyth D R. Alternative prostate treatments: stent or catheter for the frail. J Managed Care 1997; 1:24–26

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Page 539 30. Derry F, Fellows G, Frankel H. Methicillin-resistant Staphylococcus aureus cleared using a spiral thermoexpandable urethral stent. Br J Urol 1997; 80:683–684 31. Shah N C, Foley S J, Edhem I, Shah J P R. Use of MEMOKATH®; temporary urethral stent in treatment of detrusor-sphincter dyssynergia. J Endourology 1997; 11: 485–488 32. Chaudry A A, Booth C M. Clinical and cost comparison of long-term catheterisation and MEMOKATH®; prostatic stenting. In: Yachia D (ed). Stenting the urinary system. Oxford: ISIS Medical Media, 1998:297–300 33. Eichenauer R H, Koll B, Schuller J. Der thermalobile Stent als therapiemoglichkeit obstruktiver Prostataerkrankungen. Medizin Bild 1998; 5:23–28 34. Itoh H, Shinomiya T, Matsumoto Y et al. Clinical experience of intraurethral catheter made of shapememory alloy (MEMOKATH®). Jpn J Urol Surg 1999; 12: 511–517 35. Mahnken A H. Einwachsen eines MEMOKATH® 028 Prostatastent—Ein Fallbericht. Akt Urol 1999; 30: 492–494 36. Hara H, Ishii N, Deguchi M et al. Clinical experience of intraurethral stent made of shape memory alloy (MEMOKATH®) for refractory urethral strictures. Jpn J Urol Surg 2000; 13:1431–1437 37. Shigeta M, Nakamoto T, Nakahara M, Usui T. Efficacy of intraurethral catheter made of shapememory Allow for complete posterior urethral rupture complicated with pelvic bone fracture. Jpn J Urol Surg 2000; 13:929–932 38. Perry M J A, Roodhouse A J, Gidlow A B et al. Thermoexpandable intraprostatic stents in bladder outlet obstruction: an 8-year study. BJU Int 2002; 90 : 216–223 39. Poulsen A L, Schou J, Ovesen H, Nordling J. Memokath: a second generation of intraprostatic spirals. Br J Urol 1993; 72:331–334 40. Booth C M, Al-Dabbagh M A, Lyth D R, Nordling J. The memokath: a second generation ‘memory alloy’ prostatic stent. Proc BAUS Ann Meet, Harrogate, June 1993; 153 41. Chaudry A A, Booth C M. Clinical and cost comparison of long term catheterization and Memokath prostatic stenting. In: Yachia D (ed). Stenting the urinary system. Oxford: ISIS Medical Media, 1998:297–300 42. Yachia D, Beyar M, Aridogan I A. A new, large calibre, self-expanding and self-retaining temporary intraprostatic stent (Prostacoil) in the treatment of prostatic obstruction. Br J Urol 1994; 74:47–49 43. Yachia D. Prostacoil in non-surgical management of BPH. In: Yachia D (ed). Stenting the urinary system. Oxford: ISIS Medical Media, 1998:301–309 44. Devonec M. Self-retaining intraurethral catheter (Trestle) for prevention of postoperative urinary retention: experience after microwave therapy of the prostate. In: Yachia D (ed). Stenting the urinary system. Oxford: ISIS Medical Media, 1998:329–334 45. Djavan B, Fakhari M, Shahrokh S et al. A novel intraurethral prostatic bridge catheter for prevention of temporary prostatic obstruction following high energy transurethral microwave thermotherapy in patients with benign prostatic hyperplasia. J Urol 1999; 16:144–151 46. Barnes D G, Yakubu A. Temporary prostatic stenting using the Barnes stent. In: Yachia D (ed). Stenting the urinary system. Oxford: ISIS Medical Media 1998; 335–338 47. Talja M, Tammela T, Pétas A et al. Biodegradable self-reinforced polyglycolic acid spiral stent in prevention of postoperative urinary retention after visual laser ablation of the prostate. J Urol 1995; 154:2089–2092 48. Pétas A, Talja M, Tammela T et al. A randomized study to compare biodegradable self-reinforced polyglycolic acid spiral stent to suprapubic catheter after visual laser ablation of the prostate. J Urol 1997; 157:173–176 49. Pétas A, Talja M, Tammela T et al. Biodegradable selfreinforced poly-DL-lactic acid (SR-PLA 96) spiral stent compared to suprapubic catheter in the treatment of postoperative urinary retention after visual laser ablation of the prostate. Br J Urol 1997; 80:439–443 50. Ouslander J G, Greengold B, Chen S. Complications of chronic indwelling catheters among male nursing home patients: a prospective study. J Urol 1987; 138:1191–1195 51. Brietenburger R B. Bacterial changes in the urine sample of patients with long-term indwelling catheters. Arch Ind Med 1984; 144:1585–1588 52. Kemppainen E, Talja M, Riihelä M et al. A biobabsorbable urethral stent. Urol Res 1993; 21:235–238 53. Pétas A. Use of biodegradable stents after visual laser ablation of the prostate. In: Yachia D (ed). Stenting the urinary system. Oxford: ISIS Medical Media 1998; 339–346 54. Laaksovirta S, Talja M, Valimaa T et al. Expansion and bioabsorption of the self-reinforced lactic and glycolic acid copolymer prostatic spiral stent. J Urol 2001; 166: 919–922 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_539.html[09.07.2009 11:55:51]

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55. Isotalo T, Talja M, Hellstrom P et al. A double-blind, randomized, placebo-controlled pilot study to investigate the effects of finasteride combined with a biodegradable selfreinforced poly L-lactic acid spiral stent in patients with urinary retention caused by bladder outlet obstruction from benign prostatic hyperplasia. BJU Int 2001; 88: 30–34

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Page 541 VI Shared Care

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Page 543 39 The impact of BPH on sexual function C C Carson Introduction Benign prostatic hyperplasia (BPH) is one of the most common conditions affecting the aging male, with more than 70% of men over the age of 70 years having evidence of BPH.1 It is well recognized that the incidence of sexual dysfunction and BPH in men increase with age.2,3 It is therefore intuitive that some men presenting with symptomatic BPH will have some degree of sexual dysfunction purely based on age alone. In the aging male, most sexual dysfunction is erectile dysfunction (ED). To date, the most recent study to examine a cross-sectional community-based random sample of ED is the Massachusetts Male Aging Study (MMAS) (Fig. 39.1).4 This study of 1209 men aged between 40 and 70 demonstrated that the combined prevalence of mild-moderate and complete ED was 52% for this sample population. The prevalence of complete ED trebled from 5% at age 40 to 15% at age 70. As one might expect, the variable most commonly associated with ED in this study was age, with the prevalence of both ED and lower urinary tract symptoms (LUTS) increasing with age. The interrelation of BPH and ED has only recently been examined in epidemiologic studies. The first study to

Figure 39.1 Association between age and prevalence of erectile dysfunction. Massachusetts Male Aging Study 1994. (Data derived from reference 4.) suggest this coexistence was the ‘Cologne study’.5 This study of 4489 men in Germany evaluated the prevalence of ED in a cohort of men over age 40 and evaluated their risk factors for ED. In addition to the usual vascular risks for ED, the investigators demonstrated an age-independent correlation of ED with LUTS of BPH. While the explanation for this relationship remains somewhat obscure, other studies have not only confirmed the relationship but strengthened their coexistence. In a study designed to specifically identify this relationship, Rosen et al. showed a strong age-independent ED/LUTS relationship at each decade of age over 40 (Fig. 39.2).6 Fortunately, because of increased public awareness of BPH, its treatments, and the consequences of these treatments, it has now become more socially acceptable for patients to discuss problems related to sexual function. Unfortunately, sexual function shares with BPH the absence of a unifying definition for which the sensitivity and specificity can be determined. A significant problem which arises discussing sexual function with patients and partners, and when reviewing the literature, is knowing which aspect of male sexual dysfunction is being referred to. The various aspects include

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Figure 39.2 International Index of Erectile Function (IIEF) impact of lower urinary tract symptoms (LUTS). (Data derived from reference 4.)

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Page 544 erectile dysfunction, ejaculation dysfunction, decreased ejaculation, decreased libido, and decreased overall sexual satisfaction. Any of these different aspects of sexual function may be affected by LUTS presumably caused by enlargement of the prostate secondary to BPH. Complex interrelationship between BPH and sexual function It is generally accepted that sexual function is an important aspect of quality of life. Analysis of the current literature shows that there is a poor understanding of the relationship between BPH and sexual function. The question of whether the presence of BPH, independent of age, adversely affects sexual function is one that heretofore has not been studied widely and the available data are conflicting. However, the more recent data would tend to support the likelihood that the presence of significant symptomatic BPH in men does contribute appreciably to male sexual dysfunction. Pearlman and Kobashi,7 in a survey in 1972 of 2801 men in private practice aged between 17 and 93 years, found that the level of ED was the same for those considered to have symptomatic BPH as for those without. O’Leary et al.8 reported that sexual dysfunction is most influenced by the severity of LUTS. Baseline LUTS were correlated not only to ED, but also to libido and sexual satisfaction by Burger et al.9 In a recent multinational study of this association called the MSAM-7, or Multinational Survey of the Aging Male, more than 14000 men aged 50 to 80 were surveyed (Fig. 39.2).6 The study reported a 49% prevalence of ED, 48% ejaculatory disorders, and a strong relationship of ED with age which correlated strongly with the severity of LUTS. Bowers et al.,10 in 1963, found a similar relationship in a study of 157 men. Two consensus statements from McConnell et al.11 in 1994 and Mebust et al.12 in 1993 both state that BPH does not directly affect sexual function. In contrast, a number of studies support the belief that the presence of BPH independent of age, affects patients’ perception of sexual life satisfaction. Hargreave and Stephenson,13 in a 1977 study of men undergoing prostatectomy, found a statistically significant relationship between the duration of poor stream and erectile dysfunction even after adjusting for age. MacFarlane et al.,14 in 1996, in a community-based study of 2011 French men aged between 50 and 80 years, assessed sexual life factors (frequency of sexual desires, sexual relations, and the frequency of difficulties with erection and ejaculation) and quantified the degree of urinary symptoms using the International Prostate Symptom Score (I-PSS). The authors found that men with urinary symptoms were more likely to be dissatisfied with their sexual life than those who had none. This analysis took into account potentially confounding variables such as frequency of sexual relations, erection difficulties, co-morbidities, and previous prostate surgery. The possibility of being dissatisfied with their sexual life increased with increasing severity of urinary symptoms, being twice as likely in those men with moderate symptoms (I-PSS 9–19) and four times more likely in those with severe symptoms (I-PSS >19) compared to those with no urinary symptoms. This is in concordance with previous work by Doll et al.15 in 1993 on 388 men undergoing transurethral resection of the prostate (TURP) which reported that patients with symptomatic bladder outflow tract obstruction were significantly more likely to consider their sexual life somewhat or considerably more spoiled compared to those without symptoms of bladder outflow tract obstruction. Frankel et al.,16 in 1998, studied 423 men in a community-based population and 1271 men in a clinic population aged over 45 years using the ICSmale and ICSsex questionnaires. Sexual dysfunction was found to be common, with sex lives reported to be affected by BPH symptoms in 8% of community men and 46% in the clinic. A significantly increased risk of sexual dysfunction was found in those with LUTS, especially for those with storage symptoms resulting in incontinence. This study also demonstrated that older men might be just as bothered by their sexual symptoms as younger men, a factor which has been demonstrated previously by Namasivayam et al.17 and Helgason et al.18 It could be hypothesized that urinary symptoms do not have a direct result on sexual life satisfaction, but instead adversely affect a sense of perceived general well-being and/or self-esteem, factors which of themselves may have an effect on sexual life satisfaction. Despite the fact that the evidence concerning BPH and sexual dysfunction continues to be studied, it has now generally become accepted that a sexual questionnaire should be routinely used to ascertain the baseline level of sexual health before embarking on treatments for BPH in either a clinical or research setting. Indeed, BPH with LUTS and ED has a significant effect on quality of life (QoL).19 Measuring the impact of BPH and sexual function on a QoL scale Quality of life is defined as the patient’s self-evaluation of his condition and its impact on his functional status, wellbeing, and opportunity.20 One of the primary goals of QoL questionnaires should be to quantify the patients’

