Testosterone. Substitution. Action Deficiency. E. Nieschlag H. M. Behre (Eds.) Editorial Assistant: S. Nieschlag. With 78 Figures and 20 Tables

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2 E. Nieschlag H. M. Behre (Eds.) Testosterone Action Deficiency Substitution Editorial Assistant: S. Nieschlag With 78 Figures and 20 Tables Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona

3 Professor Dr. med. EBERHARD NIESCHLAG Dr. med. HERMANN M. BEHRE Institute of Reproductive Medicine, University of Munster Steinfurter StraBe 107, Munster Editorial Assistant: SUSAN NIESCHLAG, MA ISBN ISBN (ebook) DOI / Library of Congress Cataloging in Publication Data Testosterone-action, deficiency, substitution / E. Nieschlag, H. M. Behre (eds.), editorial assistant, S. Nieschlag. p. cm. ISBN Includes bibliographical references and index. 2. Testosterone-Physiological effect. 3. Testosterone Therapeutic use. I. Nieschlag, E. ll. Behre, H. M. (Hermann M.), QP572.T4T '1-dc CIP This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its current version, and a copyright fee must always be paid. Violations fall under the prosecution act of the Gennan Copyright Law. Springer-Verlag Berlin Heidelberg 1990 Softcover reprint of the hardcover 1st edition 1990 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for" general use. Product Liability: The publisher can give no guarantee for infonnation about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other phannaceutical literature. 2123/ Printed on acid-free paper

4 Preface Testosterone has been in clinical use since its isolation and chemical synthesis in the 1930s. For many years testosterone esters, given either intramuscularly or orally, have been the most frequently used modalities for the treatment of male hypogonadism. Although sufficient to compensate for many symptoms of androgen deficiency, this treatment is not ideal. For this reason, new modalities have been or are being developed. Some of them are ready for wide clinical application and perhaps also for use in male contraception. The present book summarizes our knowledge about testosterone and describes new developments. It begins with the biochemistry of testosterone, its biosynthesis, metabolism and mechanisms of action in target organs. Three chapters deal with specific aspects of testosterone action, namely its role in spermatogenesis, its psychotropic effects and its effects on bones. Syndromes caused by androgen resistance are described in order to highlight the importance of properly functioning enzymes and receptors in the target organs. Causes and symptoms of male hypogonadism, the major indication for testosterone treatment, are described. Five chapters are devoted to the pharmacology, pharmacokinetics and clinical uses as well as abuses of testosterone preparations. Side effects of testosterone treatment are reviewed. The possible role of androgens in the development of prostatic hypertrophy and carcinoma is discussed extensively since this question is of major concern to the clinician, in particular with regard to testosterone substitution in senescence. While coverage of the topics is comprehensive, the authors do not hesitate to point out gaps in our knowledge and areas for future research. This book was initiated in parallel with the preparations for a symposion on "Testosterone: Action, Deficiency, Substitution". At this symposion the authors presented their topics and submitted their manuscripts. Rather than as proceedings of a meeting, however, the chapters are intended as contributions to a textbook which, it is hoped, may serve as a reference book on testosterone, summarizing the state of the art as of early The contributors deserve our appreciation for their prompt and reliable collaboration. The symposion took place at Castle Velen near Munster in Westphalia. We are grateful to the generous sponsorship provided by the STADA Arzneimittel AG (Bad Vilbel), who made the amenities of the castle available for the symposion. We are particularly grateful to Peter Hoof, president of the company, as well as to Dr. Rainer Dittmann and Dr. Rainer Wierichs for their support.

5 VI Preface Much of the editorial work was performed by Susan Nieschlag, M. A. whose untiring help is gratefully acknowledged. Word processing of the manuscripts was done by Sabine Baha who deserves thanks for her patient endurance. Finally, we would like to thank Springer Verlag for supporting the project and expediting its publication. Munster, May 1990 EBERHARD NIESCHLAG HERMANN M. BEHRE

6 Contents Testosterone: an overview of biosynthesis, transport, metabolism and action. F. F. G. ROMMERTS. With 9 Figures The role of testosterone in spermatogenesis. G. F. WEINBAUER and E. NIESCHLAG. With 4 Figures Psychotropic effects of testosterone. W. HUBERT. With 4 Tables Syndromes caused by androgen resistance. H.-u. SCHWEIKERT and G. ROMALO. With 7 Figures Pharmacology and clinical use of testosterone. E. NIESCHLAG and H. M. BEHRE. With 1 Figure and 2 Tables Comparative pharmacokinetics of androgen preparations: Application of computer analysis and simulation. H. M. BEHRE, F. OBERPENNING, and E. NIESCHLAG. With 16 Figures and 1 Table Pharmacology of testosterone pellet implants HANDELSMAN. With 10 Figures Percutaneous dihydrotestosterone (OHT) treatment. G. SCHAISON, K. NAHOUL, and B. COUZINET. With 8 Figures Transdermal testosterone replacement through genital skin. V. A. PLACE, L. ATKINSON, O. A. PRATHER, N. TRUNNELL, and F. E. YATES. With 6 Figures and 4 Tables Safety aspects of androgen therapy. L. 1. G. GOOREN and K. H. POLDERMAN. With 1 Table Effects of androgens on bone metabolism. 1. S. FINKELSTEIN and A. KLIBANSKI. With 8 Figures

