LHRH and Its Analogs Contraceptive and Therapeutic Applications Advances in Reproductive Health Care Series Editor: E. S. E. Hafez LHRH and Its Analogs: Contraception and Thera­ peutic Applications Edited by B. H. Vickery, J. J. Nestor Jr. and E. S. E. Hafez Spontaneous Abortion Edited by E. S. E. Hafez Voluntary Termination of Pregnancy Edited by E. S. E. Hafez Biomedical Aspects of IUDs Edited by H. Hasson, W. A. A. van Os and E. S. E. Hafez Prostaglandins and Fertility Regulation Edited by M. Toppozada, M. Bygdeman and E. S. E. Hafez Male Fertility and Its Regulation Edited by T. Lobi and E. S. E. Hafez Advances in Reproductive Health Care LHRH and Its Analogs Contraceptive and Therapeutic Applications Editors B. H. Vickery J. J. Nestor Jr. and E. S. E. Hafez ~ .MTP PRESS LIM.ITED 111... ~ a member of the KLUWER ACADEMIC PUBLISHERS GROUP ,_ , LANCASTER / BOSTON / THE HAGUE / DORDRECHT 11IIIIIIII- Published in the UK and Europe by MTP Press Limited Falcon House Lancaster, England British Library Cataloguing in Publication Data LHRH and its analogs.-{Advances in reproductive health care; ) 1. Generative organs-Diseases-Chemotherapy 2. Luteinizing hormone releasing hormone­ Therapeutic use I. Vickery, B. H. II. Nestor, J. J. III. Hafez, E. S. E. IV. Series 616.6'5061 RC877 ISBN-13: 978-94-010-8963-0 e-ISBN-13: 978-94-009-5588-2 001: 10.1007/978-94-009-5588-2 Published in the USA by MTP Press A division of Kluwer Boston Inc 190 Old Derby Street Hingham, MA02043, USA Library of Congress Cataloging in Publication Data Main entry under title: LHRH and its analogs. {Advances in reproductive health care; Bibliography: p. Includes index. 1. Luteinizing hormone releasing hormone-Ag­ onists -Congresses. 2. Luteinizing hormone releas­ ing hormone-Antagonists-Congresses. 3. Lu­ teinizing hormone releasing hormone-Physiological effect-Congresses. 4. Contraceptive drugs-Con­ gresses. I. Vickery, B. H. (Brian H.), 1941- . II. Nestor, J. J. (John J.), 1945- . III. Hafez, E. S. E., 1922- . IV. Series. V. Title: L.H.R.H. and its analogs. RG137.6.L78L46 1984 612.6 84--4532 Copyright©1984 MTP Press Limited Softcover reprint of the hardcover 1st edition 1984 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 prior permission from the publishers. Typeset by Macmillan India Ltd, Bangalore. Andrew V. ScbaUy Roger Guillemin DEDICATION The present advanced status of our knowledge of the mechanism of in­ teraction of the hypothalamus and adenohypophysis rests on the solid foundation laid down by many workers over the past four decades. Foremost amongst these contributions have been the isolation, structure determination and syntheses of hypothalamic releasing factors in the laboratories of Drs Andrew V. Schally and Roger Guillemin. These contributions were recog­ nized in 1977 by the award of the Nobel Prize in Chemistry to Dr Guillemin and Dr Schally. 