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Page 545 perception of and satisfaction with the way they function. Review of the current literature revealed several QoL questionnaires that were designed to quantify the degree of impact of BPH, or its treatment, on sexual function.13,16,18–28 Many of the earlier papers concerned themselves with the effect of BPH treatment on the patients’ QoL and sexual function, whereas more recently, there has been a shift to try to ascertain the baseline level of sexual function and its relationship to BPH in advance of the planned treatment and to repeat the assessment after the treatment has been administered. Now there are several sophisticated alternatives, including the benign prostatic hypertrophy health-related QoL (BPH-HRQoL) questionnaire, the Brief Sexual Function Inventory, the International Continence Society sex questionnaire (ICSsex), the Radiumhemmets scale of sexual function, and the International Index of Erectile Function (IIEF).29 The I-PSS QoL explores the bother of the patients’ symptoms rather than quality of life and its usefulness lies in trying to determine which patients should receive treatment, rather than in assessing the association between BPH and sexual function. The BPH-HRQoL devised by Lukacs et al.24 in 1994 is designed to assess physical/mental social/sexual items and general aspects of QoL. In its original form the questionnaire consisted of 20 visual analog scales, but it was shortened in 199725 to nine items with three axes: general well-being, patients’ perceived sexuallife status, and BPH-specific interference with activities. The Brief Male Sexual Function Inventory was devised by O’Leary et al.23 in 1995. It is composed of 11 items and was originally designed for urologic practice and research. There are five modules covering sexual drive, erections, ejaculation, perception of problems in each area, and overall satisfaction (Table 39.1). The ICSsex questionnaire contains four questions concerned with sexual function: rigidity of erections, quantity of ejaculation, pain on ejaculation, and perceived impact of LUTS on sex life. The ICS questionnaire is being updated presently and will be available shortly as the PROTOsex questionnaire with additional items concerned with satisfaction with sex and changes in sex life. The Radiumhemmets scale of sexual function was originally designed to assess the sexual function in men with prostate cancer,30 but it can also be used to assess the effects of treatment for men with BPH. The questionnaire assesses the frequency and intensity of seven aspects of sexual function: sexual desire, penile rigidity, intercourse, orgasm, ejaculate volume, pain, and general health matters. One paper has sounded a note of caution with respect to the cultural variation between patients in different countries regarding the responses to QoL questionnaires,26 demonstrating that there may not be cross-cultural validity for some QoL questionnaires. The development of the International Index of Erectile Function (IIEF) questionnaire (Table 39.2) by Rosen et al.29 is an attempt to solve this potential problem by exhaustive linguistic validation carried out in ten languages. The questionnaire comprises 15 items in five factors: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. There is a constant thread throughout most QoL studies regarding BPH impact, which reflects the fact that anxiety, worry, and well-being are affected by the symptoms of BPH and this is proposed as one of the determining factors in the development of subsequent male sexual dysfunction.30 It is only by seeking to measure and quantify the degree of the problem that we can adequately hope to understand the complex relationships resulting in a secondary unwanted outcome from our therapy for BPH. BPH-treatment-related sexual dysfunction Medical therapies α-Adrenergic antagonists α-Adrenergic antagonists have been shown to be effective in treating the clinical manifestations of BPH.31–33 The rationale for using α-antagonists in the treatment of BPH was based on the observation that the contractile properties of prostatic smooth muscle were mediated by α1-adrenoreceptors. It is known that the stromal to epithelial tissue ratio increases in BPH. This stromal tissue is composed of varying amounts of smooth muscle and fibrous connective tissue. The highest concentration for α1adrenoreceptors is in the bladder neck and prostatic capsule. α1-Adrenoreceptors have also been found on the vas deferens and seminal vesicles. In addition, α-antagonists have been successfully used for the treatment of ED. Indeed, oral phentolamine has undergone phase III studies and is clinically available in several countries in South America.34 Ejaculation disorders, reduced potency, and decreased libido have been reported with the use of all the α-antagonists. While for many men being prescribed these agents there may already be a pre-existing deficit of sexual functioning, these side-effects must be borne in mind, especially when prescribing for the younger patient. file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_545.html[09.07.2009 11:55:53]

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Page 546 Table 39.1 A brief sexual function inventory (from reference 23 with permission). 1 During the past 30 days on how many days No days Only a few Some Most have you felt sexual drive? 0 days days days 1 2 3 2 During the past 30 days, how would you rate your level of sexual drive? Erections 3 Over the past 30 days how often have you had partial or full erections when you were sexually stimulated in any way? 4 Over the past 30 days, how often have you had erections; how often were they firm enough to have sexual intercourse? 5 How much difficulty did you have getting an erection during the last 30 days?

None at all 0   Not at all 0 Not at all 0 Did not get erections 0

Almost every day 4 Low Medium Medium High 1 2 high 4 3         A few Fairly Usually Always times often 3 4 1 2 A few Fairly Usually Always times often 3 4 1 2 A lot of Some Little No difficulty difficulty difficulty difficulty 1 2 3 4

Ejaculation 6 Over the past 30 days how much difficulty have No sexual A lot of Some Little No you had in ejaculating when you have been stimulation in difftculty difficultydifftculty difficulty sexually stimulated? the past month 1 2 3 4 0 7 In the past 30 days how much did you consider Did not climax Big Medium Small No the amount of semen you ejaculate? 0 problem problem problem problem 1 2 3 4 Problem assessment 8 In the past 30 days, to what extent have you Big problem Medium Small Very No considered lack of sex drive to be a problem? 0 problem problem small problem 1 2 problem 4 3 9 In the past 30 days, to what extent have you 0 1 2 3 4 considered your ability to get and keep an erection a problem? 10In the past 30 days, to what extent have you 0 1 2 3 4 considered your ejaculation to be a problem? Overall satisfaction 11Overall during the past 30 days, how satisfied Very dissatisfied Mostly Neutral- Mostly Very have you been with your sex life? 0 dissatisfied mixed satisfied satisfied 1 2 3 4 Sexual drive is defined as a feeling that may include wanting to have a sexual experience (masturbation or intercourse), thinking about having sex, or feeling frustrated due to lack of sex. Ejaculation disorders may occur with variable frequency with patients who take α-adrenergic antagonists due to antagonism of α1-adrenoreceptors in the bladder neck, vas deferens, or seminal vesicles with consequent relaxation of these tissues (Table 39.3). This may present as retrograde ejaculation, the absence of ejaculate, or reduced ejaculate volume. In most patients reporting retrograde ejaculation, this symptom occurs within the first 2–3 weeks of treatment and ejaculatory function recovers after discontinuation of the medication. Surprisingly, few patients discontinue their α-antagonists despite this sideeffect.35,36 Erectile dysfunction is not as common a consequence of the use of α-antagonists as retrograde ejaculation; however, the percentages of patients suffering are still significant (Table 39.4).

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Page 547 It has been suggested that α-antagonists may improve the sexual function in patients with BPH and hypertension. It is noteworthy that both these conditions have a degree of sympathetic overactivity associated with them. Lukacs et al.,47 in 1996, studied 5489 men with BPH in a general practitioner setting and measured the effect of alfuzosin on the patient perceived health-related quality of life (HRQoL) and sexuality. It was observed that there was a time-dependent improvement in the patients’ perception of BPH-HRQoL status. The magnitude of the improvement in BPH-HRQoL was significantly more pronounced for those patients who had moderate or severe nocturia and daytime frequency at baseline than for those who had mild levels of the same symptoms. Improvement in patients’ perceived sexuality was significant at 12 months and was correlated with age. These data agree with previous data for doxazosin from the Treatment of Mild Hypertension Study (TOMHS).48 As stated above, LUTS suggestive of BPH may have a negative impact on sexual function, reducing many patients’ QoL. The mechanisms by which α-adrenoreceptor antagonists achieve this improvement are not elucidated. The findings may reflect the overall improvement in QoL associated with the greater improvement in LUTS achieved by active treatment. It is likely that as the patients are less bothered by their LUTS, they become more able to enjoy other aspects of their life. It has also been postulated that a physiologic explanation for the improvement in sexual function in men treated with an αadrenoreceptor antagonist is possible. This may result from relaxation of smooth muscle in the penile arteries and/or the corpus cavernosum causing increased flow of blood into the corpora cavernosa.49 This theory is further supported by the fact that alpha1A- and alpha1D-adrenoreceptor subtype mRNA is predominant in corpus cavernosum smooth muscle.50 Several authors have shown some success with nonspecific α-adrenoreceptor antagonists, such as phentolamine, to treat patients with erectile dysfunction.51–53 Phentolamine, in addition to its nonselective antagonism of α-adrenoreceptors, also exhibits some anti-serotonin actions and a direct nonspecific relaxant effect on blood vessels. Zorgniotti52 demonstrated the efficacy of 50 mg of phentolamine in patients with psychogenic and mild arteriogenic ED. These data were reproduced by Wagner et al.54 in 1994 in a nonrandomized nonplacebo-controlled multicenter trial where patients used 20–40 mg phentolamine impregnated on a strip of filter paper, applied to the buccal mucosa 15 minutes before coitus. In this study, 32% of patients using the drug obtained an erection suitable for intercourse, compared to 13% who were given placebo. Becker et al.,53 in 1998, performed a doubleblind, prospective randomized controlled trial with oral phentolamine in patients with ED who had a high likelihood of an organic etiology and found that high (60 mg) doses of phentolamine were of some benefit. The numbers involved in all these studies are not large enough to draw any definite conclusions but may help explain on a pharmacologic basis how α-adrenoreceptor antagonists have been shown to improve erectile function in certain studies.34 5α-Reductase inhibitors (finasteride, dutasteride) Finasteride is a competitive inhibitor of 5α-reductase and decreases the conversion of testosterone to dihydrotestosterone, causing a reduction in the size of the prostate and a modest improvement in urinary symptoms. The clinical effectiveness varies depending on the size of the prostate. The number of studies documenting the effect of finasteride on sexual function is small (Table 39.5). As can be seen from Table 39.5, finasteride may be associated with the development of ED in 5.1–9% of patients being treated for BPH compared to placebo. The incidence of ejaculation disorders is relatively constant between the three studies at 2.1%. No studies have shown decreased libido in patients taking finasteride compared to placebo.58 The effect of changes in sexual function appears to decrease over time, as demonstrated in the PLESS study and confirmed with the dutasteride studies.58 The newer 5α-reductase agent dutasteride has also been studied for sexual side-effects. In a clinical trial of 4325 men, Carson et al. reported an initial incidence of sexual side-effects of 4.6% compared with less than 2% placebo.59 At 19–24 months after beginning therapy, however, the complaints of ED, decreased libido, and ejaculatory disorder were equivalent from the dutasteride- and placebo-treated patients (Figs. 39.3 to 39.5). Surgical therapies Transurethral resection of the prostate It is estimated that 15–20% of men older than 40 years will eventually undergo TURP. 60 Most authors accept that there will be some impairment in sexual function consequent on this procedure. The exact size of the problem has been difficult to assess by reviewing the published literature. Postoperative decrease in sexual function or loss of potency has been reported to affect between 0 and 40% of men who have undergone prostatectomy.13,61–70

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Page 548 Table 39.2 The international index of erectile function (IIEF) (from reference 29 with permission). Question* Response options Q1How often were you able to get an erection during sexual activity? 0=No sexual activity Q2When you had erections with sexual stimulation, how often were your 1=Almost never/never erections hard enough for penetration? 2=A few times (much less than half the time) 3=Sometimes (about half the time) 4=Most times (much more than half the time) 5=Almost always/always Q3When you attempted sexual intercourse, how often were you able to 0=Did not attempt penetrate (enter) your partner? intercourse 1=Almost never/never Q4During sexual intercourse how often were you able to maintain your 2=A few times (much less erection after you had penetrated your partner? than half the time) 3=Sometimes (about half the time) 4=Most times (much more than half the time) 5=Almost always/always Q5During sexual intercourse, how difficult was it to maintain your 0=Did not attempt erection to completion of intercourse? intercourse 1=Extremely difficult 2=Very difficult 3=Difficult 4=Slightly difficult 5=Not difficult Q6How many times have you attempted sexual intercourse? 0=No attempts 1=One to two attempts 2=Three to four attempts 3=Five to six attempts 4=Seven to ten attempts 5=Eleven+attempts Q7When you attempted sexual intercourse, how often was it satisfactory 0=Did not attempt for you? intercourse 1=Almost never/never 2=A few times (much less than half the time) 3=Sometimes (about half the time) 4=Most times (much more than half the time) 5=Almost always/always

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Page 549 Q8 How much have you enjoyed sexual intercourse?