7 VIII Contents Androgens and human benign prostatic hyperplasia (BPH). M. KRIEG and S. TUNN. With 5 Figures Androgens and carcinoma of the prostate. F. H. SCHRODER. With 1 Figure and 2 Tables Androgens and male senescence. A. VERMEULEN. With 3 Figures and 6 Tables. 261 Subject Index

8 Contributors ATKINSON, LINDA Alza Corporation, 950 Page Mill Road, Palo Alto, CA , USA BEHRE, HERMANN M. Institut fur Reproduktionsmedizin der UniversiUit, Steinfurter StraI3e Munster, COUZINET, BEATRICE Service d'endocrinologie et des Maladies de la Reproduction, H6pital Bid~tre 78, Rue du General Leclerc, 94270, Le Kremlin, Bicetre, France FINKELSTEIN, JOEL S. Harvard Medical School, Massachusetts General Hospital, Endocrine Unit Boston, MA , USA GOOREN, LoUIS J. G. Free University Hospital, Department of Endocrinology and Andrology 1081 HV Amsterdam, The Netherlands HANDELSMAN, DAVID University of Sydney, Department of Obstetrics and Gynaecology Sydney, 2006 NSW, Australia HUBERT, WALTER Psychologisches Institut I der Universitiit, RosenstraI3e 9, 4400 Munster KLIBANSKI, ANNE Harvard Medical School, Massachusetts General Hospital Neuroendocrine Unit, Boston, MA , USA KRIEG, MICHAEL Institut fur Klinische Chemie und Laboratoriumsmedizin Berufsgenossenschaftliche Krankenanstalten Bergmannsheil der Universitat Bochum, GilsingstraI3e 14,4630 Bochum

9 x Contributors NAHOUL, KHALIL Foundation de Recherche en Hormonologie, 67, Boulevard Pasteur Fresnes, France NIESCHLAG, EBERHARD Institut fur Reproduktionsmedizin der UniversiUit, Steinfurter Stral3e Miinster, OBERPENNING, FRANK Institut fur Reproduktionsmedizin der Universitat, Steinfurter Stral3e Miinster, PLACE, VIRGIL A. Alza Corporation, 950 Page Mill Road, Palo Alto, CA , USA POLDERMAN, KAAS H. Free University Hospital, Department of Endocrinology and Andrology 1081 HV Amsterdam, The Netherlands PRATHER, DELLA A. Alza Corporation, 950 Page Mill Road, Palo Alto, CA , USA ROMALO, GABRIELA Medizinische Universitats-Poliklinik, Wilhelmstral3e 35-37, 5300 Bonn 1 ROMMERTS, FOCKO F. G. Department of Biochemistry, Medical Faculty, Erasmus University Rotterdam 3000 DR Rotterdam, The Netherlands SCHAISON, GILBERT Service d'endocrinologie et des Maladies de la Reproduction, H6pital Bicetre 78, Rue du General Leclerc, 94270, Le Kremlin, Bicetre, France SCHRODER, FRITZ H. Institute of Urology, Medical Faculty, Erasmus University Rotterdam 3000 DR Rotterdam, The Netherlands SCHWEIKERT, HANS-UDO Medizinische Universitats-Poliklinik, Wilhelmstral3e 35-37, 5300 Bonn 1 TRUNNELL, NANCY Alza Corporation, 950 Page Mill Road, Palo Alto, CA , USA

10 Contributors XI TUNN, SABINE Institut for Klinische Chemie und Laboratoriumsmedizin Berufsgenossenschaftliche Krankenanstalten Bergmannsheil der Universitat Bochum, GilsingstraJ3e 14,4630 Bochum VERMEULEN, ALEX University Hospital of Ghent, Department of Endocrinology, De Pintelaan Ghent, Belgium WEINBAUER, GERHARD F. Institut fur Reproduktionsmedizin der Universitat, Steinfurter StraJ3e MOnster, YATES, F. EUGENE Physiological Monitoring Unit, Department of Medicine University of California, Los Angeles, 1950 Sawtelle Boulevard Los Angeles, CA , USA