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 and Dan G. Blazer, Editors

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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Testosterone and Aging: Clinical Research Directions 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 and Dan G. Blazer, Editors INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Testosterone and Aging: Clinical Research Directions 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 Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate 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 Institute of Medicine Committee on Assessing the Need for Clinical Trials of Testosterone 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.

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Testosterone and Aging: Clinical Research Directions “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Shaping the future for Health

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Testosterone and Aging: Clinical Research Directions THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated 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 members, sharing with the National Academy of Sciences the responsibility for advising 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 Institute 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 Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. 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

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Testosterone and Aging: Clinical Research Directions 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

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Testosterone and Aging: Clinical Research Directions 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

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Testosterone and Aging: Clinical Research Directions 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 Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report 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

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Testosterone and Aging: Clinical Research Directions Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions 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 accordance 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.

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Testosterone and Aging: Clinical Research Directions 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 testosterone 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, particularly 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 determine if testosterone is an efficacious treatment option for older men. This

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Testosterone and Aging: Clinical Research Directions approach does not directly address the research needed to determine whether current off-label use, particularly by middle-aged men, is either efficacious or safe. The committee has concerns about the growing use of testosterone by men who do not meet the clinical definition of hypogonadism in the absence of controlled trials needed to determine efficacy and safety. This is an opportune time for examining the efficacy of testosterone therapy in aging men while carefully monitoring for safety. The use of testosterone continues to escalate at a rapid rate, and more data are needed for informed decisions. This is also a time when women’s postmenopausal hormone therapy is at the forefront of health issues, and the public is in the midst of sorting out new research results and realizing the complexities of hormone therapy issues in general. It was a privilege to chair this Institute of Medicine committee whose members brought their breadth and depth of knowledge to bear on this important topic. The committee’s work greatly benefited from the input it received from researchers in the field who made presentations at the committee’s scientific workshop and committee meetings, and from the staff members of the sponsoring federal agencies. The committee truly appreciates the work of IOM staff members Ben Hamlin and Judy Estep, who provided outstanding research and organizational support for the committee’s work. Last, but certainly not least, it has been a true pleasure to work on this project with Cathy Liverman. I could not have asked, nor could have the committee, for more assistance. In addition, she made important substantive contributions to our deliberations. The committee hopes that this report will provide useful guidance to the National Institute on Aging, the National Cancer Institute, and other interested parties as they consider next steps for research on testosterone therapy. The report may also be informative for men considering this therapy as they, along with their health professionals, become aware of the extant research available to date on potential long-term benefits and harms of testosterone therapy in aging men. Research opportunities abound, and randomized clinical trials are critical to provide the data for informed clinical decisions. Dan G. Blazer Chair

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Testosterone and Aging: Clinical Research Directions Acknowledgments The committee wishes to acknowledge the valuable contributions that were made to this study by many individuals who shared their expertise with the committee. The committee greatly benefited from the opportunity for discussion with the researchers who presented informative talks at the committee’s scientific workshop and committee meetings (Appendix A). Special thanks go to Alvin Matsumoto and Glenn Cunningham, who met with the committee on two occasions to provide their insights into the issues regarding clinical trials of testosterone therapy. This study was sponsored by the National Institute on Aging and the National Cancer Institute. The committee appreciates the insights provided by the institute directors, Richard Hodes and Andrew von Eschenbach, and their staff members including Stanley Slater, Evan Hadley, Judith Salerno, Charles Hollingsworth, Joseph Kelaghan, and William Dahut. Many thanks to Shalender Bhasin, Mitchell Harman, Randall Urban, and Stephen Winters for their technical review of sections of the report. The committee also appreciates the work of the staff members from Solvay Pharmaceuticals, Inc. and Edelman in assembling information on the current statistics regarding the sale of testosterone products and the extent of use in the United States. The contributions of Kathi Hanna, Diane Mundt, and Doug Kamerow, who served as consultants to the committee, are greatly appreciated, as is the work of their supporting staffs at Applied Epidemiology, Inc. and Research Triangle Institute.

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Testosterone and Aging: Clinical Research Directions Contents     EXECUTIVE SUMMARY   1 1   INTRODUCTION   11      Scope of this Report,   11      Aging and Hormonal Changes,   12      Testosterone, Human Development, and Health,   14      Measuring Testosterone Levels,   18      Testosterone Therapy,   18      Growing Use of Testosterone Therapy,   24      Clinical Trials,   27      Organization of the Report,   28      References,   28 2   TESTOSTERONE AND HEALTH OUTCOMES   32      Changes in Endogenous Testosterone Levels with Aging,   33      Literature Review,   39      Bone,   41      Body Composition and Strength,   47      Physical Function,   54      Cognitive Function,   58      Mood and Depression,   61      Sexual Function,   66      Health-Related Quality of Life,   72      Cardiovascular and Hematologic Outcomes,   73      Prostate Outcomes,   81