0=No intercourse 1=No enjoyment 2=Not very enjoyable 3=Fairly enjoyable 4=Highly enjoyable 5=Very highly enjoyable Q9 When you had sexual stimulation or intercourse, how often did you 0=No sexual ejaculate? stimulation/intercourse 1=Almost never/never Q10When. you had sexual stimulation or intercourse, how often did you 2=A few times (much less have the feeling of orgasm or climax? than half the time) 3=Sometimes (about half the time) 4=Most times (much more than half the time) 5=Almost always/always Q11How often have you felt sexual desire? 1=Almost never/never 2=A few times (much less than half the time) 3=Sometimes (about half the time) 4=Most times (much more than half the.time) 5=Almost always/always Q12How would you rate your level of sexual desire? 1=Very low/none at all 2=Low 3=Moderate 4=High 5=Very high Q13How satisfied have you been with your overall sex life? 1=Very dissatisfied Q14How satisfied have you been with your sexual relationship with 2=Moderately dissatisfied your partner? 3=About equally satisfied and dissatisfied 4=Moderately satisfied 5=Very satisfied Q15How do you rate your confidence that you could get and keep an 1=Very low erection? 2=Low 3=Moderate 4=High 5=Very high *All questions are preceded by the phrase ‘Over the last 4 weeks’.

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Page 550 Table 39.3 Effect of α-adrenoreceptor antagonism on ejaculation. Drug Placebo-controlled study Patients Dose (mg/day) Abnormal ejaculation (%) Alfuzosin Buzelin et al. 199737 89 10 0.3 Jardin et al. 199838 1051 5 0.0 Terazosin VA Study 199639 610 10 0.3 HYCAT trial 199640 2084 1–10 1.4 Tamsulosin Abrams et al. 199541 295 0.4 4.0 Chapple et al. 199642 575 0.4 4.5 Lepor et al. 199843 756 0.4 6.0 Schulman et al. 199844 515 0.4 4.3 Doxazosin Chapple et al. 199445 135 4 0.0 Table 39.4 Effect of α-adrenoreceptor antagonism on erectile function. Drug Placebo-controlled study Patients Dose (mg/day) Abnormal ejaculation (%) Alfuzosin Buzelin et al. 199737 124 5 2.0 Terazosin Lowe et al. 199446 996 1–10 1.6 Tamsulosin Schulman et al. 199844 515 0.4 2.9 Doxazosin Chapple et al. 199445 135 4 0.0 Table 39.5 Sexual side-effects of finasteride. Placebo-controlled study VA study39 PROWESS study53 PLESS study54 Number of patients 310 1577 1384 Follow-up (years) 1 2 4 Decreased libido 5.0% 4.0% 2.6% Impotence 9.0%* 6.6%* 5.1% Ejaculation disorder 2.0% 2.1%* 2.3%* *Statistically significant compared to placebo. Adding to this confusion is the fact that up to 30% of the men coming to TURP have experienced some erectile difficulty in the 3 months prior to the surgery.71 The problems encountered on review of the published literature relating to this are multiple. Many of the published studies are uncontrolled, with samples that are nonhomogeneous with respect to the type of prostatic disorder, type of surgery, general physical health, age, and availability of partner. Some studies group together data from men who were impotent prior to surgery with those who were fully potent. Few studies prospectively gathered data prior to surgical intervention. In general, outcome measures are nonspecific, with few studies employing standardized or physiologic measuring techniques to measure outcome. Criteria for defining adequate sexual functioning differ from study to study, with no standardization of terminology to describe good or poor sexual functioning. Despite these misgivings, there have been a number of facts to emerge from this research (Table 39.6). The risk of ED in patients who were potent before treatment is reported to be in the range of 3.3– 34.8%.11 Most large series report ED rates of between 10 and

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Page 551 15%.72 Unfortunately, most of these reports are from older studies when evaluation and treatment of ED was not as well quantified. The etiology of ED which occurs after TURP is poorly understood, but likely to be multifactorial. The intimate relationship of the cavernous nerves to the distal prostate posterolaterally at 5 and 7 o’clock is likely to partially explain its occurrence (Fig. 39.6) Use of electrical cutting and/or diathermy during hemostasis may damage these nerves. This factor, in conjunction with mechanical trauma from instrumentation and possible thermal injury, may result in thrombosis of the cavernal arteries. The impact

Figure 39.3 Incidence of impotence by study period.

Figure 39.4 Incidence of decreased libido by study period (p<0.05 versus placebo). of surgery on sexual function is dependent on the patient’s perception of his sexual ability before and after surgery as well as the availability of a sexual partner.73 Libman et al.74 studied 72 men and their partners after TURP and found that men with a good presurgical sexual adjustment had a better outcome after surgery than those with poor adjustment. Younger men would be more likely to retain good sexual function than older men. The ratings of general couple satisfaction and harmony were not adversely affected by the surgery. Regarding psychological factors, there are some reports in the literature that societal attitudes to sexuality, specifically the cultural censure

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Figure 39.5 Incidence of ejaculation disorders by study period. Table 39.6 Sexual dysfunction postTURP •Risk of ED postTURP reported to be 3.3–34.8% (commonly 10–15%). •Risk of retrograde ejaculation postTURP reported to be 25–99%. •Patients at risk for ED postoperatively are those with poor and marginal preoperative sexual functioning. •There are few cases where sexual function is significantly improved postTURP. •The amount of prostate tissue resected does not appear to be associated with sexual functioning postoperatively. •Providing patients with information about the surgery and its potential sexual consequences may reduce the rate of sexual dysfunction postoperatively.61

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Page 552 relating to sexual activity which forms the opinion held by society in general that sexual activity in older individuals is not desirable.75 Only one single study, performed by Wasson et al.,76 comparing watchful waiting and TURP did not find that endoscopic surgery was the cause of the ED. Retrograde ejaculation following TURP has been reported in between 25 and 99% of men who had normal ejaculation before therapy.1,11 This occurs as the bladder neck is not capable of closing in response to sympathetic discharge during orgasm consequent on the transurethral resection. Many authors would indeed go as far as to say that, if the patient does not have retrograde ejaculation, then an inadequate prostatic resection has been performed. If this symptom is distressing for patients, it can be treated with adrenergic drugs such as ephedrine (30–60 mg), or a tricyclic antidepressant with anticholinergic side-effects, such as desipramine (50 mg), taken 1–2 hours before sexual activity. If the issue of retrograde ejaculation and fertility is a problem, it is possible to obtain sperm from postvoided bladder washings with documented fertility rates in excess of 70% over 6 months. As an interesting corollary of the above data, it is worth noting that Thorpe et al.60 have shown that we often fail to document preoperatively in the patients’ notes these most important potential side-effects of a TURP. Kinn et al.77 have shown that of the patients who were dissatisfied with their sexual function postTURP, half blamed the operation. From a professional viewpoint we should document in the patients’ notes the sexual status of patients prior to any intervention and that the patient has been properly advised of the potential risks associated with the proposed surgical treatment. The advantage of this approach is that, in the event that the patient perceives a poor outcome, there are verifiable data as to the sexual health status of the patient prior to intervention. In addition, it serves as documentary evidence that these two common and potentially distressing side-effects of therapy were fully explained and true informed consent was obtained. Open prostatectomy The numbers of open prostatectomies being performed for benign disease have been steadily decreasing in recent years. At present, in most centers, less than 10% of all cases of symptomatic BPH will be dealt with in this manner. Indications for suprapubic prostatectomy are related to the size of the gland and often the experience of the surgeon. Many surgeons would not wish to tackle a 60 g prostate endoscopically but prefer to perform an open procedure. The risk of ED consequent on open prostatectomy (either retropubic or transvesical) is estimated to be between 4.7 and 39.2%.61 The risk of retrograde ejaculation is estimated to be 36–95%11 and most authors would state that it is likely to be the higher of these two values due to disruption of the mechanism of the bladder neck. A recent study by Gacci et al. evaluated 60 men undergoing open simple prostatectomy using the Freyer technique for removal of prostatic adenoma for the treatment of BPH with LUTS.78 Men were further evaluated in the standard fashion for LUTS and by questionnaire to evaluate LUTS, ED, and QoL. While there was no clear decrease in IIEF score with rising I-PSS score, there was a tendency for lower I-PSS to be associated with higher IIEF scores. Lower IIEF scores were associated with higher body mass index, smoking, and abstention from all alcohol. I-PSS scores, however, only showed a significant association with age. Supravesical simple prostatectomy resulted in significant improvements in flow rate, residual volumes, and I-PSS scores. In reviewing the ED evaluation with IIEF and QoL questionnaires, there was no significant deterioration of sexual performance on IIEF, but there was a surprising increase in sexual desire and sexual function related to QoL after surgery. Ejaculatory scores were not significantly affected by surgery. These results are both encouraging and thought provoking. It appears to be safe to offer patients with large-volume BPH and LUTS an open simple prostatectomy without fear of postoperative ED. Similarly, we can add these data to the growing volume of information that links BPH and LUTS with ED. The authors suggest that when a man is relieved of his bothersome LUTS, he may return to more normal sexual performance with increased desire and overall QoL. Very few surgeons presently perform perineal prostatectomies and consequently it is difficult to attach any risk of sexual dysfunction to this approach. Transurethral incision of the prostate (TUIP) There has been little published with regard to sexual dysfunction following TUIP It is conceptually easy to understand how any surgical alterations in the mechanisms that control closure of the bladder neck might result in retrograde ejaculation. Current transmission through the prostate from the incision or subsequent diathermy for hemostasis may result in damage to the cavernous nerves. The published risk of ED following this procedure is 3.9–24.5%, with a risk of retrograde ejaculation of 6–55%.11 In one review, retrograde ejaculation was found in 37% of TURP patients compared with just 13% of those undergoing TUIP.79

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Page 553 Minimally invasive surgical techniques These include: • Transurethral vaporization of the prostate (TUVP); • Transurethral microwave therapy (TUMT); • Transurethral needle ablation of the prostate (TUNA); • Interstitial laser coagulation (ILC). The objective outcomes seen with the new approaches to the treatment of symptomatic BPH are often less impressive than the standard procedures, but are borne out of an attempt to minimize the morbidity associated with TURP. The fact that so many new technologies exist is an indication that no one technique has the proven efficacy of the ‘gold standard’ of TURP and may indicate that many of these technologies will not be here to stay. Data on their efficacy are conflicting and those regarding sexual and ejaculatory dysfunction scant. TUVP has a published incidence of erectile dysfunction of 17% and of retrograde ejaculation of 72%.80 TUMT has a published incidence of ED of between 0 and 5.0%.81,82 Indeed, Francisca et al., showed a preserved erectile function with TUMT compared with TURP.83 TUNA appears to have minimal effect on sexual function. Most series found no ED or retrograde ejaculation after this procedure,84–90 and only one prospective multicenter US trial found less than 1% risk of retrograde ejaculation and 2% risk of ED.91 Interstitial laser coagulation does not seem to be associated with any published incidence of ED. The risk for ejaculation disorders for this treatment ranges from 6.0 to 11.9%.92,93 Conclusions Benign prostatic hyperplasia and male sexual dysfunction together share a number of common features. Both conditions have an increased prevalence with age and both share the ability to seriously disrupt and ruin the quality of life for a large number of aging males and their partners. Fortunately, due to increased public awareness of both conditions, patients now tend to present earlier for treatment. Whether the effect of BPH on sexual function is at some as yet undetermined pathophysiological level, or whether LUTS adversely affects a patient’s sense of perceived general well-being and/or self-esteem, the end result to the patient is still the same. It is precisely due to this complex interrelationship between BPH and sexual dysfunction that routine use of a quality of life questionnaire with elements assessing sexual function (such as the IIEF or the Brief Sexual Function Inventory) should be used to ascertain a baseline level of sexual health before embarking on treatments for BPH. It should also be borne in mind that both the medical and surgical treatments for BPH have the potential to cause or worsen male sexual dysfunction. A careful and reasoned decision on the optimal treatment for each individual patient needs to be made. This decision-making process must intimately involve the patient and also factors such as their degree of symptoms arising from BPH, any pre-existing sexual dysfunction, other co-morbidities, patient age, and desired level of sexual functioning. It remains to be seen whether the newer technologies to treat BPH will evolve to be equal to the current gold standard of TURP, but at present not one of the newer surgical procedures offers patients any guaranteed durable relief from the symptoms of bladder outlet obstruction with reduced general and sexual morbidity compared to TURP References 1. Walsh P C. BPH. In: Walsh P C, Retile A B, Stemey T (eds). Campbells urology, 6th edn. Philadelphia: W B Saunders 1992:1007–1027 2. Panser L A, Rhodes T, Girman G J et al. Sexual function of men aged 40–79 years: the Olmstead County study of urinary symptoms and health status among men. J Am Geriatr Soc 1995; 43:1107–1111 3. Newman G, Nichols C R. Sexual activities and attitudes in older persons. J Am Med Assoc 1960; 173:33–35 4. Feldman H A, Goldstein I, Dimitrios G et al. Impotence and its medical and psychosocial correlates. Results of the Massachusetts Male Aging Study. J Urol 1994; 151:54–61 5. Baum M, Wassmer G, Klotz T et al. Epidemiology of erectile dysfunction: results of the Cologne Male Survey. Int J Impot Res 2000; 12:305–311 6. Rosen R, O’Leary M, Altwein J et al. LUTS and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). J Urol 2003; 169 (Suppl): 365 7. Pearlman C K, Kobashi L I. Frequency of intercourse in men. J Urol 1972; 107:298–301 8. O’Leary M P. Lower urinary tract symptoms/benign prostatic hyperplasia: maintaining symptom control and reducing complications. Urology 2003; 62 (Suppl 1): 15–23 9. Burger B, Weidner W, Altwein J E. Prostate and sexuality: an overview. Eur Urol 1999; 35:177–184 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_553.html[09.07.2009 11:55:58]