'For their discoveries concerning the peptide hormone production of the brain'. It is with great pleasure that we dedicate this volume to Drs Andrew Schally and Roger Guillemin and their co-workers. B. H. Vickery J. J. Nestor Jr. E. S. E. HaJez Contents List of Contributors xi Preface A. Corbin xix Introduction J. J. Nestor Jr and B. H. Vickery xxi A retrospective: LHRH and its analogs: the first decade A. V. Schal/y xxvii SECTION I. CHEMISTRY AND BASIC REPRODUCTIVE PROPERTIES Development of agonistic LHRH analogs J. J. Nestor Jr. 3 2 LHRH analogs as antiovulatory agents J. Rivier, Catherine Rivier, Marilyn Perrin J. Porter and W. W. Vale 11 3 LHRH agonists and antagonists containing very hydro­ phobic amino acids J. J. Nestor Jr., Teresa L. Ho, R. Tahilramani, B. L. Horner, R. A. Simpson G. H. Jones, Georgia I. McRae and B. H. Vickery 23 4 Pharmacological regulation of pituitary LHRH receptors R. N. Clayton 35 SECTION II. REPRODUCTIVE PHYSIOLOGY AND PHARMACOLOGY IN LABORATORY ANIMALS 47 5 Biological assays utilized to characterize LHRH and its analogs D. W. Hahn J. L. McGuire, W. Vale and J. Rivier 49 6 Male contraceptive potential of nafarelin acetate assessed in the dog B. H. Vickery and Georgia I. McRae 61 7 Male fertility control with an LHRH agonist: primate studies F. Bint Akhtar, E. J. Wickings and E. Nieschlag 77 vii CONTENTS 8 LHRH agonists for control of female fertility: primate studies B. H. Vickery and Georgia I. McRae 91 9 LHRH antagonists in rhesus and cynomolgus monkeys R. Asch. J. P. Balmaceda and M. Borghi 107 10 LHRH antagonists in females Mary Nekola and D. H. Coy 125 11 Biological evaluation of a highly potent LHRH antagonist Georgia I. McRae, B. H. Vickery, J. J. Nestor Jr., W. J. Bremner and T. M. Badger 137 12 LH R H antagonists for male contraception D. Heber and R. S. Swerdloff 153 SECTION III. EXTRAHYPOPHYSIAL PARAMETERS 161 13 Direct antigonadal actions of LHRH P. B. C. Jones and A. J. W. Hsueh 163 14 Direct gonadal stimulation with LHRH H. M. Fraser, R. M. Sharpe and Rachel M. Popkin 181 15 Antisteroidal actions of LHRH agonists K. Sundaram and C. W. Bardin 197 SECTION IV. CONTRACEPTION IN WOMEN 205 16 LHRH agonists for female contraception S. J. Nillius and C. Bergquist 207 17 Postcoital contraception with intranasal buserelin A. Lemay, Nacia Faure, F. Labrie and A. T. A. Fazekas 219 18 Antifertility by discontinuous treatment with buserelin in women W. Hardt, T. Genz and M. Schmidt-Gollwitzer 235 19 Risks and benefits of LHRH agonists as antifertility agents M. Schmidt-Gollwitzer, W. Hardt and Karen Schmidt-Gollwitzer 243 SECTION V. CONTRACEPTION IN MEN 255 20 Effects of nafarelin acetate in men D. Heber, R. S. Swerdloff and M. Henzl 257 21 Antifertility effects of an LHRH agonist in men G. C. Doelle, R. M. Evans, A. Nancye Alexander and D. Rabin 271 viii CONTENTS SECTION VI. HUMAN THERAPEUTIC APPLICATIONS 283 22 LHRH therapy for hypogonadotropic hypogonadal men A. Hoffman and W. F. Crowley Jr. 285 23 Correction of infertility with LHRH agonists in the male J. Happ 299 24 LHRH analog therapy of precocious puberty Florence Comite, G. B. Cutler Jr. and D. L. Loriaux 315 25 LHRH analogs for human mammary carcinoma H. A. Harvey, A. Lipton and Devorah T. Max 329 26 Buserelin therapy for prostatic carcinoma Nacia Faure, A. Lemay, G. Tolis, F. Labrie, A. Belanger and A. T. A. Fazekas 337 27 Leuprolide therapy for prostatic carcinoma R. J. Santen B. Warner, L. M. Demers, Maria Dufau and J. A. Smith Jr. 351 SECTION VII. DIAGNOSTIC APPLICATIONS OF LHRH 365 28 Diagnostic