Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy Board on Health Sciences Policy Catharyn T. Liverman and Dan G. Blazer, Editors THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, N.W. • Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Gov- erning Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engi- neering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for ap- propriate balance. Support for this project was provided by the National Institute on Aging and the National Cancer Institute. The views presented in this report are those of the Insti- tute of Medicine Committee on Assessing the Need for Clinical Trials of Testoster- one Replacement Therapy and are not necessarily those of the funding agencies. Library of Congress Cataloging-in-Publication Data Testosterone and aging : clinical research directions / Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy, Board on Health Sciences Policy ; Catharyn T. Liverman, Dan G. Blazer, editors. p. ; cm. Includes bibliographical references. ISBN 0-309-09063-6 (pbk.); 0-309-52720-1 (PDF) 1. Longevity. 2. Aging—Prevention. 3. Testosterone—Physiological effect. [DNLM: 1. Aging—drug effects. 2. Testosterone—physiology. 3. Testosterone— therapeutic use—Aged. WT 104 T3455 2004] I. Liverman, Catharyn T. II. Blazer, Dan G. (Dan German), 1944- III. National Research Council (U.S.). Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy. RA776.75.T45 2004 612.6’8—dc22 2003026323 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2004 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe Shaping the Future for Health The National Academy of Sciences is a private, nonprofit, self-perpetuating soci- ety of distinguished scholars engaged in scientific and engineering research, dedi- cated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its mem- bers, sharing with the National Academy of Sciences the responsibility for advis- ing the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal gov- ernment. Functioning in accordance with general policies determined by the Acad- emy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing ser- vices to the government, the public, and the scientific and engineering communi- ties. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org COMMITTEE ON ASSESSING THE NEED FOR CLINICAL TRIALS OF TESTOSTERONE REPLACEMENT THERAPY DAN G. BLAZER, (Chair), J.P. Gibbons Professor of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina ELIZABETH BARRETT-CONNOR, Chief, Division of Epidemiology, University of California, San Diego BARUCH A. BRODY, Director, Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas ROBERT M. CALIFF, Director, Duke Clinical Research Unit, Duke University Medical Center, Durham, North Carolina JOSEPH P. COSTANTINO, Professor, Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pennsylvania DANIEL D. FEDERMAN, Senior Dean, Alumni Relations and Clinical Teaching, Harvard Medical School, Boston, Massachusetts LINDA P. FRIED, Professor, Schools of Medicine and Public Health, Director, Center on Aging and Health, Director, Division of Geriatric Medicine and Gerontology, Johns Hopkins Medical Institutions, Baltimore, Maryland DEBORAH G. GRADY, Professor, School of Medicine, University of California, San Francisco WILLIAM R. HAZZARD, Professor, School of Medicine, University of Washington, Seattle STEVEN B. HEYMSFIELD, Professor, School of Medicine, Columbia University College of Physicians and Surgeons, New York STEPHEN W. LAGAKOS, Henry Pickering Walcott Professor and Chairman of Biostatistics, Harvard School of Public Health, Boston, Massachusetts MARK S. LITWIN, Professor, David Geffen School of Medicine and School of Public Health, University of California, Los Angeles PAUL A. LOMBARDO, Associate Professor and Director, Program in Law and Medicine, University of Virginia, Charlottesville PETER S. NELSON, Associate Professor, Fred Hutchinson Cancer Research Center, Seattle, Washington ERIC S. ORWOLL, Program Director, General Clinical Research Center, Oregon Health and Science University, Portland LESLIE R. SCHOVER, Associate Professor, M.D. Anderson Cancer Center, University of Texas, Houston E. DARRACOTT VAUGHAN, JR., Chairman Emeritus, Department of Urology, Weill Medical College of Cornell University, New York v Board on Health Sciences Policy Liaison Leslie Benet, Chairman, Department of Biopharmaceutical Sciences, University of California, San Francisco IOM Project Staff Catharyn T. Liverman, Study Director Benjamin Hamlin, Research Assistant Judith L. Estep, Senior Project Assistant IOM Board on Health Sciences Policy Staff Andrew M. Pope, Director Troy Prince, Administrative Assistant Carlos Gabriel, Financial Associate vi Independent Report Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC’s Report Review Commit- tee. The purpose of this independent review is to provide candid and criti- cal comments that will assist the institution in making its published re- port as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: John H. J. Bancroft, The Kinsey Institute for Research in Sex, Gender and Reproduction, Indiana University Jeri S. Janowsky, Department of Neurology, Oregon Health and Science University Curtis L. Meinert, Center for Clinical Trials, Johns Hopkins Bloomberg School of Public Health Jonathan D. Moreno, Center for Biomedical Ethics, University of Virginia Peter J. Snyder, School of Medicine, University of Pennsylvania David H. Solomon, University of California, Los Angeles Marcia L. Stefanick, Stanford University School of Medicine Patrick C. Walsh, Brady Urological Institute, Johns Hopkins Hospital Christina Wang, Department of Medicine, Harbor-UCLA Medical Center Kristine Yaffe, School of Medicine, University of California, San Francisco vii viii INDEPENDENT REPORT REVIEWERS Although the reviewers listed above have provided many construc- tive comments and suggestions, they were not asked to endorse the con- clusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Robert B. Wallace, Professor of Epidemiology and Internal Medicine, College of Public Health, University of Iowa. Appointed by the National Research Council and Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accor- dance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution. Preface In the popular literature, testosterone has been linked with youth, vitality, and strength. These perceptions seem to fuel interest in the use of testosterone as a means of delaying or averting the effects of aging, as is evident by the growing numbers of middle-aged and older men using testosterone products. In November 2002, the National Institute on Aging and the National Cancer Institute requested that the Institute of Medicine conduct a study to provide an independent assessment of clinical research on testosterone therapy and make recommendations on future research directions for this field. As the committee examined the state of research on testosterone therapy, it was struck by the paucity of randomized controlled clinical trials, particularly in middle-aged or older men. Those clinical trials that have been conducted are generally of short duration and involved small numbers of participants. In some ways this is not surprising, as testoster- one products have been approved by the Food and Drug Administration primarily to treat hypogonadism, a medical condition that can occur in younger men and involves markedly low levels of testosterone and other symptoms. Many of the studies of testosterone therapy to date have thus been in young hypogonadal males. Further, conducting clinical trials of testosterone therapy in older men is fraught with complexities, particu- larly considerations regarding the potential effects of testosterone on the prostate gland and other potential adverse health outcomes. The committee’s task was to identify the research needed to deter- mine if testosterone is an efficacious treatment option for older men. This ix