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10. Bowers L M, Cross R R, Lloyd F A. Sexual function and urologic disease in the elderly male. J Am Geriatr Soc 1963; 11:647–652

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Page 554 11. McConnell J D, Barry M J, Bruskewitz R C et al. Benign prostatic hyperplasia a diagnostic and treatment quick reference guide for clinicans. AHCPR publication number 94–0583. Rochville, MD: Agency for Health Care Policy and Research. Public Health Service. US Department of Health and Human Services, February 1994 12. Mebust W K, Bosch R, Donovan J L et al. Symptom evaluation and quality of life and sexuality. In: Cockett A T K, Khoury S, Aso Y, Chatelain C (eds). Proceedings of the second WHO international consultation on BPH. Jersey: Scientific Communication International, 1993:129–150 13. Hargreave T B, Stephenson T P. Potency and prostatectomy. Br J Urol 1977; 49:683–688 14. MacFarlane G J, Botto H, Sagnier P P et al. The relationship between sexual life and urinary condition in the French community. J Clin Epidemiol 1996; 49:1171–1176 15. Doll H A, Black N A, Flood A B et al. Differences in outcome of transurethral resection of the prostate for benign prostatic hypertrophy between three diagnostic categories. Br J Urol 1993; 72:322–330 16. Frankel S J, Donovan J L, Peters T I et al. Sexual dysfunction in men with lower urinary tract symptoms. J Clin Epidemiol 1998; 51:677–685 17. Namasivayam S, Minhas S, Brooke J et al. The evaluation of sexual function in men presenting with symptomatic benign prostatic hyperplasia. Br J Urol 1998; 82:842–846 18. Helgason A R, Adolfsson J, Dickman P et al. Sexual desire, erection, orgasm and ejaculatory functions and their importance to elderly Swedish men: a population based study. Age Ageing 1996; 25:285–291 19. O’Leary M. LUTS, ED, QOL: alphabet soup or real concerns to the aging male? Urology 2000; 56 (Suppl): 7–11 20. Schipper H, Clinch J, Powell V. Definitions and conceptual issues. In: Spilker B (ed). Quality of life assessments in clinical trials. New York: Raven Press, 1990:11–24 21. Fowler F J, Wennberg J E, Timothy R P et al. Symptom status & quality of life following prostatectomy. J Am Med Assoc 1998; 259:3018–3022 22. Anonymous. A comparison of quality of life with patient reported symptoms and objective findings in men with BPH. The Department of Veterans’ Affairs cooperative study of transurethral resection for benign prostatic hyperplasia. J Urol 1993; 150:1696–1700 23. O’Leary M P, Fowler F J, Lenderking W R et al. A brief male sexual function inventory for urology. Urology 1995; 46:697–706 24. Lukacs B, Le Plege A, McCarthy C, Comet D. Construction and validation of a BPH specific health related quality of life scale (with special attention to sexuality) for medical outcome research studies. In: Cockett A T K, Khoury S, Aso Y et al. (eds). Proceedings of the second international consultation on benign prostatic hyperplasia (BPH). Paris: Scientific Communication International, 1994:139–143 25. Lukacs B, Comet D, Grange J C, Thibault P. Construction and validation of a short form BPH health related quality of life questionnaire. BJU Int 1997; 80:722–730 26. Calais da Silva F, Marquis P, Deschaseaux P et al. Relative importance of sexuality and quality of life in patients with BPH symptoms. Eur Urol 1997; 31:272–280 27. Zlotta A R, Schullman C C. BPH and sexuality. Eur Urol 1999; 36 (Suppl 1): 107–112 28. Donovan J L. The measurements of symptoms quality of life and sexual function. BJU Int 2000; 85 (Suppl 1): 10–19 29. Rosen R C, Riley A, Wagner G et al. An international index of erectile function (IIEF): a multidimensional scale for assessment of erectile function. Urology 1993; 49: 822–830 30. Helgason A R. Prostate cancer treatment and quality of life, a three level epidemiological approach [dissertation]. Stockholm: Kongl Carolinska Medico Chirurgiska Institute, 1997 31. Altwein J E, Keuler F U. Benign prostatic hyperplasia and erectile dysfunction: a review. Urol Int 1992; 48:53–57 32. Lowe F C, Stark E. The use of alpha blockers in the management of benign prostatic hyperplasia. NY State Med J 1993; 93:169–173 33. Lowe F C, Lepor H. Alpha blockade in the management of benign prostatic hyperplasia. In: Romas A M, Vaughan E D (eds). Alternate methods for the management of benign prostatic hyperplasia. Berlin: Springer-Verlag. 1993; 173–183 34. Goldstein I, Carson C C, Rosen R P. Oral phentolamine in the treatment of erectile dysfunction. World J Urol 2000; 56:165–178 35. Boreham P F, Braithwaite P, Milewski P, Pearson H. Alpha adrenergic blockers in prostatism. Br J Surg 1977; 64: 756–757 36. Hofner K, Claes H, DeReitjke T M et al. Tamsulosin 0.4 mg once daily: effect on sexual function in file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_554.html[09.07.2009 11:55:58]

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patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999; 36:335–341 37. Buzelin J M, Roth S, Geffriaud-Ricoyard C, DelaucheCavallier M L. Efficacy and safety of sustained release alfuzosin 5 mg in patients with benign prostatic hyperplasia. ALGEBI study group. Eur Urol 1997; 31:190–198 38. Jardin A, Debruyne F M J, McCarthy C and the Alfin Study Group. Sexual function in men with benign prostatic hyperplasia treated with either an alpha adrenergic blocker alfuzosin or the alpha reductase inhibitor finasteride or the combination. A European randomised study in 1051 patients. J Urol 1998; 159 (Suppl): abstract 1271 39. Lepor H, Auerbach S, Puras-Baez A et al. A randomized placebo controlled trial of the efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. J Urol 1992:148:1467–1474

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Page 555 40. Roehrborn L G, Oesterling J E, Aurbach S et al. The Hytrin Community Assessment Trial study (HYCAT): a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. HYCAT Investigator Group. Urology 1996; 47: 159–168 41. Abrams P, Schulmann C, Vaage S et al. Tamsulosin a selective alpha-1-c adrenoreceptor antagonist: a randomized controlled trial in patients with benign prostatic hyperplasia. Br J Urol 1995; 76:325–336 42. Chapple C R, Wyndaele J J, Nording J et al. Tamsulosin the first prostate selective alpha one c adrenoreceptor antagonist. Eur Urol 1996; 29:155–167 43. Lepor H, Willford W O, Barry M J et al. The efficacy of terazosin, finasteride or both in benign prostatic hyperplasia. N Engl J Med 1996; 335:553–559 44. Schulman C C, Loch T, Buzelin J M and the European Tamsulosin group. Tamsulosin 3 year follow up of efficacy and safety in 516 patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. J Urol 1998; 159 (Suppl): abstract 983 45. Chapple C R, Carter P, Christmas T J et al. A three month double blind study of doxazosin as treatment for benign prostatic outlet obstruction. Br J Urol 1994; 74; 50–56 46. Lowe F C. Safety assessment of terazosin in the treatment of patients with symptomatic BPH: a combined analysis. Urology 1994; 44:46–51 47. Lukacs B, Leplege A, Thibault P, Jardin A. Prospective study of men with clinical benign prostatic hyperplasia treated with alfuzosin by their general practitioner: one year results. Urology 1996:48:731– 740 48. Nealon J D, Grimm R H, Prineas R J et al. Treatment of mild hypertension study: final results. J Am Med Assoc 1993; 270:713–724 49. Anderson K E, Stief C G. Neurotransmission and the contraction and relaxation of penile erectile tissues. World J Urol 1997; 15:14–20 50. Price D T, Schwin D A, Kim J H et al. Alpha I adrenergic subtypes in mRNA expression in human corpus cavernosum. J Urol 1993; 149 (Suppl 4): 285, abstract 287 51. Gwinup G. Oral phentolamine in non-specific erectile insufficiency. Ann Intern Med 1988; 109:162 52. Zorgniotti A W. ‘On demand’ erection with oral preparations for impotence. Int J Impot 1992; Res 4 (Suppl 2): A 99 53. Becker A J, Stief C G, Machtens S et al. Oral phentolamine as treatment for erectile dysfunction. J Urol 1998; 159:1214–1218 54. Wagner G, Lacy S, Lewis R. Buccal phentolamine, a pilot trial for management of erectile dysfunction at three separate locations. Int J Impot Res 1994; 6 (Suppl 1): D78 55. Wessels H, Roy J B, Bannow J et al. Incidence and severity of sexual adverse events in finasteride and placebo treated men with benign prostatic hyperplasia. Urology 2003; 61:579–584 56. Kaplan S A, Holtgrewe L, Brushkewitz R et al. Comparison of the safety and efficacy of finasteride in older versus younger men in the treatment of benign prostatic hyperplasia. Urology 2001; 53:1073–1077 57. Zlotta A R, Schulman C. BPH and sexuality. Eur Urol 1999; 36(Suppl): 107–112 58. Downs T M, O’Leary M. Sexual dysfunction in patients with benign prostatic hyperplasia. Curr Opin Urol 1999: 9: 9–14 59. Carson C C, Harkaway R, Marks L, McNicholas T. Effect of maximal dihydrotestosterone suppression with dutasteride on sexual function and gynecomastia. J Urol 2003; 169(Suppl):478 60. Thorpe A C, Cleary R, Coles J et al. Written consent about sexual function in men undergoing transurethral resection of the prostate. Br J Urol 1994; 74:479–484 61. Bolt J W, Evans C, Marshall V R. Sexual dysfunction after prostatectomy. Br J Urol 1986; 58:319– 322 62. Bryant J E, Bueschen A J, Cohn J H, Nading A M. Transurethral resection of the prostate. Analysis and comparison of four clinical series. Southern Med J 1990; 83: 386–389 63. Cytron S, Simon D, Segenreic E et al. Changes in the sexual behaviour after prostatectomy. Eur Urol 1987; 13:35–38 64. Dixon A R, Lord P H, Madigan M R. The Madigan prostatectomy. J Urol 1990; 144:1401–1403 65. Edwards L E, Buchnall T E, Pittam M R et al. Transurethral resection of the prostate and bladder neck incision. A review of 700 cases. Br J Urol 1985; 57:168–171 66. Finkle A L, Prian D V. Sexual potency in elderly men before and after prostatectomy. J Am Med Assoc 1966; 196:139–143 67. Madorsky M L, Ashamalla M B, Schussler I et al. Post prostatectomy impotence. J Urol 1976; 115:401–403 68. Malone P R, Cook A, Edmonson R et al. Prostatectomy: patients’ perception and short term follow file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_555.html[09.07.2009 11:55:59]

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up. Br J Urol 1988; 61:234–238 69. So E P, Ho P C, Bodenstals W et al. Erectile impotence associated with transurethral resection of the prostate. Urology 1982; 19:259–262 70. Vereeken R L. Sexual activity of men presenting with prostatism. Effect of prostatectomy. Eur Urol 1989; 16: 328–332 71. Samdal F, Vada K, Lundino P. Sexual function after transurethral resection of the prostate. Scand J Urol Nephrol 1993; 27:27–29 72. Zohar J, Meiraz D, Maoz B, Durst N. Factors influencing sexual activity after prostatectomy. A prospective study. J Urol 1975; 116:332–334