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Testosterone and Aging: Clinical Research Directions      Other Health Outcomes,   93      Multiple Outcomes,   93      Summary,   99      References,   100 3   FUTURE RESEARCH DIRECTIONS   112      Strategy for Future Clinical Trials in Older Men,   113      Recommendations,   117      Initial Efficacy Trials in Older Men,   119      Protection of Research Participants,   137      Additional Areas of Research,   152      Recommendations,   152      References,   152 4   CONCLUDING REMARKS   159      Need for Efficacy Studies in Older Men,   159      Clinical Studies in Middle-Aged Men,   161      Summary,   163      References,   163     APPENDIXES     A   Data Sources and Methods   165 B   Randomized Placebo-Controlled Trials of Testosterone Therapy in Older Men   173 C   Additional Studies of Testosterone Therapy   182 D   Testosterone Levels in Clinical Studies   198 E   Acronyms   202 F   Biographical Sketches of Committee Members and Staff   205     INDEX   211

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Testosterone and Aging: Clinical Research Directions Tables, Figures, and Boxes TABLES 1-1   Similarities of Changes in Body Composition, Muscle Strength, Aerobic Capacity, and Metabolic Variables with Aging and in Hormone Deficiency/Excess States,   14 2-1   Selected Studies of Endogenous Testosterone Levels and Age,   35 2-2   Total and Bioavailable (non-SHBG Bound) Testosterone Levels and Proportions Less Than Various Cut Points Among 827 Men, the Rancho Bernardo Study, 1984-1987,   40 2-3   Selected Studies of Endogenous Testosterone Levels and Bone Outcomes,   44 2-4   Randomized Placebo-Controlled Trials of Testosterone Therapy and Bone Outcomes in Older Men,   46 2-5   Selected Studies of Endogenous Testosterone Levels and Body Composition and Strength,   48 2-6   Randomized Placebo-Controlled Trials of Testosterone Therapy and Body Composition and Strength in Older Men,   50 2-7   Physical Functioning in Community-Dwelling Men, 70 Years and Older, U.S.,   55 2-8   Randomized Placebo-Controlled Trials of Testosterone Therapy and Physical Function in Older Men,   56 2-9   Selected Studies of Endogenous Testosterone Levels and Cognitive Function,   59

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Testosterone and Aging: Clinical Research Directions 2-10   Randomized Placebo-Controlled Trials of Testosterone Therapy and Cognitive Function in Older Men,   60 2-11   Selected Studies of Endogenous Testosterone Levels and Mood and Depression,   63 2-12   Randomized Placebo-Controlled Trials of Testosterone Therapy and Mood and Depression in Older Men,   64 2-13   Selected Studies of Endogenous Testosterone Levels and Sexual Function,   69 2-14   Randomized Placebo-Controlled Trials of Testosterone Therapy and Sexual Function in Older Men,   70 2-15   Randomized Placebo-Controlled Trials of Testosterone Therapy and Quality of Life in Older Men,   74 2-16   Selected Studies of Endogenous Testosterone Levels and Cardiovascular Risk Factors and Diabetes,   77 2-17   Randomized Placebo-Controlled Trials of Testosterone Therapy and Cardiovascular or Hematologic Outcomes in Older Men,   82 2-18   Selected Studies of Endogenous Testosterone Levels and Prostate Outcomes,   90 2-19   Randomized Placebo-Controlled Trials of Testosterone Therapy and Prostate Outcomes in Older Men,   94 2-20   Selected Randomized Placebo-Controlled Trials of Testosterone Therapy and Multiple Outcome Measures,   98 3-1   Effect of Family History of Prostate Cancer on Lifetime Risk of Clinical Prostate Cancer,   139 3-2   Chance of Cancer as a Function of Serum Prostate Specific Antigen Level and Digital Rectal Examination Findings,   140 3-3   PSA Thresholds Based on Age and Race,   141 B-1   Randomized Placebo-Controlled Studies of Testosterone Therapy in Middle-Aged and Older Men,   174 D-1   Testosterone Levels in Clinical Studies,   200 FIGURES 1-1   Pathways of tesosterone synthesis in human testis,   15 1-2   Regulation of testosterone and sperm production by LH and FSH,   16 1-3   Testosterone partitions in the serum,   17 1-4   Testosterone therapy prescription trend,   25 1-5   Growth in the number of testosterone treated patients,   26 1-6   Total retail patient count by age for 2002,   26

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Testosterone and Aging: Clinical Research Directions 2-1   Longitudinal effects of aging on date-adjusted testosterone and free testosterone index,   37 2-2   Levels of endogenous total and bioavailable testosterone in 810 men aged 24 to 90, by 5-year age group,   38 2-3   Levels of endogenous total and bioavailable estradiol in 810 men aged 24 to 90, by 5-year age group,   39 3-1   Continuum of diminished physical function and disability,   126 A-1   Categorization of studies on testosterone therapy,   166 BOXES ES-1   Key Conclusions and Considerations,   2 ES-2   Recommendations,   8 2-1   Major Cohort Studies Examining Endogenous Testosterone Levels and Health Outcomes,   34 3-1   Key Conclusions and Considerations,   115 3-2   Recommendations,   150 A-1   Workshop Speakers and Participants,   168 A-2   Workshop Agenda,   170

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