uses of LHRH z. Laron Ruth Prager-Lewin and Z. Dickerman 367 SECTION VIII. APPLICATIONS IN ANIMALS 375 29 Actions of LHRH and its analogs in lower vertebrates L. W. Crim 377 30 LHRH and analogs in relation to livestock B. D. Schanbacher 385 SECTION IX. METABOLIC PARAMETERS 395 31 Enzymatic degradation of LHRH and analogs G. Flourer. Mary A. Stettler-Stevenson F. A. Carone and D. R. Peterson 397 32 Metabolism of [D-Trp6]LHRH J. Barron E. Griffiths, G. Tsalacopoulos and R. P. Millar 411 33 Absorption and metabolism of LHRH and analogs S. T. Anik, Lynda M. Sanders, M. D. Chaplin, S. Kushinskyand C. Nerenberg 421 SECTION X. PERSPECTIVES 437 34 Prospects for LHRH analogs as contraceptives M. J. K. Harper 439 ix CONTENTS 35 The therapeutic potential of LHRH and LHRH analogs R. A. Edgren and D. R. Shevlin 449 36 Epilog E. S. E. Hafez 459 Subject index J. J. Nestor Jr. 465 x List of Contri butors Fatima Bint Akhtar J. P. Balmaceda Department of Experimental Assistant Professor Endocrinology Department of Obstetrics and University Women's Hospital Gynecology Domagkstrasse 11 Univ. Texas Health Science Centre 0-4400 Munster, F. R. Germany 7703 Floyd Curl Drive San Antonio, TX 73230 USA A. Nancye Alexander Rabin Associate C. Wayne Bardin Director, Center for Biomedical Shabir Anik Research Staff Researcher The Population Council Institute of Pharmaceutical Sciences Rockefeller University Syntex Research R1-140 York Avenue & 66th Street 3401 Hillview Avenue New York, NY 10021 USA Palo Alto, CA 94304 USA Jeffrey L. Barron Ricardo H. Asch Department of Chemical Pathology Jane & Roland Blumberg University of Cape Town Medical Professor of Obstetrics & School Gynecology Observatory 7925 Department of Obstetrics & Cape Town, South Africa Gynecology University of Texas Health Science Alain Bltlanger Center Molecular Endocrinology 7703 Floyd Curl Drive Laboratory San Antonio, TX 78284 USA Le Centre Hospitalier de I'Universite Laval Thomas M. Badger 2705 Lauvier Boulevard Assistant Professor Quebec G1 V 4G2 Canada Department of Obstetrics & Gynecology Christer Bergquist Vincent Research Laboratories Section for Reproductive Massachusetts General Hospital Endocrinology and Infertility Boston, MA 02114 USA Department of Obstetrics and Gynaecology University Hospital S-751 85 Uppsala Sweden xi LIST OF CONTRIBUTORS Mario Borghi Alan Corbin Postdoctoral Fellow Associate Director Department of Obstetrics and Biological Research Gynecology (Endocrinology) Univ. Texas Health Science Centre Wyeth Laboratories 7703 Floyd Curl Drive P.O. Box 8299 San Antonio, TX 73230 USA Philadelphia, PA 19101 USA William J. Bremner David H. Coy Chief, Endocrine Section Research Professor Division of Endocrinology/ Department of Medicine Metabolism Tulane University School of University of Washington Medicine Medical Center 1430 Tulane Avenue Veterans Administration Hospital New Orleans, LA 70112 USA 4435 Beacon Avenue South Laurence W. Crim Seattle, WA 98108 USA Memorial University of Frank A. Carone Newfoundland Morrison Professor and Deputy Marine Sciences Research Chairman of Pathology Laboratory Northwestern University Medical St. John's Newfoundland School Canada A 1 C 5S7 303 E. Chicago Avenue William F.