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Page 556 73. Lindner A, Golomb J, Korzcak D et al. Effects of prostatectomy on sexual function. Urology 1991; 38:26–28 74. Libman E, Fichten C S, Creti C et al. Transurethral resection of the prostate, differential effects of age category and pre-sexual functioning on post-prostatectomy sexual adjustment. J Behav Med 1989; 12:469–485 75. Winn R C, Newton N. Sexuality and aging. A study of 106 cultures. Arch Sexual Behav 1982; 11:283–298 76. Wasson J H, Reda D J, Bruskewitz R C et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The VA cooperative study group on transurethral resection of the prostate. N Engl J Med 1995; 332:75–79 77. Kinn A C, Helmy-Dhejne C, Larsson J. Sexual function one year after transurethral prostate resection. Patients’ own assessments. Scand J Urol Nephrol 1998; 32:33–35 78. Gacci M, Bortoletti R, Figlioli S et al. Modifications of urinary symptoms, sexual function and quality of life after open prostatectomy for BPH. BJU Int 2003; 192: 1466–1491 79. Hollander J B, Diokno A C. Prostatism: benign prostatic hyperplasia. Urol Clin North Am 1996; 23:75–86 80. Hammadeh M Y, Madaan S, Singh M, Philip T. Two year follow up of a prospective randomized trial of electrovaporisation versus resection of the prostate. Eur Urol 1998; 34:188–192 81. de la Rosette J J M C H, de Wildt M J A M, Hofner K et al. High energy thermotherapy in treatment of benign prostatic hyperplasia. Results of the European BPH study group. J Urol 1996; 156:97–102 82. Kirby R S, Williams G, Witherow R et al. The prostatron transurethral microwave device in treatment of bladder outflow tract obstruction due to BPH. Br J Urol 1993; 72: 190–200 83. Francisca E A E, d’Ancona F C H, Mueleman E J et al. Sexual functioning following high energy microwave ther motherapy: Results of a randomized controlled study comparing transurethral thermotherapy to transurethral prostatectomy. J Urol 1999; 161:486–490 84. Kaplan S A. Minimally invasive alternative therapeutic options for lower urinary tract symptoms. Urology 1998; 51 (Suppl 4A): 32–37 85. Schulman C C, Zlotta A R. Transurethral needle ablation of the prostate for the treatment of benign prostatic hyperplasia. Early clinical experience. J Urol 1995; 45:230–233 86. Steele G S, Sleep D J. TUNA: a urodynamic based study with two year follow up. J Urol 1997; 158:1834–1838 87. Campo B, Bergamaschi F, Corrada P, Ordesi G. Transurethral needle ablation (TUNA) of the prostate. A clinical and urodynamic evaluation. Urology 1997; 49: 847–850 88. Bruskewitz R, Issa M M, Roehrborn C G et al. A prospective randomized one year trial comparing transurethral needle ablation to transurethral resection of the prostate for treatment of symptomatic benign prostatic hyperplasia. J Urol 1998; 159; 1588–1594 89. Issa M M, Oesterling J E. Transurethral needle ablation (TUNA). An overview of radiofrequency thermal therapy for the treatment of benign prostatic hyperplasia. Curr Opin Urol 1996; 6:20–27 90. Dixon C M. Transurethral needle ablation for the treatment of benign prostatic hyperplasia. Urol Clin North Am 1995; 22:444–453 91. Roehrborn C G, Issa M M, Bruskewitz R et al. Transurethral needle ablation for benign prostatic hyperplasia. 12 month results of a prospective multicentre US study. Urology 1998; 51:415–421 92. Arai Y, Kazitoshi O, Takashi O et al. Interstitial laser coagulation for management of benign prostatic hyperplasia. A Japanese experience. J Urol 1998; 159:1961–1965 93. Perlmutter A P, Muschiter R. Interstitial laser prostatectomy. Mayo Clin Proc 1998; 73:903–907

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Page 557 Index AAH see adenomatous hyperplasia, atypical acetylcholine (ACh), AUR 182 acetylcholinesterase-positive nerve fibers 7–8 acinar atrophy, PAH as diagnostic category 102–4 acute urinary retention see urinary retention (AUR) adenocarcinoma 268 adenomatous hyperplasia, atypical (AAH) clinical significance 106–7 differential diagnosis 104, 106–7, 271 estrogen-associated 51 Gleason primary grade 1 106 immunohistochemistry 106 needle biopsies 271 premalignancy 106–7, 271 adenosis see adenomatous hyperplasia, atypical adrenoceptors 87–93, 164, 429 alpha-1 binding affinities 433 bladder 430–1, 545 cardiovascular system 432 contractile response 89–92, 357 distribution 89 heterogeneity 87–9 molecular and pharmacological properties 87–9 peripheral and central nervous system structures 431–2 prostatic 430 radioligand-binding studies 89–92 seminal vesicles 545 urethral 430 alpha-1A, contractile role 92, 164, 430 alpha-2 92 beta 93 classification 87–8 historical background 87 neuronal localization 432 subtypes 357, 365–6, 391–2 adrenoceptor antagonists apoptosis induction 353 AUR 184 blood pressure effects 434–5 differential effects on prostate tissue growth 351–5 physiologic uroselectivity 432–3 serum lipids 370 side effect limitations 430 vs watchful waiting 289 see also alfuzosin; doxazosin; phenoxybenzamine; tamsulosin; terazosin alpha-1 92, 164, 357–8, 545–7 5-ARI combination therapy 184–5 LUTS 358 in vivo effects 93 ejaculation complications 546, 550 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_557.html[09.07.2009 11:56:00]

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erectile dysfunction 550 adrenocorticotropic hormone (ACTH) 31–2 African plum tree (Pygeum africanum) 415, 419–20 age-related changes 30–4 androgen/aging theory of BPH pathogenesis 98 Baltimore longitudinal study of WW 287 connective tissue and epithelium 13–14 glandular lumen 13–14 MSAM-7 544 PSA 216 PVR 144, 146, 233 smooth muscle density 13–14 and telomerase 45 testosterone 30 urinary flow rate 230 age-specific prevalence of BPH 97, 141–2, 190, 193, 216, 270 longitudinal studies 193 prostate cancer 216, 269, 270 prostate enlargement 192, 193 see also population studies AHCPR (Agency for Health Care Policy & Research) guidelines, BPH diagnosis 145 alcohol consumption, BPH risks 170–1 ALFIN study 341–2 ALFORTI study, alfuzosin 384–5, 387 ALFUS study, alfuzosin 384–5 alfuzosin 377–88 alpha-adrenoceptor affinity 377–8 blood pressure 378, 380–1 clinical studies 381–8 ALFORTI 384–5, 387 ALFUS 384–5 combination therapy, finasteride 385, 387 efficacy 381–6 formulation comparisons 383–4 hemodynamic effects 380–1 pharmacodynamic effects 380–1 pharmacokinetic properties 379 pharmacologic profile 377 prostate/plasma concentrations 378–9 safety and adverse events 386–8 selectivity profile 93 therapeutic applications 388 urodynamic effects 380

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Page 558 urethral pressure 378, 380 ALLHT (lipid-lowering treatment to prevent heart attack) trial 370 alpha-adrenergic antagonists see adrenoceptor antagonists 5-alpha-reductase (5-AR) deficiency, pseudohermaphroditism 16, 20–1, 320 fetal prostate development 20–1 types I and II 320 5-alpha-reductase inhibitors (5-ARI) 98 alpha-blocker combination therapy 184–5 AUR 184 DHT 327 dual isoforms 320–1 phytotherapeutic agents 417 prostate volume 163 see also dutasteride; finasteride American dwarf palm (Serenoa repens) 346, 415–20 American Urological Association (AUA) 34 Bother Score 152, 290 BPH Clinical Trials Subcommittee 298 combination therapy guidelines 346 Symptom Index 190, 202 WW treatment guidelines 291 see also I-PSS amphiregulin 75 anaesthetics 443 anal sphincter abnormalities, EMG 282 androgen ablation/deprivation 351 androgen receptors (ARs) A/B activation domains 40 AR-positive LNCaP line 44, 71, 79 gene, CAG repeats 128, 129 prostatic development 17–18, 34–5, 48 androgens 30–6 aging theory of BPH pathogenesis 98 DHT-binding 34–5 mediation of BPH 70 metabolism 34 peptide growth factors 18–19 stromal-epithelial interactions 16 see also DHA; DHT; testosterone androstane 34 androstanediols 31 androstenedione 31, 34, 52 anencephaly 11 angiogenesis 40, 41 anti-estrogen therapy 54–6 antibiotics, surgical procedures 443 antihypertensives see doxazosin; terazosin AP-1 transcription factors 47–8 apoptosis alpha-adrenoceptor antagonists 353–4 cell death control 44–5 prostate growth 43–4, 164 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_558.html[09.07.2009 11:56:00]

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aromatase enzymes 52 aromatase inhibitor 54 ARs see androgen receptors ASAP see small acinar proliferation, atypical Asian BPH study 157 AUA see American Urological Association autonomic neuropathy, PVR 235 balloon dilatation vs cystoscopy, placebo/sham controlled trials 308–10 Baltimore longitudinal study of aging, WW 287 Barnes stent 536 basal cell adenoma 104–5 basal cell adenomatosis 105 basal cell hyperplasia (BCH) atypical 104–5 differential diagnosis 104–5 immunohistochemical findings 105 basal cells, role 105–6 bcl-2 gene 44–5, 131 myc, and apoptosis 45 bek gene, KGF 35 benign disease, molecular basis 119–20 benign prostatic hyperplasia see BPH betacellulin 75 biochemical markers 270 see also PSA; other markers biodegradable stent 537 biopsies see needle biopsies bladder adrenoceptors 431 compensation/decompensation 195, 233–4 conductance factor 248 diverticula, USCD 260 innervation 279–80 instability development 250 obstruction-induced alterations 116 volume, urinary flow rates 229–30 weight, BOO 114 bladder dysfunction alpha-1-adrenoceptors 432 compliance, chronic retention 235 motor neuron lesions 281 neurologic examination 279–80 bladder outlet obstruction (BOO) 113–16 bladder hypertrophy and growth factors 164 bladder neck contracture, complication of surgery 459–61 BPH diagnosis 148 definition 227, 237 and estrogens 51–2 evaluation guidelines 237 flow rates 230, 237 natural history 52 patient selection 237–8 tolterodine/tamsulosin combination therapy 345–6 urodynamic studies 242

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Page 559 WW 288 see also detrusor overactivity; postvoid residual urine; urinary flow rate bladder stones 195 excretory urography 256 USCD 260 blood pressure effects adrenoceptor antagonists 434–5 alfuzosin 378, 380–1, 405 doxazosin 368–70 tamsulosin 398, 401, 405, 407–8 terazosin 360–1, 363, 434 blood pressure measurement 280–1 BMI (body mass index), BPH risk factor 169–70, 176 bombesin, immunocytochemistry 7 bombesin/gastrin-releasing peptide 39 BOO see bladder outlet obstruction Boyarsky score, BPH natural history progression 190, 202 BPH (benign prostatic hyperplasia) complications 193–6 development aspects 11–22 endocrinology 17–18 flow rate relationship 245 glandular pattern 12 peptide growth factors 20–1 tubular proliferation 12 epidemiology AUR 181–5 BPH measurement and assessment, population groups 141–58 description 151–8 LUTS 144–6 peak uroflow 143–4 prostatic enlargement 142–3 PVR 144 etiology 163–77 evaluation 268 gene therapy 131 genetics aneuploidy 122–3 animal models 130–1 linkage analyses 120–2 molecular genetics 122–30 tumor suppressor genes 123–7 histopathologic variants 101–8, 270–4 historical perspective 351–4 microvascular remodeling 79 molecular expression 250 morphometry 101 natural history 189–96 defined 189–90 early studies 191–2 placebo effects 192, 300, 302 study evaluations 190–3 pathogenesis 51–4, 97–8 future directions 80 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_559.html[09.07.2009 11:56:01]

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stem-cell model 41–2 pathology 98–100 population studies 141–58, 191 measurement and assessment 141–8 sampling methods 158 prevalence and clinical manifestations 146–8 prostate cancer association 101 risk factors 164–76 treatment preferences 290 see also prostatic growth/development breast cancer, incidence, East/West 57 C19 steroids 30 c-fms-like tyrosine kinase receptor-1 (FLT-1) 130 c-fos 125 c-met/HGF 125 c-mys 125 c-sis 125 cactus flower extracts 420 calcitonin, secretion 39 calcium mobilization, contractile dysfunction 116 calculi see bladder stones caldesmon protein, smooth muscle contractile dysfunction 115–16 Canadian BPH study 154 carcinogenesis, and diet 57–60 cardiovascular system, alpha-1-adrenoceptors 432 catheterization, AUR 183–4, 195 cauda equina bladder dysfunction 280 EMG 283 PVR 235 CD44 family, proteoglycans 77 cDNA microaarays 128–30 cell cycle control, and DNA synthesis 43–4 cell death control 44–5 cell growth, control by extracellular matrix 78–80 cell proliferation and apoptosis 42–3 prostate growth 164 cernitin, Serenoa repens, beta-sitosterol and vitamin E combination therapy 346 chromogranins 41 secretion 39 chronic renal failure (CRF), prostatectomy-associated 195 cirrhosis, BPH risks 170–1 citrate production, increase, BPH association 173 clean intermittent self-catheterization (CISC), AUR 184 CLIM computer program, urodynamic studies 247–8 coagulation laser endoscopic 507–8 interstitial 508

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Page 560 coffee consumption 175–6 collagen deposition, BOO 114 collagen-I 79 computed tomography (CT) 256–8 connective tissue, age-related changes 13–14 Copenhagen BPH study 152 coronary heart disease (CHD), doxazosin 370 corpora amylacea 7 imaging 255 PAH 103 corticosteroid-binding globulin (CBG) 32 CRF (chronic renal failure) 195 cribriform hyperplasia, differential diagnosis 104, 106 Cucurbita pepo (pumpkin) 415, 420 cyclin-dependent kinases 43–4 cystic degeneration, TRUS 262 cystometrogram (CMG) 242 motor neuron lesions 281 cystoscopy vs balloon dilatation, placebo/sham controlled trials 308–10 cytogenetics 122–8 cytokeratins 41–2 daidzein 57–9 DAMPF (detrusor-adjusted mean passive urethral resistance factor) classification 250 Danish BPH study 152 Danish Prostate Symptom Score (DAN-PSS-1), LUTS severity measurement 202, 205 detrusor contractility bladder output relation 245 DAMPF 250 duration 248 involuntary (IDC) 242, 249 quantitative assessment 245 detrusor overactivity (DO) 227 BOO 113, 116, 238 PVR 235 tolterodine/tamsulosin combination therapy 345–6 detrusor pressure, obstruction diagnosis 244–5 detrusor-sphincter dyssynergia, EMG 282 developed world, incidence of prostate and breast cancer 57 DHA (dehydroepiandrosterone) 30–1 DHT (dihydrotestosterone) 5-ARI 327 binding to androgen receptor 33 BPH development 319–20 BPH levels 98 DHT-AR 48, 128 CAG repeats 128 dutasteride treatment 322–4 and IGF 75 prostatic development 17–21, 47, 319 regulation of stroma-derived matrices 79 stromal-epithelial interactions 16 structure 34 synthesis 31, 34 testosterone metabolism 163 UGS differentiation 11 diabetes mellitus, PVR 235 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_560.html[09.07.2009 11:56:01]

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diet, and carcinogenesis 57–60 diuretics, AUR association 236 DNA microaarays 128–30 DNA synthesis, and cell cycle control 43–4 DO see detrusor overactivity doxazosin 365–73 ALLHAT trial 370 antihypertensive effects 368–70 effect on apoptotic indexes 54 GITS formulation 371–2 adverse events 372 HABIT 369–70 HALT 370 MTOPS 185, 331–3, 343–5, 367 onset of action 365, 373 PREDICT 342–3, 367 safety and efficacy adverse events 368–9 long-term 352–3, 367 safety profile 367–8 short-term 366–7 selectivity profile 93 sexual dysfunction 370–1, 373 TOMHS 370, 547 uroselectivity 434–5 DRE (digital rectal examination), prostate cancer 212, 270 drugs, meta-analyses 333, 409–10, 421–3 Dunning tumor model of prostate cancer 71, 73 dutasteride 163, 319–24 adverse events 322–3 clinical experience 321–3 combination therapy 324 vs finasteride 323–4 preclinical development 321 sexual side-effects 547 structure 321 Dutch BPH study 153 East/West, incidence of prostate and breast cancer 57 EGF see epidermal growth factor ejaculation abnormalities 398, 401–3, 405, 463 retrograde ejaculation 463 tamsulosin 398, 401–3, 405 ejaculation complications alpha-adrenergic antagonists 546, 550 following TUIP 444, 463 electromyography (EMG) anal sphincter abnormalities 282 cauda equina lesions 283 detrusor-sphincter dyssynergia 282, 283

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Page 561 pelvic floor and urethral sphincter 282 pseudodyssynergia 243 sacral reflexes and cortical evoked responses 283 electrovaporization laser vaporization 486 transurethral, of prostate (TUVP) 447–8 embryology, prostate 11–22 embryonic reawakening theory of pathogenesis 98, 164 EMG see electromyography endocrinology, development aspects 17–18 endoscopic laser coagulation 507–8 enkephalin, AUR 182 enterohepatic circulation, steroid changes 56 enterolactone 57–8 epidermal growth factor (EGF) activation of ErbB-1 75 prostatic development 19–20, 35, 46 epidermal growth factor (EGF) family, six members 75 epiregulin 75 epithelial compartment 35–7 neuroendocrine cells 40 epithelium age-related changes 13–14 cytokeratins 22 development 12–13 functional activity 39 mesenchyme interactions 17–20 transitional zone 7 see also stroma-epithelium interactions equol 58 ErbB-1, activation by EGF 75 ErbB-1/EGF receptor tyrosine kinase 76 ErbB-2/HER-2 124–5 ErbB-2/Neu 75, 123 ErbB-3 and ErbB-4 75 erectile dysfunction alpha-adrenergic antagonists 550 impotence post surgery 461–3 see also sexual dysfunction erectile function and age 543 impact of LUTS 543 international index (IIEF) 548–9, 552 intraoperative 447 phentolamine 545, 547 ERs see estrogen receptors ESPIRIT (European standardized pressure flow investigation trial) 399 estradiol binding to SHBG 53 role in BPH 53, 164 estradiol-17beta 32, 52 estrogen receptors (ERs) estrogen receptor-alpha 53 estrogen receptor-beta cloning 53 prostatic development 18, 37 estrogenic response 34 estrogenic substances in plants 58–60 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_561.html[09.07.2009 11:56:02]

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estrogens 51–4 anti-estrogen therapy 54–6 estrogen/DHT ratio 51 imprinting on fetal prostate 51 male production 32 theory of BPH pathogenesis 98 estrone, structure 32, 52 excretory urography 255–6 extracellular matrix 76–80 changes in BOO 114 control of cell growth 78–80 glycoproteins 78 matrix-associated factors 77 remodeling during tumorigenesis 77 extrinsic/intrinsic factors, prostatic growth 34–6 fatty acids, highly unsaturated, BPH risk 176 FDA, placebo/sham control groups 298 fetal prostates, glandular pattern 12 fibers, for visual laser-assisted prostatectomy 483–5 fibroblast growth factor (FGF) 71–4 BPH pathogenesis 98 FGF-1 37, 71, 73–4 FGF-2 35, 37, 71, 73–6 FGF-7 (keratinocyte growth factor) 35 FGF-8 37 FGF-R2exonIIIc (bek) gene 35, 37 FGF-R 35 prostatic development 19, 35–7 fibronectin 78 finasteride 163, 327–34, 334 adverse events 331 ALFIN study 341–2 alfuzosin combination therapy 385, 387 AUR 182, 184 clinical studies 329–33 development 327–8 vs dutasteride 323–4 hematuria 196, 333–4 meta-analysis 333 mode of action 328 MTOPS study 148, 184, 331–3, 343–5 NA phase III trial 122 vs placebo 547 PREDICT study 342–3, 367 prostatic growth 328–9 PSA effects 218–19, 334 sexual side-effects 547, 550 terazosin interactions 340–1 VA Cooperative Study 191–2, 288–9, 333, 339–41 vs watchful waiting 289 Finnish BPH study 153

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Page 562 flavonoids 58–9 Flint Men’s Health Study (Michigan) 155 foot deformities, cauda equina 280 Fos protein 47 French national BPH survey 152 frontal lobe disorders, bladder dysfunction 280 ganglion cells, autonomic 8–10 genetics 97 animal models of BPH 130–1 BPH risk 56–7, 171–2 polymorphisms 173–5 cytogenetics 122–8 linkage analyses 120–2 molecular genetics 119–38 mouse models of BPH 130–1 genistein 58–9 giant prostatic hyperplasia 100 GITS formulation see doxazosin glandular lumen, age-related changes 13–14 Gleason primary grade 1, AAH classification 106 growth factors 163–4 BOO 114 BPH pathogenesis 98 DHT-receptor complex 320 finasteride 328 prostatic development 18–19 soluble, role in prostatic growth 35–7, 46–7, 54, 71–6 growth regulation 163–4 [S]3[s]H-prazosin binding sites 377 HABIT (hypertension and BPH intervention study), doxazosin evaluation 369–70 HALT (hypertension and lipid trial), doxazosin 370 Hawthorne effect 190 longitudinal studies 191 Hayflick phenomenon 45 HCG-like peptide, secretion 39 hematuria 195–6 dutasteride treatment 324 finasteride 333–4 stent insertion, TRUS evaluation 265 hemidesmasome-associated integrin 79 heparan sulfate proteoglycans (HSPGs) 77 heparin-binding EGF-like growth factor (HB-EGF) 75–6 hepatic cirrhosis, BPH risks 170–1 hepatocyte growth factor/scatter factor (HGF/SF) 74 heregulins 75 holmium laser, VLAP 492–3 hormonal imprinting 13–14 hormone response elements (HREs) 34, 48 hormones, growth regulation 163–4 human kallikrein 2, prostate cancer screening 216 hydrocephalus, bladder dysfunction 280 hyperplasia adrenoceptor antagonist differential effects 351–5 atrophy/postatrophic, histology 102–4 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_562.html[09.07.2009 11:56:02]

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histologic variants and associated benign lesions 101–8 mesonephric remnants, differential diagnosis 108 stromal/nonstromal, MRI 257–8 hypertension 280–1 BPH risks 172 TOMHS 370, 547 hyperthermia devices, placebo/sham controlled trials 298, 308–10 hypotension, tamsulosin 398–9, 401, 404, 405–6, 408, 410 Hypoxis rooperi (South African star grass) 415 [S]124[s]I-HEAT 377 I-PSS (International Prostate Symptom Score) 190, 202–5 French national survey 152, 544 LUTS 144–6, 202 tamsulosin 399, 400 IGF see insulin-like growth factor IIEF (international index of erectile function) 548–9, 552 ILC see interstitial laser therapy imaging techniques 255–65 CT 256–8 excretory urography 255–6 MRI 257–8 urethrography 256 imidazoline binding sites 92 impotence, complication of prostatectomy 461–3 incontinence 457–9 inflammation/growth factor theory of pathogenesis 98 insulin production, prostate cancer risk 101 insulin-like growth factor (IGF) BPH pathogenesis 74–5, 98 mitogenic and anti-apoptotic effects 164 prostatic development 19, 35 integrins 77–9 interleukin-converting enzyme (ICE) 44 International Continence Society (ICS) LUTS severity measuring 202 male short form questionnaire (ICSmale SF) 204–7 International Prostate Symptom Score see I-PSS interstitial laser therapy 507–15 current clinical experience 511–13 discussion 513–15 endoscopic laser coagulation 507–8 interstitial laser coagulation 508, 510 photodynamic therapy (PDT) 507 interstitial prostate surgery, urodynamic studies 250 intraurethral catheter (IUC), first-generation stent 531–3 Ipertrofan 55–6 isoflavonoids 58–9 Japanese BPH study 157 Jun protein 47

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Page 563 kallikrein 2, prostate cancer screening 216 keratinocyte growth factor (KGF) 35, 46–7, 54, 73 keratins 41–2 kidneys, ureters, and bladders (KUB) urographic films, prostatomegaly 255 Kip1 79 Korean BPH study 157 KTP laser, VLAP 491–2 laminin 78 lasers see interstitial laser therapy; transurethral laser prostatectomy; VLAP legumes, daidzein and genistein 58–9 leiomyoma, atypical, stromal hyperplasia 105 lignans 58–9 linseed 58 lipids, alpha-blocker effects 370, 410 low flow/low pressure syndrome 231 defined 243 detrusor contractility impairment 235 multichannel urodynamic studies 243 lower limb symptoms, bladder dysfunction 280 lower urinary tract schematic diagram 3 TRUS 260–5 lower urinary tract symptoms see LUTS LPURR (linear passive urethral resistance relation) 246–7 luteinizing hormone (LH), testosterone regulation 177 LUTS (lower urinary tract symptoms) alpha-adrenoceptor antagonist therapy 358 BPH pathogenesis 98 cigarette smoking relationship 168–9 dutasteride treatment 322 epidemiology 144–8 erectile function 543 metabolic syndrome association 172–3 obesity relationship 170 PSA elevation and prostate cancer 213 symptom and physiology correlation 206 symptom severity measurements 202 clinical practice and research 206–8 terazosin therapy 357–63 urodynamic studies 249–50 WW prospective study 287–8 lymphatic drainage 3 alpha2-macroglobulin, PSA complex (PSA-A2M) 216–18 Madsen-Iversen index 202 magnetic resonance imaging (MRI) 257–8 Maine Medical Assessment Program (MMAP) 202 MAPK (mitogenic-activated protein kinase) 46 matairesinol 58 matrix metalloproteinase-2 (MMP-2) 79 meatotomy, prophylactic 459 median lobe hyperplasia 99 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_563.html[09.07.2009 11:56:03]

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Memokath, second-generation stent 533–5 mepartricin 55 structure 56 mesenchymal-epithelial interactions 17–20, 69–71 mesenchyme, urogenital (UGM) 69–71 fetal prostate development 21 metabolic syndrome, BPH risk 172–3 alpha-methylacyl-CoA racemase (AMACR), prostate cancer marker 101 microwave therapy (TUMT) 250, 448–9 urodynamic studies 250 micturition BPH and TRUS imaging 264 bulbospinal noradrenergic pathways 431 multichannel urodynamic studies 243 reflex inactivation, PVR 234–5 migration, diet, and carcinogenesis 57–8 mitogenic-activated protein kinase (MAPK) 46 molecular biology 250 aspects of BPH 69–80 control of prostatic growth 29–66 molecular genetics, BPH 119–38 mortality, following surgical procedures, delayed 468–76 motor neuron lesions, bladder dysfunction 281 mouse mammary tumor virus (MMTV), LTRs 130 mouse prostate reconstitution (MPR) model, TGF-beta1 130 MTOPS (medical treatment of prostatic symptoms) trial 148, 184, 331–3, 343–5, 367 5-MU (5-methylurapidil) selectivity profile 93 uroselectivity 434 MUDI (male uroflow diagnostic interpretation) variables 230 Multinational Survey of Aging Male (MSAM-7), sexual function 544 multiple system atrophy (MSA), bladder dysfunction 280–1, 282–3 muscle fibers, prostatic urethra 4 myelomeningocele (MMC) prostates 21–2 myosin protein studies, smooth muscle contractile dysfunction 115–16 Nd:YAG laser ILC 508–10 VLAP 486–91 NE cells see neuroendocrine cells needle ablation see TUNA needle biopsies adenocarcinoma 273–4 BPH evaluation 268 histologic BPH 148 histopathologic interpretation and clinical significance 267–74 PAH 103 prostate cancer 219, 268–9 sextant technique 219, 269

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Page 564 transition zone 99–100, 219 unimportant malignancies 268 nerve growth factor (NGF), BOO 116 Netherlands, BPH study 153 neu differentiation factors (NDFs) 75 neuroendocrine cells epithelial compartment 40 prostate development 22 neurologic and neurophysiologic assessment 279–83 neuropeptide Y (NPY) 8 AUR 182 neuropeptides, see also vasoactive intestinal polypeptide neurotransmitter modulation, AUR 181–2 New Zealand BPH study 157 NGF (nerve growth factor) 116 Nissenkorn intraurethral catheter 533 nitric oxide (NO) 53–4 AUR 182 as second messenger 55 smooth muscle modulation 8 VIP co-functional role 9 nitric oxide synthase (NOS) 8–9, 53 nonadrenergic noncholinergic (NANC) neurotransmitters AUR 181–2 BOO 115 nonbacterial prostatitis, TUNA 501 noradrenaline (NAd) AUR 182 contractile effects 89–92, 430 noradrenergic nerves 7–8 noradrenoceptor imidazoline binding sites 92 North American BPH studies 154–7 Norwegian BPH study 153 obesity, BPH risks 169–70, 176 Olmsted County Study of Urinary Symptoms and Health Status Among Men 122, 155–7, 302–3 oncogenes 123–7 Onuf s nucleus, loss in MSA 282 open prostatectomy complications 457–64 delayed mortality 468–76 retreatment rates 463–4, 465–7 retropubic (OPSR) 452–4 sexual dysfunction 552–3 suprapubic (OPSS) 449–52 Opuntia (cactus) 420 orthostatic hypotension, tamsulosin 398–9, 401, 404, 405–6, 408, 410 oxidoreductase theory of pathogenesis 98 p27-KIP1 cell cycle inhibitor 79, 126, 127, 130–1 p53 gene 123, 126, 131 mutations 127 p53 protein 44–5 immunostaining 127 PAH see post-atrophic hyperplasia pain treatment, placebo effects 299 palmetto, saw (Sabal serrulata) 415 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_564.html[09.07.2009 11:56:03]

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parathyroid hormone-related protein, secretion 39 Parkinson’s disease, urinary symptoms 280, 283 PCNA, proliferation marker 40 pelvic floor, EMG 282–3 peptide growth factors 18–19 fetal prostate development 20–1 stimulatory and inhibitory interrelationship 20 peptides, secretion 39 peripheral neuropathy, generalized, bladder dysfunction 280 phenoxybenzamine 357–8, 365 phentolamine, erectile function 545, 547 photodynamic therapy (PDT) 507 phytoestrogens 58–60 properties 60 phytotherapeutic agents 415–23 5-alpha-reductase inhibition 417 active constituents 416 combination preparations 420 France and Germany 289–90 meta-analyses 420–3 mode of action 416 origin 415–16 pharmacotherapy combination therapy 346 phytosterols/beta-sitosterol 418–19 Picea (spruce) 415 PIN (prostatic intraepithelial neoplasia) bcl-2 gene 44 carcinoma precursor 74, 212 differential diagnosis 273 needle biopsies 272–3 premalignancy 271–2 Pinus (pine) 415 PIVOT (Prostate Cancer Intervention vs Observation Trial) 219–20 pl clinical studies see placebo/sham effect; named studies placebo/sham effect 295–314 balloon dilatation vs cystoscopy studies 308–10 baseline symptom severity 311 biopsychosocial determinants 296–7 definitions and theoretical considerations 295–7 device treatment studies 308–11 ethical considerations 298 hyperthermia treatment studies 298, 308–10 improvement perception 313 long-term natural history of disease progression 311–13 medical treatment studies 304–8 natural history studies 300, 304 Olmsted County study 302–3 pain therapy studies 299 phytotherapeutic agents, Serenoa repens 418 quantitative symptom scores 306–7

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Page 565 regression to the mean 300–1 surgical procedure studies 299–300 therapeutic theory 295–6 TUMT 521 watchful waiting studies 300, 302–4 plants estrogenic substances 58–60 phytoestrogens 58–9 phytotherapeutic agents 415–23 platelet-derived growth factor (PDGF), BPH pathogenesis 74, 98 PLESS (Proscar long-term efficacy and safety study) 329–31 BP natural history evaluation 192 population groups, BPH 141–58 population studies BPH incidence and prevalence 165 BPH measurement and assessment 141–8 descriptive epidemiology 151–8 longitudinal, BPH natural history evaluation 191 PVR 144, 146 sampling methods 158 post-atrophic hyperplasia (PAH), differential diagnosis 102–4 postural hypotension 280–1 postvoid residual urine (PVR) 227–38 age and population groups 144, 146 age-related changes 233 bladder volume 229–30 BOO 235 chronic retention 235 clinical significance 235–6 detrusor contractility impairment 235 epidemiology 144 measurement recommendations 237 measurement techniques 233 micturition reflex inactivation 234–5 neuropathy 235 normal bladder emptying 232 pathogenesis 233–5 self-assessment 233 treatment indications 290 UTI 236 variability 233 PREDICT (prospective European doxazosin and combination therapy) study 342–3, 367 pressure-flow relationship see urodynamic studies prolactin, prostate enlargement 163 prolactin (PRL) gene 131 proliferation markers 40 Prostacoil, second-generation stent 535–6 Prostakath, first-generation stent 530–1 ProstAsure index, prostate cancer 218 prostate, see also prostatic prostate cancer biochemical markers 270 and BPH 101 characteristics and site of origin 102 Dunning tumor model 71, 73 epidemiology, mortality estimates 211 incidence, East/West 57 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_565.html[09.07.2009 11:56:04]

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rectal examination 212, 270 sclerotic metastases 255 screening 211–20 transrectal ultrasound (TRUS) 212–13 prostate-specific antigen see PSA prostatectomy bladder decompensation 195 complications bladder neck contracture 459–61 impotence 461–3 incontinence 457–9 hematuria 196 laser-assisted see VLAP (visual laser-assisted prostatectomy) outcomes 454–6 perioperative morbidity 456–7 retreatment rates 463–4, 465–7 retropubic (OPSR) 452–4 risk factors AUR 194–5, 236 BPH 193–4 CRF 195 IDC 249 PVR 236 smoking 168 UTIs 195 sexual dysfunction 552–3 suprapubic (OPSS) 449–52 symptom improvement 455–6 urinary flow rate 454–5 low flow/low pressure syndrome 231 pre-operative 230–1, 455 TUIP and TURP compared 455 see also TURP prostatic concretions 7 prostatic growth/development 29–60 cell proliferation control 354 epidermal growth factor (EGF) 19–20, 35 extrinsic/intrinsic factors 34–6 factors involved 36 fibroblast growth factor (FGF) 19, 35–7 finasteride 328–9 inductive signals 69–70 profile with increase of microscopic BPH 51 steroid hormones, regulatory balance 38 stromal-epithelial interrelationship 35–7 prostatic infarction, AUR 181–2 prostatic intraepithelial neoplasia see PIN prostatic size/volume age-stratified prevalence 192 AUR risk predictor 183 BPH natural history progression 190, 193

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Page 566 cancer detection 269 doxazosin 371 dutasteride 322, 347 epidemiology 142–3 finasteride 328, 331, 333, 348 MRI 258 obesity 169–70 peak flow rate relationship 156 serum PSA relationship 215 terazosin growth effects 362 TRUS 261 prostatic structure blood supply 3 branching morphogenesis, human/rat 50 ductal system 37–8 epithelium 6–7 histologic structure 5–6 histopathology 270–4 innervation 7–8, 429–30 instability development 250 lobes/zones 5–6, 11 median, prostatomegaly 256 MRI 257–8 peripheral zone 5–6, 100 TRUS 262 zonal anatomy 14–15 macro-anatomy 3–9 morphology 11–16 prepubertal 13–14 stromal and epithelial compartments 35–7 prostatic urethra 3–5 prostatism BOO bladder dysfunction 113 WW over 5 years 288 prostatitis, granulomatous 270, 272 prostatomegaly, imaging 255–6, 259 proteoglycans CD44 family 77 heparan sulfate (HSPGs) 77 proto-oncogenes, upregulation, BOO 114 PSA (prostate-specific antigen) age-specific ranges 216 AUR risk predictor 183 BPH natural history progression 190 cleavage forms 270 density 215 dutasteride treatment 322–4 ejaculate free from 216 finasteride 218–19, 334 free to total ratio 216–17, 270 LNCaP cell line 44, 71, 79 molecular forms 216–18 alpha2-macroglobulin (PSA-A2M) 216–18 multiplying by two rule 218–19 needle biopsies 267–9 cut-off levels 269–70 optimal reflex ranges 216–17 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_566.html[09.07.2009 11:56:04]

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prostate cancer 213–18 serum changes 267 specificity and sensitivity 214 velocity (PSAV) 214–15 pseudodyssynergia, EMG 243 pseudohermaphroditism, 5-AR deficiency 320 pumpkin (Cucurbita pepo) 415, 420 PURR (passive urethral resistance relationship) 246–7 PVR see postvoid residual urine Pygeum africanum 415, 419 rye grass pollen extract comparative study 420 quality of life scales AUR 183 BPH 155–6, 544–5 post surgery 552 racial considerations, BPH risk factors 165 radiofrequency energy principles, TUNA 495–6 red clover, isoflavonoids 58–9 renal failure, CRF 195 retinoblastoma (Rb) gene 127, 126 protein 43–4 retreatment rates 463–8 TUNA 468, 502 retropubic prostatectomy 452–4 rhabdosphincter 4 rigid-tube hydrodynamic theory, resistance factors 244–5 rye (Secale cereale) 415, 419–20 meta-analyses 421–2

Sabal serrulata (saw palmetto) 415 sacral reflexes and cortical evoked responses, EMG 283 sacral root injury, PVR 235 Scandinavian BPH survey 152–3 Schafer’s urodynamics model 247 sclerosing adenosis, differential diagnosis 104, 107–8 screening for PC 211–20 algorithm 220 WHO definition 211–12 Secale cereale (rye) 415, 419–20 secoisolariciresinol 58 Serenoa repens (American dwarf palm) 415, 416–18 cernitin, beta-sitosterol and vitamin E combination therapy 346 clinical trials 417–18 combination therapy 420 meta-analyses 421 serotonin, secretion 39 sesame seed 58 sex hormone-binding globulin (SHBG) 31–4 synthesis 31

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Page 567 sexual function/dysfunction 173, 176, 543–53 BPH treatment-related 544–53 doxazosin 371–3 dutasteride 322–3 ejaculation abnormalities 398, 401–3, 405 ejaculation complications 444, 463, 546, 550 inventory 546 MTOPS data 345 Multinational Survey of Aging Male (MSAM-7) 544 and TURP 547–52 sham controls see placebo/sham effect Shy-Drager syndrome see multiple system atrophy Singapore BPH study 157 beta-sitosterol meta-analysis 421 phytotherapeutic agents 418–19 Serenoa repens, cernitin and vitamin E combination therapy 346 small acinar proliferation, atypical (ASAP) suspicious for malignancy differential diagnosis 107 repeat biopsies 107 of uncertain significance 107 smoking, BPH risk factor 165–9 smooth muscle age-related density changes 13–14 alpha-blockers 351 ARs 17–18 BOO, phenotype changes 114–15 contractility changes 115–16, 357 somatostatin AUR 182 secretion 39 South African star grass (Hypoxis rooperi) 415 soya bean 58 Spanish BPH study 154 spinal cord lesions/injuries bladder dysfunction 280 PVR 235 spruce (Picea) 415 squamous metaplasia 100 stem-cell marker, telomerase 45–6 stem-cell model, pathogenesis of BPH 41–2 stents 529–38 first-generation 529–33 intraurethral catheter (IUC) 531–3 Prostakath 530–1, 537 Urospiral 529–30 second-generation 533–6 Memokath 533–5, 537 Prostacoil 535–6, 537 short-term use 536–7 Barnes stent 536 biodegradable stent 537 self-retaining intraurethral catheter 536 TRUS, insertion 264–5 steroid changes, enterohepatic circulation 56 steroid hormones, regulatory balance 38 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_567.html[09.07.2009 11:56:05]

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steroids, C19 30 stinging nettle (Urtica dioica) 415, 419 combination therapy 420 stroma alpha-1-adrenoceptors 89, 353 changes in PAH 103 development 12–13 hyperplasia with atypical giant cells, differential diagnosis 104–5 morphology 270 stroma-epithelium interactions complexity 49–50 in functional differentiation 69–71 growth regulatory factors 50–1 prostate development 16–17, 20, 164 ratio AUR 181–2 and castration 70 treatment 101 stromal nodules 15–16, 22 BPH pathology 98–100 formation and enlargement 97 genesis 15–16 hemorrhagic necrosis 100 MRI 257–8 peripheral zone 100 substance P, AUR 182 suprapubic catheterization 183–4 suprapubic prostatectomy 449–52 surgical procedures 441–76 anaesthetic considerations 443 antibiotics 443 complications 457–64 delayed mortality 468–76 history 441 indications 441–3 minimally invasive see ILC; UMT; TUNA; TUVP placebo effects 299–300 retreatment rates 464–8 risk BPH natural history 193–4 finasteride 329 MTOPS data 344 see also prostatectomy; TUIP; TUNA; TURP sympathetic nervous systems, noradrenaline contractile effects 89–92 symptom evaluation and functional status 201–8 symptom measurement principles 201–2 systemic circulation, PSA protease inhibitor complexes 216 tamoxifen 54 tamoxifen-like factors 58

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Page 568 tamsulosin 391–411, 407–8 adrenoceptor affinity 392 adverse events 398–9, 402, 403, 409–10 blood pressure effects 401 chemical structure 354, 391 clinical studies 392–411 direct comparative studies 404–7 European phase II 393–5 European phase III 393–8 European phase IV 398–9 Japanese phase II 392–3, 394, 395, 396 long-term studies 402–4 US phase III 399–402 co-medication 407–8 dosages and formulations 392, 410 efficacy and tolerability 398, 402, 404, 407–8, 411 ESPIRIT 399 meta-analysis 409–10 onset of action 397, 400–1 previous treatment comparisons 408–9 tolterodine combination therapy 345–6 uroselectivity 434 physiologic 392 tea 58–9 telomerase, and aging 45–6 terazosin 361, 363 adverse events 360, 363 BP effects 360–1, 434 chemical structure 354 finasteride interactions 340–1 historic background 358 long-term efficacy 352–3, 359–60 LUTS therapy 358 prostate apoptosis effect 352 prostate gland growth 362 safety profile 360 selectivity profile 93 short-term efficacy 359 urogenital tract effects 361–2 uroselectivity 434–5 VA Cooperative Study 191–2, 288–9, 333, 339–41 testicular feminization syndrome (Tfm) 16–17 testosterone 30–6 binding to SHBG 31 decline with age 30 dutasteride treatment 322–4 free, levels 32 hormonal imprinting 13–14 LH regulation 177 metabolism to DHT 163 production 31 structure 34, 52 Tfm (testicular feminization syndrome) 16–17 TGF-beta see transforming growth factor-beta thyroid-stimulating hormone-like peptide, secretion 39 tolterodine, tamsulosin combination therapy 345–6 TOMHS (treatment of mild hypertension study), doxazosin evaluation 370, 547 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_568.html[09.07.2009 11:56:05]

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transcription factors (TFs) 47 transcription-activating function (TAF-1) 48 transforming growth factor-alpha (TGF-alpha) 40 and EGF 75 transforming growth factor-beta (TGF-beta) 38, 39 beta-sitosterol effects 418–19 BPH pathogenesis 98, 130 mouse prostate reconstitution model 130 prostatic development 19–20 transition zone cell metaplasia 100 density, PSA density specificity 215 epithelium 7 histology 5–6 morphology 15 needle biopsies 99–100, 219, 268–9 prostate cancer 101 size/volume 97 dutasteride 322 TRUS 261–2 transition zone index (TZI), AUR predictor 183 transrectal ultrasound see TRUS transurethral electrovaporization of prostate see TUVP transurethral incision of prostate see TUIP transurethral laser prostatectomy 483–93 coagulation treatment 485–6 types of fibers 483–5 types of treatment 485 see also VLAP (visual laser-assisted prostatectomy) transurethral microwave thermotherapy see TUMT transurethral needle ablation of prostate see TUNA transurethral resection of prostate see TURP Trestle self-retaining intraurethral catheter 536 TRPM-1 gene 44 TRUS (transrectal ultrasound) 258–65 abnormalities and needle biopsy 269 lower urinary tract dysfunction 260–5 postoperative TURP 264 prostate cancer 212–13 stent insertion 264–5 tubular proliferation, fetal prostate 12 TUIP (transurethral incision of prostate) 443–4 delayed mortality 468–76 retreatment rates 463–4 sexual dysfunction 553 urinary flow rate, prostatectomy and TURP compared 455 tumor suppressor genes 123–7 TUMT (transurethral microwave thermotherapy) 250, 448–9, 519–25 costs 524 indications 521 morbidity 523–4

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Page 569 results 521 retention studies 523–4 retreatment rates 458, 524 sexual dysfunction 553 sham studies 521 technical details 519–20 temperature achieved 520 vs TURP 522 TUNA (transurethral needle ablation of prostate) 448, 495–504 adverse effects 501–3 animal and human studies 496 costs 503–4 indications and limitations 502–3 mechanism of action 503 in nonbacterial prostatitis 501 patients in retention 500–1 preservation of prostatic urethra 497 procedure 497–8 radiofrequency energy principles 495–6 results 498–500 retreatment rates 468, 502 TUNA catheter and generators 496–7 urodynamic studies 501 TUR (transurethral resection) syndrome 447 TURP (transurethral resection of prostate) 444–7 AUR 185 complications incontinence 457–9 intraoperative 447 renal failure 195 sexual dysfunction 547–52 urethral stricture/bladder neck contracture 459–61 vs conservative management 288 delayed mortality 468–76 indications 290 postoperative TRUS 265 resection specimens, recommendations 101 retreatment rates 463–4, 465–7 risk factors 193–5 obesity 170 PVR 236 smoking 168 urinary flow rate preoperative flow rates 231, 455 prostatectomy and TUIP compared 455 USCD 259–60 WW of patient waiting list 288 TUVP (transurethral electrovaporization of prostate) 447–8 retreatment rates 467–8 sexual dysfunction 553 see also VLAP (visual laser-assisted prostatectomy) TWOC (trial without catheter) 184 AUR 195 tyrosine kinase 46 tyrosine-specific protein kinase 46 inhibitor 48, 49

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UGS (urogenital sinus) 11 ultrasound abdominal BOO 237 PVR 233 USCD 258–60 see also transrectal ultrasound (TRUS) ultrasound cystodynamogram (USCD) 258–60 anatomic information 258 bladder diverticula 260 physiologic information 259 TURP follow-up 259–60 United Kingdom BPH studies 153–4 urethra, prostatic 3–5 urethral catheterization, AUR 183–4 urethral crest 4 urethral imaging TRUS 261 normal appearance 261 urethral pressure alfuzosin 378–80 alpha-1-adrenoceptors 430 urethral pressure profilometry (UPP) 243 urethral resistance see urodynamic studies urethral sphincter, EMG 282 urethral stents, AUR 185 urethral stricture, and/or bladder neck contracture, complication of surgery 459–61 urinary bladder see bladder urinary flow rate 227–38 age-related changes 230 bladder volume, normograms 229–30 BOO diagnosis 230, 237 BPH natural history progression 190 diurnal variation 228 ESPIRIT study 399 flow meters 228 individual variation 228 MUDI 230 normal range parameters 156 normograms 229–30 peak uroflow epidemiology 143–5 prostate volume relationship 156 self-assessment 227–38 treatment indications 290–1 variability 228–30 learning effect 228 WHO guidelines 237 see also postvoid residual urine urinary retention, acute 236 alfuzosin 381 BPH complication 194–5

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Page 570 epidemiology 181–5 future research 185 MTOPS data 344–5 natural history 182–3 risk factors 182–3, 236 prostatectomy 185, 194–5, 236 spontaneous and precipitated 195 treatment 183–5 TUMT 523–4 TUNA ablation 500–1 see also postvoid residual urine urinary retention, chronic, bladder compliance 235 urinary symptoms health-care-seeking behavior 156 scoring systems 281 see also LUTS (lower urinary tract symptoms) urinary tract infection (UTI) prostatectomy 195 PVR 236 urodynamic studies 241–51 Abrams-Griffiths (AG) normogram 246–7 autonomic enervation injury 250 BOO 237 BPH natural history progression 190 BPH symptomatic, pathologic and molecular expression 250 clinical applications 248–50 diagnostic accuracy 248–9 computer analysis 247–9 contractility parameters 245 cystometry 242 DAMPF classification 250 doxazosin 366–7 LPURR 246–7 multichannel/video multichannel 242–4 neurologic disorders 281 normogram 246 OBI 247 Parkinson’s disease 283 PURR 246 quantitative analyses 244–8 rigid tube hydrodynamic theory 244–5 Schafer’s model 247 TRUS pre-assessment 263 TUNA 501 URA 246–7 watchful waiting 249–50 see also detrusor contractility urogenital mesenchyme (UGM) 69–71 fetal prostate development 21 urogenital sinus (UGS) 11 uroselectivity 429–35 clinical 433–4 defined 435 pharmacologic, alpha-1-adrenoceptors 430 physiologic 432–3 Urospiral, first-generation stent 529–30 Urtica dioica (stinging nettle) 415, 419, 420 file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_570.html[09.07.2009 11:56:06]

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USCD see ultrasonography vaporization laser 486 in VLAP 486 vascular endothelial growth factor (VEGF) 40–1, 76 vasectomy, BPH risk 173 vasoactive intestinal polypeptide (VIP) 8, 9 AUR 182 NO co-functional role 9 verumontanum mucosal gland hyperplasia, differential diagno sis 108 Veterans’ Affairs (VA) Cooperative Study 191–2, 288–9, 333, 339–41 vitamin E, beta-sitosterol, Serenoa repens and cernitin combination therapy 346 VLAP (visual laser-assisted prostatectomy) 483–93 coagulation vs vaporization 485–6 results holmium laser 492–3 KTP laser 491–2 Nd:YAG laser 486–91 see also transurethral laser prostatectomy; TUVP (transurethral electrovaporization of prostate) Wastenaw County (Michigan) urological survey 154–5 watchful waiting (WW) 190–1, 287–91 vs medical therapy 289 placebo/sham effect 300, 302–5, 313–14 strategy 291 treatment indications 290–1 urodynamic studies 249–50 Western world, incidence of prostate and breast cancer 57 WHO, placebo/sham control groups 298 Y chromosome 122 ZM-252868, tyrosine-specific protein kinase inhibitor 48

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file:///H|/...8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_570.html[09.07.2009 11:56:06]